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ABSTRACT: Mouse embryonic spinal cord neurons in culture exhibit spontaneous calcium oscillations from day in vitro (DIV) 6 through DIV 10. Such spontaneous activity in developing spinal cord contributes to maturation of synapses and development of pattern-generating circuits. Here we demonstrate that these calcium oscillations are regulated by κ opioid receptors (KORs). The κ opioid agonist dynorphin (Dyn)-A (1-13) suppressed calcium oscillations in a concentration-dependent manner, and both the nonselective opioid antagonist naloxone and the κ-selective blocker norbinaltorphimine eliminated this effect. The KOR-selective agonist (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69593) mimicked the effect of Dyn-A (1-13) on calcium oscillations. A κ-specific peptide antagonist, zyklophin, was also able to prevent the suppression of calcium oscillations caused by Dyn-A (1-13). These spontaneous calcium oscillations were blocked by 1 μM tetrodotoxin, indicating that they are action potential-dependent. Although the L-type voltage-gated calcium channel blocker nifedipine did not suppress calcium oscillations, the N-type calcium channel blocker ω-conotoxin inhibited this spontaneous response. Blockers of ionotropic glutamate receptors, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline and dizocilpine maleate (MK-801), also suppressed calcium oscillations, revealing a dependence on glutamate-mediated signaling. Finally, we have demonstrated expression of KORs in glutamatergic spinal neurons and localization in a presynaptic compartment, consistent with previous reports of KOR-mediated inhibition of glutamate release. The KOR-mediated inhibition of spontaneous calcium oscillations may therefore be a consequence of presynaptic inhibition of glutamate release.
Molecular pharmacology 03/2011; 79(6):1061-71. · 4.53 Impact Factor
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ABSTRACT: Male Sprague Dawley rats were allowed to self-administer cocaine (0.5 mg/kg) during 90 min sessions for a period of 15 days. On day 16, rats were either held abstinent in their home cage environment or experienced an extinction session in which the active lever had no programmed consequences. Facilitating N-methyl-D-aspartate (NMDA) receptor activity with the coagonist D-serine (100 mg/kg i.p.) before or following the extinction session significantly reduced the subsequent cocaine-primed reinstatement of drug-seeking behavior tested on day 17. D-serine significantly reduced drug-primed reinstatement only when combined with extinction, and its effectiveness when administered following the training session suggested that an enhancement of consolidation of extinction learning had occurred. In contrast, D-serine treatment did not reduce sucrose-primed reinstatement, indicating that the beneficial effects of this adjunct pharmacotherapy with extinction training were specific to an addictive substance (cocaine) and did not generalize to a natural reward (sucrose).
Neurobiology of Learning and Memory 08/2009; 92(4):544-51. · 3.42 Impact Factor
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ABSTRACT: The resumption of drug-seeking behavior after abstinence or extinction is commonly studied model for relapse in addiction. For the benefits of extinction training over a given withdrawal period to be determined, it is necessary to discriminate between the potentially overlapping occurrence of incubation with that of spontaneous recovery. This comparison has been assessed using a between-subjects design in groups of abstinent and extinguished rats tested at various withdrawal periods after cocaine self-administration. Multiple forms of priming were used to evoke the resumption of drug seeking, as different priming stimuli have been reported to use distinct neurobiological mechanisms and therefore may exhibit different temporal characteristics. In abstinent animals (30 days), neither the noncontingent conditioned stimuli-primed nor the noncontingent cocaine-primed drug seeking displayed incubation, whereas the drug seeking provoked by exposure to the contextual cues of the operant chamber significantly increased. In extinguished animals, evidence of spontaneous recovery of responding was observed after priming with exposure to either contextual or cocaine-priming stimuli. Finally, extinction training remained effective in reducing the reinstatement response levels after contextual or cocaine priming even if such training was initiated after an extended period (24 days) of abstinence. These findings provide further insight into the time-dependent effects of abstinence and extinction on the resumption of drug-seeking behavior.
Behavioural pharmacology 04/2009; 20(2):195-203. · 2.85 Impact Factor
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ABSTRACT: Although the process of extinction has been well documented for various forms of behavioral responses, the effects of extinction on the reinstatement of drug-seeking behavior are relatively understudied. In this report, the effectiveness of an extinction training protocol to reduce primed reinstatement responses was compared with the effectiveness of an equivalent period of enforced abstinence. We found that extinction training performed in the drug taking environment significantly reduced reinstatement behavior subsequently primed by either contextual cues, conditioned cues, or cocaine infusion. The ability of extinction to reduce cocaine primed reinstatement was blocked by the systemic administration of the competitive NMDAR antagonist ((+/-)CPP, 5mg/kg i.p.) administered prior to each extinction training session. Interestingly, this pharmacological intervention had no impact on the effectiveness of extinction to reduce drug-seeking behavior primed by either contextual cues or conditioned cues. These results suggest that an extinction training experience involves multiple mechanisms that can be dissociated into nonNMDAR and NMDAR dependent components with respect to the type of reinstatement (i.e. context-, conditioned stimuli (CS)-, or drug-induced) being assessed.
Behavioural Brain Research 01/2008; 185(2):119-28. · 3.42 Impact Factor
