Accumbens shell-hypothalamus interactions mediate extinction of alcohol seeking.
The nucleus accumbens shell (AcbSh) is required to inhibit drug seeking after extinction training. Conversely, the lateral hypothalamus (LH), which receives projections from AcbSh, mediates reinstatement of previously extinguished drug seeking. We hypothesized that reversible inactivation of AcbSh using GABA agonists (baclofen/muscimol) would reinstate extinguished alcohol seeking and increase neuronal activation in LH. Rats underwent self-administration training for 4% (v/v) alcoholic beer followed by extinction. AcbSh inactivation reinstated extinguished alcohol seeking when infusions were made after, but not before, extinction training. We then used immunohistochemical detection of c-Fos as a marker of neuronal activity, combined with immunohistochemical detection of the orexin and cocaine- and amphetamine-related transcript (CART) peptides, to study the profile and phenotype of neural activation during reinstatement produced by AcbSh inactivation. AcbSh inactivation increased c-Fos expression in hypothalamus, as well as in paraventricular thalamus and amygdala. Within hypothalamus, there was an increase in the number of orexin and CART cells expressing c-Fos. Finally, we hypothesized that concurrent inactivation of LH would prevent reinstatement produced by inactivation of AcbSh alone. Our results confirmed this. Together, these findings suggest that AcbSh mediates extinction of reward seeking by inhibiting hypothalamic neuropeptide neurons. Reversible inactivation of the AcbSh removes this influence, thereby releasing hypothalamus from AcbSh inhibition and enabling reinstatement of reward seeking. These ventral striatal-hypothalamic circuits for extinction overlap with those that mediate satiety, and we suggest that extinction training inhibits drug seeking because it co-opts neural circuits originally selected to produce satiety.
Millan
E Zayra
EZ
School of Psychology, The University of New South Wales, Sydney, New South Wales 2052, Australia.
Furlong
Teri M
TM
McNally
Gavan P
GP
D019973:Alcohol-Related Disorders / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005108:Extinction, Psychological; D007026:Hypothalamic Area, Lateral / Q000378:metabolism / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D009714:Nucleus Accumbens / Q000503:physiopathology*; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012201:Reward; D012646:Self Administration; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D000431:Ethanol