Involvement of the Mesocorticolimbic DA System in the Positive Reinforcement Effects of Nicotine

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The involvement of mesocorticolimbic DA system in the reinforcing effects of nicotine is supported by several experimental data.

1. Selective 6-hydroxydopamine (OHDA) lesions of the nucleus accumbens reduce nicotine self-administration (95).

2. Low doses of systemic administration of neuroleptics attenuate nicotine self-administration in rats (96).

3. In humans, neuroleptics increase nicotine plasma levels in smokers (97), suggesting that the individuals smoke more to counteract the effects of the drug and experience rewarding effects.

4. Postmortem DA and DA metabolite levels were found to beincreased in the striatum of smokers when compared with nonsmoker controls (61).

5. The indirect DA agonist bupropion has been used successfully to reduce the relapse rate in smokers who have manifested the intention to quit smoking (98).

In rats, nicotine self-administration is attenuated by VTA microinfusions of the □4D2-preferential competitive antagonist dihydro-D-erythroidine, but not by the muscarinic antagonist atropine (99). This procedure perturbates the nicotinic-dependent cholinergic input from the pedunculopontine tegmental nucleus (PPT) into the VTA, probably by reducing nAChR-dependent facilitation of DA neuronal firing. Thus, the rewarding effects of nicotine self-administration are most likely mediated by nAChR, and not by muscarinic transmission (14).

The lack of enhancing effects of nicotine on firing in VTA neurons and on DA release in nucleus accumbens and striatum observed in the D2 mutant mice (51) strongly suggests a role for D2-containing nAChR in mediating the reinforcing properties of nicotine through the activation of the mesolimbic DA system. In support of a direct effect of nAChR on DA release, no changes of D1-D4 DA receptor levels and affinity nor of DA transporter were reported in mutant mice.

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