Liberacion de glutamato en el nucleo acumbens es necesaria para la adicción de herorína

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3170 • The Journal of Neuroscience, March 19, 2008 • 28(12):3170 –3177

Behavioral/Systems/Cognitive

Glutamate Release in the Nucleus Accumbens Core Is Necessary for Heroin Seeking
Ryan T. LaLumiere and Peter W. Kalivas
Neurobiology of Addiction Research Center, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425

Long-term changes inglutamate transmission in the nucleus accumbens core (NAcore) contribute to the reinstatement of drug seeking after extinction of cocaine self-administration. Whether similar adaptations in glutamate transmission occur during heroin and cueinduced reinstatement of heroin seeking is unknown. After 2 weeks of heroin self-administration and 2 weeks of subsequent extinction training, heroin seekingwas induced by a noncontingent injection of heroin or by presentation of light/tone cues previously paired with heroin infusions. Microdialysis was conducted in the NAcore during reinstatement of heroin seeking in animals extinguished from heroin self-administration or in subjects receiving parallel (yoked) noncontingent saline or heroin. Reinstatement by either heroin or cue increasedextracellular glutamate in the NAcore in the self-administration group, but no increase was elicited during heroin-induced reinstatement in the yoked control groups. The increase in glutamate during heroin-induced drug seeking was abolished by inhibiting synaptic transmission in the NAcore with tetrodotoxin or by inhibiting glutamatergic afferents to the NAcore from the prelimbic cortex. Supportingcritical involvement of glutamate release, heroin seeking induced by cue or heroin was blocked by inhibiting AMPA/kainate glutamate receptors in the NAcore. Interestingly, although a heroin-priming injection increased dopamine equally in animals trained to self-administer heroin and in yoked-saline subjects, inhibition of dopamine receptors in the NAcore also blocked heroin- and cueinduced drugseeking. Together, these findings show that recruitment of the glutamatergic projection from the prelimbic cortex to NAcore is necessary to initiate the reinstatement of heroin seeking. Key words: self-administration; dialysis; dopamine; reinstatement; addiction; prelimbic

Introduction
Despite the debilitating personal and societal impact of heroin addiction, the mechanisms underlying relapseto heroin use are not clear (Kreek et al., 2005). Recent findings using the reinstatement animal model of relapse indicate that components of the brain circuitry involved in cocaine seeking, such as the prelimbic cortex and the nucleus accumbens core (NAcore), are also necessary for heroin seeking (Rogers et al., 2008). However, other components of heroin- and cocaine-seeking circuitry aredistinct, such as involvement of the amygdala, accumbens shell, and infralimbic cortex in heroin- but not cocaine-induced drug seeking (McFarland and Kalivas, 2001; Rogers et al., 2008). It is thought that a key feature of the circuitry underlying cocaine seeking is enhanced glutamate release into the NAcore by afferents from prelimbic cortex. Thus, not only does inactivation of either the NAcoreor prelimbic cortex prevent cue-, stress-, or cocaineinduced reinstatement of cocaine seeking (McFarland and Kalivas, 2001; McLaughlin and See, 2003; Di Ciano and Everitt, 2004;

Received Nov. 19, 2007; revised Jan. 19, 2008; accepted Feb. 9, 2008. This work was supported by National Institutes of Health Grant USPHS 015369 (P.W.K.) and National Research Service Award USPHS DA 021460 (R.T.L.).We thank Jesse Smith, Jay Hutson, Kerranna Williamson, Kristin Trzcinski, Kyle Smith, Kate Niehoff, Hayden Alewine, Stephanie Kehoe, and Louisa Young for their excellent technical assistance. Correspondence should be addressed to Dr. Ryan T. LaLumiere, 173 Ashley Avenue, BSB 403, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425. E-mail: lalumie@musc.edu....
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