The impact of ostensibly aversive social stresses on triggering, amplifying and prolonging intensely rewarding drug taking is an apparent contradiction in need of resolution. Social stress encompasses various types of significant life events ranging from maternal separation stress, brief episodes of social confrontations in adolescence and adulthood, to continuous subordination stress, each with its own behavioral and physiological profile. The neural circuit comprising the VTA–accumbens–PFC–amygdala is activated by brief episodes of social stress, which is critical for the DA-mediated behavioral sensitization and increased stimulant consumption. A second neural circuit comprising the raphe–PFC–hippocampus is activated by continuous subordination stress and other types of uncontrollable stress. In terms of the development of therapeutics, brief maternal separation stress has proven useful in characterizing compounds acting on subtypes of GABA, glutamate, serotonin and opioid receptors with anxiolytic potential. While large increases in alcohol and cocaine intake during adulthood have been seen after prolonged maternal separation experiences during the first two weeks of rodent life, these effects may be modulated by additional yet to be identified factors. Brief episodes of defeat stress can engender behavioral sensitization that is relevant to escalated and prolonged self-administration of stimulants and possibly opioids, whereas continuous subordination stress leads to anhedonia-like effects. Understanding the intracellular cascade of events for the transition from episodic to continuous social stress in infancy and adulthood may provide insight into the modulation of basic reward processes that are critical for addictive and affective disorders.

The duration of the heroin withdrawal period is an important factor in the manifestation of (1) footshock stress-induced reinstatement of heroin seeking and (2) extinction of the heroin-reinforced behavior. Finally, the time-dependent changes in footshock stress-induced reinstatement following withdrawal from heroin were not correlated with alterations in CRF mRNA in the CeA and BNST.

The effect of footshock on reinstatement of heroin seeking generalizes to food deprivation, and appears to be dependent on the environment in which the stressor is given. The data with BSR indicate that the phenomenon of footshock-induced reinstatement is not selective for drug reinforcers.

Studies in rats have shown that intermittent footshock stress reinstates drug seeking after prolonged drug-free periods. Recently, we found that another environmental stressor, acute 1 d food deprivation, potently reinstates heroin seeking in rats. Here we report that this effect of food deprivation can be blocked by leptin, a hormone involved in the regulation of energy balance and food intake. Rats were trained to self-administer heroin (0.05-0.1 mg/kg, i.v., per infusion, three 3 hr sessions per day) for 8-10 d. The heroin-reinforced behavior was then extinguished for 10-13 d, during which lever presses had no reinforced consequences. Subsequently, rats were tested for reinstatement after 1 d of food deprivation (experiment 1) or exposure to intermittent footshock (15 min, 0.6 mA) and heroin priming injections (0.25 mg/kg, s.c.) (experiment 2). Acute food deprivation reinstated heroin seeking, an effect that was attenuated by leptin (2 or 4 microgram/rat, i.c.v.; two infusions, given 21 hr and 20-30 min before the start of the test sessions). In contrast, leptin had no effect on reinstatement of heroin seeking induced by intermittent footshock or priming injections of heroin. These data indicate that food deprivation can provoke relapse to heroin seeking via a leptin-dependent mechanism, which is not involved in relapse induced by footshock stress or reexposure to heroin.

Alpha -2 adrenoceptor agonists (lofexidine, clonidine) are used to alleviate short-term opioid withdrawal in humans. In rats, acute injections of these agents attenuate stressinduced reinstatement of heroin and cocaine seeking at time points that are beyond the acute drug withdrawal phase.Here, we studied whether exposure to lofexidine would attenuate reinstatement of a heroin-cocaine mixture (speedball) seeking induced by exposure to stress or to drugassociated cues. Rats were trained to lever press for speedball for 10 days, and the drug-reinforced behavior was then extinguished for 11 days in the presence (Experiment 1) or the absence (Experiment 2) of the drug cues. Subsequently, rats were tested for reinstatement of drug seeking after exposure to intermittent footshock stress (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) Experiment 1) A number of studies reported that a significant proportion of drug addicts use both heroin and cocaine, including a heroin-cocaine combination, speedball (Hoffman et al. 1998;Schutz et al. 1998). At present, no effective medications exist for the treatment of this type of polydrug use (Mendelson and Mello 1996). Preclinical studies reported that speedball is readily self-administered in rats (Duvauchelle et al. 1998;Hemby et al. 1996) and monkeys (Mello et al. 1995;Rowlett et al. 1999). It was also found that while opioid and dopamine (DA) receptor antagonists have some effects on speedball self-administration (Hemby et al. 1996;Negus and Mello 1998;Rowlett et al. 1999), a more effective way to attenuate speedballmaintained behavior is to block both opioid and DA receptors (Mello and Negus 1999). These data indicate that both receptor types are involved in the maintenance of speedball self-administration behavior and are in concordance with previous studies on the pharmaFrom the Behavioral Neuroscience Branch, IRP/NIDA, Baltimore, MD. or the drug cues (Experiment 2). Starting on day 7 of training, rats received daily injections of saline or lofexidine (0.1 or 0.2 mg/kg). Repeated lofexidine treatment significantly attenuated footshockinduced reinstatement, but did not alter drug cues-induced reinstatement of speedball seeking. In addition, lofexidine did not have a consistent effect on speedball selfadministration and extinction behavior. Results extend previous reports with acute drug injections, indicating that lofexidine maintains its effect on stress-inducedAddress correspondence to: Dr. Yavin Shaham, Behavioral Neuroscience Branch, IRP/NIDA/NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224. Received January 24, 2000; revised December 19, 2000; accepted January 8, 2001.Online publication: 1/11/01 at www.acnp.org/citations/Npp 01120167.N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 3 Lofexidine and Relapse to Speedball Seeking 321 cology of heroin and cocaine reinforcement (Ettenberg et al. 1982). Recent studies have shown that speedball injections increase DA levels in the nucleus accumbens (NAc), a brain area involved in the reinforcing effects of abused drugs (Wise 1...