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Serotonin Reduces the Hyperpolarization-Activated Current (I_h) in Ventral Tegmental Area Dopamine Neurons: Involvement of 5-HT₂ Receptors and Protein Kinase C

Departments of ¹Physiology and Biophysics and ²Emergency Medicine, University of Illinois, Chicago, Illinois 60612

Submitted 24 March 2003; accepted in final form 23 July 2003

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 µM) 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 -methylserotonin (25 µM) and reversed by the 5-HT₂ antagonist ketanserin (25 µM). 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 µM) and the selective protein kinase C inhibitor chelerythrine (25 µM). The protein kinase C activator phorbol 12, 13 diacetate (PDA, 2 µM) 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.

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