Diazepam attenuates the effects of cocaine on locomotion, 50-kHz ultrasonic vocalizations and phasic dopamine in the nucleus accumbens of rats.

BACKGROUND AND PURPOSE: Currently, there is no effective drug to treat cocaine-use disorder, which affects millions of people worldwide. Benzodiazepines are potential therapeutic candidates, as microdialysis and voltammetry studies have shown that they can decrease dopamine concentrations in the nucleus accumbens of rodents and block the increase in dopamine levels and appetitive 50-kHz ultrasonic vocalizations (USVs) induced by amphetamine in rats. EXPERIMENTAL APPROACH: Here, we tested whether administration of 2.5-mg·kg-1 diazepam (i.p.) in adult male rats could block the effects of 20-mg·kg-1 cocaine (i.p.) on electrically evoked phasic dopamine signals in the nucleus accumbens measured by fast-scan cyclic voltammetry, as well as 50-kHz USV and locomotor activity. KEY RESULTS: Cocaine injection increased evoked dopamine signals up to threefold within 5 min, and the increase was significantly higher than baseline for at least 75 min. The injection of diazepam, 5 min after cocaine, attenuated the cocaine effect by nearly 50%, and this attenuation was maintained for at least 40 min. Behaviourally, cocaine increased the number of appetitive 50-kHz calls by about 12-fold. Diazepam significantly blocked this effect for the entire duration of the session. Also, cocaine-treated rats were more active than controls and diazepam significantly attenuated cocaine-induced locomotion, by up to 50%. CONCLUSION AND IMPLICATIONS: These results suggest that the neurochemical and psychostimulant effects of cocaine can be mitigated by diazepam. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.

Ultrasonic vocalizations and individual differences in rats performing a Pavlovian conditioned approach task.

Rats emit distinct types of ultrasonic vocalizations (USV), including high-frequency 50-kHz USV, which occur in appetitive situations. Such 50-kHz USV are thought to reflect positive affective states, for example in case of reward anticipation, and are linked to dopamine signaling. The present study was conducted to investigate whether rats emit 50-kHz USV during a Pavlovian conditioned approach task and whether trait-like differences in 50-kHz USV emission are associated with sign- versus goal-tracking. We hypothesize that individuals engaging more with a cue predicting a food reward will also elicit more 50-kHz USV. In order to test this, we investigated 34 female rats and gauged USV while they underwent a Pavlovian conditioned approach training and extinction paradigm. For one, we found a high subject-dependent variability in the emission of 50-kHz calls. These were not largely affected by state differences, since these 50-kHz USV were observed throughout the task. During task progress and in most subjects, there was a rather complete shift toward goal-tracking, but subjects engaging more with the cue predicting a reward also emitted higher numbers of appetitive 50-kHz calls. This supports the hypothesis that sign-tracking is positively associated with the emission of 50-kHz USV. The high subject-dependent variability in the emission of 50-kHz calls warrants special attention in future appetitive studies.