X

*Data also refer to studies not reviewed here on the effects of acute and chronic food restriction on IV drug SA and CPP (see Gaiardi et al., 1987; Bell et al., 1997; Carroll, 1999).

Abbreviations: no effect; [, decrease; f, increase; t- inconsistent results or insufficient data to reach a conclusion on the direction of the effect; B, binge self-administration (unlimited access); CPP, conditioned place preference; CRF, corticotropin-releasing factor; DMCM, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, a GABAergic inverse agonist; I, initiation of drug self-administration; IVSA, intravenous self-administration; M, maintenance of drug self-administration; blank cells, no data are available. In the reinstatement column, IVSA refers to reinstatement studies using the intravenous self-administration procedure, and CPP refers to reinstatement studies using the conditioned place preference procedure.

rats spend more time in the drug-paired environment when given a choice between the two environments during a drug-free test day (Van der Kooy, 1987). Results from many studies using the CPP procedure indicate that opiate and psychostimulant drugs can serve as Pavlovian reinforcers (Bardo and Bevins, 2000).

In the reinstatement procedure, animals are initially trained to self-administer drugs intravenously or orally. Subsequently, lever presses for drug infusions or delivery are extinguished by removing the drug. After extinction of drug-taking behavior, the effect of noncontingent exposure to drug or nondrug stimuli on reinstatement of operant responding is examined (Stewart and de Wit, 1987). More recently, a CPP reinstatement procedure has been introduced (Mueller and Stewart, 2000) wherein rats are initially trained for CPP as described above. This acquired preference for the drug-paired environment can be extinguished by daily injections of saline in the previously drug-paired environment or by repeatedly exposing rats to both compartments in the drug-free state (extinction). After extinction of the acquired CPP, the effect of a single noncontingent exposure to drug or nondrug stimuli on reinstatement of place preference is examined. Using a procedural variation of the CPP model, it was also recently found that both drug injections and footshock stress "reactivate" CPP for morphine (that is no longer observed) following extended drug-free periods, during which the rats are not exposed to extinction conditions (Lu et al, 2000b). Studies using reinstatement and reactivation procedures have shown that reexposure to the previously self-administered drug and drug cues as well as exposure to stressors, stimuli, reported to provoke relapse in humans (Meyer and Mirin, 1979; Shiffman and Wills, 1985), reinstate drug-taking behavior in laboratory rats (Shalev et al, 2002).

Stress and intravenous drug self-administration

Defeatjthreat stress

Defeat stress is a procedure in which a smaller "intruder" rat is introduced into the cage of a larger and aggressive "resident" rat. The resident rat usually attacks the intruder rat until it manifests a submissive posture (Miczek et al, 1991). In addition, the mere presence of the resident rat (a threat condition) is sufficient to provoke physiological and behavioral stress responses in the intruder rat (Miczek and Tornatzky, 1996).

Using relatively low training doses of cocaine (0.25-0.32 mg/kg/infusion), two studies reported enhanced acquisition of cocaine SA following defeat/ threat exposure for several days (Kabbaj et al, 2001) or weeks (Haney et al, 1995) prior to training. Kabbaj et al. (2001) also found that the effect of defeat stress is selectively observed in high-responder (HR), but not low-responder (LR) rats, classified according to their locomotor response to a novel environment (Piazza and Le Moal, 1996). However, when a higher training dose (0.75mg/kg/infusion) was used, prior exposure to defeat/threat had no effect on the initiation of cocaine SA (Covington and Miczek, 2001).

The effect of defeat/threat stress on the maintenance of cocaine SA is less clear. Miczek and Mutchler (1996) performed a dose-response determination and found that while the stressor (given just prior to each session) increased the rate of responding during a timeout period, it had no effect on total cocaine intake. In a subsequent study, Covington and Miczek (2001) found that prior exposure to defeat/ threat had no effect on the dose-response curve for cocaine under either fixed-ratio 5 (FR-5; each 5th lever press is reinforced) or progressive ratio (PR) schedules. In the PR schedule, the response requirements for obtaining a reinforcer are progressively increased within a session in order to determine the maximum effort that the subject will exhibit (Hodos, 1961). The highest response requirement emitted by the subject before a specified period of no responding occurs is defined as the final ratio or the breakpoint value and is thought to provide an index of the reinforcing efficacy of the drug (Richardson and Roberts, 1995). Finally, an important finding in the study of Covington and Miczek was that prior exposure to defeat/threat increased "binge" cocaine responding when rats were given unlimited access to cocaine.

Taken together, the available data indicate that prior exposure to defeat/threat stress can accelerate the initiation of cocaine SA for low, but not higher, doses. When the stressor is administered just prior to the daily SA sessions, it also increases the initiation of SA for higher cocaine doses. Under limited access to drug during the maintenance phase, there is little evidence that the stressor can alter the reinforcing effects of cocaine. However, defeat/threat exposure can increase cocaine SA when rats are given unlimited access to the drug. Finally, little is known on the neuronal mechanisms mediating the effect of defeat/threat on cocaine SA. Threat exposure modestly increases dopamine (DA) release in the nucleus accumbens (NAc) (Tidey and Miczek, 1996). DA in this brain area is involved in the reinforcing effects of cocaine (Wise, 1996). However, as the stressor did not alter the reinforcing effects of cocaine (Miczek and Mutchler, 1996; Covington and Miczek, 2001), it is unlikely that alterations in DA utilization in the NAc is the critical mediator of the effect of defeat/threat on cocaine SA.

Intermittent shock

Beck and O'Brien (1980) found that when each lever press for morphine was accompanied by a mild shock to the foreleg (300 Hz for 0.2 sec), which was immediately followed by an infusion of morphine, rats self-administered lethal doses of the drug. These are paradoxical findings that are different from the results of previous studies on the suppressive effect of shock made contingent on lever pressing (punishment procedure) for food (Estes and Skinner, 1941) or cocaine (Johanson, 1977). One potential explanation for Beck and O'Brien's data is that rats learned to associate the morphine infusions with the relief of pain. Data from a study of Dib and Duclaux (1982) may provide support for this hypothesis. These authors trained rats to lever press for morphine into the lateral ventricles during 1 h daily sessions and found that when rats were exposed to 15 min of intermittent footshock during the daily session they increased their lever-pressing.

In another study, Shaham and Stewart (1994) found that exposure to intermittent footshock just prior to the heroin SA sessions had no effect on the initiation of lever-pressing under an FR-1 or FR-2 schedules. The stressor, however, modestly increased responding for heroin under a PR schedule. The authors interpreted these data to indicate that footshock increases the reinforcing efficacy of heroin. However, as the PR procedure also incorporates an extinction component (the lever-pressing behavior is not reinforced for long periods when the response requirements for each infusion progressively increase), an alternative interpretation of these data is that the stressor increased resistance to extinction. Tentative support for this interpretation is the finding of Highfield et al. (2000) that intermittent footshock increases resistance to extinction in rats with a history of heroin SA when the stressor was administered just prior to each of the daily extinction sessions.

Ramsey and Van Ree (1993) reported that the initiation of lever pressing for a very low dose of cocaine (0.031 mg/kg/infusion) was accelerated in rats observing other rats receiving footshock (a "psychological stressor"), but not in rats receiving intermittent footshock. In contrast, Goeders and Guerin (1994, 1996) found that footshock given during sessions of food SA, just prior to the cocaine SA sessions, increases the initiation of drug SA. These authors also found that the effect of stress on cocaine SA was only observed for low, but not high doses, and that corticosterone levels, measured prior to the test sessions, were correlated with the initiation of cocaine SA.

Taken together, it appears that under certain conditions intermittent shock can increase opiate and cocaine SA behavior. The effects of shock on opiate SA behavior appears to be most pronounced when the stressor is given during the SA session, possibly by allowing the rats to associate drug intake with the relief of pain.

Maternal separation

Matthews et al. (1999) examined the effect of maternal separation (6h/day for 10 days) on the initiation of cocaine SA in adult male and female rats. When the dependent measure was the number of infusions/ session, maternal separation appeared to modestly retard the initiation of cocaine SA for the low dose (0.05 mg/infusion) but not for the higher doses (0.08-0.5 mg/infusion). However, when lever discrimination was used as the dependent measure, no consistent effects of maternal separation was found. In addition, following the initiation of cocaine SA, maternal separation did not have a consistent effect on the dose-response curve for cocaine. In contrast, Kosten et al. (2000) reported that maternal separation increases the acquisition of cocaine SA. The reasons for the different results of the two studies are not known. Matthews et al. (1999) determined a between-subjects dose-response curve during initiation, the separation manipulation was done at ages 5-20 days for 6 h/day, and pups were maintained at a temperature of 32-33°C when separated from their mothers. In contrast, Kosten et al. (2000) determined a within-subjects ascending dose-response curve, the separation manipulation was done from ages 2 to 9 days for 1 h/day, and pups were maintained at a temperature of 30°C during the separation manipulation. Thus, in light of these different results, a clear picture has yet to emerge concerning the effects of maternal deprivation on cocaine SA.

Social isolation

There are several reports on the effects of social isolation on opiate and psychostimulant SA. With the exception of the study of Bozarth et al. (1989), isolation rearing started post-weaning. Schenk et al. (1987) found that isolated, but not group-housed, rats initiated cocaine SA (0.1, 0.5, or 1.0mg/kg/ infusion) at the higher doses (0.5-1.0mg/kg). On the other hand, Boyle et al, (1991) found that isolation increased lever-pressing for a low cocaine dose (0.04mg/kg/infusion), but not for higher doses (0.08-1.0). In agreement with Boyle et al, (1991), Bozarth et al, (1989) did not find differences between isolated and group-housed rats for the initiation of cocaine SA when a high drug dose (1.0mg/kg/ infusion) was used. These authors also reported higher drug intake during the initiation of heroin SA (l.Omg/kg/infusion) in isolated rats. The higher intake in the isolated rats may reflect a decrease rather than an increase in the reinforcing effects of the drug. This heroin dose is on the descending limb of the dose-response curve, and decreased responding for a given dose on this limb may reflect enhanced drug reinforcement (Yokel, 1987).

Schenk et al, (1988) found that isolation rearing had no effect on the initiation of amphetamine

SA. However, the authors used a within-subjects descending-dose procedure in which rats initiated drug SA with the higher dose (0.25 mg/kg/infusion) and different lower drug doses were introduced over the 15 days of training. This procedure may not be optimal for detecting group differences because the effects of environmental conditions on drug SA are more likely to be detected when low doses are used during the initiation phase (Piazza and Le Moal, 1996; Vezina et al, 2002).

Phillips et al. (1994b) reported that isolation rearing decreased lever-pressing for a high dose of cocaine (1.5 mg/kg/infusion) during the initiation phase. This is an unexpected finding that is not predicted from the studies reviewed above and from previous studies on increased psychomotor activation by psychostimulant drugs in isolated rats (Robbins et al, 1996). However, it is not known from the data of Phillips et al. whether isolation rearing decreases or increases cocaine reinforcement. As discussed previously, a decrease in responding for a high dose can reflect an increase in the drug's reinforcing effects. However, Phillips et al. (1994b) also reported a shift to the right in the cocaine dose-response curve during the maintenance phase indicating a reduction in the drug's reinforcing effects. In addition, in a companion study, Phillips et al. (1994a) reported that isolation retards the acquisition of intra-NAc amphetamine SA, data which appear to support the view that isolation retards psychostimulant reinforcement. In contrast, more recent data from Howes et al. (2000) do not support the hypothesis that isolation rearing decreases the reinforcing effects of psychostimulant drugs. These authors found a shift to the left in the dose-response curve for the initiation of cocaine SA (0.083, 0.25 or 1.5 mg/kg/infusion). In agreement with these data, Bardo et al. (2001) found that isolation increases the initiation of amphetamine SA reinforced by a low (0.03 mg/kg/infusion), but not a high dose (0.1 mg/kg/infusion) in both male and females rats. During the maintenance phase, rates of lever-pressing under a PR schedule were similar in the isolated and group-housed rats.

The data of Bardo et al. (2001) should be interpreted with caution. Rats were trained to lever-press for sucrose prior to the initiation of amphetamine, and for the low dose of the drug, isolated and group-housed rats pressed at high rates on day 1. However, while the isolated rats continue to press at higher rates, lever-pressing in the group-housed rats decreased over time. An alternative interpretation of the data, therefore, is that isolation increases resistance to extinction of lever-pressing previously reinforced by sucrose. Several studies reported that isolation increases resistance to extinction of operant responding (Morgan et al, 1975; Robbins et al, 1996). In addition, previous studies have shown that isolation enhances the ability of amphetamine to potentiate the conditioned reinforcing effects of cues paired with sucrose (Jones et al, 1990). Thus, another alternative explanation for the data of Bardo et al, (2001) is that differential acquisition rates for the low amphetamine dose may be due to its different effects on responding for cues previously associated with a sucrose reinforcer in isolated rats.

Taken together, isolation can enhance the initiation of psychostimulant SA, an effect that is more likely to be found when a low training dose is used. In contrast, there is no clear evidence that isolation can alter drug-taking behavior during the maintenance phase. Finally, the effect of isolation on opiate SA is a subject for future research. Only one study explored this question, but isolation was performed in adulthood rather than commencing after weaning. There are many studies that demonstrate that isolation during the post-weaning period and during adulthood have different physiological and behavioral effects (Hall, 1998).

Other stressors

Maternal stress

Deminiere et al. (1992) studied the effect of maternal stress (female rats were restrained 3 times per day for 45min) during the last week of pregnancy on acquisition of amphetamine SA. Adult offspring rats were trained to press a lever for a low dose of amphetamine (0.03 mg/kg/infusion) for 5 sessions. The authors reported that amphetamine maintained lever-pressing behavior in rats from the maternal-stress group, but not in rats from the control condition.

Tail pinch

Piazza et al. (1990) found that lever-pressing for a low dose of amphetamine (0.01 mg/kg/infusion) was maintained in rats previously exposed repeatedly to tail pinch, but not in rats from the control condition.

Unstable social environment

Two studies explored the effect of unstable social environment (replacing the colony members every day for several weeks) on the initiation of amphetamine SA. Using colonies that included both male and female rats, Maccari et al. (1991) found that lever-pressing for a low dose of amphetamine was maintained in male rats from the stable condition, but not in those from the unstable condition. Lemaire et al. (1994) determined the impact of the social environment in colonies that included either males and females or males only. In both the stable and unstable conditions, higher responding over the 4 days of amphetamine SA training was observed in male rats that were housed with female rats. However, there was no evidence that the low dose of amphetamine (0.01 mg/kg/infusion) maintained responding over time in any of the groups. Therefore, it is not clear what can be interpreted from the data of this study. In addition, in both studies the investigators did not assess the social status of the rats (dominant vs. subordinate) in the social environment, a factor that can impact drug-reinforced behavior (see Coventry et al, 1997; Morgan et al, 2002).

Summary

We reviewed studies on the elfect of different stressors on opiate and psychostimulant SA. It appears that some stressors, but not others, can alter drug SA behavior. Thus, defeat/threat, intermittent shock, social isolation, and tail pinch were found to increase drug SA. However, with the exception of the data of Beck and O'Brien (1980), in most other studies the effects of stressors on drug SA is relatively modest. In contrast, it cannot be concluded that maternal separation and unstable social environments can alter drug SA.

Another conclusion is that the neuronal mechanisms involved in the effects of the different stressors on drug SA are not known. Pharmacological and surgical manipulations that inhibit corticoster-one secretion decrease cocaine SA (Marinelli and Piazza, 2002). These manipulations also decrease opiate- and psychostimulant-induced locomotor activity and DA release in the NAc (Piazza and Le Moal, 1996; Marinelli and Piazza, 2002). Thus, stress-induced corticosterone secretion may mediate the effects of stressors on drug SA (Goeders, 1997; Piazza and Le Moal, 1998). It should be pointed out however, that despite the appeal of this hypothesis direct evidence to support it (e.g., attenuation of stress-induced potentiation of drug SA by inhibition of corticosterone secretion) is not available. There are also reports that isolation rearing increases psychos-timulant-induced locomotor activity and DA utilization in the striatum (Sahakian et al., 1975; Jones et al., 1992), which may be involved in the effect of isolation on psychostimulant SA (Robbins et al., 1996; Hall, 1998). However, evidence to support this hypothesis does not exist, and the demonstration that isolation impairs intra-NAc SA of amphetamine is not be compatible with this idea.

Stress and conditioned place preference Chronic mild stress

In the chronic mild stress (CMS) procedure, rats are exposed to different durations of unpredictable mild stressors (e.g., overnight illumination, white noise, food and water deprivation, soiled cages, tilted cages, changes in the housing conditions) for 1-2 months (Willner et al., 1992). This manipulation was found to decrease sucrose and brain stimulation reward, and these effects are reversed by chronic treatment with antidepressants (Moreau, 1997; Willner, 1997b). Based on these and other findings it has been suggested that the CMS model can provide a suitable animal model of depression (Willner et al., 1992).

Papp et al. (1991, 1992, 1993) found that several weeks of CMS attenuates CPP for morphine, amphetamine and quinpirole, a D2-like agonist. CMS exposure, however, does not impair the development of conditioned place aversion to the opiate receptor antagonist, naloxone, suggesting that this procedure does not cause nonspecific impairments in associative learning (Papp et al., 1992). More recently, Valverde et al. (1997) found that CMS decreases morphine CPP, an effect reversed by chronic treatment with the antidepressant imipramine. These authors also found that the coadministration of morphine with the cholecystokinin-b (CCK-b) receptor antagonist, PD-134,308, reverses the inhibition of morphine CPP by CMS. The effect of PD-134,308 may be due to the potential antidepressant effects of blockade of CCK-b receptors (Hernando et al., 1994) or due to its direct effect on morphine reinforcement (Valverde et al., 1996).

Alterations in DA functioning may be involved in the reward deficits induced by CMS. In rats exposed to CMS, intra-NAc infusions of quinpirole fail to induce CPP (Papp et al., 1993). In addition, repeated administration of quinpirole during stress exposure induces locomotor sensitization, a DA-dependent phenomenon (Robinson and Becker, 1986), and reverses CMS-induced decreases in both sucrose consumption and quinpirole CPP. CMS also decreases D2-like receptor binding in limbic forebrain areas and this effect is reversed by treatment with antidepressant drugs (Papp et al., 1994). These data, and those on the reversal of CMS-induced decreases in sucrose consumption by D2-like agonists, suggest that reward deficits induced by CMS are mediated by DAergic hypofunction (Willner, 1997a). Taken together, CMS exposure was found to decrease opiate and psychostimulant CPP. This effect may involve DAergic hypofunction induced by exposure to this stressor.

Defeat

Coventry et al. (1997) examined the effect of defeat stress and its interaction with the social hierarchy (dominant vs. submissive rats in a paired-housing condition) on morphine CPP. In the no-stress condition, only dominant, but not submissive, male rats demonstrated CPP for morphine. Dominant rats were then subjected to defeat by an aggressive male for 1 h. Interestingly, 3 days following defeat, the dominant rats failed to demonstrate morphine CPP, which was now present in their submissive partners.

In addition, 7 days following stress exposure, morphine CPP was absent in defeated rats that became submissive, but was present in defeated rats that had maintained their status. The authors also found that defeat stress attenuates morphine CPP in single-housed rats. Thus, it appears that the social status is an important factor in the manifestation of the effect of stressors on morphine CPP.

Inescapable shock

Will et al., (1998b) examined the effects of uncontrollable and controllable tail shock on morphine and amphetamine CPP. The stressor was administered in Plexiglas restrainer tubes for 1 h, one day prior to the training for morphine or amphetamine CPP. Uncontrollable, but not controllable, shock strongly enhanced morphine, but not amphetamine CPP, an effect that persisted even when the stressor was administered 6-7 days prior to CPP training. These authors also found that the effect of uncontrollable shock is mimicked by the anxiogenic agent, DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-car-boxylate). In a subsequent unpublished report, Will et al. (1998a) found that the removal of circulating corticosterone by adrenalectomy (ADX) had no effect of morphine CPP, but it blocked the potentiation of this response by uncontrollable shock.

Restraint

The effect of restraint stress on amphetamine and morphine CPP was recently examined. Rats were restrained for 2h for either 1 day (acute) or 7 days (repeated) prior to CPP training; training for CPP started one day after restraint exposure (Capriles and Cancela, 1999; del Rosario Capriles and Cancela, 2002). The authors reported that acute, but not repeated, restraint enhances drug CPP for the medium doses (1.5mg/kg amphetamine, 2mg/kg morphine), but not for the low or higher doses. However, the interpretation of these data is not straightforward because neither amphetamine nor morphine induced CPP in the no-stress or the repeated-stress condition. Other studies found robust CPP at the dose range used by these authors (Van der Kooy, 1987; Bardo and Bevins, 2000).

Capriles and Cancela (1999) reported that the potentiation of amphetamine CPP by acute restraint is blocked by D2-like receptor antagonists, haloper-idol and sulpiride, and by the selective Dl-like receptor antagonist, SCH-23390; the DAergic agents were given prior to restraint exposure. The opiate antagonist, naltrexone, had no effect. In the case of morphine CPP, the potentiation effect of acute restraint was blocked by similar DAergic manipulations and by naltrexone (del Rosario et al., 2002). Cancela and colleagues also reported that acute restraint potentiates amphetamine-induced DA release in the striatum and that pharmacological manipulations that block restraint-induced alterations in CPP for morphine or amphetamine (see above) also attenuate restraint-induced potentiation of locomotor activity induced by these drugs (del Rosario et al., 2002; Pacchioni et al., 2002).

Finally, in the study described above of Will et al., (1998b) rats in the no-shock condition were restrained in Plexiglass tubes for 1 h. This stress experience, however, had no effect on morphine CPP. Taken together, under certain conditions, exposure to acute, but not repeated, restraint can enhance CPP for morphine and amphetamine, an effect that appears to be dependent on the activation of DA receptors. However, in some of the studies reviewed it has not been established that morphine or amphetamine can induce CPP in the no-stress condition. Thus, it is not clear whether the reported effects of restraint are related to its effects on drug CPP or other unknown experimental parameters.

Social isolation

Schenk et al. (1983, 1985) reported that isolation rearing after weaning results in a shift to the right in the dose-response curve for heroin CPP. This effect of isolation on heroin CPP is only observed in rats isolated at weaning, but not in rats isolated at the age of 4 months. Two more recent studies also reported that isolation attenuates morphine CPP in rats (Wongwitdecha and Marsden, 1996a) and mice (Coudereau et al., 1997). Isolation did not impair performance in the Morris water-maze test and in a passive avoidance test (Wongwitdecha and Marsden, 1996b; Coudereau et al., 1997), suggesting that nonspecific learning deficits cannot account for the effect of isolation on opiate CPP. The results from the studies on the effects of isolation on morphine and heroin CPP extend the data from other reports on the attenuation of the behavioral effects of opiate drugs by this condition, including analgesia and sedation (Katz and Steinberg, 1970; Kostowski et al, 1977). Isolation rearing also was found to decrease opioid receptor binding in the brain (Schenk et al. 1982), an effect that may mediate the decrease in the behavioral effects of morphine and heroin in isolated rodents.

The results on the effect of isolation on psychostimulant CPP are mixed. Schenk et al. (1986) found that isolation blocked cocaine CPP, but had no effect on amphetamine CPP. Bowling et al. (1993) reported that while rats reared in an enriched environment showed enhanced amphetamine CPP, no differences were found between the isolated rats and the group-housed rats. On the other hand, Wongwitdecha and Marsden (1995) found that isolation attenuates amphetamine CPP. The reasons for these discrepant results are not known.

Taken together, studies on the effects of isolation rearing clearly demonstrate that this manipulation impairs opiate CPP. In contrast, no clear picture has emerged concerning the effect of isolation on psychostimulant CPP.

Summary

The review of the studies indicates that different stressors have qualitatively different effects on drug CPP. It also appears that different stressors can have different effects on opiate versus psychostimulant CPP. Thus, prior exposure to uncontrollable shock can profoundly enhance morphine, but not amphetamine, CPP. In the case of restraint however, under certain conditions, acute, but not repeated, exposure can enhance both morphine and amphetamine CPP. There is also evidence that the anxiogenic agent, DMCM, can enhance morphine CPP. On the other hand, acute defeat stress profoundly decreases morphine CPP and CMS exposure consistently decreases opiate and psychostimulant CPP. Finally, isolation rearing robustly attenuates morphine CPP, but its effect on psychostimulant CPP has not been clearly established.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis and mesolimbic DA may be involved in the effects of uncontrollable shock and acute restraint on drug CPP, respectively. In addition, disruptions in endogenous opioid systems are possibly involved in the effect of isolation on morphine CPP. In the case of CMS, it is likely that a decrease in DA functioning mediates the attenuation of opiate and psychostimulant CPP by this stressor. However, it cannot be concluded from the available data that alterations in DA functioning mediate the effects of isolation on drug CPP. Isolation potentiates psychostimulant-induced locomotor activity and DA utilization in the striatum (Robbins et al, 1996; Hall, 1998). Based on these data, and the known role of the mesolimbic DA system in opiate and psychostimulant CPP (Wise, 1996; De Vries and Shippenberg, 2002), it would have been expected that isolation would enhance drug CPP. However, as mentioned above, such an effect of social isolation on psychostimulant CPP has not been reported.

Stress and reinstatement of drug seeking

Carroll (1985) probably provides the first demonstration of stress-induced reinstatement. Rats were trained to self-administer cocaine and were food restricted (approximately 30-40% of total daily ration) every three days. She found that rats experiencing food restriction during training increased nonreinforced responding (reinstatement) when this condition was reintroduced during an extinction phase. Subsequently, Shaham and Stewart (1995) found that intermittent footshock stress reinstates heroin seeking and suggested that the reinstatement model can be used to study stress-induced relapse to drug seeking. In recent years, the effects of different stressors on reinstatement of opiate and psychostimulant seeking was determined.

Intermittent footshock

Shaham and Stewart (1995) and Erb et al. (1996) reported that exposure to intermittent footshock reinstates heroin and cocaine seeking after 1-2 weeks of extinction training and after an additional 4- to 6-week drug-free period. Similar findings were reported by several laboratories Using different training doses, schedule requirements, footshock parameters and strains of rats (Ahmed and Koob, 1997; Mantsch and Goeders, 1999; Martin-Fardon et al, 2000). Using a CPP procedure, intermittent footshock was found to reinstate morphine seeking after extinction training (Der-Avakian et al, 2001) and to reactivate morphine and cocaine seeking following drug-free periods of up to 37 days (Lu et al, 2000a; Wang et al, 2000; Lu et al, 2001).

The effect of footshock on reinstatement of heroin seeking is dependent on the amount of drug intake during training, on the duration of the withdrawal period, and on the context of shock exposure. Ahmed et al. (2000) found that rats trained to lever-press for heroin for 11 h/day demonstrate higher rates of responding during tests for footshock-induced reinstatement than rats trained for 1 h/day. Shalev et al. (2001a) found that following withdrawal from heroin SA, the effect of footshock at different drug-free periods (1, 6, 12, 25, and 66 days) follows an inverted U-shaped curve, with maximal responding on days 6 and 12. Surprisingly, footshock did not reinstate heroin seeking on day 1 of withdrawal. Shalev et al. (2000) also reported that intermittent footshock does not reinstate heroin seeking when given in a novel, nondrug context. On the other hand, the stressor reliably reinstates heroin seeking when given in the context previously associated with drug SA.

Several studies were concerned with the pharmacological and neuroanatomical bases of footshock-induced reinstatement (Shaham et al, 2000a). CRF receptor antagonists attenuate footshock-induced reinstatement of heroin and cocaine seeking (Shaham et al, 1997; Erb et al, 1998; Shaham et al, 1998) and reactivation of morphine and cocaine CPP (Lu et al, 2000a, 2001). Studies using endocrine methods indicate that footshock-induced rise in corticosterone is not involved in its effect on reinstatement (Shaham et al, 1997; Erb et al, 1998). The data from these studies suggest that the effect of the CRF receptor antagonists on reinstatement is mediated via their actions on extrahypotha-lamic sites, independent of their effects on the HPA-axis (Shaham et al, 2000a). ^-adrenoceptor agonists, that decrease noradrenaline (NA) cell firing and release (Mongeau et al, 1997), also block footshock-induced reinstatement of heroin and cocaine seeking (Erb et al, 2000; Shaham et al, 2000b; Highfield et al, 2001).

Blockade of CRF receptors in the ventrolateral bed nucleus of stria terminalis (BNST) (but not the central nucleus of the amygdala, CeA) and antagonism of postsynaptic (3-adrenoceptors in both the ventrolateral BNST and CeA attenuates footshock stress-induced reinstatement of cocaine seeking (Erb and Stewart, 1999; Leri et al, 2002). Erb et al, (2001) also reported that inactivation of the CeA with tetrodotoxin in one hemisphere and blockade of CRF receptors in the ventrolateral BNST of the other hemisphere (to functionally disconnect the CRF-containing pathway from the CeA to the BNST) attenuates footshock-induced reinstatement of cocaine seeking. In addition, reversible inactivation of the CeA and ventrolateral BNST attenuates footshock-induced reinstatement of heroin seeking (Shaham et al, 2000a), and permanent lesions of the CeA, but not the basolateral amygdala (BLA), attenuate footshock-induced reactivation of CPP for morphine (Wang et al, 2002). Finally, lesions of the ventral NA bundle (VNAB) attenuate footshock-induced reinstatement of heroin seeking (Shaham et al, 2000b) and reactivation of morphine CPP (Wang et al, 2001). The VNAB neurons originate from the lateral tegmental NA cell groups and innervate the CeA and the BNST (Fritschy and Grzanna, 1991; Aston-Jones et al, 1999). In contrast, there is no evidence that the dorsal NA bundle, originating from the locus coeruleus (Moore and Bloom, 1979), is involved in footshock-induced reinstatement (Shalev et al, 2002).

Other brain areas also are involved in footshock-induced reinstatement (Shaham et al, 2003). Inactivation of the medial prefrontal cortex (mPFC, prelimbic area) or the orbitofrontal cortex with tetrodotoxin attenuates footshock-induced reinstatement of cocaine seeking (Capriles et al, 2003). These authors also found that intra-mPFC and intra-orbitofrontal infusions of a Dl-like receptor antagonist attenuate footshock-induced reinstatement of cocaine seeking (Capriles et al, 2003). In addition, Sanchez et al. (2003) reported that both Dl-like agonists and antagonists attenuate reinstatement of cocaine CPP induced by restraint stress, suggesting that DA tone in this brain area is critical for the manifestation of footshock stress-induced reinstatement.

Taken together, intermittent footshock was found to reinstate drug seeking in both operant and classical conditioning paradigms. At the neurobio-logical level, it appears that an interaction between CRF and NA within the BNST and amygdala plays a critical role in footshock-induced reinstatement of drug seeking. More recent studies also have identified a role of the medial prefrontal and orbitofrontal cortices in footshock stress-induced reinstatement.

Conditioned fear

In the conditioned-fear procedure, a neutral cue (e.g., tone, the conditioned stimulus) is repeatedly paired with a fear-inducing stimulus such as footshock (the unconditioned stimulus). Following the classical (Pavlovian) conditioning pairing, exposure to the previously neutral cues in the absence of shock elicits conditioned-fear responses (Davis, 1994). Sanchez and Sorg (2001) found that stimuli paired with shock (tone or odor) reinstate cocaine CPP after extinction. Conditioned-fear stimuli (tone or a compound tonelight cue), however, did not reinstate drug seeking in rats with a history of either cocaine or heroin SA (Shaham et al, 2000a). One potential reason for these different results is that the predominant effect of cues paired with shock is freezing (LeDoux, 2000), a behavioral effect which is incompatible with lever-pressing behavior.

Food deprivation

Shalev et al. (2000) found that rats deprived of food for 21 h reinstate heroin seeking. In a subsequent study, this deprivation condition also was found to reinstate cocaine seeking (Shalev et al, 2003). The finding that acute food deprivation reinstates cocaine seeking extends a previous report on the effect of 1 day of food restriction (30^10% of free feeding) on reinstatement of cocaine seeking (Carroll, 1985). In this earlier study, food restriction reinstated cocaine seeking only in rats with a history of exposure to this condition during training for cocaine SA. In the studies of Shalev et al, however, 1 day of food deprivation reinstates cocaine and heroin seeking in rats that were not food deprived/restricted during SA

training. The more severe food deprivation in the latter studies may account for these different results. Finally, Highfield et al. (2002) reported a robust effect of 1 day of food deprivation on reinstatement of cocaine seeking in 129Xl/SvJ mice.

The neuronal mechanisms underlying reinstatement of drug seeking by acute food deprivation are largely unknown. In heroin-trained rats, ventricular infusions of leptin, a hormone involved in energy balance and body weight regulation, attenuate reinstatement induced by food deprivation, but not by heroin priming or footshock (Shalev et al, 2001b). Shalev et al. (2003) recently found that adrenalectomy attenuates food deprivation-induced reinstatement of cocaine seeking. This effect, however, can be reversed by replacement of basal levels of corticos-terone. This finding suggests that while basal levels of corticosterone are necessary for the manifestation of food deprivation-induced reinstatement, the increase in corticosterone secretion by the deprivation condition (Dallman et al, 1999) is not involved in the effect of this stressor on reinstatement of cocaine seeking.

Pharmacological stressors

Reinstatement of drug seeking was reported following infusions of CRF into the lateral ventricles (Shaham et al, 1997) or the BNST (Erb and Stewart, 1999), and following systemic injections of metyr-apone (Shaham et al, 1997). CRF is involved in stress responses via its actions on hypothalamic and extrahypothalamic sites (Vale et al, 1981; de Souza, 1995). Metyrapone is a synthesis inhibitor of corticosterone (Jenkins et al, 1958). Therefore, its effect on reinstatement may arise from high levels of CRF (from reduced negative feedback). However, the removal of circulating corticosterone by adrenalectomy had no effect on footshock-induced reinstatement of heroin seeking (Shaham et al, 1997). Thus, the effect of metyrapone on reinstatement is likely due to the nonspecific adverse side effects of this drug (Shaham et al, 1997; Rotllant et al, 2002).

In another study, Highfield et al. (2000) reported that footshock-induced reinstatement of heroin seeking can be mimicked by reversible inactivation of the medial septum with the sodium channel blocker, tetrodotoxin. Previous studies reported that septal lesions mimic to some degree of physiological and psychological responses to stress (Holdstock, 1967; Gray, 1987).

Restraint

Shalev et al. (2000) found that restraint (5, 15, or 30min) stress, administered outside the drug SA context had no effect on reinstatement of heroin seeking. This lack of effect might have resulted from the context in which restraint was given. As mentioned, when footshock was administered in a different (nondrug) environment it had no effect on reinstatement of heroin seeking. Using a CPP procedure, however, Sanchez et al. (2003) reported that exposure to restraint (15min), administered in the neutral compartment of the CPP apparatus, reinstates cocaine seeking. Studies on the effect of restraint on reinstatement of drug seeking in rats with a history of cocaine SA were not published. Thus, the different results in the above studies may be due to the type of drug used, the type of procedure (CPP vs. IVSA) or other unknown experimental conditions.

Summary

Intermittent footshock was found to reinstate opiate and psychostimulant seeking under several different experimental conditions. For rats with a history of heroin SA, the effect of footshock on reinstatement can be modulated by the amount of drug intake during training, the duration of the drug-free period and the context in which the stressor is experienced. These context- and time-dependent effects of footshock on reinstatement argue against the idea that pain is the critical factor in this phenomenon. Furthermore, as footshock reinstates CPP for morphine and cocaine, it appears unlikely that stress-induced nonspecific behavioral activation accounts for its effect on reinstatement in the operant model. It has been convincingly argued by several investigators that locomotor activation is not an experimental confound in the CPP model (Van der Kooy, 1987; Bardo and Bevins, 2000).

There is also evidence that stressors other than intermittent footshock can reinstate opiate and psychostimulant seeking. Acute 1-day food deprivation reinstates heroin and cocaine seeking in both rats and mice. These data extend the early report of Carroll (1985). Furthermore, pharmacological stressors were found to reinstate drug seeking, including CRF, metyrapone and inactivation of the medial septum; these manipulations have been shown in previous studies to mimic certain aspects of the stress response. In contrast, in rats with a history of drug SA, neither restraint stress nor cues paired with shock (conditioned-fear stimuli) reinstates drug seeking. Surprisingly, these stressors were found to reinstate cocaine CPP after extinction. The reasons for the different effects of these stressors in the CPP versus the IVSA reinstatement procedures are not known, but in the case of conditioned fear, a likely explanation is that it induces a behavioral response (freezing) that is incompatible with lever-pressing.

Studies on the neurobiological bases of footshock-induced reinstatement indicate that an interaction between CRF and NA within the BNST and amygdala plays an important role in reinstatement induced by this stressor. More recent studies also have identified a role of the medial prefrontal and orbitofrontal cortices in footshock-induced reinstatement of cocaine seeking. There is also evidence that leptin is involved in acute food deprivation-induced reinstatement of heroin seeking, and that corticoster-one is involved in reinstatement of cocaine seeking induced by this stressor. The brain sites involved in the effects of food deprivation on reinstatement are not known.

Conclusions

As can be seen in Table 1, stressors are important modulators of opiate- and psychostimulant-taking behavior. However, the effect of stress on drug-seeking behavior is to some degree stressor-specific, procedure-specific and drug-specific. This pattern of results is not surprising because different stressors, and even different parameters of the same stressor, can elicit distinct stress responses (Mason, 1975; Cohen et al., 1986; Chrousos and Gold, 1992). It is also not surprising that stressors would have drug-specific and/or procedure-specific effects. The different behavioral models measure different processes: acute reinforcing effects of drugs in an operant paradigm (drug SA), conditioned reinforcing effects of drugs in a Pavlovian paradigm (CPP), and resumption of non-reinforced drug seeking after extinction (reinstatement). Furthermore, while the neuronal mechanisms underlying opiate and psychostimulant reinforcement and reinstatement overlap, they are not identical (Wise, 1996; Shalev et al, 2002).

At the neurobiological level, little is known on the mechanisms underlying the effects of stressors on opiate and psychostimulant SA. Two potential mediators are corticosterone and mesolimbic DA, but the degree of their involvement is a subject for future research. More information is available on the mechanisms involved in the effects of stressors on opiate and psychostimulant CPP. Thus, alterations in endogenous opioid function by social isolation are likely to be involved in the attenuation of opiate CPP by this stressor. In the case of CMS, attenuation of DA functioning may be involved in the retardation of drug- and nondrug CPP induced by exposure to this stressor. There is also preliminary evidence that activation of the HPA-axis and mesolimbic DA may be involved in the effect of uncontrollable tail shock and acute restraint, respectively, on drug CPP. In the case of reinstatement, CRF and NA within the BNST and amygdala, as well as DA within the medial prefrontal and orbitofrontal cortices are involved in the effect of intermittent footshock on reinstatement and drug seeking. In addition, leptin and corticosterone play a role in food deprivation-induced reinstatement.

The present review can be used to identify at least one topic for future research. Specifically, humans are typically exposed to multiple stressors, both chronically and acutely. In addition, prior exposure to early-life stressors can enhance physiological and behavioral responses to other acute environmental stressors in adulthood (Meaney, 2001). However, the interaction between chronic and acute stressors in the modulation of drug reinforcement and relapse has yet to be determined. This issue appears to be especially pertinent for reinstatement studies, in which investigators have only employed acute stressors.

Finally, studies on the effects of stressors on opiate-and psychostimulant-taking behavior may have implications for the development of medications for drug addiction. For example, to the degree that the rat reinstatement model can provide a suitable means to study relapse processes (Shaham et al, 2003), pharmacological agents that block stress-induced reinstatement of drug seeking may be considered for clinical trials for the prevention of relapse to drugs. Two potential drug classes are CRF receptor antagonists and a-2 adrenoceptor agonists that attenuate footshock-induced reinstatement of heroin, cocaine and alcohol seeking (Shaham et al, 2000a; Sarnyai et al, 2001; Le and Shaham, 2002).

Abbreviations

ADX adrenalectomy

BLA basolateral amygdala nucleus

CCK cholecystokinin

CeA central nucleus of the amygdala

CMS chronic mild stress

CPP conditioned place preference

CRF corticotropin-releasing factor

DA dopamine

DMCM methyl-6,7-dimethoxy-4-ethyl-beta-carbo-line-3-carboxylate

FR Fixed-ratio

HPA hypothalamic pituitary- adrenal

IV intravenous

IVSA intravenous self-administration mPFC medial prefrontal cortex

NA noradrenaline

NAc nucleus accumbens

PR progressive ratio

SA self-administration

VNAB ventral noradrenergic bundle

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