Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats

Rationale and objectives: Footshock stress reliably reinstates heroin seeki ng in rats. but the time course of the development of this effect following drug withdrawal is not known. Here we studied the effect of intermittent f ootshock stress on reinstatement of heroin seeking following different with drawal periods (1-66 days). We also studied whether changes in corticotropi n-releasing factor (CRF) mRNA in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) are correlated with this reinstatement after 1 day and 6 days of heroin withdrawal. Methods: Rats w ere trained to self-administer heroin (9 h/day; 0.1 mg/kg per infusion) for 10 days. Tests for extinction behavior and footshock-induced reinstatement of heroin seeking were then conducted after 1, 6, 12, 25, or 66 days of he roin withdrawal. On the test day, rats were given five to ten 60-min extinc tion sessions until they reached the extinction criterion of less than 15 r esponses per 60 min on the lever previously associated with heroin. Rats we re then exposed to intermittent footshock (0.8 mA; 10 min), and lever-press ing behavior was recorded for 120 min. Results: Reinstatement of lever-pres sing behavior by footshock followed an inverted U-shaped curve with maximal responding after 6 days and 12 days of heroin withdrawal. Surprisingly, fo otshock did not reinstate lever-pressing behavior on day 1 of withdrawal. L ever pressing during extinction, prior to exposure to footshock, also follo wed an inverted U-shaped curve, with higher responding after 6, 12, and 25 days of heroin withdrawal. Finally, compared with control groups not expose d to shock, CRF mRNA levels in response to footshock were increased in the CeA (day I of withdrawal) and the dorsal BNST (day 1 and day 6), but not in the ventral BNST. Conclusions: The duration of the heroin withdrawal perio d is an important factor in the manifestation of (1) footshock stress-induc ed reinstatement of heroin seeking and (2) extinction of the heroin-reinfor ced behavior. Finally, the time-dependent changes in footshock stress induc ed reinstatement following withdrawal from heroin were not correlated with alterations in CRF mRNA in the CeA and BNST.