Serotonin reduces the hyperpolarization-activated current (Ih) in ventral tegmental area dopamine neurons:: Involvement of 5-HT2 receptors and protein kinase C

Dopaminergic neurons of the ventral tegmental area (VTA) have been implicated in the rewarding properties of drugs of abuse and in the etiology of schizophrenia; serotonin modulation of these neurons may play a role in these phenomena. Whole cell patch-in-the-slice recording in rat brain slices was used to investigate modulation of the hyperpolarization-activated cationic current I-h by serotonin in these neurons. Serotonin (50-500 muM) reduced the amplitude of I-h in a concentration-dependent manner; this effect was reversible after prolonged washout of serotonin. This effect was mimicked by the 5-HT2 agonist alpha-methylserotonin (25 muM) and reversed by the 5-HT2 antagonist ketanserin (25 muM). Serotonin reduced the maximal I-h current and conductance (measured at -130 mV) and caused a negative shift in the voltage dependence of I-h activation. The serotonin-induced reduction in I-h amplitude was antagonized by intracellular administration of the nonspecific protein kinase inhibitor H-7 (75 muM) and the selective protein kinase C inhibitor chelerythrine (25 muM). The protein kinase C activator phorbol 12, 13 diacetate (PDA, 2 muM) reduced I-h amplitude; when PDA and serotonin were applied together, the effect on I-h was less than additive. These data support the conclusion that serotonin reduces I-h in dopaminergic VTA neurons by acting at serotonin 5-HT2 receptors, which activate protein kinase C. This reduction of I-h may be physiologically important, as the selective inhibitor of I-h, ZD7288, significantly increased dopamine inhibition of firing rate of dopaminergic VTA neurons, an effect that we previously demonstrated with serotonin.