Through classical conditioning, environmental and interoceptive stimuli paired with injections of psychoactive drugs develop the ability over time to produce pharmacological responses somewhat similar to those produced by the drug alone. Such conditioned drug effects have important implications for understanding processes such as addiction to drugs of abuse as well as the dynamics of drug effects seen over a course of prolonged treatment. Previous studies from our laboratory focused on defining the neurobiological mechanisms that mediate the energizing actions of stimuli associated with drugs of abuse ( such as cocaine ) which we have postulated to reflect the operation of incentive-motivation and craving driving the addictive process. In these studies we used a rather simple paradigm in which cocaine was paired with a distinct environment to establish classical conditioning to contextual cues. Such conditioning conferred to these contextual cues the ability to elicit significant increases in locomotor behavior when presented alone or with a small priming dose of cocaine. We have found that such conditioning developed rapidly, was rather persistent, and obeyed the principles of classical conditioning. In our early studies, dopamine ( DA ) depleting lesions of the n. accumbens and to a lesser degree, the amygdala, before conditioning were found to disrupt the acquisition of conditioned responding, while DA depleting lesions of the striatum and frontal cortex, neurotoxin- induced lesions of the raphe and locus coeruleus, and radiofrequency lesions of the dorsal and ventral hippocampus as well as the cerebellum were ineffective. Such findings suggested that intact DA function in the n. accumbens and, to a lesser degree in the anygdala, is necessary for the formation of cocaine conditioned behavior. The expression of such conditioned effects also involve mesolimbic DA, since DA depleting lesions of the n. accumbens were effective in eliminating conditioned effects in response to conditioned contextual cues. Presentation of conditioned cues to rats were also found to enhance the release of DA in the n. accumbens using microdialysis procedures. In current studies, using freely moving and uncatheterized rats, we have found increases in glucose uptake in the baso-lateral amygdala, core and shell of the n. accumbens, ventral tegmental area, and prefrontal cortex by contextual cues associated with cocaine. Considering all these findings, it appears that psychostimulant-associated cues activate the prefrontal cortex, anterior cingulate, basolateral amygdala and the meso-accumbens DA system. These regions appear to be part of a neural circuit activated by conditioned drug cues. Although considerable effort has been made by us as well as others toward understanding the mechanisms underlying the acquisition and expression of drug-induced conditioning, nothing is known regarding its extinction. Understanding the processes underlying extinction could have implications for the development of new strategies in dealing with drug addiction and other pathological behaviors based on conditioning. The purpose of our current studies was to determine whether DA stimulation or blockade or glutamatergic blockade would alter the extinction process. We found that pretreatment of rats with eticlopride ( a D2-DA antagonist ) and MK-801 ( a non-competitive glutamate antagonist) prior to extinction sessions, prevented the extinction of conditioned behavior elicited by cocaine associated cues. Eliclopride also completely eliminated the expression of cocaine conditioned effects by cocaine associated cues. Pretreatment with SCH 23390 ( a D1-DA antagonist or apomorphiine ( a DA agonist ) had no effect. In order for extinction to proceed, it appears that intact D2 DA function is necessary. Extinction may require the activation of D2 DA meso-accumbens DA receptors in the absence of reinforcement ( e.g., cocaine) . WWe have previously postulated that the classical conditioning of drug effects to environmental cues underlies the development of incentive-motivation, which is probably the neurobehavioral substrate responsible for craving. Accordingly, the findings from these studies would suggest that while D2-DA antagonists may prevent the expression of craving, such drugs will impede the extinction of such acquired motivational processes. D1-DA receptor blockade and enhanced DA activity does not appear to alter extinction, although the D1 receptor blocker SCH 23390 did seem to attenuate the expression of the conditioned behavior. It is possible that D1-DA antagonists may serve as useful pharmacotherapeutic adjuncts in the treatment of cocaine addiction.Since intact glutamatergic function also appears to be necessary for extinction to proceed, it may be possible to enhance extinction by manipulating glutamine function.
