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

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.

SUBMITTER: Solecki WB

PROVIDER: S-EPMC9386374 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Solecki Wojciech B WB Kielbinski Michał M Bernacka Joanna J Gralec Katarzyna K Klasa Adam A Pradel Kamil K Rojek-Sito Karolina K Przewłocki Ryszard R

Frontiers in behavioral neuroscience 20220804

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 ...[more]

PMID: 35990723

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Project description:During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.

Dataset Information

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

Publications

Alpha<sub>1</sub>-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning.

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