The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of K opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.Since it was established that drugs abused by humans are rewarding (i.e., give an interoceptive pleasurable effect) for humans and for animals (1), a great deal of research has been devoted to clarifying the biological mechanism of drug abuse. Drugs that are abused are from diverse and apparently antithetic classes (central depressants, central stimulants, narcotic analgesic drugs, etc.), suggesting that they act through various primary mechanisms. This, however, does not exclude the possibility that these drugs might secondarily activate a final common pathway that mediates their rewarding properties.Among central nervous system neurotransmitters and neuromodulators, dopamine is a candidate to transmit the rewarding properties of drugs of abuse (2, 3). According to this hypothesis, drugs of abuse would act by stimulating dopamine-mediated transmission along specific pathways.This hypothesis, however, has been challenged because (i) experimental studies utilizing lesions or pharmacological manipulations to explore the role of dopamine in drug reward have provided highly conflicting results (4-7), except for studies with amphetamine (8, 9); and (ii) direct in vivo evidence that drugs of abuse indeed stimulate dopamine transmission in vivo is lacking, again except for studies with amphetamine (10,11), as a result of the difficulties inherent in the in vivo quantitation of dopaminergic transmission.Brain dialysis has been developed for measuring extracellular synaptic dopamine concentrations, which can be used as an index of dopamine transmission in freely moving animals (10-12). With this method, we have studied the effects of various drugs of abuse on the extracellular concentration of dopamine and its metabolites in two anatomically and functionally distinct...

The effects of the active ingredient of Cannabis , Δ 9 -tetrahydrocannabinol (Δ 9 -THC), and of the highly addictive drug heroin on in vivo dopamine transmission in the nucleus accumbens were compared in Sprague-Dawley rats by brain microdialysis. Δ 9 -THC and heroin increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2. SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of Δ 9 -THC but not those of heroin. Naloxone, a generic opioid antagonist, administered systemically, or naloxonazine, an antagonist of μ 1 opioid receptors, infused into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopamine transmission. Thus, Δ 9 -THC and heroin exert similar effects on mesolimbic dopamine transmission through a common μ 1 opioid receptor mechanism located in the ventral mesencephalic tegmentum.

The question of whether nicotine, the neuroactive compound of tobacco, is addictive has been open to considerable scientific and public discussion. Although it can serve as a positive reinforcer in several animal species, including man, nicotine is thought to be a weak reinforcer in comparison with addictive drugs such as cocaine and heroin, and has been argued to be habit forming but not addictive. Here we report that intravenous nicotine in the rat, at doses known to maintain self-administration, stimulates local energy metabolism, as measured by 2-deoxyglucose autoradiography, and dopamine transmission, as estimated by brain microdialysis, in the shell of the nucleus accumbens. These neurochemical and metabolic effects are qualitatively similar to those of other drugs, such as cocaine, amphetamine and morphine, which have strong addictive properties. Our results provide functional and neurochemical evidence that there are specific neurobiological commonalities between nicotine and addictive drugs.

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The nucleus accumbens is considered a critical target of the action of drugs of abuse. In this nucleus a "shell" and a "core" have been distinguished on the basis of anatomical and histochemical criteria. The present study investigated the effect in freely moving rats of intravenous cocaine, amphetamine, and morphine on extracellular dopamine concentrations in the nucleus accumbens shell and core by means of microdialysis with vertically implanted concentric probes. Doses selected were in the range of those known to sustain drug self-administration in rats. Morphine, at 0.2 and 0.4 mg/kg, and cocaine, at 0.5 mg/kg, increased extracellular dopamine selectively in the shell. Higher doses of cocaine (1.0 mg/kg) and the lowest dose of amphetamine tested (0.125 mg/kg) increased extracellular dopamine both in the shell and in the core, but the effect was significantly more pronounced in the shell compared with the core. Only the highest dose of amphetamine (0.250 mg/kg) increased extracellular dopamine in the shell and in the core to a similar extent. The present results provide in vivo neurochemical evidence for a functional compartmentation within the nucleus accumbens and for a preferential effect of psychostimulants and morphine in the shell of the nucleus accumbens at doses known to sustain intravenous drug self-administration.

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