Activation of alpha1-adrenoceptors enhances glutamate release onto ventral tegmental area dopamine cells

Abstract

The ventral tegmental area (VTA) plays an important role in reward and motivational processes that facilitate the development of drug addiction. Glutamatergic inputs into the VTA contribute to dopamine (DA) neuronal activation related to reward and response-initiating effects in drug abuse. Previous investigations indicate that alpha1-adrenoreceptors (α1-AR) are primarily localized at presynaptic elements in the ventral midbrain. Studies from several brain regions have shown that presynaptic α1-AR activation enhance glutamate release. Therefore, we hypothesized that glutamate released onto VTA-DA neurons is modulated by pre-synaptic α1-AR. Recordings were obtained from putative VTA-DA cells of male Sprague-Dawley rats (28–50 days postnatal) using voltage clamp techniques. Phenylephrine (10 µM) and methoxamine (80 µM), both α1-AR agonists, increased AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) amplitude evoked by electrical stimulation of afferent fibers (p<0.05). This effect was blocked by the α1-AR antagonist prazosin (1 µM). Phenylephrine decreased the paired-pulse ratio and increased spontaneous EPSCs frequencies but not their amplitudes suggesting a presynaptic locus of action. No changes in miniature EPSCs (0.5 µM TTX) were observed after phenylephrine’s application which suggest that α1-AR effect was action potential dependent. Normal extra- and intracellular Ca2+ concentration seems necessary for the α1-AR effect since phenylephrine in low Ca2+ ACSF and depletion of intracellular Ca2+ stores with thapsigargin (10 µM) failed to increase the AMPA EPSCs amplitude . Chelerythrine (1 µM, PKC inhibitor) but not Rp-cAMPS (11 µM, PKA inhibitor) blocked the α1-AR activation effect on AMPA EPSCs, indicating that a PKC intracellular pathway is required. These results demonstrated that presynaptic α1-ARs activation modulates glutamatergic inputs that affect VTA-DA neurons excitability. α1-ARs action might be heterosynaptically localized at glutamatergic fibers terminating onto VTA-DA neurons. It is suggested that drug-induced changes in α1-AR could be part to the neuroadaptations occurring in the mesocorticolimbic circuitry during the addiction process.

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

“…Indeed, methoxamine mimicked the effects of norepinephrine on RLi sEPSC frequency. This finding is a similar to that seen in VTA dopamine neurons (Velasquez-Martinez et al 2012). In the RLi, the frequency of mEPSCs increases with the activation of α 1 -ARs.…”

“…Similarly, activation of α 1 -ARs leads to an enhancement of glutamatergic transmission onto VTA dopamine neurons (McElligott et al 2010, McElligott & Winder 2008, Velasquez-Martinez et al 2012). In the presence of the α 1 -AR antagonist prazosin, we found that norepinephrine did not increase excitatory transmission.…”

“…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.…”

Specificity and impact of adrenergic projections to the midbrain dopamine system

“…Contrary to the effect of inhibitory postsynaptic currents, activation of α1 adrenoceptors increased presynaptic glutamate release. Phenylephrine increased the amplitude of evoked and frequency of spontaneous AMPA excitatory postsynaptic currents (Velasquez-Martinez et al, 2012; Williams et al, 2014). Taken together, the presynaptic α1 actions are in accordance to an activation of DA neurons favoring glutamate over GABA inputs.…”

The Selective Dopamine β-Hydroxylase Inhibitor Nepicastat Attenuates Multiple Aspects of Cocaine-Seeking Behavior

“…It is unclear how this mechanism could account for the nepicastat-induced block of reinstatement, as DA receptor activation in the PFC actually facilitates reinstatement of cocaine seeking (Sun and Rebec, 2005). Other mechanisms that contribute to the effects of nepicastat are also possible, such as noradrenergic modulation of glutamate transmission in the mesocorticolimbic circuit (Velasquez-Martinez et al, 2012;Gaval-Cruz and Weinshenker, 2009;Mitrano et al, 2012).…”