Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Abstract

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory Gprotein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaine's reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction. Significance StatementG-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamine's complex roles in reward and addiction is poorly understood.Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq-and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction-and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

Divergent mesolimbic dopamine circuits support alcohol-seeking triggered by discrete cues and contexts

“…Next, we tested CStriggered alcohol-seeking by presenting the CS without alcohol in the neutral context 30 min after an intraperitoneal injection of vehicle or CNO (10 mg/kg or 20 mg/kg; Fig. 2a) 20,21 . PreCS responding was minimal at test, and CS port entries were reduced in a dose-related manner by CNO ( Fig.…”

“…Next, three tests for CS-triggered alcohol-seeking in the neutral context were conducted after systemic i.p. administration of vehicle, CNO at 10 mg/kg, or CNO at 20 mg/kg 20,21 . Tests were intervened by four retraining sessions, two in the alcohol context and two in the neutral context.…”

Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release

“…Thus, bidirectional modulation of dopamine release is capable of enhancing or depressing operant responding for cocaine across multiple unit doses and does not result in a simple shift in cocaine potency. Further, Gq-DREADD-mediated stimulation of VTA dopamine neurons potentiated cue and cocaine-priming induced reinstatement, whereas Gi-DREADD reduced reinstatement ( Mahler et al, 2018 ).…”

Augmenting glutamatergic, but not dopaminergic, activity in the nucleus accumbens shell disrupts responding to a discrete alcohol cue in an alcohol context

“…Next, three CS responding tests in the neutral context were conducted after rats received systemic i.p. injections of vehicle, CNO at 10 mg/kg, or clozapine at 0.1 mg/kg (Mahler et al, 2014, 2018; Valyear et al, 2020). One retraining session in the alcohol context and one in the neutral context separated each of the three tests.…”