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

Wojciech B Solecki; Michał Kielbinski; Joanna Bernacka; Katarzyna Gralec; Adam Klasa; Kamil Pradel; Karolina Rojek-Sito; Ryszard Przewłocki

doi:10.3389/fnbeh.2022.969104

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

Front Behav Neurosci. 2022 Aug 4:16:969104. doi: 10.3389/fnbeh.2022.969104. eCollection 2022.

Authors

Wojciech B Solecki¹, Michał Kielbinski¹, Joanna Bernacka^{1

2}, Katarzyna Gralec³, Adam Klasa¹, Kamil Pradel⁴, Karolina Rojek-Sito⁵, Ryszard Przewłocki³

Affiliations

¹ Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Jagiellonian University, Kraków, Poland.
² Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
³ Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
⁴ Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.
⁵ Department of Behavioral Neuroscience and Drug Development, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.

Abstract

Activity of the alpha₁-adrenergic receptor (α₁-AR) in the ventral tegmental area (VTA) modulates dopaminergic activity, implying its modulatory role in the behavioral functions of the dopamine (DA) system. Indeed, intra-VTA α₁-AR blockade attenuates conditioned stimulus dependent behaviors such as drug seeking responses signifying a role of the noradrenergic signaling in the VTA in conditioned behaviors. Importantly, the role of the VTA α₁-AR activity in Pavlovian associative learning with positive outcomes remains unknown. Here, we aimed to examine how intra-VTA α₁-AR blockade affects acquisition of cocaine-induced Pavlovian associative learning in the conditioned place preference (CPP) paradigm. The impact of α₁-AR blockade on cocaine-reinforced operant responding and cocaine-evoked ultrasonic vocalizations (USVs) was also studied. In addition, both α₁-AR immunoreactivity in the VTA and its role in phasic DA release in the nucleus accumbens (NAc) were assessed. We demonstrated cellular localization of α₁-AR expression in the VTA, providing a neuroanatomical substrate for the α₁-AR mechanism. We showed that prazosin (α₁-AR selective antagonist; 1 μg/0.5 μl) microinfusion attenuated electrically evoked DA transients in the NAc and dose-dependently (0.1-1 μg/0.5 μl) prevented the acquisition of cocaine CPP but did not affect cocaine-reinforced operant responding nor cocaine-induced positive affective state (measured as USVs). We propose that the VTA α₁-AR signaling is necessary for the acquisition of Pavlovian associative learning but does not encode hedonic value. Thus, α₁-AR signaling in the VTA might underlie salience encoding of environmental stimuli and reflect an ability of alerting/orienting functions, originating from bottom-up information processing to guide behaviors.

Keywords: Pavlovian associative learning; alpha1-adrenergic receptor; phasic dopamine; salience; ventral tegmental area (VTA).