Nicotinic receptor-mediated regulation of dopamine transporter activity in rat prefrontal cortex.
The objective of this study was to determine whether nicotine could selectively influence dopamine levels in the prefrontal cortex as compared with other dopaminergic areas of brain. Using a superfusion system, we found that nicotine and other agonists at nicotinic acetylcholine receptors enhanced the release of radiolabeled dopamine that was stimulated by 10 microM amphetamine from slices prepared from rat prefrontal cortex. In contrast, nicotine had no effect on amphetamine-stimulated [(3)H]dopamine release from slices of nucleus accumbens nor striatum. Under the conditions used, which included no added calcium to exclude contribution by exocytotic release, nicotine had no effect on basal release of [(3)H]dopamine. The enhancement by nicotine was concentration-dependent, reaching a maximum at 5 microM, and producing less release at higher concentrations. Enhancement by nicotine was fully reversed by 30 microM dihydro-beta-erythroidine, and by 10 microM mecamylamine, but was not affected by alpha-bungarotoxin. The potencies of nicotine, epibatidine, cytisine, and A85380 to enhance amphetamine-stimulated dopamine release, as well as the sensitivity of nicotine enhanced release to antagonists, are consistent with mediation via a high-affinity nicotinic acetylcholine receptor containing alpha 4 and beta 2 subunits, the major species of nicotinic receptor in forebrain. Since low dopaminergic activity in prefrontal cortex is correlated with cognitive deficits in schizophrenia, our findings may help explain why these deficits are improved in schizophrenics by smoking or nicotine administration.
Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA.
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Drew
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Derbez
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Werling
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D000661:Amphetamine; D004298:Dopamine