Intra-median raphe nucleus (MRN) infusions of muscimol, a GABA-A receptor agonist, reinstate alcohol seeking in rats: role of impulsivity and reward.
OBJECTIVE
We previously found that the inhibition of median raphe nucleus (MRN) 5-HT transmission by local injections of a 5-HT1A agonist 8-OH-DPAT or corticotrophin-releasing factor (CRF) mimic the effect of foot shock stress to reinstate alcohol seeking. In this study, we further explored the role of the MRN by examining the effect of inhibition of MRN neurons, by injecting the GABA-A receptor agonist muscimol, on the reinstatement of alcohol seeking.


METHODS
Male rats were trained to lever press for 12% alcohol. Cannulae were implanted aimed at the MRN; some rats were also given intra-MRN injections of 5,7-DHT to destroy ascending 5-HT neurons. After retraining, alcohol responding was extinguished for 14 days. Subsequently, we tested the effect of muscimol injections into the MRN (0, 12.5, 25, 50 ng) on reinstatement. We also tested the effect of MRN muscimol injections on a measure of reward, conditioned place preference (CPP) and performance in the five-choice serial reaction time task (5-CSRTT), which tests a variety of psychological processes including sustained attention and impulsivity.


RESULTS
MRN muscimol injections strongly reinstated alcohol seeking and this effect was not reversed by the depletion of 5-HT with 5,7-DHT. MRN muscimol injections did not induce a CPP, but did significantly impair multiple aspects of performance on the 5-CSRTT, including a marked increase in premature, or impulsive, responding.


CONCLUSIONS
Together with our previous findings, these results suggest that the inhibition of MRN projection neurons provokes alcohol seeking. Results from the 5-CSRTT suggest that increased impulsivity may contribute to these effects.
Lê
Anh Dzung
AD
Department of Neuroscience, Centre for Addiction and Mental Health, 33 Russell Street, Toronto, ON M5S 2S1, Canada. Anh_Le@camh.net
Lê Dzung
Anh
A
Funk
Douglas
D
Harding
Stephen
S
Juzytsch
Walter
W
Li
Zhaoxia
Z
Fletcher
Paul J
PJ
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D058785:GABA-A Receptor Agonists; D007175:Impulsive Behavior / Q000503:physiopathology*; D007267:Injections; D008297:Male; D009042:Motivation; D009118:Muscimol / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D011903:Raphe Nuclei / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012008:Recurrence; D012646:Self Administration; D012691:Serial Learning / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology
D058785:GABA-A Receptor Agonists; D018490:Serotonin Agents; D009118:Muscimol; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin