PT  - JOURNAL ARTICLE
AU  - Brennon R. Luster
AU  - Elizabeth S. Cogan
AU  - Karl T. Schmidt
AU  - Dipanwita Pati
AU  - Melanie M. Pina
AU  - Kedar Dange
AU  - Zoé A. McElligott
TI  - Male and female mice demonstrate divergent cellular responses in the bed nucleus of stria terminalis (BNST) following morphine withdrawal
AID  - 10.1101/369173
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 369173
4099  - http://biorxiv.org/content/early/2018/07/13/369173.short
4100  - http://biorxiv.org/content/early/2018/07/13/369173.full
AB  - The United States is experiencing an opioid epidemic of significant proportions, imposing enormous fiscal and societal costs. While prescription opioid analgesics are essential for treating pain, the cessation of these drugs can induce a withdrawal syndrome, and thus opioid use often persists to alleviate or avoid these symptoms. Therefore, it is essential to understand the neurobiology underlying this critical window of withdrawal from opioid analgesics to prevent continued usage. To model this, we administered a low dose of morphine, and precipitated withdrawal with naloxone to investigate the behavioral and cellular responses in C57BL/6J male and female mice. Following 3 days of administration, both male and female mice sensitized to the repeated bouts of withdrawal, as evidenced by their composite global withdrawal score. Female mice exhibited increased withdrawal symptoms on some individual measures, but did not show characteristic weight loss observed in male mice. Because of its role in mediating withdrawal-associated behaviors, we examined neuronal excitability and inhibitory synaptic transmission in the bed nucleus of the stria terminalis (BNST) 24 hours following the final precipitated withdrawal. In male mice, morphine withdrawal increased spontaneous GABAergic signaling compared to controls. In contrast, morphine withdrawal decreased spontaneous GABAergic signaling, and increased BNST projection neuron excitability in female mice. Intriguingly, these opposing GABAergic effects were dependent on within slice excitability. Our findings suggest that male and female mice manifest divergent cellular responses in the BNST following morphine withdrawal, and alterations in BNST inhibitory signaling may be a significant factor contributing to the expression of behaviors following opioid withdrawal.Authors’ contributionsB.R.L. conceived of project, performed behavior, performed electrophysiology, wrote manuscript; E.S.C. performed behavior, performed electrophysiology, edited manuscript; K.T.S. performed behavior, edited manuscript; D.P. performed electrophysiology, edited manuscript; M.M.P. performed electrophysiology, edited manuscript; K.D. performed behavior; Z.A.M. conceived of and supervised project, supervised BRL, ESC, KTS, KD, performed behavior, wrote manuscript