Acevedo-Rodriguez Alexandra, Zhang Lifen, Zhou Fuwen, Gong Suzhen, Gu Howard, De Biasi Mariella, Zhou Fu-Ming, Dani John A
Department of Neuroscience, Baylor College of Medicine Houston, TX, USA.
Department of Pharmacology, University of Tennessee College of Medicine Memphis, TN, USA.
Front Synaptic Neurosci. 2014 Sep 4;6:19. doi: 10.3389/fnsyn.2014.00019. eCollection 2014.
Nicotinic acetylcholine receptors (nAChRs) potently regulate dopamine (DA) release in the striatum and alter cocaine's ability to reinforce behaviors. Since cocaine is a weak nAChR inhibitor, we hypothesized that cocaine may alter DA release by inhibiting the nAChRs in DA terminals in the striatum and thus contribute to cocaine's reinforcing properties primarily associated with the inhibition of DA transporters. We found that biologically relevant concentrations of cocaine can mildly inhibit nAChR-mediated currents in midbrain DA neurons and consequently alter DA release in the dorsal and ventral striatum. At very high concentrations, cocaine also inhibits voltage-gated Na channels in DA neurons. Furthermore, our results show that partial inhibition of nAChRs by cocaine reduces evoked DA release. This diminution of DA release via nAChR inhibition more strongly influences release evoked at low or tonic stimulation frequencies than at higher (phasic) stimulation frequencies, particularly in the dorsolateral striatum. This cocaine-induced shift favoring phasic DA release may contribute to the enhanced saliency and motivational value of cocaine-associated memories and behaviors.
烟碱型乙酰胆碱受体（nAChRs）有力地调节纹状体中多巴胺（DA）的释放，并改变可卡因强化行为的能力。由于可卡因是一种弱nAChR抑制剂，我们推测可卡因可能通过抑制纹状体中DA终末的nAChRs来改变DA释放，从而主要通过抑制DA转运体来促成可卡因的强化特性。我们发现，具有生物学相关性的可卡因浓度可轻度抑制中脑DA神经元中nAChR介导的电流，并因此改变背侧和腹侧纹状体中的DA释放。在非常高的浓度下，可卡因还会抑制DA神经元中的电压门控钠通道。此外，我们的结果表明，可卡因对nAChRs的部分抑制会减少诱发的DA释放。通过nAChR抑制导致的DA释放减少，对低频率或紧张性刺激频率诱发的释放影响比对较高（相位性）刺激频率诱发的释放影响更大，特别是在背外侧纹状体中。这种可卡因诱导的偏向相位性DA释放的转变，可能有助于增强与可卡因相关的记忆和行为的显著性及动机价值。
