Alpha-2 noradrenergic receptor activation inhibits the hyperpolarization-activated cation current (Ih) in neurons of the ventral tegmental area

Abstract

The ventral tegmental area (VTA) is the source of dopaminergic projections innervating cortical structures and ventral forebrain. Dysfunction of this mesocorticolimbic system is critically involved in psychiatric disorders such as addiction and schizophrenia. Changes in VTA dopamine (DA) neuronal activity can alter neurotransmitter release at target regions which modify information processing in the reward circuit. Here we studied the effect of α-2 noradrenergic receptor activation on the hyperpolarization-activated cation current (I h ) in DA neurons of the rat VTA. Brain slice preparations using whole-cell current and voltage-clamp techniques were employed. Clonidine and UK14304 (α-2 receptor selective agonists) were found to decrease I h amplitude and to slow its rate of activation indicating a negative shift in the current's voltage dependence. Two non-subtypeselective α-2 receptor antagonists, yohimbine and RS79948, prevented the effects of α-2 receptor activation. RX821002, a noradrenergic antagonist specific for α-2A and α-2D did not prevent I h inhibition. This result suggests that clonidine might be acting via an α-2C subtype since this receptor is the most abundant variant in the VTA. Analysis of a second messenger system associated with the α-2 receptor revealed that I h inhibition is independent of cyclic adenosine monophosphate (cAMP) and resulted from the activation of protein kinase C. It is suggested that the α-2 mediated hyperpolarizing shift in I h voltage dependence can facilitate the transition from pacemaker firing to afferent-driven burst activity. This transition may play a key role on the changes in synaptic plasticity that occurs in the mesocorticolimbic system under pathological conditions.

Specificity and impact of adrenergic projections to the midbrain dopamine system

“…Clonidine and UK14304, α 2 agonists, both inhibited the hyperpolarization-activated cation current by activating the protein kinase C signaling pathway (Inyushin et al, 2010). Similarly, NE and UK14304 activate a non-specific cationic conductance that produced a small inward current (Cathala et al, 2002).…”

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

“…An A-current represents a rapidly-inactivating potassium current that can contribute to spike after hyperpolarization and is involved in the regulation of firing frequency of dopaminergic VTA neurons (Koyama and Appel, 2006a). On the other hand, h-current is a characteristic current of dopaminergic VTA neurons that is activated at membrane potentials about 20 mV negative to the resting membrane potential; it may contribute to the spontaneous firing rate of dopaminergic VTA neurons from mice (Okamoto et al 2006; McDaid et al 2008) but not those from rats (McDaid et al 2008; Appel et al 2003), but its major role is likely to be in the regulation of excitability and synaptic signal integration in dopaminergic VTA neurons (Inyushin et al 2010). The authors noted a right-ward voltage shift produced by ACD on I A (Melis et al, 2007).…”

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

“…An A-current represents a rapidly-inactivating potassium current that can contribute to spike after hyperpolarization and is involved in the regulation of firing frequency of dopaminergic VTA neurons (Koyama and Appel, 2006a). On the other hand, hcurrent is a characteristic current of dopaminergic VTA neurons that is activated at membrane potentials about 20 mV negative to the resting membrane potential; it may contribute to the spontaneous firing rate of dopaminergic VTA neurons from mice (Okamoto et al 2006;McDaid et al 2008) but not those from rats (McDaid et al 2008;Appel et al 2003), but its major role is likely to be in the regulation of excitability and synaptic signal integration in dopaminergic VTA neurons (Inyushin et al 2010). The authors noted a rightward voltage shift produced by ACD on I A (Melis et al, 2007).…”