EXPLORING SEX DIFFERENCES IN MORPHINE WITHDRAWAL-INDUCED ALTERATIONS OF THE VENTRAL TEGMENTAL AREA
Morris-bobzean, Samara a
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Opioid withdrawal syndrome is a feature common to chronic opioid use that often serves as a powerful motivator of continued drug use. GABA-ergic neurons in the tail of the ventral tegmental area (tVTA) are implicated in mediating responses to opioids and opioid withdrawal. The tVTA regulates the effects of opioids on VTA dopamine neurons and a number of earlier studies have shown that alterations in levels of CREB within the tVTA profoundly affect drug-motivated behaviors. Unfortunately, the mechanisms underlying morphine withdrawal have been studied almost exclusively using men and male animals. The objectives of the current study are to investigate sex effects on the expression and duration of spontaneous somatic morphine withdrawal behavior; and to identify the relationship(s) between spontaneous somatic morphine withdrawal behavior and CREB activity in GABAergic neurons of the tVTA in both males and females. Intact adult, male and female Long Evans rats were made morphine-dependent using twice-daily injections of escalating doses of morphine (2.5-40mg/kg) for 10 days. Spontaneous somatic morphine withdrawal behavior was recorded at 12, 24, 36, 48, 60, and 72 hours after the last morphine administration; all animals were sacrificed via exsanguination after the last behavioral observation (72 hours). The spontaneous withdrawal paradigm used here revealed that while both male and female morphine-dependent rats developed somatic symptoms of withdrawal, males expressed more severe symptoms earlier in withdrawal (within the first 36 hours) compared to females. While, females demonstrated lower overall symptom severity, these symptoms persisted for a longer period of time; as a result, withdrawal symptoms in females were collectively more severe compared to males at the 72 hour time point. CREB activation in tVTA GABAergic cells was significantly higher for morphine-withdrawn females compared to controls 72 hours after the end of treatment. Taken together, these results demonstrate that the timing of the expression of somatic withdrawal is different for males and females. Furthermore, our data suggest that males and females differ in the timing of withdrawal-induced activation of tVTA CREB. These differences in CREB activation likely impact expression of behaviors associated with opioid withdrawal.