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bioRxiv · 10.1101/2020.10.13.338343

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

Sanchez Luna, W. N.·Pochapski, J. A.·Jessen, L. F.·Ellenberg, M.·Robinson, D. L.·Schwarting, R. K.·Andreatini, R.·da Cunha, C.
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Abstract

Background and PurposeCurrently, no effective drug exists to treat cocaine use disorders, which affect millions of people worldwide. Benzodiazepines are potential therapeutic candidates, as microdialysis and voltammetry studies have shown that they can decrease dopamine release in the nucleus accumbens of rodents. In addition, we have recently shown that diazepam blocks the increase in dopamine release and the affective marker 50-kHz ultrasonic vocalizations (USV) induced by DL-amphetamine in rats. Experimental ApproachHere we tested whether administration of 2.5 mg{middle dot}kg-1 diazepam (i.p.) in adult male Wistar rats could block the effects of 20 mg{middle dot}kg-1 cocaine (i.p.) on electrically evoked phasic dopamine release in the nucleus accumbens measured by fast-scan cyclic voltammetry, as well as 50-kHz USV and locomotor activity. Key ResultsCocaine injection increased evoked dopamine release up to 3-fold within 5 min and the increase was significantly higher than baseline for at least 90 min. The injection of diazepam 15 min later attenuated the cocaine effect by nearly 50% and this attenuation was maintained for at least 30 min. Stimulant drugs, natural rewards and reward predictive cues are known to evoke 50-kHz USV in adult rats. In the present study, cocaine increased the number of 50-kHz USV of the flat, step, trill, and mixed kinds by 12-fold. This effect was at maximum 5 min after cocaine injection, decreased with time and lasted at least 40 min. Diazepam significantly blocked this effect for the entire duration of the session. The distance travelled by control rats during a 40-min session of exploration in an open field was at maximum in the first 5 min and decayed progressively until the end of the session. Cocaine-treated rats travelled significantly longer distances when compared to the control group, while diazepam significantly attenuated cocaine-induced locomotion by up to 50%. Conclusions and implicationThese results suggest that the neurochemical, affective, and stimulant effects of cocaine can be mitigated by diazepam. What is already knownO_LIDiazepam decreases dopamine release in the rodent nucleus accumbens (NAc) and reduces some effects produced by DL-amphetamine. C_LI What this study addsO_LIDiazepam attenuated the increase in phasic dopamine release caused by cocaine. C_LIO_LIDiazepam blocked the effect of cocaine on 50-kHz USV and locomotor activity. C_LI Clinical significanceO_LIThis study demonstrates that diazepam can block specific effects of cocaine that likely contribute to addiction. C_LI

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Sanchez Luna, W. N., Pochapski, J. A., Jessen, L. F., Ellenberg, M., Robinson, D. L., Schwarting, R. K., Andreatini, R., da Cunha, C.. 2020-10-14. Diazepam attenuates the effects of cocaine on locomotion, 50-kHz ultrasonic vocalizations and phasic dopamine release in the nucleus accumbens of rats. https://doi.org/10.1101/2020.10.13.338343

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