Presynaptic inhibition of glutamate transmission by α2 receptors in the VTA

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 alpha-2 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 13,408 (40 μM), both alpha-2 receptor agonists, reduced (~ 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 (20μM) and two other alpha-2 adrenergic receptor antagonists, idaxozan (40 μM) and atipemazole (20μM), we demonstrated that the inhibitory action is specifically mediated by alpha-2 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. An increased paired-pulse ratios and changes in spontaneous and miniature excitatory postsynaptic currents frequencies but not amplitudes indicated that the alpha-2 agonist’s effect 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.

Adrenoreceptor modulation of oromotor pathways in the rat medulla

“…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.…”

“…Furthermore, studies in many different brain regions show that ␣ 2 -adrenoreceptor activation attenuates EPSC amplitude (Bertolino et al 1997;Hayar and Guyenet 1999;Jiménez-Rivera et al 2012). The ␣ 2 -adrenoreceptor is coupled to G i/o intracellular signaling pathways, and its activation can inhibit both neuronal activity and neurotransmitter release from synaptic terminals.…”

Excitatory drive onto dopaminergic neurons in the rostral linear nucleus is enhanced by norepinephrine in an α1 adrenergic receptor-dependent manner

“…Since the α 2 -AR agonist UK-14,304 led to a depression of sEPSC frequency and a trend toward a decrease in sEPSC amplitude, this decrease in excitatory transmission is likely due to the activation of α 2 -ARs. Similarly, activation of α 2 -ARs decreases excitatory transmission in the BNST and onto VTA dopamine neurons (Egli et al 2005, Jimenez-Rivera et al 2012, Shields et al 2009). It is possible that this decrease in glutamatergic transmission is also due to the blockade of tonically active α 1 -ARs (Grenhoff & Svensson 1993).…”

“…Norepinephrine acts as a powerful modulator of excitatory neurotransmission in many limbic brain areas. Activation of β, α 1 , and α 2 -ARs have been shown to enhance or attenuate glutamatergic transmission in a variety of brain regions, including the hippocampus, CeA, BNST and VTA (Egli et al 2005, Flavin & Winder 2013, Gereau & Conn 1994, Jimenez-Rivera et al 2012, McElligott et al 2010, McElligott & Winder 2008, Nobis et al 2011, Shields et al 2009, Velasquez-Martinez et al 2012). Therefore, norepinephrine might modulate glutamatergic transmission on RLi dopamine neurons.…”

Modulação do sistema catecolaminérgico pelos receptores glutamatérgicos e de angiotensina II no bulbo de ratos

“…Sabe-se que este sistema está presente em neurônios e astrócitos bulbares, e que ele interage com diversos sistemas de neurotransmissão em todo o sistema nervoso, como, por exemplo, o sistema glutamatérgico (Bhuiyan et al, 2009;Jimenez-Rivera et al, 2012) e o angiotensinérgico (Fior et al, 1994). (Van Giersbergen et al, 1992).…”