5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking.
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 DRNNAc 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.
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.|Department of Molecular Therapeutics, The Scripps Research Institute-Florida, Jupiter, FL, USA.
In-Jee
IJ
You
Department of Molecular Therapeutics, The Scripps Research Institute-Florida, Jupiter, FL, USA.
Sherie R
SR
Wright
Department of Psychiatry, Columbia University, New York, NY, USA.
Alvaro L
AL
Garcia-Garcia
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Andrew R
AR
Tapper
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Paul D
PD
Gardner
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.|National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
George F
GF
Koob
Department of Psychiatry, Columbia University, New York, NY, USA.|New York State Psychiatric Institute, New York, NY, USA.
E
E
David Leonardo
Department of Molecular Therapeutics, The Scripps Research Institute-Florida, Jupiter, FL, USA.
Laura M
LM
Bohn
Department of Molecular Therapeutics, The Scripps Research Institute-Florida, Jupiter, FL, USA.
Sunmee
S
Wee
D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D003192:Compulsive Behavior / Q000503:physiopathology*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D015198:Designer Drugs / Q000008:administration & dosage; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000503:physiopathology*; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000502:physiology*; D012201:Reward; D059326:Serotonergic Neurons / Q000187:drug effects / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000008:administration & dosage
D017660:Autoreceptors; D015198:Designer Drugs; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D003042:Cocaine