Acute and chronic stress reinstates drug-seeking behavior. Current animal models show that these effects are contingent (temporally, contextually, or both) on the drug-conditioning environment. To date, no paradigm exists to model the common human situation in which stressors that are distinct from the experience of drugs can lead to relapse.
Rats were allowed to self-administer cocaine or saline over 8 days. They then underwent extinction training, during which responding was not reinforced with drug infusions. After 16 days of extinction, rats were submitted to a brief cold swim stress and then tested for seeking behavior (responding not reinforced with drug infusions) for 4 days.
All rats developed self-administration behavior. Following extinction, cold swim stress induced reinstatement of drug-seeking behavior in cocaine-trained rats, an effect that was still present 3 days after stress exposure.
This study indicates that cold swim stress can have long-term effects on drug-seeking behavior and may provide us with a suitable model to study the latent effects of stress on relapse to drug abuse.
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"We tested the hypothesis that kappa opioid receptor activation blocks LTP GABA in VTA dopaminergic neurons following acute cold water swim stress. A similar stressor has recently been shown to induce reinstatement to drug seeking in rats, an effect that lasts for several days after stress (Conrad et al., 2010). We report here that a KOR antagonist given prior to acute stress rescues LTP GABA . "
[Show abstract][Hide abstract] ABSTRACT: Stress facilitates reinstatement of addictive drug seeking in animals and promotes relapse in humans. Acute stress has marked and long-lasting effects on plasticity at both inhibitory and excitatory synapses on dopamine neurons in the ventral tegmental area (VTA), a key region necessary for drug reinforcement. Stress blocks long-term potentiation at GABAergic synapses on dopamine neurons in the VTA (LTP), potentially removing a normal brake on activity. Here we show that blocking kappa opioid receptors (KORs) prior to forced-swim stress rescues LTP. In contrast, blocking KORs does not prevent stress-induced potentiation of excitatory synapses nor morphine-induced block of LTP. Using a kappa receptor antagonist as a selective tool to test the role of LTP in vivo, we find that blocking KORs within the VTA prior to forced-swim stress prevents reinstatement of cocaine seeking. These results suggest that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse.
[Show abstract][Hide abstract] ABSTRACT: Excitatory synaptic transmission in the nucleus accumbens (NAc) regulates the reinstatement of drug seeking, an animal model of relapse in human drug addicts. However, the functional adaptations at NAc synapses that mediate reinstatement are not clearly understood.
We assessed the behavioral responses of mice to cocaine administration by measuring locomotor stimulation and the acquisition, extinction, and reinstatement of conditioned place preference. Synaptic function was then examined by preparing acute brain slices and performing whole cell voltage-clamp recordings from individual medium spiny neurons in the NAc shell.
We find that reduced excitatory synaptic strength in the NAc shell is a common functional adaptation induced by multiple experiences known to cause reinstatement, including stress and drug re-exposure. The same synaptic adaptation is observed shortly after reinstatement of conditioned place preference by a cocaine priming injection.
This common synaptic modification associated with stress, drug re-exposure, and reinstatement defines a potential synaptic gateway to relapse.
[Show abstract][Hide abstract] ABSTRACT: RATIONALE AND BACKGROUND: High relapse rates during abstinence are a pervasive problem in drug addiction treatment. Relapse is often associated with stress exposure, which can provoke a subjective state of drug craving that can also be demonstrated under controlled laboratory conditions. Stress-induced relapse and craving in humans can be modeled in mice, rats, and monkeys using a reinstatement model in which drug-taking behaviors are extinguished and then reinstated by acute exposure to certain stressors. Studies using the reinstatement model in rats have identified the role of several neurotransmitters and brain sites in stress-induced reinstatement of drug seeking, but the degree to which these preclinical findings are relevant to the human condition is largely unknown. OBJECTIVES AND HIGHLIGHTS: Here, we address this topic by discussing recent results on the effect of alpha-2 adrenoceptors and substance P-NK1 receptor antagonists on stress-induced reinstatement in mice and rats and stress-induced craving and potentially stress-induced relapse in humans. We also discuss brain sites and circuits involved in stress-induced reinstatement of drug seeking in rats and those activated during stress-induced craving in humans. CONCLUSIONS: There is evidence that alpha-2 adrenoceptor agonists and NK1 receptor antagonists decrease stress-induced drug seeking in rats and stress-induced craving in humans. Whether these drugs would also prevent stress-induced drug relapse in humans and whether similar or different brain mechanisms are involved in stress-induced reinstatement in non-humans and stress-induced drug craving and relapse in humans are subjects for future research.