Abstract

Symptoms of opiate withdrawal include disturbances in circadian rhythms. Here, we examined in male Wistar rats the effects of a daily, mid-morning morphine injection
(5-40mg/kg, i.p.) and the subsequent withdrawal of morphine on 24-h patterns of wheel running and expression of the clock protein, PERIOD2 (PER2), in the master circadian
clock, the suprachiasmatic nucleus (SCN), and regions of the limbic forebrain. Rats were killed either within 24 h of the last morphine injection or 2 days later. Nighttime
wheel running was suppressed during daily morphine injections and following the withdrawal of morphine. Daily morphine injections and their subsequent withdrawal did
not affect PER2 expression in the SCN, but blunted the normal daily peak of PER2 in the dorsal striatum, oval nucleus of the bed nucleus of the stria terminalis (BNSTov),
central nucleus of the amygdala (CEA), basolateral amygdala (BLA), and dentate gyrus of the hippocampus (DG). We then examined the effect of injecting the D2/3 dopamine
agonist, quinpirole (1 mg/kg, i.p.), or the alpha 2 adrenergic agonist, clonidine (0.1 mg/kg, i.p.), two drugs that alleviate opiate withdrawal symptoms, following withdrawal of the daily morphine injection. Quinpirole restored the daily PER2 pattern in the BNSTov and CEA, whereas clonidine restored and entrained a new PER2 pattern in the striatum, BLA, and DG. Together, these findings suggest that disruption of daily PER2 patterns in the forebrain might contribute to the circadian symptoms observed in opiate withdrawal. Furthermore, pharmacological treatments for withdrawal can restore PER2 patterns in regions of the limbic forebrain.