In their article "The Neural Mechanisms of Drug Addiction," Hyman, Malenka, and Nestler (2006) approach the long-standing problem of drug addiction from the point of view of understanding the addictive nature of drugs as being rooted in the ability of the addictive substances to hijack the brain circuitry normally involved in reward-related learning. Specifically, they believe that the cause for the compulsive nature of drug addiction (i.e., the fact that addicts continue self-administering the addictive substances despite full knowledge of the negative consequences of doing so) is to be found among the same areas of the brain as are responsible for associative learning and the formation of long-term memories. These areas of the brain include the ventral (or "underside of") and dorsal (or "upper side of") regions of the striatum, an area of the brain involved in the anticipation of reward, (Speert, 2012), which, as Hyman, Malenka, and Nestler (2006) go on to explain, is sensitive to electrochemical signals from dopamine neurons located in the midbrain.
       Hyman et. al (2006) begin their article by introducing drug addiction, and especially the problem of relapse despite a patient's willingness to stop self-administering a particular drug, as a serious public health problem, the solution to which- the creation of improved treatment programs- can only come as a result of greater understanding of the specific neural processes involved in the addiction process itself, (Hyman, Malenka, and Nestlar, 2006).
       While Hyman et al. (2006) note that a large amount of progress, especially involving the use of animal models, has already been made, (this has largely been possible because the drugs themselves can readily be identified as the cause of the addiction), they emphasize the importance- and the difficulty- of linking these findings obtained with animals (whose worlds can be carefully controlled by experimenters in the laboratory), to the experiences of human beings, whose worlds are far more complex and not subject to careful control and experimental manipulation. They argue, for example, that while much is known about the immediate and short-term effects of the binding of addictive drugs to specific sites in the brain, the question of the long-term effects of such binding and the changes in the brain they might engender merits additional research. Thus far, as they explain, it has been found that several distinct types of adaptation to long-term drug exposure occur, including those of homeostatic adaptation [this was discussed in a previous blog post in the context of opponent-process theory of human motivation, in terms of the gradual strengthening, over the course of repeated drug self-administrations,  of a "b" process, which would come online to balance out the effects of a stimulus-dependent "a" process, (which, in this case, would represent the disruption of homeostasis caused by the self-administration of a psychoactive drug)- and how, over time, the "b-process," which would come to be initiated by cues related to the impending self-administration of a drug, would become stronger and come online sooner, resulting in a decreased overall effect of drug-taking and the phenomenon of the buildup of drug-tolerance (the need for an addict to take an ever-increasing amount of a drug of abuse in order to get the same effect as they did earlier, before the b-process became strengthened via repeated exposure to cues signaling the impending self-administration of a drug- and the disruption of homeostasis that would inevitably come as a result, (Domjan, 2009, p. 117))]- as well as, in the words of Hyman et al. (2006), "synapse-specific 'Hebbian' adaptations of the type thought to underlie specific long-term associative memory," (Hyman, Malenka, and Nestler, 2006, p. 566).
      Hyman et al.  (2006) begin their discussion by noting that while the amount and variety of natural stimuli that activate the reward circuitry of the brain is relatively large, the amount of substances which can "hijack" this circuitry, thereby mimicking the effects of natural rewards, is actually relatively small- limited to just "the psychostimulants (cocaine and amphetamine), the opiates, nicotine, ethyl alcohol, and the cannabinoids..." (Hyman, Malenka, and Nestler, 2006, p. 567). Interestingly, however, once they are exposed to these drugs, humans and other animals rapidly learn the cues that predict their availability, and (as is further discussed in previous blog posts), exposure to these conditioned stimuli initiates strong cravings for the drugs, and may lead to relapse among recovering addicts.  Hyman et al. (2006),  go on to describe this in terms of a conditioned place preference model- one in which, if rats or mice have been previously exposed to a pleasurable unconditioned stimulus (such as a  drug) in a particular location, they will come to develop a preference for being in that location over other locations within the same enclosure or other general space (presumably due to the association which they have formed between the conditioned stimulus of being in that location and the unconditioned stimulus of receiving the reinforcing stimulus of the drug (Hyman et al., 2006). An interesting study of this was conducted by Akins (1998, Experiment 1). In that study, which involved male quail, the conditioned stimuli associated with being in a particular location within the cage, were conditioned to predict the availability of sexual reinforcement, in the form of the presence of a female quail. In that study, the male quail were placed in an enclosure which had two compartments, both of which looked visually appeared very different. After a test designed to establish the baseline preference of the male quail in regards to which of the two compartments they preferred to be in, the compartment which the quail preferred least was chosen to be the one for which preference would be conditioned (with the visual cues related to being in this compartment coming to be conditioned as the visual stimuli). The quail were then divided into two groups, an experimental group and a control group. The conditioning itself consisted of having one male quail from the experimental group at a time enter the chamber for which the male quail had originally demonstrated less preference, and remain there for a duration of five minutes, after which a sexually-receptive female quail was placed into the chamber with them, also for a duration of five minutes. Thus, for the male quail in the experimental group, the conditioned stimulus of the visual and other stimuli denoting the previously-less-preferred conditioning chamber were paired with the unconditioned stimulus of the appearance of a sexually-receptive female bird. For the quail in the control group, by contrast, the sexually receptive female quail was presented to them in a different location and a full 120 minutes before their subsequent exposure to the previously-less-preferred conditioning chamber and its related contextual stimuli. Thus, for the quail in the control group, the conditioned stimulus of the visual and other appearance of the previously-less-preferred experimental chamber and the presence of the sexually-receptive female quail were presented in what was essentially an explicitly unpaired fashion, preventing the conditioning of an association between these two cues among members of the control group. As was predicted, members of the experimental group of quail came to develop a preference for being in the previously-less-preferred chamber following the pairings of the visual and other cues representative of this chamber with the unconditioned stimulus reinforcer of the presence of the sexually-receptive female quail (Akins, 1998, Experiment 1).
     Furthermore, Hyman et al. (2006) go on to mention that while repeated self-administrations of any drug will result in homeostatic adaptations within the circuitry of the regions of the brain stimulated by the drug, the specific means by which this happens and the resulting likelihood of the development of drug tolerance and addiction, and the ways in which such phenomena might become manifest vary markedly between different types of addictive substances, "... depending on the expression patterns of each drug's receptors and the signaling mechanisms engaged by the drug stimulation in relevant cells," (Hyman, Malenka, and Nestler, 2006, p. 567). Similarly, they note that substance dependence- which they characterize as the unmasking of the changes in the brain that have been caused by the self-administration of a particular drug which become evident as soon as regular drug self-administrations cease- can also vary greatly depending upon the drug taken and the specific neural circuitry involved. They go on to give the examples of how "... withdrawal from opiates or ethanol can produce serious physical symptoms, including flu-like symptoms and abdominal cramps (opiates), or hypertension, tremor, and seizures," (Hyman, Malenka, and Nestler, 2006, p. 568).
       This variability in the withdrawal symptoms which come following an individuals' ceasing to self-administer a drug to which they have become accustomed, is consistent with Siegel's Conditioning Model of Drug Tolerance, according to which repeated self-administrations of a drug lead to the cues related to the impending administration of the drug coming to be conditioned to predict the physiological effects of the impending drug administration- which in turn leads to the earlier and increased activation of a "b process," which comes to attenuate the "high" or other pleasurable sensation experienced following an individual's self-administration of a drug, leading to the buildup of drug tolerance (Domjan 2009). As Domjan (2009) also explains, over the course of repeated conditioning trials, the stimuli related to the impending self-administration of a drug come to elicit a conditioned response . According to Pavlov's Stimulus Substitution model, which argues that, in the development of conditioned responding, the conditioned stimulus comes to operate in the exact same way as the unconditioned stimulus did previously, with the conditioned stimulus coming to activate the same neural connections as the unconditioned stimulus previously activated (Domjan 2009), cues related to the impending administration of a drug should then come to lead to the experience of the same physiological effects as the administration of the drug itself. While in many cases, the  conditioned response to the self-administration of a drug is indeed just like the unconditioned response to the drug would be [an example of this is a study conducted by Ehrman, Robbins, Childress, and O'Brien (1992),  in which two groups of participants- one, a group of former cocaine users, and another, a group of men with no history of using cocaine, were exposed to three experimental conditions: one in which they were exposed to cues related to the use of cocaine, one in which they were exposed to cues related to the use of heroin (none of the participants had any experience with using heroin), and another condition in which cues unrelated to the use of either drug were presented. Interestingly, in that study, the group of former cocaine users specifically experienced an increase in heart rate when exposed to the cues related to the cocaine-related stimuli (and not in response to the heroin-related or neutral stimuli)- a result exactly in line with Pavlov's Stimulus Substitution Model! In that particular case, the conditioned response to the conditioned stimuli of the cocaine-related cues came to evoke exactly the same response as the unconditioned response the former cocaine users would normally have to cocaine- that is, an increase in heart rate from baseline], this is not always the case; in fact, in many cases,  the form of the conditioned response to environmental cues which have come to be associated with the self-administration of the drug is just like the form of the compensatory unconditioned response, rather than the primary unconditioned response. The case of the opioid drug heroin, for instance, is a great example of this. When heroin is administered, the drug itself is an Unconditional Stimulus (US) which elicits two distinct unconditioned responses- one of these is the primary unconditioned response, (this response has also been mentioned above in the context of the opponent process theory of motivation as being the "primary" or "a" process), which moves the system out of homeostasis, and another of which is the compensatory unconditioned response, (discussed above as being the "b process" in the opponent-process theory of motivation), which counteracts the effects of the primary unconditioned response and returns the system to homeostasis. In the case of heroin and many other drugs, the form of the conditioned response to drug-related cues is just like the form of the compensatory response; thus, while the primary unconditioned response to a self-administration of heroin would be a lower heart rate, lower blood pressure, and analgesia (decreased sensitivity to pain), the compensatory unconditional response is an increase in heart rate and blood pressure, and an unpleasant increase in sensitivity to pain. This stands in sharp contrast to what Pavlov's Stimulus Substitution Model would predict- but goes some distance in explaining why the withdrawal symptoms of many drugs (i.e., heroin, alcohol, etc.) appear to be almost "the opposite of" those of the primary unconditioned response to the self-administration of these drugs; these effects are seen because, in the case of these drugs, the conditioned response an individual might have to being exposed to cues related to the consumption of the drugs is similar to the compensatory unconditioned response, rather than the primary unconditioned response to them! The fact that this conditioned response may be similar to or different from the primary unconditioned response also might go some distance in explaining the extent of the variation in symptoms, as Hyman et al. (2006) describe them,  which individuals withdrawing from different types of drugs might experience.
    However, as Hyman et al. (2006) note, "Whereas avoidance of withdrawal likely contributes to ongoing drug use (especially with opiates, alcohol, and tobacco), it does not explain the most frustrating characteristic, from a clinical point of view, of addiction: the persistence of a relapse risk long after a person has ceased taking drugs," (Hyman, Malenka, and Nestlar, 2006, p. 569). Instead, Hyman et al. argue that "... the primary neural substrates of persistent compulsive drug use are not homeostatic adaptations leading to dependence and withdrawal, but rather long-term associative memory processes occurring in several neural circuits that receive input from midbrain dopamine neurons," (Hyman, Malenka, and Nestlar, 2006, p. 569). Such a model of drug dependence can also go further to explain why drug addiction can be so persistent and difficult to overcome; in the words of Hyman et al., (2006), "Long-term memories, unlike most homeostatic adaptations, can last for many years or even a lifetime," (Hyman, Malenka, and Nestlar, 2006, p.569). Given this, and the fact that, as they also mentioned, many instances of relapse are fueled by exposure to stimuli previously associated with drug cues, it becomes more easy to understand the possible reasons why individuals might suddenly resume a drug-taking habit, even years after initially attempting to (or perhaps even totally) "quitting."
       Furthermore, while noting a possible role for emotional stress as well as the initiation of drug cravings following exposure to drug-related stimuli, Hyman et al. (2006) nonetheless go on to emphasize the role of brain pathways in drug addiction. Crucially, they emphasize that while drugs and other addictive substances do operate upon the same circuitry as natural rewards, the "hijacking," of natural reward circuitry in which addictive substances engage in is particularly detrimental, both because, "unlike natural rewards, drug rewards tend to become overvalued," (Hyman, Malenka, and Nestlar, 2006, p. 574), and because "... unlike natural rewards, addictive drugs do not serve any beneficial homeostatic or reproductive function, but instead often prove detrimental to health and functioning," (Hyman, Malenka, and Nestlar, 2006, p. 571).
       Furthermore, they note that evidence suggests that, in the case of both natural rewards and those related to the self-administration of drugs, it is the increase in synaptic dopamine in the nucleus accumbens region of the brain. As Hyman, Malenka, and Nestlar (2006) go on to note, many of the neurons within the nucleus accumbens region of the brain have dendritic projections which allow for the binding of many molecules at once through synapses, with these neurons receiving signals  from neurons that themselves release an opioid, made within the brain, which attaches to what is called a "mu receptor." Furthermore, more dopamine neurons in the ventral tegmental area of the midbrain also supply neurons within the nucleus accumbens region of the brain with additional dopamine. Psychoactive drugs can also influence the activity of neurons in the nucleus accumbens by influencing the release of both opioids and dopamine made within the brain, directly influencing the dopamine-sensitive neurons within the nucleus accumbens, or by having an impact upon the actions of the neurons which generate the inhibitory neurotransmitter GABA (and thereby regulate neural activity). Furthermore, neurons within the cortex can also have an influence upon the neurons within the nucleus accumbens, through their release of the excitatory neurotransmitter glutamate. Significantly, changes in how the post-synaptic (receiving) cell responds to the release of glutamate can trigger long-term changes in how a particular neural circuit operates- which in term can have important implications for learning processes (Hyman et al., 2006). In the specific case of the cortex and its release of glutamate onto the nucleus accumbens, the release of glutamate from the cortex is believed to provide the nucleus accumbens with crucial information regarding the engagement of particular sensory systems. To complete the picture, neurons in the cortex also release dopamine onto the neurons in the nucleus accumbens- with the latter neurotransmitter providing neurons within the nucleus accumbens with crucial information regarding the motivational state of the organism. When these two cues are taken together (and indeed, they often occur at the same time), the dopamine being released by the cortex can be seen as assigning a reward value of sorts to the level of engagement of various sensory systems (which can be gauged by the organism via noting the current level of release of glutamate neurotransmitter by the cortex) (Hyman et al. 2006). Crucially, what the animal seems to actually learn from this pairing of glutamate and dopamine release from the cortex onto the nucleus accumbens appears to be the difference between the level of reward it expected, and the level of reward it actually obtained, (Schultz, 2006).  As Domjan (2009) notes, this learning-by-surprise parallels the way learning is hypothesized to occur in the Rescorla-Wagner equation, wherein, if a US is no longer surprising for any reason, including if it is already being perfectly predicted by a conditioned stimulus previously conditioned to asymptote at the time when an additional conditioned stimulus is added, then no additional learning will take place. In the case of dopamine release onto the ventral tegmental area of the nucleus accumbens, the same principle applies; if a forthcoming burst of dopamine from the cortex is already being accurately predicted by one stimulus, then another stimulus predicting the same phenomenon will fail to result in any additional learning taking place. In the case of drug abuse, psychoactive drugs have an unfair advantage in this process: since they can artificially ramp up dopamine release by the cortex- and this unexpected release of dopamine results in surprise, which stimulates the learning of a pairing between the sensory cues associated with the drugs of abuse and the dopamine release in the cortex- drugs can thus artificially acquire motivational value- which, tragically,  makes the habit of using them all the harder to break.
   

                                                                      References

Akins, C.K. (1998). Context excitation and modulation of conditioned sexual behavior. Animal Learning & Behavior, 26, 416-426.


 Domjan, M. (2009). Learning and behavior. (6 ed., pp. 107, 115). Belmont, CA: Wadsworth, Cengage Learning.


 Ehrman, R. N., Robbins, S. J., Childress, A. R., & O'brien, C. P. (1992). Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology, 107(4), 523-529. doi: 10.1007/BF02245266


 Hyman, S. E., Malenka, R. C., & Nestlar, E. J. (2006). Neural mechanisms of addiction: The role of reward-related learning and memory. Annual Review of Neuroscience, 29, 565-598. doi: 10.1146/annurev.neuro.29.051605.113009


Schultz, W. (2006). Behavioral theories and the neurophysiology of reward. Annual Review of Psychology, 57, 87-115. doi: 10.1146/annurev.psych.56.091103.070229

 Speert, D. (2012, February 02). Neuroeconomics: Money and the brain. Retrieved from http://www.brainfacts.org/In-Society/In-Society/Articles/2012/Neuroeconomics-Money-and-the-Brain
     

       Another way of understanding substance abuse is through looking at how the consumption of illicit substances progresses from an initial point, during which a drug is consumed voluntarily and the motivation for doing so is tied to the drug being perceived as having pleasurable and reinforcing effects, to an ultimate end point at which an addict consumes a drug in a compulsive manner and complains of being "unable to quit," and how this transition is correlated with changes in activity in specific areas of the brain.  A study by Everitt and Robbins called "Neural systems of reinforcement for drug addiction: from actions to habits to compulsion" did just that.
       Interestingly, Everitt and Robbins (2005) argued that such transitions depend upon "interactions between pavlovian and instrumental learning processes," (Everitt and Robbins, 2005, p. 1481). As Domjan (2009) explains, the difference between pavlovian (or "classical") conditioning processes and instrumental (or "operant") conditioning processes is that, while undergoing classical conditioning, an organism develops an understanding of relationships between processes in its environment which it cannot directly control, and develops appropriate responses to these processes. Thus, classical conditioning can be seen as more "passive." By contrast, during instrumental conditioning (sometimes called "operant" conditioning, in the sense that an organism "performs operations" on its environment, in the pursuit of a specific goal), "responding is necessary to produce a desired environmental outcome," (Domjan, 2005, p. 144).
       At the neural level, Everitt and Robbins hypothesized that such a change from voluntary and purposeful self-administration of a drug to the more compulsive drug-seeking and self-administration which most people would see as characterizing an addict "... represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation," (Everitt and Robbins, 2005, p. 1481). In unpacking this statement, it's important to note that while the cortex, near the front of the brain, is an area involved with higher-order thinking and planning, ("Mapping the brain," 2012), striatum is an area lying deeper within the brain that is involved with reward and anticipation of pleasurable outcomes (Speert, 2012).
       As Everitt and Robbins go on to explain, the striatum as a whole has increasingly been implicated in both drug abuse and subsequent drug addiction and dependence. As they note, this view has gained traction due to both increased understanding of how various parts of the striatum are linked to one another, and of how behavioral output (i.e., the actions an organism engages in) is a product of both classical and instrumental conditioning. They argue that the two types of learning initially occur in parallel, but that, as drug-seeking and self-administration continues, instrumental learning comes to dominate. They also argue that, as a whole, these processes eventually result in "action- outcome and stimulus-response ('habit') learning," (Everitt and Robbins, 2005, p. 1481).
       It is interesting to look at how the "action-outcome and stimulus-response ('habit') learning," (Everitt and Robbins, 2005, p. 1481) mentioned by Everitt and Robbins relates to the pioneering psychologists Thorndike's conceptualization of instrumental behavior and its outcomes as "... reflecting the learning of an S-R association," (Domjan, 2009, p. 146). As Domjan explains, Thorndike's Law of Effect "states that if a response in the presence of a stimulus is followed by a satisfying event, the association between the stimulus (S) and the response (R) is strengthened. If the response is followed by an annoying event, the S-R association is weakened," (Domjan, 2009, p. 146). Furthermore, as Domjan is careful to note, "... the consequence of the response is not one of the elements in the association. The satisfying or annoying consequence simply serves to strengthen or weaken the association between the preceding stimulus and response," (Domjan, 2009, p. 147).
      Thus, in order for Thorndike's Law of Effect to successfully map onto the increasingly-compulsive drug-seeking and drug-taking behavior of addicts, the addicts' behavior would have to function such that the association between their response (that of self-administration of the drug), which would necessarily be taking place in the presence of particular stimuli (i.e., the inside of a particular apartment, building, or other environment; the presence of the addicted individual's friends who share their interest in taking the drug, etc.) would be strengthened if administration of the drug leads to a desirable consequence (i.e., a pleasurable "high") and weakened self-administration of the drug were to lead to a negative consequence (i.e., foolishly smoking marijuana while onboard an airplane, resulting in the airplane's smoke detectors, which might lead to a large fine or even arrest for the offender).
      It is important to note how, in the above example, while the setting of "onboard an airplane" may seem a bit contrived, it illustrates something important about how such "S-R" (as Thorndike saw them) associations function; in that case, the addict's association between smoking and being on an airplane would be weakened- but would be no change in any associations the addict may have formed between smoking and positive/negative consequences in general.
      This is an important point, as it might serve to explain  why in a previous study performed by Caddy and Lovibond (1976), wherein participants, in the context of a highly-controlled therapeutic setting, were exposed to a discriminated aversive conditioning procedure, which involved the participants entering a specific room in which the bookshelves and other surfaces contained numerous empty canisters from various alcoholic beverages, and other stimuli relating to the consumption of alcohol. While in this setting, the participants were fitted with shock electrodes (these were attached to their larynx). The participants were then encouraged (by the therapeutic personnel) to continue consuming alcohol beyond a pre-prescribed limit of 0.065% (as measured by a breath analysis test). If the participants did indeed continue drinking above this limit, electric shock was then administered to them (through the electrodes with which they had been outfitted). While the idea in that study was to get the participants to form an association between consuming alcohol above a certain pre-prescribed limit, what might perhaps have actually happened is that the participants formed an association, in line with Thorndike's Law of Effect, between the environmental stimulus "being in the highly-controlled therapeutic setting (i.e., "being in that room with all the bottles on display and other stimuli which were related to alcohol and its consumption) and the response of "consuming alcohol." Since the consumption of alcohol was, in that study, followed by the aversive stimulus [according to the criteria described by Domjan (2009), this would be called "punishment" or "positive punishment," (Domjan, 2009, p. 154)] of the administration of shock, the participants' association between that setting and the consumption of alcohol was then weakened. However, upon completion of the study, and after the participants returned to the real world, wherein the settings were quite different from the highly-controlled therapeutic setting which they had just left-[especially because, in Caddy and Lovibond's (1976) study, the criteria for "success" in treatment allowed for the participants to still engage in moderate drinking- so the participants were still likely to frequent the same bars and other alcohol-centered environments which they had previously gone to]-  and because the participants had no previously-formed association between the environments and settings of the outside world (a new "S") and the response of drinking (the same "R)- they were far less successful in abstaining from drinking when they returned to the outside world than they had been while in therapy; while Caddy and Lovibond (1976) cite success rates as high as 85% of the participants showing some type of improvement at 12 months follow-up, this figure drops to a far-lower 59% at 24 months follow-up. Perhaps Thorndike's Law of Effect and the specific types of associations the participants will have formed during the experiment can go some distance in explaining this- especially given that the "S" part of the "S-R" association which (according to Thorndike's Law of Effect) is formed during conditioning includes the stimulus and the response- but not the eventual consequence of making that response (in which case, the results of that particular type of learning might be limited to a particular type of setting).
       In terms of how their study, Everitt and Robbins (2005), argue that drugs act as 'instrumental reinforcers' (Everitt and Robbins, 2005, p. 1481), thus making them the "reinforcers" in Thorndike's Law of Effect. They thus "increase the likelihood of the responses that produce them, resulting in drug self-administration of 'drug-taking,'" (Everitt and Robbins, 2005, p. 1481). Furthermore, the "S" or "stimuli" portion of Thorndike's Law of Effect would be covered by the stimuli that have contiguity (close association in time and space) with the administration of the drugs. According to Everitt and Robbins, these would "gain incentive salience through pavlovian conditioning," (Everitt and Robbins, 2005, p. 1418). They argue that the "rewarding" effects of a drug likely result from the increasing attention to interoceptive physiological cues which they produce, as well as (in the case of hallucinogens and the like) the changes in perception of the environment and other external cues that drug taking results in. They go on to mention that this can be particularly reinforcing if it occurs in relation to Conditioned Stimuli (those which are reliably paired with the occurrence of important environmental events). Crucially, Everitt and Robbins (2005) argue that it is the sense of control over environmental and interoceptive cues that an individual who is using drugs feels that using the drug of choice allows them to obtain which acts as the instrumental reinforcer (R) in the context of Thorndike's Law of Effect, as applied to drug abuse and addiction. 
       Interestingly, Everitt and Robbins (2005) mention that conditioned stimuli (CSs) which act as signals for the impending delivery of positive reinforcers can have several other effects, aside from simply eliciting approach and consummatory behaviors. For instance, when conditioned stimuli are presented unexpectedly, increased rates of responding often result- which, according to Everitt and Robbins (2005), implies that conditioned stimuli can have motivational effects.  This effect of the unexpected presentation of conditioned stimuli resulting in increased rates of responding is also consistent with the results of an experiment on the effects of a shift in the quantity of a reinforcer conducted by Mellgren (1972). In his experiment, Mellgren tested the performance of four groups of rats in an experiment involving a runway apparatus. Initially, rats in two of the four groups received a food reward of two food pellets for every successful completion of the runway task, while rats in the other two groups were rewarded with a comparatively much-larger reward of twenty-two food pellets for each successful trip down the runway which they achieved. Then, in the second phase of the experiment, Mellgren took one group of rats from each of the two reward conditions (i.e., one of the two groups of rats from the two-pellet-reward condition, and one of the two groups of rats from the twenty-two pellet reward condition), and switched them with two groups of rats in the corresponding reward condition (i.e., one group of rats that had previously been in the two-pellet reward condition suddenly found itself in the twenty-two pellet reward condition, while another group of rats which had previously been in the twenty-two pellet reward condition suddenly found itself in the two pellet reward condition. The other two groups of rats continued to receive the same amount of food reinforcement for each successful completion of the runway task as they had been before. Interestingly, while following the completion of the first phase of the experiment, rats that were initially assigned to the twenty-two pellet reward condition ran only slightly faster than rats that had been assigned to the two-pellet condition, following the switch, the rats that had suddenly been switched into the twenty-two pellet food condition from the two-pellet condition were suddenly running much faster than they had been before, while rats that were suddenly switched into the two-pellet condition from the twenty-two pellet condition were suddenly running much slower than they had been before the switch. These phenomena- with the one where the rats began running much faster than before following the increase in reward from the baseline level being called positive contrast (Mellgren, 1972, page 185), and the other one where the rats began running much more slowly than before following the decrease in reward from the baseline level being called negative contrast (Mellgren, 1972, page 185), is led Mellgren to conclude that there are emotional and motivational aspects to conditioned responding- which is similar to the conclusion drawn by Everitt and Robbins (2005) regarding there sometimes being an emotional component to conditioned responding- such as might become evident upon the unexpected presentation of a conditioned stimulus.
       Everitt and Robbins also argued that, on a neural level, it is the "midbrain dopamine neurons" (dopamine is a neurotransmitter involved in pleasure and reward) (Kullmann and Jennings, 2011) that "show fast phasic burst firing in response to such CSs..." (Everitt and Robbins, 2005, p. 1481). In testing this, Everitt and Robbins (2005) also found that unexpected presentations with conditioned stimuli that were normally paired with the administration of drugs also "resulted in dopamine release in the core but not in the shell region of the nucleus accumbens," (Everitt and Robbins, 2005, p.1482). Furthermore, Everitt and Robbins (2005) found that disabling the sensitivity of the nucleus accumbens to dopamine (as done through either selective lesioning of core areas of the nucleus accumbens, or administration of NMDA or dopamine antagonists during conditioning), results in greatly attenuated conditioned responding, while infusing either NMDA or dopamine antagonists into the core region of the nucleus accumbens after results in the subject having poor memory of the conditioned procedure (Everitt and Robbins, 2005).
       However, Everitt and Robbins (2005) caution that while, from the above-mentioned data, it may thus seem that drug addiction depends upon the presentation of the above-mentioned factors, (i.e., that drug addiction might be dependent on either the presentation of a conditioned stimulus that was previously paired with a drug, resulting in approach to that conditioned stimulus, or that drug-seeking and, thus, self-administration can be made more frequent via the unexpected presentation of a conditioned stimulus). Everitt and Robbins (2005) argue that while these effects have been proven to be  causally involved in the conditioning of animals with natural rewards, these same effects have yet to be proven definitively in regards to the drug-seeking behaviors of humans.
       Everitt and Robbins (2005) do note, however, that "In certain circumstances, CSs can also function as conditioned reinforcers," (Everitt and Robbins, 2005, p. 1482). As they go on to explain, this occurs when certain stimuli which were "initially motivationally neutral," [i.e., they did not have anything about them which made them immediately responsible to an organism' biological needs], became reinforcing in their own right via association with primary reinforcers such as food or drugs. These stimuli help to maintain instrumental responding by bridging delays to the ultimate goal..." (Everitt and Robbins, 2005, p. 1482).  Such "bridging reinforcement" via conditioned reinforcers that have come to function in the manner of primary reinforcers is important, because conditioned responding can be severely disrupted by even seemingly-insignificant temporal delays in the delivery of a reinforcer. Domjan (2009) explains that this occurs for several reasons, including the fact that a delay can make it difficult for a participant to determine which of several actions or responses they provided (as they have likely performed several different actions since the time of the delivery of the previous reinforcer, i.e., a lever press, walking about the cage in a circle, sniffing the food delivery magazine, etc.) is the one which actually led to the delivery of the reinforcer! Using a conditioned stimulus that was previously trained with and has thus come to be associated with the reward is one way to overcome this potential difficulty (Domjan, 2009). 
A study by Cronin (1980) involving pigeons and a visual discrimination task confirmed these results. In her study, Cronin divided a group of pigeons into three groups, and varied the conditions to which they were exposed during the delay interval between an instrumental response and reinforcement between the groups. One group, called the "nondifferential" (Cronin 1980, p. 352) group, was presented with the same type of stimulus in between an instrumental response and a reward, whether they had made a correct or an incorrect response. The other three groups of pigeons, by contrast, were exposed to different stimuli during the delay period between making an instrumental response and receiving a reinforcer, based on whether they had made a correct or incorrect choice. One of these latter three groups, the "differential"(Cronin 1980, p. 352) group, received the differential stimuli (differential depending on whether the response the pigeon made was correct or not) over the course of the entire delay period. Another of the latter three groups, the "reinstatement"(Cronin 1980, p. 352) group, received the differential stimulus during the ten seconds immediately following their response (whether correct or incorrect, although the nature of the stimulus varied, of course, with whether the previously made response had been correct or incorrect), and during the ten seconds immediately preceding the reinforcer. The last of the differential groups, this one called the "reversed cue group,"(Cronin 1980, p. 352) was treated in the same way as the "reinstatement"(Cronin 1980, p. 352) group (in that they were exposed to the differential stimulus during the ten seconds immediately following their making a response, and during the ten seconds prior to the actual delivery of the reinforcer), although for  this "reversed cue" (Cronin 1980, p. 352) group, cues were indeed "reversed" in that the same cue which was presented ten seconds following an incorrect responses was also presented ten seconds before the reinforcing stimulus following correct responses (hence the reversal!)- and, likewise, for this group, the stimulus which was normally presented ten seconds after a correct response was also presented ten seconds before a lack of reward on nonreinforced trails (trials on which the birds had failed to make the correct response). The results of the study indicated that pigeons in the "nondifferential"(Cronin 1980, p. 352) group failed to learn how to make appropriate instrumental responses to the task, while birds in both the "differential"(Cronin 1980, p. 352) and "reinstatement" (Cronin 1980, p. 352) conditions had no difficulty learning the task. Finally, the "reversed-cue" (Cronin 1980, p. 352) birds learned to make a response- but the wrong response! Thus, this study highlights the importance of the delay interval between the making of an instrumental response and the presentation of a reinforcer (or nonreinforcement) and the stimuli which are presented during it, which can either aid in the formation of conditioned responding, or prevent the formation of conditioned responding, or even condition responding- but responding involving the giving of incorrect responses!
       In their discussion of how CSs can sometimes come to act as conditioned reinforcers, Everett and Robbins (2005) specify that "The effects of conditioned reinforcers, especially drug-related conditioned reinforcers, are pervasive and profound. For example, they support the learning of new drug-seeking responses, an effect that persists for at least two months without any further experience of self-administered cocaine and that is resistant to the extinction of the original CS-drug association. Drug-associated conditioned reinforcers also help maintain responding under second-order schedules of reinforcement." (Everitt and Robbins, 2005, p. 1483) Thus, it would appear that the use of drugs as conditioned reinforcers not only seems to be something that leads further into itself (with such use of drugs as conditioned reinforcers leading to further increases in drug-seeking behavior), but the fact this effect still persists even after extinction of the original CS-US association is truly remarkable, and indeed sheds some light on some of the factors making drug addictions so difficult to overcome!
       Everitt and Robbins (2005) do qualify these claims about the potency of drugs as secondary reinforcers, however, with the statement that "The CSs must be presented as conditioned reinforcers (that is, their presentation must depend on the animal's behavior); merely presenting them unexpectedly fails to increase drug seeking. This seems to contradict the 'incentive salience' model of drug-seeking behavior, which would predict enhancement from pavlovian, or unexpected presentations of the CS,"(Everett and Robbins, 2005, p.1483). This latter point underscores both the importance of contingency, as well as contiguity in instrumental conditioning, and fits nicely with Staddon and Simmelhag's (1971) attempted replication (and resulting re-interpretation) of Skinner's famous "superstitious behavior" experiment. In their study, Staddon and Simmelhag (1971) used more systematic measures of pigeon behaviors than Skinner had utilized- and, crucially, they also specified when, in relation to prior and subsequent deliveries of free food, each type of behavior occurred, labeling such responses as occurred just prior to the next delivery of food "terminal responses,"(Staddon and Simmelhag, 1971, p. 4) and responses that occurred closer to the middle of the time interval between deliveries of food "interim activities," (Staddon and Simmelhag, 1971, p.4). Furthermore, they found the effects of accidental reinforcement (i.e., reinforcement occurring in the absence of the target response, as if "by accident") to be minimal; according to them, presentations of reinforcement in the absence of the target response merely strengthened the termal responses, but had little other influence (Staddon and Simmelhag, 1971).

                                                                    References

1). Caddy, G. R., & Lovibond, S. H. (1976). Self-regulation and discriminated aversive conditioning in the modification of alcoholic's drinking behavior.Behavior Therapy, 7(2), 223-230. doi: 10.1016/S0005-7894(76)80279-1


2). Cronin, P. B. (1980). Reinstatement of postresponse stimuli prior to reward in delayed-reward discrimination learning by pigeons. Animal Learning & Behavior, 8(3), 352-358. Retrieved from http://www.springerlink.com/content/c016725275680566/

3). Domjan, M. (2009). Learning and behavior. (6 ed., pp. 59-60). Belmont, CA: Wadsworth, Cengage  Learning.

4). Everitt, R. J., & Robbins, T. W. (2005). Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neuroscience,8(11), 1481-1489. doi: 10.1038/nn1579


5).Kullmann, D., & Jennings, A. (2011, June 01).Dopamine and addiction. Retrieved from http://www.brainfacts.org/Diseases-Disorders/Addiction/Articles/2011/Dopamine-and-Addiction

6). Mapping the brain. (2012, April 01). Retrieved from http://www.brainfacts.org/Brain-Basics/Neuroanatomy/Articles/2012/Mapping-the-Brain

7). Mellgren, R. L. (1972). Positive and negative contrast effects using delayed reinforcement. Learning and Motivation, 3(2), 185-193. doi: 10.1016/0023-9690(72)90038-0

8). Staddon, J. E., & Simmelhag, V. L. (1971). The "superstition" experiment: A reexamination of its implications for the principles of adaptive behavior . Psychological Review, 78(1), 3-43. doi: 10.1037/h0030305


9). Speert, D. (2012, February 02). Neuroeconomics: Money and the brain. Retrieved from http://www.brainfacts.org/In-Society/In-Society/Articles/2012/Neuroeconomics-Money-and-the-Brain

Another study investigating the effects of aversive conditioning on alcohol consumption was conducted by Caddy and Lovibond, at the University of New South Wales. Specifically, their study involved the placement of sixty alcoholics into one of the following four conditions:
1). aversion plus self-regulation - which included blood alcohol concentration feedback training, discriminated aversive conditioning, training in self-regulation, education, and psychotherapy
2). self-regulation - which was the same as the "aversion plus self-regulation" treatment condition, in that it also included blood alcohol concentration feedback training, discriminated aversive conditioning, training in self-regulation, education, and psychotherapy except that, in this latter condition, no shock was used.
3). aversion - which was also the same as the "aversion plus self-regulation" treatment condition, except that, in the aversion condition, no emphasis was given to the self-regulatory processes.

       For purposes of Caddy and Lovibond's study, the term discrimination training referred to patients being "taught to discriminate their own blood alcohol concentrations within the limits of 0-0.08% (expressed as g/100 ml)." (Caddy and Lovibond, 1976). This was achieved by providing each patient with a scale specifying the visible behavioral symptoms which might be expected to accompany specific blood alcohol concentration levels. Each patient was then instructed to ingest a variety of beverages containing alcohol, and, following this, to introspectively report on his own current blood alcohol concentration, using criteria such as his own subjective experience, current behavior, and the amount of alcohol consumed, to come up with an estimate of his own current blood alcohol concentration.
       The accuracy of each estimate was then verified using a breath analysis procedure conducted twenty minutes after the patient consumed each drink. The results were then reported back to the patient, allowing them  to verify the accuracy of their own previous prediction.
       Essentially, the idea was to get patients to associate their subjective impressions of their current state with objective measures of both how much alcohol they had consumed and descriptions of how consumption of such an amount of alcohol might be expected to impact an individual, with the end goal of such training being that of empowering individuals to make better decisions about their alcohol consumption by giving them the tools to estimate how consuming a particular amount of alcohol will impact their emotions and behavior.
      Interestingly, according to the reports of Caddy (1976), patients were able to come up with remarkably accurate predictions (estimation errors of less than 0.01%) within the very short time of less than three training sessions! Furthermore, this remarkable accuracy of estimation reportedly persisted both throughout the duration of the training and during a subsequent follow-up period.
       In Caddy and Lovibond's (1976) study, education was actually a component of the above-described discrimination-training procedure, and referred to the provision to patients of detailed informational materials describing the medical and social effects of alcohol consumption, as well as an explanation of what exactly was meant by the term "blood-alcohol concentration" and the emotional and behavioral effects which might be expected as a function of increases in its point value.
        A significant aspect of the treatment procedure in Caddy and Lovibond's (1976) study was that of discriminated aversive conditioning. This aspect of the treatment was initiated following the end of the second discrimination training session, when the patient's blood alcohol concentration was equal to 0.065% (as measured by a breath analysis test). At this time, shock electrodes were placed near the patients larynx. Following their attachment, the patient was offered the option of continuing to drink. If and only if the patient did indeed make the decision to continue, a "highly aversive" (Caddy and Lovibond, 1976, p. 224) shock of "up to 8.2mA x 6 sec" (Caddy and Lovibond, 1976, p. 224), was administered, the idea being that conditioned aversion of a type inspired by this operant conditioning procedure of sorts would be inspired, as the patient learned an association between continuing to drink beyond a pre-prescribed maximum limit and an aversive stimulus (such as a shock). To make the learning effects less subject to extinction, a variable ratio (see previous post) schedule of reinforcement was used (although in this case, the unconditional stimulus was that of positive punishment, as provided through the administration of shock, rather than any type of positive reinforcement). Use of such a schedule also added to the study's external validity; in a real life situation, an individual would not necessarily be able to define the specific amount of alcohol, above a legally-prescribed limit, that they will have to have consumed before the onset of various negative consequences (i.e., getting arrested for drunk driving is also "enforced" on a variable ratio schedule; while everyone is well aware that doing so is both illegal and immoral, it is impossible for an individual who, for whatever reason, chooses to engage in this behavior to predict the specific instance of the occurrence of the behavior following which they will be arrested. Likewise, it would be exceedingly difficult or even impossible for a recovering alcoholic to predict the specific instance of alcohol consumption above a previously specified limit which will lead them to relapse into their previous pattern of uncontrollable and excessive alcohol consumption- but they can nonetheless be sure that continued alcohol consumption above such a limit will indeed eventually lead  to relapse). Thus, inclusion of this specific type of reinforcement schedule allows the study to more closely simulate real-life conditions, allowing individuals to obtain within the lab skills which will remain useful to them even once they leave it.
       An criticism of this type of conditioning procedure, however, can be based on the fact that evidence has shown that the "extent to which a CS is relevant to or belongs with a US" (Domjan 2009 p. 107) can have a significant impact on the rate at which conditioned responding is acquired. A good example illustrating this is a study by Garcia and Koelling (1966) which compared the rates of learning of conditioned aversion to either a taste conditioned stimulus or an audiovisual conditioned stimulus among a group of laboratory rats involved in a lick suppression experiment. This experiment consisted of a group of mildly water-deprived rats drinking from a drinking tube, the water in which had been flavored with either a salty or a sweet taste. As the rats licked the tube, (the fact that they were mildly water-deprived particularly motivated them to do so), they activated an audiovisual stimulus, which in this case consisted of a click and a flash of light, which they encountered at the same time as they did the flavor of the water they were drinking (either salty or sweet). These taste and audiovisual conditioned stimuli were then followed by an unconditioned stimulus, which in this case consisted of either a brief cutaneous shock (this shock was administered to their paws through the grid floor), or of the rats being made nauseous. Following this aversion conditioning procedure, the investigators tested the rats to see what type of aversions had been acquired to each of the two conditioned stimuli (the taste of the water and the audiovisual stimuli) separately. This was done by presenting each of the conditioned stimuli separately and measuring the rat's response to them. Specifically, the rats' response to the conditioned stimulus of taste was measured by presenting them with water that was flavored in the same way as before (i.e., either salty or sweet), but the licking of which no longer resulted in the activation of the audiovisual stimulus (which had been previously been paired with taste). Similarly, during tests of the audiovisual cues, the water was now unflavored, but licking it did activate the previously-seen audiovisual cue. The degree of aversion to a particular conditioned stimulus (either taste or the audiovisual stimulus) was measured through the degree of conditioned lick suppression (the degree to which the amount which the rats were drinking decreased as a function of the presentation of one or the other of the conditioned stimuli). Crucially, the results of the study indicated both that "It seems that given reinforcers are not equally effective for all classes of discriminable stimuli. The cues, which the animal selects from the welter of stimuli in the learning situation, appear to be related to the consequences of the subsequent reinforcer" (Garcia and Koelling, 1966, p. 124). In other words, the results of Garcia and Koelling's experiment indicated that, in order to be effective  (and to compete effectively with the multitude of other stimuli present in an experimental situation), a Conditioned Stimulus has to be meaningfully related to the Unconditioned Stimulus that is employed. For example, as Garcia and Koelling also stated in their discussion, natural selection likely predisposed animals to be particularly responsive to cues (such as conditioned stimuli) relating to taste and smell being paired with internal discomfort (such as the experimentally-induced nausea used in this experiment). Likewise, natural selection may also have predisposed animals to be particularly sensitive to cutaneous shock being paired with audiovisual stimuli. As Domjan (2009) states, this makes sense from an evolutionary standpoint, because "In their natural environment, rats are likely to get sick after eating a poisonous food. In contrast, they are likely to encounter peripheral pain after being chased and bitten by a predator that they can hear and see" (Domjan, 2009, p. 107). Given all of this, it seems somewhat strange that Caddy and Lovibond's (1976) study employed a pairing of a gustatory stimulus (the taste and smell of alcohol) with that of cutaneous shock specifically- when Garcia and Koelling's experiment demonstrates that the effectiveness of taste as a conditioned stimulus is highest when it is paired with the unconditioned stimulus of illness, and that the effectiveness of audiovisual cues as stimuli is greatest when they are paired with peripheral pain (such as that induced by electrodes being placed on the skin, as in Caddy and Lovibond's experiment). 
       Another important criticism which can be leveled at Caddy and Lovibond's study is that of its categorization of "moderate drinking" as an acceptable outcome of treatment.  Specifically, while Caddy and Lovibond's study claimed that one of the purposes of the treatment administered to each participating patient was to get them to "... recognize the degree to which his excessive drinking was under stimulus control" (Caddy and Lovibond, 1976, p. 224), and, subsequently, to get each patient to "... change his own environment in order to reduce drinking," (Caddy and Lovibond, 1976, p. 224), the behaviors it encourages in practice seem to detract from these outcomes. For instance, Caddy and Lovibond's study cites, as an example of appropriate treatment, a case in which "... a patient was taught ways of avoiding the pressure of the tradition in Australia which requires each individual in turn to buy drinks for the whole group. One method involved the subject in buying the drinks early, drinking slowly, and dropping out of most subsequent rounds," (Caddy and Lovibond, p. 224). Common sense seems to indicate that a recovering alcoholic, just fresh out of treatment, should not be in situations where stimuli which might cause him to incite him to resume his previous drinking behavior in the first place; if, as Caddy and Lovibond's study asserts, drinking is "under stimulus control," (Caddy and Lovibond, 1976, p. 224), why allow a patient to expose himself to stimuli which might encourage a return to the previous drinking behavior in the first place, instead of condoning such dangerous exposures? All of this is particularly surprising when it is noted that Caddy and Lovibond's study itself mentions that "The maintenance of behavioral changes induced in the laboratory or clinic probably depends largely upon the extent to which environmental contingencies support the new behavior," (Caddy and Lovibond, 1976, p.225). While Caddy and Lovibond's study also defined the treatment of a patient as "completely successful" if "(a) he were drinking in a controlled fashion and was exceeding a blood alcohol concentration of 0.07% less than once a month (b) he and his family collateral were both extremely satisfied with his alcohol related behavior and (c) the therapist and follow-up staff were satisfied that the patient was drinking in an essentially normal and moderate fashion" (Caddy and Lovibond, 1976, p. 227)-it and thus, the criteria upon which the investigators based their judgment of treatment success was at least internally consistent- that does not necessarily make it valid.
       As Domjan (2009) states, convergent evidence already suggests that "the administration of a drug constitutes a conditioning trial in which cues related to drug administration are paired with the pharmacological effects of the drug," (Domjan, 2009, p. 115). This in itself leads to some interesting questions regarding how these conditioned cues then come into play in drug addictions and other drug-related problems.
      A study by Ehrman, Robbins, Childress, and O'Brien (1992) sheds some light on this issue. In that study, a group of men, all of whom had a history of abusing cocaine (through such means as free-basing as well as smoking), but who at the same time had no history of heroin use were compared with a control group of men, none of whom had used cocaine or heroin. The participants were exposed to three different types of test conditions, specifically, those of being exposed to cocaine-related cues (such as listening to an audio tape of people talking about their cocaine usage, watching a video of cocaine-related activities, and role-playing the motions of using cocaine), being exposed to similar types of cues, but as related to heroin, rather than cocaine, and being exposed to unrelated, control stimuli. Responses to the three types of stimuli were measured and recorded using both physiological and self-report measures. Interestingly, both the physiological and self-report measures provided data that indicating that the cocaine-related stimuli elicited conditioned responses- including increases in heart rate and symptoms of cocaine withdrawal- but, interestingly, these effects were to be found among only the participants who had previously been users of cocaine. Neither the participants who had previously been habitual users of heroin, nor the participants who had no previous exposure to those drugs experienced those same changes. The fact that these changes were both pronounced and limited to only members of the group who had previously been exposed to cocaine would indicate that the increased heart rate and other symptoms which members of the group were experiencing were indeed coming as a consequence of the formation of conditioned associations formed over the course of their drug use. Furthermore, the fact that the participants who had previous experience with cocaine experienced (as the study mentioned) strong cravings for cocaine would indicate that individuals who have previously struggled with a particular drug should stay away from both that drug and cues related to it (to prevent the onset of strong drug-related cravings and withdrawal symptoms)- in contrast to how, in Caddy and Lovibond's study, a former addict could still be considered "successful" in overcoming his addiction, despite occasionally still engaging in drinking alcohol!
      Furthermore, as Domjan (2009) goes on to elaborate on this issue, "For drug addicts, the beginnings of a buzz or high are typically followed by substantial additional drug intake and a more intense high. Therefore, the early weak drug effect can serve as a CS signaling additional drug intake and can elicit drug cravings and other drug conditioned reactions. In this case, the CS is an internal or introceptive cue. The additional craving elicited by a small dose of the drug makes it difficult for addicts to use drugs in moderation. This is why abstinence is their best hope for controlling cravings," (Domjan, 2009, p. 116).
       Thus, it would seem that in oder to achieve the stated goal of Caddy and Lovibond's therapeutic program of getting recovering alcoholics to realize that their addiction really is stimulus-dependent, and that, as such, it can largely be mitigated through the avoidance of particular stimuli, it is indeed best, as Domjan mentions, to encourage total abstinence from both drug related cues and both large and small doses of the drugs themselves, in order to facilitate the recovery of former alcoholics.
       When this is combined with the conditioning model of drug tolerance described by Domjan (2009), in which, as a habitual user of a particular drug continues taking it on multiple successive occasions, the initial response or "high" that he obtains (this "high" is brought on by the stimulus-dependent "a process" of the opponent process model discussed in a previous post), is, over time, compensated for to an ever-larger extent by the compensatory "b-process" of the same opponent process theory of motivation model (the "b-process" comes online as a response of the body to being thrown violently out of homeostatic equilibrium by the effects of the "a process;" over time, cues related to the forthcoming administration of a particular drug become conditioned, and, thus, the "b process" is able to start earlier in response to the onset of those cues and before the body has been thrown too greatly out of equilibrium by the "a-process"-and the b-process also remains active for longer periods of time once it has been activated, often outlasting the "a process")- the user has to take ever-larger doses of the drug in order to obtain the same "effect" he had originally gotten (where "originally" would refer to such a time as before the "b process" became more readily activated by certain conditioned cue related to forthcoming drug administration, and before it would come on earlier and remain active for longer)- a phenomenon referred to as the buildup of tolerance (Domjan, 2009, p. 117).. An interesting feature of this phenomenon is that, because the drug user has built up so much tolerance in relation to particular drugs (a tolerance which is largely dependent on the consistent administration of the drugs in the same types of environments and under the same types of circumstances, with these cues serving to activate the compensatory "b process" which serves to help restore homeostasis), a habitual user is often able to take a much larger dose of a particular drug than someone who is naive to the drug. And in fact, habitual users of particular drugs often do take such much-larger doses, and indeed, they are protected from any particularly dangerous effects of such an increased dose because they do so in the same types of environments and under similar circumstances.
       Taking the results of all of these studies together, however, it should become evident that recovering alcoholics and former drug-users of all types should stay away from any cues that might remind them of their former drug-use patterns! From the Ehram et al (1972) study, it should become evident that exposure to such cues will only result in withdrawal symptoms- which might lead the previous user might give into, allowing themselves "just a tiny bit" (and, in fact, the criteria for success in Caddy and Lovibond's study would still label them as a "treatment success" if they did so!) However, according to Domjan's (2009) elaboration on this, such a slight dosage of the drug might serve as a CS which would stimulate the expectation that additional drug intake would soon be taking place. If it did, that would be bad enough in itself (as it might lead to relapse)- but, when the results of the conditioning model of drug tolerance and the fact that such a recovering user might be taking an especially high dose in an unfamiliar context and perhaps under different circumstances than those under which they had consumed the drug in the past (since, at this point, the recovering alcoholic will have just completed treatment)-such an event might actually result in tragedy!
Thus, contrary to the specifications denoted in the study by Caddy and Lovibond (1992), convergent evidence would indeed suggest that total abstinence, rather than any other means of treatment, really is "the way to go" for recovering alcoholics and other drug users.
                                                           
                                                                           References
1). Caddy, G. R., & Lovibond, S. H. (1976). Self-regulation and discriminated aversive conditioning in the modification of alcoholic's drinking behavior.Behavior Therapy, 7(2), 223-230. doi: 10.1016/S0005-7894(76)80279-1

2). Domjan, M. (2009). Learning and behavior. (6 ed., pp. 107, 115). Belmont, CA: Wadsworth, Cengage Learning.


3). Ehrman, R. N., Robbins, S. J., Childress, A. R., & O'brien, C. P. (1992). Conditioned responses to cocaine-related stimuli in cocaine abuse patients.Psychopharmacology, 107(4), 523-529. doi: 10.1007/BF02245266


4). Garcia, J., & Keolling, R. A. (1966). Relation of cue to consequence in avoidance learning. Psychonomic .Sci., 4, 123-124. Retrieved from http://www.houptlab.org/Papers/classicCTA.html

PAT (Pharmacological Aversion Treatment) for the People?

       One segment of the population among whom substance abuse and dependence is a particularly salient problem is that of federal prisoners. Indeed, recent figures indicate that some 59.6% of federal prisoners are incarcerated due to drug-related offenses (Schaffer). Their continued upkeep, including exorbitantly high expenditures for security and medical care, comes as an enormous burden upon both the prison system and the wallets of taxpayers. (R.E. Geiselman, class lecture, January 10, 2012). Perhaps one of the most frustrating aspects of the situation is the fact that, following release, some 70% of these individuals reoffend and subsequently find themselves once again incarcerated within the dreary walls of the prison from which they had so recently been discharged (R.E. Geiselman, class lecture, February 2, 2012).
       There are many reasons for this astronomically high rate of recidivism, including the fact that prisoners are freed with little more than the clothes on their backs and $200-something dollars in their pocket, often right back into the community from which they came, complete with the same gang members, drug suppliers, drug customers, drinking buddies, fellow drug users, etc., as before. As if the environmental cues alone were insufficient for catapulting a newly-released offender into relapse, prisoners are also limited in their efforts to better their lives by stringent and unforgiving external constraints, including the fact that they cannot legally apply for a job without notifying a potential employer that they are a convicted felon (failure to do so is a felony in and of itself), and the like (R.E. Geiselman, class lecture, March 8, 2012). It seems that the cards are indeed very much stacked against newly-released convicts- and that is exactly why it is essential to intervene  among members of this group, not only to aid them in breaking their current cycle of dependence, but also to strengthen their resolve and coping skills for when they are released back into society and find themselves once again confronted with all the environmental cues that accompanied and reinforced their previous drug habit.
       A highly effective form of behavioral treatment for substance abuse which might serve this purpose particularly well is that of "Aversion Treatment" or "Aversion Conditioning." This type of therapy relies upon the principles of classical conditioning to cement a relationship (in the mind of a patient undergoing treatment) between the ingestion of a particular drug of abuse and symptoms of nausea and illness (Howard, 2001, p.561). Aversion treatment operates upon the same principles described by Domjan (2009) in relation to taste aversion conditioning, but as applied in a different context. Results of taste aversion conditioning studies performed by Capaldi, Hunter, & Lin, and also by Ramirez [as cited by Domjan (2009)], "A conditioned taste aversion may be learned if ingestion of a novel flavor is followed by an aversive consequence such as indigestion or food poisoning. In contrast, a taste preference may be learned if a flavor is paired with nutritional repletion or other positive consequences" (Domjan, 2009, p. 80-81). The fact that taste aversions found in humans are also the result of Pavlovian conditioning has been established by Scalera (2002) (as cited by Domjan, 2009). Two findings in regard to conditioned taste aversions are particularly significant- first, that "... a flavor-illness experience can produce a conditioned aversion in just one trial, and the learning can occur even if the illness is delayed several hours after ingestion of food" (Domjan, 2009, p. 81) and second, that "... food aversion learning can be independent of rational thought processes and can go against a person's conclusions about the causes of their illness" (Domjan, 2009, p.81). These findings are significant in that they correlate with separate findings more specifically related to the Pharmacological Aversion Treatment for alcohol dependence pioneered by Howard (2001).
       According to Elkins (as cited in Howard, 2001), "taste aversion conditioning, the process by which  alcohol aversions are established, is a phylogenetically old and highly efficient form of learning" (Howard, 2001, p. 562). As Howard goes on to explain, the results of the more than 1300 studies on human taste aversion conditioning performed since 1985 (Riley and Tuck, 1985, as cited by Howard, 2001), indicate that "(a) taste aversions can be established to highly familiar substances through repeated conditioning trials and discrimination training [in the context of classical conditioning, "discrimination" refers to "a procedure in which one stimulus (the CS+) is paired with the unconditioned stimulus on some trials and and another stimulus (the CS-) is presented without the unconditioned stimulus on other trials. As a result of this procedure the CS+ comes to elicit a conditioned response and the CS- comes to inhibit this response," (Domjan, 2009, p. 297)] (b) cognitive mediation is not necessary for the formation of taste aversions and (c) conditioned taste aversions are often highly resistant to extinction," (Howard, 2001, p. 562).
       The fact that Pharmacological Aversion Treatment [an adaptation of taste aversion conditioning used by Howard (2001) to establish an aversion to the taste and smell of alcohol in a group of hospitalized substance abuse patients] can be learned relatively quickly, following as little as one trial (although in Howard's study, five trials were used), and the fact that the results are at least relatively long-lasting, as well as the fact that, since the process of establishing taste aversions seems to be ingrained in the human psyche and  does not seem particularly dependent upon higher cognitive processes (Howard, 2001), makes it a good option for the treatment of alcohol addiction (and perhaps other substance abuse disorders) in the prison setting, where a shorter length of treatment, (and the cost savings that come with this) might make it an appealing choice for lawmakers and taxpayers alike, while the fact that the process can operate relatively independently of higher thought processes allows it to get around the problems with administration of psychotherapy within the prison setting cited by Robert G. Slater (former acting chief psychiatrist of California State Prison, San Quentin), including his assertion that the unbearable stress imposed upon the human psyche by the constant, unrelenting and deafening noise, as well as the constant threat of being severely physically harmed inherent to the prison setting makes effective psychotherapy impossible, and that, in fact, perhaps the best that can be done for people within the system is to provide them with anxiolytics (to lower their anxiety levels) as well as creative outlets for their feelings (such as classes and involvement in arts-and-crafts activities), and to avoid harming them further while they await their date of release (Slater, 1986); since the effectiveness of Pharmacological Aversion Therapy is rooted in human evolution and the ease with which the human brain is hard-wired to make connections between particular evolutionarily-significant pairs of stimuli (i.e., "consumables" and "gastrointestinal distress that results in severe nausea and vomiting" (Howard, 2001, p. 562)). Furthermore, the fact that higher-level thought processes are not deemed essential to the effectiveness of this treatment might make it easier to standardize and administer than the Cognitive Behavioral Therapy traditionally used in such cases, since, because Cognitive Behavioral Therapy generally focuses upon changing maladaptive cognitions, as well as behaviors (Carroll & Onken, 2005), it's effectiveness is more likely to be dependent upon the skill level of the person administering it (and their ability to assist clients with the process of gaining insight into their difficulties) whereas the effectiveness of Pharmacological Aversion Therapy appears to be inherent in its biological bases, with the result that (if proper procedures for its administration are followed) there should be much less inter-therapist variability and variation in its resulting effectiveness.
        In Howard's (2001) study of Pharmacological Aversion Therapy for alcohol abuse, this type of therapy was given to eighty-two hospitalized alcoholics. In this case, treatment consisted of five Pharmacological Aversion Therapy treatments, delivered (following the obtainment of informed consent) over a ten day period. While participants in this study completed numerous physiological as well as psychological tests (measuring everything from heart rate to their current, self-perceived appetite for alcohol and their self-perceived ability to resist ingesting it), the essential "treatment" in this study consisted of the participants being taken to a treatment room in which the shelves were lined with empty containers from a variety of alcoholic beverages, and where there were advertisements featuring various brands of alcohol on the walls. In this setting, one of the medical staff administering the treatment (either a doctor or a nurse) would pour the participant a glass of the type of alcohol they most liked to pursue, mixing it with an equal amount of warm water (the purpose of the warm water was to enhance the smell and taste of the alcoholic beverage). During initial trials, participants were then encouraged to have contact with the alcohol through smelling it and taking it into their mouth and swishing it around, but to stop short of swallowing it; during later trials, participants were encouraged to actually swallow the alcoholic beverage (although, because vomiting was induced soon after the alcohol was consumed, little alcohol was actually absorbed into the bloodstream). After each such session (a "session" generally lasted between 20 and 30 minutes), the participant was allowed to return to their hospital room. Approximately 30 minutes later and in this new location, the participant was served with their preferred alcoholic beverage- but this time, it contained "oral emitine or tartar emitic" (Howard, 2001, p. 567)- drugs specifically designed to make participants vomit between 5 and 8 minutes following their administration  (it was the relationship between the administration of this vomiting-inducing drug and the taste, smell, and consumption of alcohol that the procedure of the study was designed to reinforce). Furthermore, while the initial treatment of participants (during the first trial of the study) involved administering to participants 4 servings of their alcoholic beverage of choice (the specific type of alcohol they had previously been addicted to), later trials involved administering many different types of alcoholic beverages to the participants, in order to enable them to "generalize the conditioned aversion to a range of alcoholic flavors" (Howard, 2001, p. 567). (Howard, 2001).
       The results of the study, particularly given it's short duration and limited number of trials, (as you will remember, Domjan (2009) also stated that "... a flavor-illness experience can produce a conditioned aversion in just one trial" (Domjan, 2009, p. 81)), are impressive. For instance, prior to treatment, participants, (to whom a measure called the "Alcohol Expectancy Questionnaire" (Howard, 2001, p. 567) was administered), "endorsed an average of 65.9 positive alcohol-related outcome expectancies; the mean number of posttreatment positive outcome expectancies was 35.0" (Howard, 2001, p. 574). With t=-12.2 and a p-value of p<.001 (Howard, 2001, p.567) , such results are statistically significant. Furthermore, on another measure, the "Situational Confidence Questionnaire" (Howard, 2001, p. 567), designed to measure participants confidence that they would be able to resist cues that might, if they failed to have enough self-control to resist them, induce participants to return to their previous drug-taking habit, the "mean participant pretreatment SCQ score was 105.5, compared to a posttreatment score of 198.2 (t= 19.8, p<.001)" (Howard, 2001, p. 567). Thus, it is readily apparent that "confidence that abstinence could be maintained in the face of high-risk situations for relapse increased substantially following PAT" (Howard, 2001, p. 567).
       While self-perceived "self-efficacy" in resisting the urge to return to previous patterns of drug abuse might not, at first glance, appear particularly significant in the context of felony drug offenders just getting released from prison and the like, research into the importance of self-efficacy, including Albert Bandura's 1977 paper 'Self-Efficacy: Toward a Unifying Theory of Behavioral Change' (as cited by Cherry, 2012), would indicate otherwise.
       However, as Howard (2009) readily admits, definitive statements about the effectiveness of Pharmacological Aversion Treatment in the treatment of substance abuse disorders cannot be made until larger-scale studies are conducted and the results of the present study are replicated (Howard, 2001).

                                                                      References

1). Carroll, K. M., & Onken, L. S. (2005). Behavioral therapies for drug addiction. The American Journal  of Psychiatry, 162(8), 1452-1460. Retrieved from ajp.psychiatronline.org

2). Cherry, K. (2012). What is self-efficacy?. Retrieved from http://psychology.about.com/od/theoriesofpersonality/a/self_efficacy.htm

3). Domjan, M. (2009). Learning and behavior. (6 ed., pp. 80-81, 297). Belmont, CA: Wadsworth, Cengage Learning.

4). Howard, M. O. (2001). Pharmacological aversion treatment of alcohol dependence.i. production and prediction of conditioned alcohol aversion. The American Journal of Drug and Alcohol Abuse,27(3), 561-585. doi: 10.1081/ADA-100104519

5). Schaffer, C. A. (n.d.). Basic facts about the war on drugs. Retrieved from http://druglibrary.net/schaffer/Library/basicfax.htm


6). Slater, R.  (1986). Psychiatric intervention in an atmosphere of terror. American Journal of Forensic Psychiatry,7(1), 5-12.