TY - JOUR
T1 - Neural basis of benzodiazepine reward
T2 - Requirement for α2 containing GABA a receptors in the nucleus accumbens
AU - Engin, Elif
AU - Bakhurin, Konstantin I.
AU - Smith, Kiersten S.
AU - Hines, Rochelle M.
AU - Reynolds, Lauren M.
AU - Tang, Wannan
AU - Sprengel, Rolf
AU - Moss, Stephen J.
AU - Rudolph, Uwe
N1 - Funding Information:
The project described was supported by Award Number R03DA027051 of the National Institute on Drug Abuse and Award Number RO1MH080006 of the National Institute of Mental Health to UR. RMH was supported by a Canadian Institutes for Health Research Postdoctoral fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institute of Mental Health or the National Institutes of Health. In the last 3 years, UR has received compensation for professional services from Sunovion and from Concert Pharmaceuticals. SJM is supported by NIH–National Institute of Neurological Disorders and Stroke Grants NS051195, NS056359, NS081735, and MH097446; and by Citizens United for Research in Epilepsy and the Simons Foundation. SJM serves as a consultant for Sage Therapeutics and Astra Zeneca, relationships that are regulated by Tufts University and do not impact on this study.
PY - 2014/7
Y1 - 2014/7
N2 - Despite long-standing concerns regarding the abuse liability of benzodiazepines, the mechanisms underlying properties of benzodiazepines that may be relevant to abuse are still poorly understood. Earlier studies showed that compounds selective for α1-containing GABA A receptors (α1GABA A Rs) are abused by humans and self-administered by animals, and that these receptors may underlie a preference for benzodiazepines as well as neuroplastic changes observed in the ventral tegmental area following benzodiazepine administration. There is some evidence, however, that even L-838, 417, a compound with antagonistic properties at α1GABA A Rs and agonistic properties at the other three benzodiazepine-sensitive GABA A receptor subtypes, is self-administered, and that the α2GABA A Rs may have a role in benzodiazepine-induced reward enhancement. Using a two-bottle choice drinking paradigm to evaluate midazolam preference and an intracranial self-stimulation (ICSS) paradigm to evaluate the impact of midazolam on reward enhancement, we demonstrated that mice carrying a histidine-to-arginine point mutation in the α2 subunit which renders it insensitive to benzodiazepines (α2(H101R) mice) did not prefer midazolam and did not show midazolam-induced reward enhancement in ICSS, in contrast to wild-type controls, suggesting that α2GABA A Rs are necessary for the reward enhancing effects and preference for oral benzodiazepines. Through a viral-mediated knockdown of α2GABA A Rs in the nucleus accumbens (NAc), we demonstrated that α2 in the NAc is necessary for the preference for midazolam. Findings imply that α2GABA A Rs in the NAc are involved in at least some reward-related properties of benzodiazepines, which might partially underlie repeated drug-taking behavior.
AB - Despite long-standing concerns regarding the abuse liability of benzodiazepines, the mechanisms underlying properties of benzodiazepines that may be relevant to abuse are still poorly understood. Earlier studies showed that compounds selective for α1-containing GABA A receptors (α1GABA A Rs) are abused by humans and self-administered by animals, and that these receptors may underlie a preference for benzodiazepines as well as neuroplastic changes observed in the ventral tegmental area following benzodiazepine administration. There is some evidence, however, that even L-838, 417, a compound with antagonistic properties at α1GABA A Rs and agonistic properties at the other three benzodiazepine-sensitive GABA A receptor subtypes, is self-administered, and that the α2GABA A Rs may have a role in benzodiazepine-induced reward enhancement. Using a two-bottle choice drinking paradigm to evaluate midazolam preference and an intracranial self-stimulation (ICSS) paradigm to evaluate the impact of midazolam on reward enhancement, we demonstrated that mice carrying a histidine-to-arginine point mutation in the α2 subunit which renders it insensitive to benzodiazepines (α2(H101R) mice) did not prefer midazolam and did not show midazolam-induced reward enhancement in ICSS, in contrast to wild-type controls, suggesting that α2GABA A Rs are necessary for the reward enhancing effects and preference for oral benzodiazepines. Through a viral-mediated knockdown of α2GABA A Rs in the nucleus accumbens (NAc), we demonstrated that α2 in the NAc is necessary for the preference for midazolam. Findings imply that α2GABA A Rs in the NAc are involved in at least some reward-related properties of benzodiazepines, which might partially underlie repeated drug-taking behavior.
UR - http://www.scopus.com/inward/record.url?scp=84902543822&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902543822&partnerID=8YFLogxK
U2 - 10.1038/npp.2014.41
DO - 10.1038/npp.2014.41
M3 - Article
C2 - 24553732
AN - SCOPUS:84902543822
SN - 0893-133X
VL - 39
SP - 1805
EP - 1815
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 8
ER -