Alpha-1 Adrenergic Receptors Modulate Glutamate and GABA Neurotransmission onto Ventral Tegmental Dopamine Neurons during Cocaine Sensitization

Abstract

The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs’ amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs’ function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics.

Alpha1-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning

“…This observation potentially favors a direct, post-synaptic effect via I h /SK channels ( Goertz et al, 2015 ), given the evidence that DA neurons constituting the mesolimbic pathway, but not DA neurons projecting to the mPFC, express high levels of those channels ( Juarez and Han, 2016 ). Corroborating this hypothesis is the recent observation that behavioral sensitization to cocaine by repeated exposure also desensitized α 1 -AR located on glutamatergic, but not GABAergic terminals ( Velasquez-Martinez et al, 2020 ). Yet, in previous studies, we have shown that α 1 -AR blockade in the VTA remains effective in attenuating cocaine seeking behavior despite the necessary prolonged pre-exposure to cocaine ( Solecki et al, 2018 , 2019a ).…”

Characterisation of methylphenidate-induced excitation in midbrain dopamine neurons, an electrophysiological study in the rat brain

“…Contradictory data exist in the literature regarding the direct 1 adrenergic receptor modulation on dopamine neurons. While some 1 noradrenergic receptors are present post-synaptically on dopamine neurons (Mitrano et al, 2012;Rommelfanger et al, 2009), immunohistochemical study showed that α1 adrenergic receptors are also co-localized with GABA-positive terminals in the VTA (Mitrano et al, 2012) -Martinez et al, 2020-Martinez et al, , 2015. Such a combined effect may be able to potentiate the glutamatergic tone on dopamine neurons, partially by removing tonic GABAergic inhibition.…”

“…Interestingly, intracellular studies have shown that the -adrenoreceptor-mediated activation on glutamatergic transmission is no longer present after a chronic cocaine treatment, and this desensitization persists after the withdrawal period (while the inhibitory effect of adrenoreceptor on GABA release remains) (Velasquez-Martinez et al, 2020). Therefore, psychostimulant-induced dopamine cell activation may be a relevant mechanism involved in sensitization to drugs of addiction.…”

Acute stress modulates noradrenergic signaling in the ventral tegmental area‐amygdalar circuit

“…In the VTA, the α 1 ‐AR antagonist terazosin could reduce evoked DA through a variety of candidate mechanisms: direct postsynaptic modulation of cell excitability (Goertz et al, 2015), regulation of neurotransmitter release at local glutamatergic and GABA terminals (Velásquez‐Martinez et al, 2020, 2012, 2015) and interaction with other receptors (Paladini et al, 2001; Tovar‐Díaz et al, 2018; Williams et al, 2014). When infused into the VTA, the α 2 ‐AR antagonist RX‐821002, in line with our previous findings in NAc core, potently inhibits electrically evoked DA release in BLA, likely by a mechanism involving cross‐activation of D 2 receptors by NA (Arencibia‐Albite et al, 2007; Grenhoff et al, 1995).…”