Potentiation of amphetamine-induced changes in dopamine and 5-HT by a 5-HT6 receptor antagonist

Although recent data has shown that 5-HT6 receptor antagonists' can enhance basal cholinergic and glutamatergic neurotransmission in the cortex and hippocampus, the distribution of this receptor within terminal regions of the dopaminergic system suggests a possible role for this receptor in the modulation of dopamine (DA). Therefore, the role of the 5-HT6 receptor was examined in the rat striatum in the presence and absence of the DA transport inhibitor/releaser, amphetamine. Amphetamine (0.3 mg/kg s.c.) induced a selective increase in extracellular DA reaching a maximum of 311.3 +/- 73.5% of preinjection levels. Administration of SB-271046 (1 and 10 mg/kg s.c.) followed by amphetamine produced an augmentation of amphetamine-induced changes in both DA and 5-hydroxytryptamine (5-HT), reaching maximum levels of 510.1 +/- 110.5% and 271 +/- 93.4% of preinjection values, respectively. Similarly, local infusion of amphetamine (100 nM) resulted in an increase in striatal DA levels reaching a maximum of 365.7 +/- 73.3% of preinfusion values. However, combination treatment with SB-271046 (1 mg/kg s.c.) and amphetamine produced no augmentation of amphetamine-induced increases in extracellular levels of DA or in any other neurotransmitter measured. Taken together these data indicate that the 5-HT6 receptor is not playing a role in the tonic modulation of NA, DA, 5-HT or glutamate neurotransmission in the striatum. However, when dopaminergic neurotransmission is enhanced the 5-HT6 receptor appears to have a modulatory influence on not only DA but also 5-HT systems. This is the first direct neurochemical evidence that the 5-HT6 receptor may have modulatory influences on both DA and 5-HT systems in the rat striatum. (C) 2002 Elsevier Science Inc. All rights reserved.