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

Maria Carolina Velasquez-Martinez,Bermary Santos-Vera,Maria E Velez-Hernandez,Carlos A Jimenez-Rivera,Rafael Vazquez-Torres

doi:10.3390/ijms21030790

Maria Carolina Velasquez-Martinez, Bermary Santos-Vera + Show 3 more

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https://doi.org/10.3390/ijms21030790

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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.

Highlights

The mesocorticolimbic system is composed of dopamine (DA) neurons projecting mainly from the ventral tegmental area (VTA) to cortical and ventral forebrain structures [1,2,3]
We first tested the effect of α1-ARs activation on glutamate release in animals treated with one cocaine injection
The present results showed that α1-AR-mediated activation on glutamatergic transmission is no longer present after 5 days of cocaine sensitization protocol, even after withdrawal period

Summary

Introduction

The mesocorticolimbic system is composed of dopamine (DA) neurons projecting mainly from the ventral tegmental area (VTA) to cortical and ventral forebrain structures [1,2,3]. The activation of VTA DA neurons has been implicated in motivated behaviors as well as in mediating the reinforcing actions of drug abuse [4,5,6]. The VTA contains alpha-1 adrenoreceptors (α1-ARs) [10], which are located primarily in presynaptic elements [11,12,13]. NE inputs have been shown to facilitate VTA DA neuronal transmission and induce changes in burst firing via α1-ARs [14,15,16]. Activation of α1-ARs at presynaptic terminals increase glutamate (Glu) and decreased GABA release onto VTA DA neurons, changing their excitability [12,13]

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