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Previously, we have shown that brief optogenetic inhibition of VTA DA neurons with 1\u00a0s pulses delivered every 9\u00a0s attenuates cocaine seeking under extinction conditions in rats without producing overt signs of dysphoria or locomotor sedation. Whether recruitment of neuronal pathways inhibiting VTA neuronal activity would suppress drug seeking remains unknown. Here, we asked if optogenetic stimulation of the lateral habenula (LHb) efferents in the rostromedial tegmental nucleus (RMTg) as well as RMTg efferents in VTA would reduce drug seeking. To investigate this, we measured how recruitment of elements of this inhibitory pathway affects cocaine seeking in male rats under extinction conditions. The effectiveness of brief optogenetic manipulations was confirmed electrophysiologically at the level of electrical activity of VTA DA neurons. Real\u2010time conditioned place aversion (RT\u2010CPA) and open field tests were performed to control for potential dysphoric\/sedating effects of brief optogenetic stimulation of LHb\u2010RMTg\u2010VTA circuitry. Optogenetic stimulation of either RMTg or LHb inhibited VTA DAergic neuron firing, whereas similar stimulation of RMTg efferents in VTA or LHb efferents in RMTg reduced cocaine seeking under extinction conditions. Moreover, stimulation of LHb\u2010RMTg efferents produced an effect that was maintained 24\u2009h later, during cocaine seeking test without stimulation. This effect was specific, as brief optogenetic stimulation did not affect locomotor activity and was not aversive. Our results indicate that defined inhibitory pathways can be recruited to inhibit cocaine seeking, providing potential new targets for non\u2010pharmacological treatment of drug craving.<\/jats:p>","DOI":"10.1111\/ejn.15885","type":"journal-article","created":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T09:48:00Z","timestamp":1670492880000},"page":"4487-4501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Recruitment of inhibitory neuronal pathways regulating dopaminergic activity for the control of cocaine seeking"],"prefix":"10.1111","volume":"58","author":[{"given":"Micha\u0142","family":"Wilczkowski","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Neuropsychology, Institute of Applied Psychology Jagiellonian University  Krakow Poland"},{"name":"Department of Brain Biochemistry Maj Institute of Pharmacology Polish Academy of Sciences  Krakow 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