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

Department of Physiology, Universidad Central del Caribe, Medical School, PO Box 60-327, Bayamón, Puerto Rico.
Neuroscience (Impact Factor: 3.33). 05/2010; 167(2):287-97. DOI: 10.1016/j.neuroscience.2010.01.052
Source: PubMed

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 alpha-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 (alpha-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-subtype-selective alpha-2 receptor antagonists, yohimbine and RS79948, prevented the effects of alpha-2 receptor activation. RX821002, a noradrenergic antagonist specific for alpha-2A and alpha-2D did not prevent I(h) inhibition. This result suggests that clonidine might be acting via an alpha-2C subtype since this receptor is the most abundant variant in the VTA. Analysis of a second messenger system associated with the alpha-2 receptor revealed that I(h) inhibition is independent of cyclic AMP (cAMP) and resulted from the activation of protein kinase C. It is suggested that the alpha-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.

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Available from: Mikhail Inyushin, Jan 08, 2014
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    • "On the other hand, application of 30 mM ZD7288 induced a decay of firing activity, similar in extent to that induced by MPP + (2.18 Ϯ 0.31 Hz vs. 1.5 Ϯ 0.25 Hz, -31 Ϯ 20%, n = 4, P = 0.017 vs. control, P = 0.28 vs. MPP + , Figure 2C, right). MPP + inhibits I h by slowing its gating properties and reducing current amplitude Previous reports have shown that pharmacological block of Ih reduces the firing rate of SNc DA neurons (Seutin et al., 2001; Zolles et al., 2006; Inyushin et al., 2010). On this basis, we tested whether the rapid action of MPP + on firing frequency of SNc DA neurons could depend on modulation of Ih. "
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    ABSTRACT: BACKGROUND AND PURPOSE: 1-methyl-4-phenylpyridinium (MPP(+) ), a potent parkinsonizing agent in primates and rodents, is a blocker of mitochondrial complex I, therefore MPP(+) -induced parkinsonism is believed to depend largely on mitochondrial impairment. However, it has recently been proposed that other mechanisms may participate in MPP(+) -induced toxicity. We tackled this issue by probing the effects of an acute application of MPP(+) on substantia nigra pars compacta (SNc) dopamine (DA) neurons. EXPERIMENTAL APPROACH: The effects of MPP(+) on SNc DA neurons in acute midbrain slices were investigated with electrophysiology techniques. KEY RESULTS: MPP(+) (50 μM) was able to (1) hyperpolarize SNc DA neurons by ∼ 6 mV, (2) cause an abrupt and marked (over 50%) reduction of the spontaneous activity and (3) inhibit the hyperpolarization-activated inward current (I(h) ). MPP(+) shifted I(h) activation curve towards negative potentials by ∼11 mV both in Wistar rats and C57/BL6 mice. Inhibition was voltage- and concentration-dependent (I(max) = 47%, IC(50) = 7.74 μM). MPP(+) slowed I(h) activation kinetics at all potentials. These effects were not dependent on (i) block of mitochondrial complex I/fall of ATP levels, (ii) activation of type 2 dopamine receptor and (iii) alteration of cAMP metabolism. Finally, MPP(+) -dependent inhibition of I(h) facilitated temporal summation of eEPSPs in SNc DA, but not in CA1 hippocampal neurons. CONCLUSIONS AND IMPLICATIONS: Reduced functionality of I(h) in SNc DA neurons, via increased responsiveness towards synaptic excitation, might play a role in MPP(+) -induced parkinsonism and, possibly, in the pathogenesis of human Parkinson's.
    British Journal of Pharmacology 01/2013; 169(1). DOI:10.1111/bph.12104 · 4.99 Impact Factor
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    • "that this evoked current was due to AMPA receptor activation by blocking the response with the potent and selective AMPA receptor antagonist NBQX (30 lm; data not shown). Similar to previous studies (Arencibia-Albite et al., 2007; Inyushin et al., 2010), recorded cells were located lateral to the fasciculus retroflexus and medial to the medial terminal nucleus of the accessory optic tract (Paxinos & Watson, 2007). Cells exhibited a pronounced I h , slow spontaneous activity and relatively regular interspike intervals, which are common accepted electrophysiological features for DA neurons in this area (Bunney et al., 1973; Grace & Bunney, 1983; Grace & Onn, 1989). "
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    ABSTRACT: The ventral tegmental area (VTA) forms part of the mesocorticolimbic system and plays a pivotal role in reward and reinforcing actions of drugs of abuse. Glutamate transmission within the VTA controls important aspects of goal-directed behavior and motivation. Noradrenergic receptors also present in the VTA have important functions in the modulation of neuronal activity. Here we studied the effects of α2 noradrenergic receptor activation in the alteration of glutamate neurotransmission in VTA dopaminergic neurons from male Sprague-Dawley rats. We used whole-cell patch-clamp recordings from putative VTA dopaminergic neurons and measured excitatory postsynaptic currents. Clonidine (40 μm) and UK 14,304 (40 μm), both α2 receptor agonists, reduced (approximately 40%) the amplitude of glutamate-induced excitatory postsynaptic currents. After clonidine administration, there was a dose-dependent reduction over the concentration range of 15-40 μm. Using yohimbine (20 μm) and two other α2 adrenergic receptor antagonists, idaxozan (40 μm) and atipemazole (20 μm), we demonstrated that the inhibitory action is specifically mediated by α2 receptors. Moreover, by inhibiting protein kinases with H-7 (75 μm), Rp-adenosine 3',5'-cyclic (11 μm) and chelerythrine (1 μm) it was shown that the clonidine-induced inhibition seems to involve a selective activation of the protein kinase C intracellular pathway. Increased paired-pulse ratios and changes in spontaneous and miniature excitatory postsynaptic current frequencies but not amplitudes indicated that the effect of the α2 agonist was presynaptically mediated. It is suggested that the suppression of glutamate excitatory inputs onto VTA dopaminergic neurons might be relevant in the regulation of reward and drug-seeking behaviors.
    European Journal of Neuroscience 05/2012; 35(9):1406-15. DOI:10.1111/j.1460-9568.2012.08029.x · 3.67 Impact Factor
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    • "Given that the spontaneous firing rate of DA neurons strongly relies on A-type potassium currents (Putzier et al., 2009), it may be hypothesized that as for haloperidol, chronic treatment with quinpirole upregulated A-type potassium channel expression, leading to the observed decrease in DA neuron pace-maker activity. Other channels, such as Ih, Im and calcium channels, also known to contribute to the excitability and pacemaker activity of DA neurons, could also be involved (Kang & Kitai, 1993; Seutin et al., 2001; Liu et al., 2003; Zhang et al., 2005; Wanat et al., 2008; Putzier et al., 2009; Inyushin et al., 2010). Whatever its mechanism, long-term changes in the firing rate of DA neurons could have extensive impact not only on DA release but also on the synaptic input integration by these neurons, as suggested by recent work using dynamic patchclamp (Putzier et al., 2009). "
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    ABSTRACT: Dysfunctional dopamine (DA)-mediated signaling is implicated in several diseases including Parkinson's disease, schizophrenia and attention deficit and hyperactivity disorder. Chronic treatment with DA receptor agonists or antagonists is often used in pharmacotherapy, but the consequences of these treatments on DA neuron function are unclear. It was recently demonstrated that chronic D2 autoreceptor (D2R) activation in DA neurons decreases DA release and inhibits synapse formation. Given that DA neurons can establish synapses that release glutamate in addition to DA, we evaluated the synapse specificity of the functional and structural plasticity induced by chronic D2R activation. We show that chronic activation of the D2R with quinpirole in vitro caused a parallel decrease in the number of dopaminergic and glutamatergic axon terminals. The capacity of DA neurons to synthesize DA was not altered, as indicated by the lack of change in protein kinase A-mediated Ser(40) phosphorylation of tyrosine hydroxylase. However, the spontaneous firing rate of DA neurons was decreased and was associated with altered intrinsic properties as revealed by a prolonged latency to first spike after release from hyperpolarization. Moreover, D2R function was decreased after its chronic activation. Our results demonstrate that chronic activation of the D2R induces a complex neuronal reorganization involving the inhibition of both DA and glutamate synapse formation and an alteration in electrical activity, but not in DA synthesis. A better understanding of D2R-induced morphological and functional long-term plasticity may lead to improved pharmacotherapy of DA-related neurological and psychiatric disorders.
    European Journal of Neuroscience 11/2010; 32(9):1433-41. DOI:10.1111/j.1460-9568.2010.07397.x · 3.67 Impact Factor
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