Dataset Information

Behavioral indicators of succeeding and failing under higher-challenge compulsion-like alcohol drinking in rat.

ABSTRACT: Intake despite negative consequences (compulsivity) contributes strongly to the harm of alcohol use disorder, making the underlying psychological and circuit mechanisms of great importance. To gain insight into possible underlying action strategies, we compared rat licking microstructure across compulsion-like and non-compulsive conditions. We previously showed that drinking under a moderate-challenge, quinine-alcohol model (Alc-ModQ) shows less variable responding in many measures, suggesting a more automatic strategy to overcome challenge. Here, we reanalyzed our original data, newly focusing on the behavioral profile of higher-challenge intake (100 mg/L quinine in alcohol, Alc-HighQ). Alc-HighQ greatly dropped consumption, yet retained aspects of greater automaticity and drive seen with Alc-ModQ, including earlier bout initiation and measures suggesting more stereotyped tongue control. In contrast, Alc-HighQ disordered bout generation and timing. Importantly, only fast-starting bouts persisted under Alc-HighQ, and while there were many fewer longer Alc-HighQ bouts, they still contributed >50 % of consumption. Also, longer bouts under Alc-HighQ had an early, several-second period with greater chance of stopping, but afterwards showed similar persistence and recovery from slow licking as other drinking conditions. Together, our findings elucidate novel behavioral indicators of successful and unsuccessful epochs of Alc-HighQ, compulsion-like intake. We also relate findings to congruent human and animal work implicating anterior insula and medial prefrontal cortices as critical for compulsion-like alcohol responding, and where ventral frontal cortex has been more associated with overall action plan and tongue control (retained under Alc-HighQ), with medial cortex more related to proximal action timing (disrupted under Alc-HighQ except after faster bout initiation).

SUBMITTER: Darevsky D

PROVIDER: S-EPMC7444822 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Compulsive drives for alcohol, where intake persists despite adverse consequences, are substantial obstacles to treating Alcohol Use Disorder (AUD). However, there are limited treatment options and thus considerable interest in identifying new, potent and safe pharmacotherapies. We found that non-canonical N-methyl-d-aspartate receptors (NMDARs), active at hyperpolarized potentials, drive compulsion-like alcohol drinking in rats without affecting regular, alcohol-only intake. Congruent human studies suggest that NMDAR inhibition reduces alcohol drinking in treatment-seekers but not non-treatment-seekers and suppresses craving. These cross-species studies of consumption under conflict indicate that inhibiting non-canonical NMDARs could be of clinical value for AUD. d-serine activates NMDARs overall, but actually inhibits non-canonical NMDARs. Also, d-serine has been widely tested in humans as a moderate NMDAR modulator, but some nephrotoxicity concerns remain, and thus any strategy that reduces d-serine exposure could be of broad utility. Here, co-administration of sodium benzoate (NaBenz), which reduces d-serine breakdown, allowed subthreshold d-serine levels to suppress compulsion-like alcohol drinking without altering normal alcohol-only consumption, providing a novel intervention for AUD and underscoring the importance of non-canonical NMDARs for compulsion-like intake. Low NaBenz doses alone had no average effect on intake. NaBenz/d-serine reduced compulsion-like intake in nearly all animals, while higher d-serine alone decreased compulsion-like intake with less of an effect in lower-drinking subjects. Thus, combining subthreshold NaBenz and d-serine suppressed compulsion-like intake, helping both to alleviate some d-serine concerns, and, importantly, to reduce consequence-resistant consumption across nearly all individuals. Therefore, NaBenz/d-serine likely represents an FDA-approved and immediately-accessible pharmacotherapy to help counteract compulsion-like drives and treat AUD.

Dataset Information

Behavioral indicators of succeeding and failing under higher-challenge compulsion-like alcohol drinking in rat.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets