UC San Diego

Increased release of the stress neurotransmitter corticotropin-releasing factor (CRF) in regions of the extended amygdala has been shown to mediate drug withdrawal behavior. These symptoms of withdrawal have been characterized by dysphoria-like signs that can be measured by assessing levels of brain reward deficits using intracranial self stimulation (ICSS). In an initial study, the dose-response curve for naloxone-precipitated elevations in brain reward thresholds following an acute or repeated (4x at daily intervals) daily injections of 10 mg/kg of morphine was determined. Using a discrete-trial brain stimulation reward procedure, male Wistar rats implanted with stimulating electrodes aimed at the medial forebrain bundle received either repeat- or acute- treatment of morphine (10 mg/kg) 4 hr prior to one of several doses of naloxone (0.01, 0.033, 0.33. 1.0 mg/kg); naloxone was administered just prior to a test session. Naloxone dose-dependently increased thresholds after acute and repeat morphine, and its potency was greater after repeated morphine treatments. Selecting an optimal dose of naloxone (1.0 mg/kg) under acute morphine pretreatment conditions, a second study examined the effects of bilateral infusion of the CRF-R1 antagonist, antalarmin (1.0, 3.3 nmol), into the CeA and NAC shell. Results suggest that 4 h after an acute morphine (10 mg/kg) pretreatment, the highest dose of antalarmin tested (3.3 nmol) in both brain regions significantly attenuated naloxone-induced elevations in reward thresholds. The data indicate that preventing endogenous CRF in the CeA and the shell of the NAC from binding to CRF-R1 receptors can significantly blunt the brain reward deficits that result from precipitated opioid withdrawal