U. Shalev et al., Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats, PSYCHOPHAR, 156(1), 2001, pp. 98-107
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.