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: 3.36). 05/2010; 167(2):287-97. DOI: 10.1016/j.neuroscience.2010.01.052
Source: PubMed


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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    • "The mechanisms by which norepinephrine operates within this multifunctional network are unclear. Norepinephrine binds to multiple adrenoreceptor subtypes and leads to multiple complex intracellular signaling pathways that can influence both postsynaptic membrane properties and presynaptic signaling mechanisms (Boychuk et al. 2011; Hermann et al. 2005; Inyushin et al. 2010; Jiménez-Rivera et al. 2012; Moore and Guyenet 1983). The present study tests the hypothesis that multiple adrenoreceptors modulate prehypoglossal neurons in the medullary reticular formation. "
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    ABSTRACT: Regulation of feeding behavior involves the integration of multiple physiologic and neurologic pathways that control both nutrient seeking and consummatory behaviors. The consummatory phase of ingestion includes stereotyped oromotor movements of the tongue and jaw that are controlled through brainstem pathways. These pathways not only encompass cranial nerve sensory and motor nuclei for processing feeding-related afferent signals and supplying the oromotor musculature, but also reticular neurons for orchestrating ingestion and coordinating it with other behaviors that utilize the same musculature. Based on decerebrate studies, this circuit should be sensitive to satiety mechanisms mediated centrally by A2 noradrenergic neurons in the caudal nucleus of the solitary tract (cNST) that are potently activated during satiety. Because the first observable phase of satiety is inhibition of oromotor movements, we hypothesized that norepinephrine (NE) would act to inhibit pre-hypoglossal neurons in the medullary reticular formation. Using patch clamp electrophysiology of retrogradely labeled pre-hypoglossal neurons and calcium imaging to test this hypothesis, we demonstrate that norepinephrine can influence both pre- and postsynaptic properties of reticular neurons through both a1- and a2-adrenoreceptors. The a1-adrenoreceptor agonist phenylephrine (PE) activated an inward current in the presence of TTX, and increased the frequency of both inhibitory and excitatory miniature postsynaptic currents. The a2-adrenoreceptor agonist dexmedetomidine (DMT) inhibited caudal NST-evoked excitatory currents as well as spontaneous and miniature excitatory currents through presynaptic mechanisms. The diversity of adrenoreceptor modulation of these pre-hypoglossal neurons may reflect their role in a multifunctional circuit coordinating both ingestive and respiratory lingual function.
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    • "The only neurotransmitter showing an effect on the h-current amplitude is NA, which causes inhibition; the effect, that could be replicated by an α2 agonist, is similar to what has been described in L4 and L5 rat dorsal root ganglion neurons [63]. Also in midbrain DA neurons NA inhibits the h-current, either with cAMP-independent mechanisms (activation of the PKC pathway, as in VTA [64]) or due to space-clamp effect (as in substantia nigra [65]). There are, however, also reports of enhancement of Ih by NA, as in thalamic neurons [66] and in CA1 hippocampal stratum oriens-alveus interneurons [67], but without a clear indication of the underlying mechanism. "
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    ABSTRACT: The properties of the hyperpolarization-activated cation current (I h) were investigated in rat periglomerular dopaminergic neurons using patch-clamp recordings in thin slices. A reliable identification of single dopaminergic neurons was made possible by use of a transgenic line of mice expressing eGFP under the tyrosine hydroxylase promoter. At 37 uC and minimizing the disturbance of the intracellular milieu with perforated patches, this current shows a midpoint of activation around 282.7 mV, with a significant level of opening already at rest, thereby giving a substantial contribution to the resting potential, and ultimately playing a relevant function in the control of the cell excitability. The blockage of I h has a profound influence on the spontaneous firing of these neurons, which result as strongly depressed. However the effect is not due to a direct role of the current in the pacemaker process, but to the I h influence on the resting membrane potential. I h kinetics is sensitive to the intracellular levels of cAMP, whose increase promotes a shift of the activation curve towards more positive potentials. The direct application of DA and 5-HT neurotransmitters, physiologically released onto bulbar dopaminergic neurons and known to act on metabotropic receptors coupled to the cAMP pathway, do not modifythe I h amplitude. On the contrary, noradrenaline almost halves the I h amplitude. Our data indicate that the HCN channels do not participate directly to the pacemaker activity of periglomerular dopaminergic neurons, but influence their resting membrane potential by controlling the excitability profile of these cells, and possibly affecting the processing of sensory information taking place at the entry of the bulbar circuitry. Citation: Pignatelli A, Borin M, Fogli Iseppe A, Gambardella C, Belluzzi O (2013) The h-Current in Periglomerular Dopaminergic Neurons of the Mouse Olfactory Bulb. PLoS ONE 8(2): e56571. doi:10.1371/journal.pone.0056571
    Full-text · Article · Feb 2013 · PLoS ONE
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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 (i) hyperpolarize SNc DA neurons by ∼6 mV; (ii) cause an abrupt and marked (over 50%) reduction of the spontaneous activity; and (iii) inhibit the hyperpolarization-activated inward current (Ih ). MPP(+) shifted Ih activation curve towards negative potentials by ∼11 mV both in Wistar rats and in C57/BL6 mice. Inhibition was voltage- and concentration-dependent (Imax = 47%, IC50 = 7.74 μM). MPP(+) slowed Ih 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 DA receptor; and (iii) alteration of cAMP metabolism. Finally, MPP(+) -dependent inhibition of Ih facilitated temporal summation of evoked EPSPs in SNc DA, but not in CA1 hippocampal neurons. Conclusion and implications: Reduced functionality of Ih 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.
    Full-text · Article · Jan 2013 · British Journal of Pharmacology
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