5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute; Tapper Lab
Mental and Social Health | Neuroscience and Neurobiology | Psychiatry | Psychiatry and Psychology | Substance Abuse and Addiction
Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNshort right arrowNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction.
DOI of Published Version
Neuropsychopharmacology. 2016 Apr;41(5):1210-22. Epub 2015 Sep 1. Link to article on publisher's site
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
You I, Wright SR, Garcia-Garcia AL, Tapper AR, Gardner PD, Koob GF, David Leonardo E, Bohn LM, Wee S. (2016). 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking. Psychiatry Publications. https://doi.org/10.1038/npp.2015.268. Retrieved from https://escholarship.umassmed.edu/psych_pp/802