Fellowship/Middleton: Nicotinic Receptor Regulation of Dopamine Transporters

Specific Aim 1: Determine the effect of repeated nicotine (NIC) administration (s.c.) on dopamine (DA) transporter (DAT) function in striatum and medial prefrontal cortex (MPFC) to assess differential brain-region specific NIC-induced regulation of DAT using in vivo voltammetry. To test the hypothesis that repeated NIC pretreatment will result in an enhancement of the NIC-induced increase in DA clearance in striatum and MPFC when compared to acute NIC administration, i.e., sensitization, rats were injected once daily for 5 days with either NIC (0.8 mgjkg for striatal experiments or 0.4 mgjkg for MPFC experiments; s.c.) or saline. These doses of NIC were chosen based on the acute dose response results showing a maximal increase in DA clearance in the respective brain regions (data not shown). Twenty-four hrs after the last NIC or saline pretreatment dose, groups of rats were anesthetized with urethane and in vivo voltammetry was performed. Voltammetric electrode-micropipette assemblies were lowered into the striatum or MPFC using a stereotaxic apparatus. DA (200mM) was pressure ejected at 5 min intervals until reproducible baseline signals were obtained. Subsequently, NIC (0.8 mgjkg or 0.4 mgjkg) or saline was injected s.c., and pressure ejection of DA continued every 5 min for 60 min. Fig. 1 shows that in both striatum and MPFC, DA peak amplitude decreased -15% of baseline following saline injection in rats repeatedly pretreated with saline. When rats which had been repeatedly pretreated with saline were injected with NIC, a NIC-induced 40% decrease in DA peak amplitude (increase in DA clearance) was observed. The observed decrease in DA peak amplitude in the chronic saline pretreatment group is consistent with our previous observations showing that NIC acutely decreased DA peak amplitude in rats not repeatedly pretreated with saline"