| Abstract No.: | 316 |
| Country: | Canada |
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| Title: | Dopamine-dependent Behavioural Effects of Addictive Drugs are Anatomically Segregated Within Mesolimbic Terminal Regions |
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| Authors/Affiliations: | Paul B.S. Clarke*1 and Laurie H.L. Sellings1,2
1Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montréal H3G 1Y6. 2Present address - Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, ON, Canada
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| Content: | Mesolimbic dopaminergic neurons play a critical role in motivating behaviour. For example, many studies suggest that the rewarding and behavioural stimulant effects of several drugs of abuse (e.g. amphetamine, cocaine, nicotine) result from their ability to promote dopamine release in the nucleus accumbens. However, recent studies described below suggest a more complicated picture.
Our main experimental approach has been to combine focal DA-depleting (6-hydroxydopamine) lesions in adult rats with a behavioural test of drug reward (conditioned place preference, CPP). In this procedure, drug effects on locomotor activity are also measured. The first such study focused on the effects of systemic amphetamine administration. Here, DA lesions in the core subregion of the nucleus accumbens inhibited locomotor stimulation whereas those in the medial shell subregion inhibited CPP. Destruction of CPP was not associated with sensory or learning/memory deficits.
Subsequent studies with cocaine and methylphenidate provided points of similarity and difference. The locomotor stimulant effects of both cocaine and methylphenidate appeared dependent on DA transmission in the accumbens core and not shell. Although medial shell lesions reduced the rewarding effect of intravenous cocaine, comparable lesions did not inhibit CPP when the same drug was given intraperitoneally. In addition, lesions of neither core nor shell inhibited CPP resulting from intravenous methylphenidate.
The olfactory tubercle is an "orphan" structure lying directly beneath the nucleus accumbens; although it receives a rich mesolimbic dopaminergic projection, its functions are virtually unknown. Dopamine-depleting lesions of this structure showed that it contributes importantly to the rewarding effects of both i.v. cocaine and methylphenidate.
Although mesolimbic dopamine is often thought to selectively guide behaviour motivated by positive reinforcers, this view has been challenged in favour of a wider role encompassing aversively motivated behaviour. This controversy is particularly striking in the case of nicotine, with opposing claims that either the rewarding or aversive effects of nicotine are critically dependent on mesolimbic dopamine transmission. We therefore examined the effects of ventral striatal 6-OHDA lesions on nicotine CPP and on behaviour motivated mainly by aversive effects of the drug (conditioned taste aversion). Dopaminergic denervation of accumbens shell was associated with decreased nicotine conditioned place preference, whereas denervation in accumbens core was associated with an increase in CPP and a decrease in conditioned taste aversion. Hence, nucleus accumbens core and medial shell dopaminergic projections appear to exert segregated effects on rewarding and aversive effects of nicotine.
We conclude that distinct compartments of the ventral striatum (nucleus accumbens core and medial shell, olfactory tubercle) contribute differentially to the stimulant, rewarding and aversive effects of certain drugs. The relative contributions of different compartments may depend in part on the particular drug and its route of administration. Implications for human brain imaging will be discussed.
Funding: CIHR and Canadian Tobacco Control Research Initiative
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