Full-length reviewStress-induced relapse to heroin and cocaine seeking in rats: a review
Introduction
Drug addiction is characterized by repeated episodes of relapse to drug self-administration, and relapse remains the primary problem for treatment [92], [139]. Until we understand the factors that determine renewed drug craving and seeking, it is unlikely that we will be able to provide effective interventions. In large part, our ideas about what controls drug self-administration and relapse stem from knowledge of the phenomenology and neurobiology of the direct actions of abused drugs, and of the effects of withdrawal from them [135]. Such knowledge may not, however, be sufficient to explain why, when drugs are unavailable for long periods of time, individuals remain vulnerable to relapse.
There are many reports that relapse to alcohol and drug use is more likely to occur in individuals exposed to high levels of life stress [19], [40], [106], [123], [189]. The reasons for this putative relationship, however, are not understood. The correlational nature of the studies in humans prevents the drawing of conclusions about a causal link between stress and relapse to drugs [140]. In addition, although individuals often report that subjective craving and relapse are associated with negative mood states [37], there are findings to suggest that this relationship is less than clear [78]. Thus, even if relapse is associated with stress, the mechanisms through which stress acts to induce relapse are not known.
In recent years, we have been using an animal model of relapse to drug seeking, known as the reinstatement procedure, to study the relationship between stress and relapse. This method was developed originally to study the ability of acute non-contingent exposure to drugs or exposure to drug-related stimuli to reinstate drug seeking after a period of extinction of the drug-reinforced behavior [41], [46], [205]. Many studies using this procedure have demonstrated that reexposure to drugs and drug-related stimuli reinstates drug seeking in rats and monkeys [29], [59], [67], [101], [125], [172], [194], [199]. The validity of this method as a model for the study of relapse [121] is reinforced by the fact that when drug-free human addicts are reexposed to drugs and to drug-related stimuli they report increased craving for drugs [32], [36], [45], [93], [127].
In initial studies of acute exposure to stress in both heroin- and cocaine-trained animals, we found that exposure to 10–15 min of intermittent footshock (0.5–1.0 mA, 0.5 s ON, a mean OFF period of 40 s) reliably reinstates drug seeking after 1–2 weeks of extinction training and after an additional 4–6-week drug-free period [55], [178]. Footshock was found to be at least as effective as priming injections of drugs in inducing high levels of responding in tests for reinstatement over a range of footshock durations and doses [177] (see Fig. 1, Fig. 2). Subsequently, similar findings were reported by a number of laboratories using different training doses, schedule requirements, footshock parameters and strains of rats [2], [3], [120], [206]. Thus, it would appear that the phenomenon of footshock stress-induced reinstatement is reproducible under a number of different experimental conditions. Furthermore, in a recent study in humans it was found that stress provokes craving for cocaine under controlled laboratory conditions [191].
Following our initial observations of stress-induced reinstatement of heroin and cocaine seeking, a number of studies were carried out to investigate the phenomenology and neurobiology of footshock-induced reinstatement. Here we review, first, studies done to determine the degree to which the phenomenon of footshock-induced reinstatement generalizes to other stressors, to other drugs, and to instrumental behaviors based on non-drug reinforcers. We then consider findings from studies done to determine the role of a number of neurotransmitter and hormonal systems in stress-induced reinstatement of heroin and cocaine seeking, and studies done to identify the brain sites mediating these effects. Finally, we consider the mechanisms that might underlie stress-induced relapse to drug use and the possible implications of the findings for the treatment of relapse to drug use in humans.
Section snippets
Can footshock-stress induce relapse to other drug and non-drug reinforcers?
Footshock has been found to induce reinstatement of drug seeking in animals trained to self-administer both alcohol and nicotine [23], [112] (Fig. 3). In the case of alcohol, when the reinstatement induced by footshock was compared directly to that induced by oral alcohol, footshock had a much greater effect on responding than did alcohol itself. In the case of nicotine, although not compared directly in the same study, the effect of footshock [23] was similar to that seen following priming
Pharmacological approaches
Using specific receptor agonists and antagonists we have studied the possible contribution of several neurotransmitter systems in stress-induced reinstatement of drug seeking. These include the opioid, dopaminergic (DA), noradrenergic (NE) and CRF systems. In addition, we have studied the possible role of the adrenal hormone, corticosterone. A summary of the results from these pharmacological studies is provided in Table 2.
Discussion
The study of stress-induced reinstatement of drug seeking has a short history and much has yet to be learned about the processes involved. In the sections below we will discuss several issues that are pertinent to the understanding of this phenomenon.
Acknowledgements
Supported by NIDA and the Medical Research Council of Canada. We thank Dr. Hans Crombag for helpful comments.
References (222)
- et al.
Persistent increase in the motivation to take heroin in rats with history of drug escalation
Neuropsychopharmacology
(2000) - et al.
The neuronal organization of the supracapsular part of the stria terminalis in the rat: the dorsal component of the extended amygdala
Neuroscience
(1998) - et al.
Chronic cocaine administration sensitizes behavioral but not neuroendocrine responses
Brain Res.
(1991) - et al.
Contextual control of the extinction of conditioned fear
Learn. Motiv.
(1979) - et al.
Sources of relapse after extinction in Pavlovian and instrumental learning
Clin. Psychol. Rev.
(1991) Disinhibition of operant response
Learn. Motiv.
(1970)The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats
Drug Alcohol Dependence
(1985)- et al.
Increased drug-reinforced behavior due to food deprivation
- et al.
Can induced moods trigger drugrelated responses in opiate abuse patients?
J. Subst. Abuse Treat.
(1994) Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders
Psychoneuroendocrinology
(1995)
Origin of noradrenergic afferents to the shell subregion of the nucleus accumbens: anterograde and retrograde tract-tracing studies in the rat
Brain Res.
Physiological and behavioral responses to corticotropin-releasing factor: is CRF a mediator of anxiety or stress responses?
Brain Res. Rev.
Selective effects of DSP-4 on locus coeruleus axons: are there pharmacologically different types of noradrenergic axons in the central nervous system?
Prog. Brain Res.
Drug-induced reinstatement of extinguished self-administration behavior in monkeys
Pharmacol. Biochem. Behav.
Imidazole fungicides provoke histamine release from mast cells and induce airway contraction
Exp. Toxicol. Pathol.
Effects of corticotropin releasing hormone on appetitive behaviors
Peptides
Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release
Neuroscience
A neuroendocrine role in cocaine reinforcement
Psychoneuroendocrinology
Comparison between the behavioural effects of septal and hippocampal lesions: a review
Neurosci. Biobehav. Rev.
Estrogenic maintenance of lordotic responsiveness: requirement for hypothalamic action potentials
Brain Res.
Substantia innominata: a notion which impedes clinical-anatomical correlations in neuropsychiatric disorders
Neuroscience
Clinical medications development for opiate addiction: focus on nonopioid and opioid antagonists for the amelioration of opiate withdrawal symptoms and relapse prevention
Semin. Neurosci.
Opiocortin and catecholamine input to CRF-immunoreactive neurons in rat forebrain
Peptides
The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking
Brain Res. Rev.
Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis
Neurosci. Biobehav. Rev.
Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity
Brain Res. Rev.
Alpha 2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo
Science
Cocaine-but not food-seeking behavior is reinstated by stress after extinction
Psychopharmacology
Stress-induced analgesia: adaptive pain suppression
Physiol. Rev.
The bed nucleus of the stria terminalis: a target site for noradrenergic actions in opiate withdrawal
Ann. NY Acad. Sci.
The locus coeruleus, A5 and A7 noradrenergic cell groups
Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression: modulation by environmental novelty
J. Neurosci.
Diversity of agents that modify opioid tolerance, physical dependence, abstinence syndrome and self-administration behavior
Pharmacol. Rev.
Contextual control of the extinction of conditioned fear: tests for the associative value of the context
J. Exp. Psychol.: Anim. Behav. Processes
Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies
Synapse
Noradrenergic mechanisms in stress and anxiety: II. Clinical studies
Synapse
The patterns of afferent innervation of the core and shell in the ‘accumbens’ part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold
J. Comp. Neurol.
Stress, vulnerability and adult alcohol relapse
J. Stud. Alcohol
Localization of the central rhythm generator involved in spontaneous consummatory licking in rats: functional ablation and electrical brain stimulation studies
Proc. Natl. Acad. Sci USA
Differences in hypothalamic-pituitary-adrenocortical activity in the rat after acute and prolonged treatment with morphine
Neuroendocrinology
Studies on the generality of the effect of stress on relapse to drug seeking
Soc. Neurosci. Abstr.
Stress reinstates nicotine seeking but not sucrose solution seeking in rats
Psychopharmacology
Food restriction enhances the central rewarding effect of abused drugs
J. Neurosci.
Stress, depression and the mesolimbic dopamine system
Psychopharamacology
Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats
Psychopharamacology
Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex
J. Neurosci.
Animal models of relapse
Exp. Clin. Psychopharmacol.
Hippocampal noradrenaline release in awake, freely moving rats is regulated by alpha-2 adrenoceptors but not by adenosine receptors
J. Pharmacol. Exp. Ther.
Meta-analysis of cue-reactivity in addiction research
Addiction
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