Nicotinic Receptor Modulation of Dopamine Transporter Function in Rat Striatum and Medial Prefrontal Cortex

Abstract

Nicotine activates nicotinic acetylcholine receptors (nAChRs) on dopamine (DA) terminals to evoke DA release, which subsequently is taken back up into the terminal via the DA transporter (DAT). nAChRs may modulate DAT function thereby contributing to the regulation of synaptic DA concentrations. The present study determined the dose-response for nicotine (0.1-0.8 mg/kg, s.c.) to modulate DA clearance in striatum and medial prefrontal cortex (mPFC) using in vivo voltammetry in urethane anesthetized rats and determined if this effect was mediated by nAChRs. Exogenous DA (200 M) was pressureejected at 5-min intervals until reproducible baseline signals were obtained. Subsequently, nicotine or saline was administered, and DA pressure ejection continued at 5-min intervals for 60 min. In both striatum and mPFC, signal amplitude decreased by ϳ20% across the 60-min session in saline-injected rats. A monophasic dose-response curve was found in striatum, with a maximal 50% decrease in signal amplitude after 0.8 mg/kg. In contrast, a U-shaped dose-response curve was found in mPFC, with a maximal 50% decrease in signal amplitude after 0.4 mg/kg. Onset of nicotine response occurred 10 to 15 min after injection in both brain regions; however, the amount of time before maximal response was 45 and 30 min in striatum and mPFC, respectively. Mecamylamine (1.5 mg/kg) completely inhibited the nicotine-induced (0.8 and 0.4 mg/kg) decrease in signal amplitude in striatum and mPFC, respectively, indicating mediation by nAChRs. Thus, nicotine enhances DA clearance in striatum and mPFC in a mecamylamine-sensitive manner, indicating that nAChRs modulate DAT function in these brain regions.Previous research on the neurobiology of reward and drug addiction has focused on the mesocorticolimbic and nigrostriatal dopamine (DA) systems, emphasizing the role of the nucleus accumbens, medial prefrontal cortex (mPFC), and striatum. The accumbens shell, which is innervated by dopaminergic projections from the ventral tegmental area, and its associated neurocircuitry are believed to encode primary appetitive stimuli associated with unconditioned drug reward

Methylphenidate Enhances the Abuse-Related Behavioral Effects of Nicotine in Rats: Intravenous Self-Administration, Drug Discrimination, and Locomotor Cross-Sensitization

“…Interestingly, nicotine can augment dopamine transporter function (Middleton et al, 2004) and density (Harrod et al, 2004), suggesting that enduring nicotine-induced alterations in dopamine transporter function and/or density may play a role in the enhanced effect of repeated methylphenidate following nicotine treatment.…”

Mice Lacking the α4 Nicotinic Receptor Subunit Fail to Modulate Dopaminergic Neuronal Arbors and Possess Impaired Dopamine Transporter Function

“…The effect of nicotine coadministration was additive at low cocaine or methylphenidate doses but became synergistic at higher concentrations, implying a cooperative interaction between DAT and nAChRmediated processes in dopaminergic neurons in vivo (Gerasimov et al, 2000). Nicotinic receptor-mediated modulation of DAT function was assessed directly using in vivo voltammetry (Middleton et al, 2004). Subcutaneous nicotine was shown to enhance DA clearance in the striatum and medial prefrontal cortex.…”

“…Direct application of nicotine to terminals in vivo (Marshall et al, 1997) results in increases in extracellular DA. Furthermore, interactions between nAChR-mediated processes and the DAT may also be important in regulating extracellular DA concentrations (Hart and Ksir, 1996;Gerasimov et al, 2000;Middleton et al, 2004). Nicotinic receptor signaling regulates DAT gene transcription in the midbrain (Li et al, 2004).…”

Nicotinic Receptor Activation Increases [3H]Dopamine Uptake and Cell Surface Expression of Dopamine Transporters in Rat Prefrontal Cortex

“…Different mechanisms also probably underlie the effects of various psychostimulants on DAT function and trafficking. For example, in vivo voltammetry studies show that cocaine and amphetamine decrease DAT function , whereas nicotine increases DAT function (Hart and Ksir, 1996;Middleton et al, 2004). nAChR modulation of DAT function also is supported by results showing that nAChR stimulation augments amphetamine-induced reverse transport of DA by DAT in rat PFC slices, but not in striatum (Drew et al, 2000).…”

“…Uptake through the plasma membrane DA transporter (DAT) is the primary mechanism for regulation of extracellular DA concentration and, thus, the most effective means of terminating DA actions at postsynaptic and presynaptic receptors (Gainetdinov and Caron, 2003). Acute administration of nicotine has been shown to increase DAT function (i.e., enhance DA clearance) in striatum, nucleus accumbens (NAc), and PFC via an nAChR-mediated mechanism (Hart and Ksir, 1996;Middleton et al, 2004). Nicotineinduced increases in DA clearance would result in decreases in extracellular DA concentrations, thus tending to compensate for the nicotine-induced enhancement of DA release.…”