Unconditioned and conditioned factors contribute to the 'reinstatement' of cocaine place conditioning following extinction in C57BL/6 mice
ABSTRACT Relapse to drug use following prolonged periods of abstinence results, in part, from the ability of contextual cues paired previously with self-administered drug to elicit drug craving and -seeking behavior. Given the popularity of the mouse for the genetic analysis of drug-induced behaviors, a place conditioning model of drug-seeking behavior was used to examine the ability of cocaine (COC) to reinstate extinguished conditioned reward in mice. In a series of experiments, COC place conditioning was produced in male C57BL/6 (B6) mice by four pairings of COC (15 or 25 mg/kg, IP) with the non-preferred compartment of a two-compartment place conditioning apparatus. Following a post-conditioning test (Post-Test), place conditioning was extinguished by repeated testing. The mice were then challenged with one of five COC doses (0, 5, 10, 15 or 25 mg/kg, IP) and allowed free access to both environments. Following extinction, COC injections reinstated place conditioning to 100% or greater, relative to the Post-Test. In a control experiment, mice received either COC or SAL paired with non-preferred compartment and were then challenged with either COC (15 mg/kg, IP) or SAL on the Post-Test. COC-conditioned, but not SAL-conditioned, mice exhibited place conditioning when tested in a COC-free state. Interestingly, COC injection on the Post-Test elicited an increase in approach behavior in both SAL- and COC-conditioned mice and this increase was equivalent to that produced by COC conditioning alone. No direct relationships were observed between the magnitude of place conditioning and either COC-induced or -conditioned locomotor hyperactivity in the non-preferred compartment. Thus, at least two independent processes appear to underlie the ability of a COC injection to elicit approach behavior towards the non-preferred compartment of a biased place conditioning apparatus in mice-reactivation of the conditioned incentive motivational properties of COC-paired cues and elicitation of unconditioned behavioral disinhibition. One or both of these processes sensitizes with the passage of time, increasing the propensity of B6 mice to approach non-preferred environments upon COC re-administration.
- SourceAvailable from: C.J. Malanga
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- "cocaine self-administration (Rocha et al., 2002) and intracranial self-stimulation studies (Malanga et al., in press). Meta-analysis of multiple studies showed that single housing does not affect the development of cocaine CPP in rats (Bardo et al., 1995), and cocaine CPP has been demonstrated in singly-housed C57Bl/6J (Szumlinski et al., 2002) and 129/Sv mice (Brabant et al., 2007). On days 2–4 each mouse was handled for 5 min daily, and on days 5–7 mice were handled for 5 min daily and injected with saline vehicle in their home cage. "
ABSTRACT: As addiction is increasingly formulated as a developmental disorder, identifying how early developmental exposures influence later responses to drugs of abuse is important to our understanding of substance abuse neurobiology. We have previously identified behavioral changes in adult mice following gestational exposure to cocaine that differ when assessed with methods employing contingent and non-contingent drug administration. We sought to clarify this distinction using a Pavlovian behavioral measure, conditioned place-preference. Adult mice exposed to cocaine in utero (40 or 20 mg/kg/day), vehicle and pair-fed controls were place-conditioned to either cocaine (5 mg/kg or 20 mg/kg, i.p.) or saline injections. The development of conditioned place-preference to cocaine was impaired in mice exposed to cocaine in utero, and was abolished by fetal malnutrition. A context-specific place-aversion to vehicle but not cocaine injection was observed in prenatally cocaine-exposed mice. Locomotor behavior did not differ among prenatal treatment groups. We conclude that early developmental exposure to cocaine may diminish the subsequent rewarding effects of cocaine in adulthood measured with classical conditioning techniques, and that this is not due to changes in locomotor behavior. Sensitivity to acute stress is also altered by prenatal cocaine exposure, consistent with earlier findings in this model.Pharmacology Biochemistry and Behavior 11/2007; 87(4):462-71. DOI:10.1016/j.pbb.2007.06.002 · 2.82 Impact Factor
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- "Moreover, the biased conditioned place preference design has the advantage of controlling for the individual animal's bias in the apparatus, allowing for the more efficient use of the animals available. It has also been demonstrated as an effective protocol for the study of extinction and reinstatement (Szumlinski et al., 2002). "
ABSTRACT: Stress contributes to the reinstatement of cocaine-seeking behavior in abstinent subjects. Kappa-opioid receptor antagonists attenuate the behavioral effects of stress, potentially providing therapeutic value in treating cocaine abuse. Presently, the peptide arodyn produced long-lasting kappa-opioid receptor antagonism, suppressing kappa-opioid receptor agonist-induced antinociception at least 3 days after intracerebroventricular administration of 0.3 nmol. C57Bl/6J mice demonstrated cocaine-conditioned place preference, extinction over 3 weeks, and a subsequent reinstatement of place preference. Arodyn pretreatment suppressed stress-induced, but not cocaine-exposed, reinstatement of cocaine place preference. These results verify that arodyn and other kappa-opioid receptor antagonists may be useful therapeutics for cocaine abuse.European Journal of Pharmacology 09/2007; 569(1-2):84-9. DOI:10.1016/j.ejphar.2007.05.007 · 2.68 Impact Factor
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- "At 10 weeks of age, the capacity of four i.p. injections of 15 mg/kg cocaine (Sigma-Aldrich, St Louis, MO) to induce place-conditioning and locomotor sensitization was assessed using a biased place conditioning procedure identical to that described previously for mice (Szumlinski et al, 2002, 2004a, 2005b). As also discussed previously (eg, Szumlinski et al, 2002), a biased place-conditioning procedure was used to reduce the probability of observing a ceiling effect upon approach behavior (Shimosato and Ohkuma, 2000). The apparatus employed in the present study enabled the assessment of three aspects of behavior: motor activity, anxiety, and cocaine-induced place conditioning . "
ABSTRACT: For decades, the sympathomimetic phenylpropanolamine (PPA; +/- -norepinephrine) was an active ingredient found in popular children's over-the-counter (OTC) cold, cough, and allergy medications. To examine the possibility that pre-adolescent PPA exposure may induce neuroadaptations that influence behavioral and neurochemical responding to cocaine, C57BL/6J mice were pretreated with PPA (0-40 mg/kg) during postnatal days 21-31. The behavioral and neurochemical responses to acute and repeated cocaine (4 x 15 mg/kg) were then assessed in adulthood when the mice were 10 weeks of age. Whereas pre-adolescent PPA exposure did not influence the acute locomotor response to 15 mg/kg cocaine, PPA pre-exposure dose-dependently enhanced the expression of cocaine-induced place conditioning, reduced the expression of locomotor sensitization, but did not influence cocaine-induced stereotypy. Pre-adolescent PPA exposure completely prevented the capacity of cocaine to elevate extracellular levels of catecholamines in the nucleus accumbens, but facilitated the development of cocaine-induced glutamate sensitization. Neither acute nor repeated cocaine altered extracellular GABA levels in the accumbens of control mice; however, 15 mg/kg cocaine lowered GABA levels by approximately 40% in PPA pretreated mice and this effect showed tolerance with repeated cocaine administration. These data provide the first evidence that early exposure to an OTC compound produces protracted effects upon cocaine-induced changes in nucleus accumbens neurotransmission that may contribute to a 'pro-addictive' phenotype in adulthood.Neuropsychopharmacology 09/2007; 32(8):1760-73. DOI:10.1038/sj.npp.1301306 · 7.83 Impact Factor