The elucidation of the mechanisms underlying 2 -receptor activation and signal transduction is crucial to the understanding of 2 -receptor function. Previous studies in our laboratory have demonstrated 2 -receptor-mediated regulation of the dopamine transporter (DAT) as measured by amphetamine-stimulated release of [ -Receptors were first identified in 1976 by Martin et al. (1976) as the sites through which the psychotomimetic effects of SKF10,047 were mediated. Since that time, progress in identifying their physiological function(s) has been relatively slow compared with other receptor systems. There are at least two types of -receptors, designated 1 and 2 (Hellewell and Bowen, 1990;Quirion et al., 1992). -Receptors are distributed widely in the periphery and central nervous system (Walker et al., 1990). In brain, they are localized especially in motor and limbic systems (Gundlach et al., 1986), areas typically subserved by catecholaminergic neurotransmission. 1 -and 2 -receptors are colocalized in most regions, and have been reported to be present in a ratio of 4.3:1 in striatum (Bouchard and Quirion, 1997). 1 -Receptors were cloned first from guinea pig liver by Hanner et al. (1996) and the corresponding human gene further characterized by Prasad et al. (1998).1 -Receptors have been associated with second messenger activation and inhibition in several model systems. There is disagreement whether 1 -receptors are coupled through G

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.

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 μM amphetamine from slices prepared from rat prefrontal cortex. In contrast, nicotine had no effect on amphetamine‐stimulated [3H]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 [3H]dopamine. The enhancement by nicotine was concentration‐dependent, reaching a maximum at 5 μM, and producing less release at higher concentrations. Enhancement by nicotine was fully reversed by 30 μM dihydro‐β‐erythroidine, and by 10 μM mecamylamine, but was not affected by α‐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 α4 and β2 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. Synapse 38:10–16, 2000. © 2000 Wiley‐Liss, Inc.