Persistent Increases in Cocaine-Seeking Behavior After Acute Exposure to Cold Swim Stress
ABSTRACT 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.
Full-textDOI: · Available from: James Edgar Mccutcheon, Aug 02, 2015
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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.Biological psychiatry 02/2011; 69(11):1124-6. DOI:10.1016/j.biopsych.2010.12.028 · 9.47 Impact Factor
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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.Psychopharmacology 04/2011; 218(1):69-82. DOI:10.1007/s00213-011-2263-y · 3.99 Impact Factor
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ABSTRACT: The interaction between stress and drugs of abuse is a critical component of drug addiction, but the underlying molecular mechanisms remain elusive. Arc/Arg3.1 is an effector immediate early gene that may represent a bridge connecting short- and long-term neuronal modifications associated with exposure to stress and drugs of abuse. This research aims to study the modulation of Arc/Arg3.1 expression as a marker of neuronal changes associated with exposure to stress and cocaine. Rats exposed to either single or repeated stress sessions were subjected to a single intraperitoneal injection of cocaine hydrochloride (10 mg/kg) and sacrificed 2 h later. RNase protection assay was used to determine changes in Arc/Arg3.1 gene expression in different brain regions. We found significant stress-cocaine interactions in the prefrontal cortex (p < 0.001) and hypothalamus (p < 0.05). In the prefrontal cortex, acute stress potentiated cocaine-induced Arc/Arg3.1 mRNA elevation, whereas prolonged stress attenuated the response to cocaine. In the hypothalamus, although markedly reduced by acute stress, Arc/Arg3.1 gene expression was still increased by cocaine. No interaction was observed following repeated stress. Notably, cocaine-induced Arc/Arg3.1 mRNA levels were not influenced by stress in striatum and hippocampus. In our experimental model, stress interacted with cocaine to alter Arc/Arg3.1 expression in a regionally selective fashion and in a way that depended on whether stress was acute or repeated. These results point to Arc/Arg3.1 as a potential molecular target modulated by stress to alter cellular sensitivity to cocaine.Psychopharmacology 05/2011; 218(1):241-8. DOI:10.1007/s00213-011-2331-3 · 3.99 Impact Factor