Lin Lu and Yavin Shaham

Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, NIHjDHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA

Abstract: Exposure to high levels of life stress is associated with opiate and psychostimulant use in humans, but a causal role has not been established and the mechanisms involved in this putative association are not known. Processes involved in drug addiction can be studied under controlled experimental conditions in laboratory animals, using the intravenous drug self-administration, conditioned place preference and reinstatement procedures. The intravenous drug self-administration and conditioned place preference procedures are regarded as suitable animal models of drug reinforcement, and the reinstatement procedure is an animal model of drug relapse. Our review of the findings from rat studies using these animal models indicates that while stressors are important modulators of opiate- and psychostimulant-reinforced behavior, the effects of stressors on behavior in the above models is stressor-specific, and to some degree also procedure-specific and drug-specific. We also review data from studies on the neuronal mechanisms involved in the effects of different stressors on opiate and psychostimulant self-administration, conditioned place preference and reinstatement. Finally, we briefly discuss the implications of the data reviewed for future research and for the treatment of drug addiction.


Studies in humans suggest that drug use is more likely to occur in individuals exposed to adverse life events or stressors (Kreek and Koob, 1998; Sinha, 2001). There are also reports on high co-morbidity between stress-related psychiatric disorders (i.e., anxiety and depression) and drug use (Kandel et al, 1997). Under laboratory conditions exposure to stress also increases cigarette smoking (Schachter, 1978) and cocaine craving (Sinha, 2001). The mechanisms underlying the putative association between stress and drug use and craving, however, are not understood.

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Here we summarize data from studies on the effects of different stressors on drug reinforcement and relapse in animal models. "Stress" is a complex construct that has yet to be adequately operationally defined (Chrousos and Gold, 1992). Because of this state of affairs, in this review, stress is defined broadly as forced exposure to events or conditions that are normally avoided by the nonhuman laboratory subject (Piazza and Le Moal, 1998); these events or conditions lead to disturbances in physiological and psychological homeostasis. These events or conditions can be further divided into two broad categories. The first includes stressors such as restraint/immobilization, intermittent footshock, tail pinch, loud noise and defeat/threat. For these conditions, the experimental manipulation consists of exposing the organism to an aversive environmental event. The second category includes stressors such as food deprivation/starvation, social isolation and maternal deprivation. For these conditions, the experimental manipulation consists of the removal of an environmental event that is important for maintaining the organism's normal physiological and psychological steady-state conditions.

Due to space limitations, the review is restricted to rat studies using opiate and psychostimulant drugs. We also do not cover two relevant topics: the early studies on the effects of stressors on oral opiate self-administration (for reviews, see Alexander and Hadaway, 1982; Shaham et al., 1996), and studies on food deprivation-induced potentiation of opiate and psychostimulant reinforcement, as measured by the drug self-administration, conditioned place preference and brain stimulation reward procedures (for reviews, see Carroll, 1999; Carr, 2002).

We review data from studies using preclinical models of the effects of environmental stressors on opiate and psychostimulant reinforcement, as measured by the intravenous (IV) drug self-administration (SA) and the conditioned place preference (CPP)

procedures, and relapse to these drugs, as measured by the reinstatement procedure. The main findings from these studies are summarized in Table 1. The basic premise of the IV (and oral) drug SA method is that psychoactive drugs, like natural reinforcers (e.g., food, water), can control behavior by functioning as positive reinforcers in an operant paradigm (Johanson et al., 1987). Opiate and psychostimulant drugs support IV drug SA in mice, rats and monkeys and a high concordance exists between drugs self-administered by laboratory animals and those abused by humans (Brady, 1991).

The CPP procedure is used to measure the reinforcing effects of unconditioned stimuli in a classical conditioning paradigm. Pavlov (1927) referred to the term reinforcement as the strengthening of the association between an unconditioned stimulus and a conditioned stimulus, which occurs when the two events are temporally paired. In CPP studies, subjects are trained to associate one distinctive environment with a drug injection and a different environment with a saline (vehicle) injection. Following training,

Table 1. The effects of different stressors on opiate and psychostimulant intravenous self-administration, conditioned place preference and reinstatement

IV self-administration Conditioned place preference Reinstatement

Stressor Opiates Psychostimulants Opiates Psychostimulants Opiates Psychostimulants

Chronic mild stress Conditioned fear Defeat/threat

restriction* Intermittent shock f (I, M) Noise stress Pharmacological stressors Maternal separation Maternal stress Restraint

Social isolation $ (I)

Tail pinch Unstable social environment t (I, B) ++ (M) t (I, M)

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