Conditioned Stimuli with Psychoactive Drugs in Rats

National Institute On Drug Abuse

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Abstract

In animals and humans, environments that are associated with drug use, can influence drug-taking and relapse. We have performed experiments to investigate the neurochemical mechanisms involved in drug-conditioning in rats. We have used the conditioned place preference (CPP) procedure. In the CPP procedure, rats are tested in a drug-free state to determine whether they prefer an environment in which they previously received drug as compared to an environment in which they previously received saline vehicle. This procedure relies on the capacity of stimuli previously associated with drug's effects to elicit approach responses and increase time spent in an environment associated with drug's effects and is used as a measure of reinforcing effects. In the first set of experiments, we have explored the influence of nicotine dose and stimulus assignment procedure on development of nicotine-induced CPP. Initial preferences for one side of a two-compartment apparatus were first determined in Sprague-Dawley rats. In subsequent conditioning trials, the compartment paired with nicotine was the initially preferred side for half of the rats, and the initially non-preferred side for the other half. Rats received either an injection of nicotine (0.01-2 mg/kg SC) before being placed in one compartment (three trials) or saline before being placed in the other compartment (three trials). Control rats had saline injections associated with both compartments. A final test trial with no injection assessed final place preference. Significant CPP were induced by 0.1-1.4 mg/kg doses of nicotine. Nicotine-induced CPP were only apparent when nicotine was paired with the initially non-preferred side. Moreover, a very high dose of nicotine (2 mg/kg) induced conditioned place aversion when paired with the initially preferred side of the apparatus. These experiments indicate that nicotine induces significant CPP across a wide range of doses, in accordance with its role as the primary addictive component of tobacco. Small preferences for one side of the apparatus played a major role in the development of nicotine-induced CPP. These findings suggest that biased procedures may be more suitable than unbiased procedures for evaluation of reinforcing effects of nicotine using CPP paradigms. We also have tested various innovative pharmacological approaches to reducing the effects of nicotine-associated environmental stimuli: Among the five identified dopamine receptors, the dopamine D3 receptor has distinct features suggesting its involvement in the reinforcing effects of abused drugs. Dopamine D3 receptors are expressed in the mesolimbic brain reward circuit and their density is elevated in the brains of long-term cocaine abusers and in the brains of animals chronically treated with cocaine or nicotine. We have found that selective D3 receptor ligands are able to block the effects of nicotine-associated environmental stimuli over behavior measured using the CPP paradigm. These experiments suggest that dopamine D3 receptor ligands might represent potentially useful pharmacological tools for decreasing relapse to drug use in abstinent drug-abusers. Another pharmacological approach that we have evaluated is the blockade of the cannabinoid CB1 receptor antagonist by selective antagonists such as Rimonabant (SR141716). Acute administration of SR141716 blocks the expression of nicotine-induced conditioned place preferences in rats. In contrast, SR141716 does not block the discriminative-stimulus effects of doses of nicotine ranging from 0.01 to 0.6 mg/kg in rats. These findings support the proposed use of SR141716 for smoking cessation and indicate that it would selectively reduce the influence of environmental stimuli that contribute to persistent smoking behavior, without affecting subjective responses to nicotine.