Nicotinic receptor-mediated regulation of the dopamine transporter in rat prefrontocortical slices following chronic in vivo administration of nicotine.
Low levels of dopaminergic activity in prefrontal cortex are thought to contribute to negative symptoms of schizophrenia. Negative symptoms are associated with the prefrontocortical area of the brain. Schizophrenic patients have a high rate of smoking, which by subjective as well as objective measures produces a cognitive benefit. We have previously shown that agonists at nicotinic receptors containing alpha4 and beta2 subunits can enhance amphetamine-stimulated [3H]dopamine ([3H]DA) release via the dopamine transporter (DAT) from slices of rat prefrontal cortex. This effect is selective for prefrontal cortex; the enhancement does not occur in striatum or nucleus accumbens. The enhancement is dependent upon activation of protein kinase C (PKC). In the current study, we show that the enhancement of amphetamine-stimulated [3H]DA release is maintained after 10 days of chronic nicotine treatment, delivered subcutaneously twice daily. There are no significant changes in the ability of prefrontocortical brain slices to take up [3H]DA in tissue prepared from nicotine-treated vs. saline-treated rats. Nicotinic receptors mediating enhancement of amphetamine-stimulated [3H]DA release are at least partially localized to nerve terminals, as an enhancement in release is also observed in synaptosomal preparations. Finally, the sensitivity of the nicotine enhancement in release to the PKC inhibitor chelerythrine is also seen in synaptosomal preparations, suggesting that the signaling mechanism activated through alpha4beta2 receptors is intact.
Drew
Allison E
AE
Department of Pharmacology, The George Washington University Medical Center, 2300 Eye Street NW, Washington, DC 20037, USA.
Werling
Linda L
LL
D000470:Alkaloids; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D053119:Benzophenanthridines; D046508:Culture Techniques; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D007279:Injections, Subcutaneous; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009538:Nicotine / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology; D014029:Tobacco Use Disorder / Q000503:physiopathology*
D000470:Alkaloids; D053119:Benzophenanthridines; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010617:Phenanthridines; D011978:Receptors, Nicotinic; C493216:Slc6a3 protein, rat; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D000661:Amphetamine; C016299:chelerythrine; D011493:Protein Kinase C; D004298:Dopamine