The Neurobiology of Addiction Research Center (NARC)
Ron. E. See, Ph.D.Project 4 - Evalution of Anti-Relapse Medications
Relapse to drug use following abstinence is the major impediment in the treatment of cocaine dependence. Development and application of appropriate testing paradigms for new medications that may prevent relapse would be a significant advancement in addressing the problem of cocaine dependence, as well as other drugs of abuse. Although various factors (e.g., conditioned cues) that contribute to relapse have been studied in preclinical animal models, there has been surprisingly limited application of these models for systematic testing of novel compounds.
Project 4 will take intervention strategies identified through the NARC projects aimed at reducing relapse to cocaine-seeking. The advantages of having such a project within the NARC include: a) the ability to use standardized procedures through the NARC Animal Core of cocaine self-administration and reinstatement, b) providing acute and chronic drug treatment protocols that inhibit cocaine-seeking that can be used in other NARC projects to assess the validity of cocaine-induced neuroplasticity for drug target development, and c) integrating the NARC preclinical animal model of relapse with the NARC Clinical Pilot Core as a transition to clinical assessment of promising pharmacotherapies. Project 4 will initially focus on a few selected strategies of drug intervention by targeting dopaminergic activity via a partial DA receptor agonist, enhancement of glutamatergic homeostasis, and antagonism of the orexin 1 receptor.
Since the focus of this project is the assessment of compounds that can be applied in a clinical environment, we will concentrate on systemically available, approved drugs for use in humans. However, in the later years of the Center, we intend to take identified compounds from the NARC that can be thoroughly assessed using the relapse model. Together, Project 4 will provide for the systematic examination of testable drug interventions derived from studies within the NARC. Other projects within the NARC, in particular Project 1, will identify future targets of intervention for systemic prevention of relapse. By applying a seamless model of testing in conjunction with the NARC Animal Core, we will use a template for the testing of putative medications as they are derived from NARC projects to serve as a bridge to clinical application of such agents through the NARC Pilot Core.
Recent Primary Papers from the NARC, Project #4.
Berglind WJ, Case JM, Parker MP, Fuchs RA, See RE (2006) Dopamine D1 or D2 receptor antagonism within the basolateral amygdala differentially alters the acquisition of cocaine-cue associations necessary for cue-induced reinstatement of cocaine-seeking. Neuroscience 137:699-706.
Fuchs RA, Branham RK, See RE (2006) Different neural substrates mediate cocaine seeking following abstinence versus extinction training: A critical role for the dorsolateral caudate-putamen. Journal of Neuroscience 26(13):3584-3588.
Kippin TE, Fuchs RA, See RE (2006) Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine-seeking in rats. Psychopharmacology 187:60-67.
Fuchs RA, Feltenstein MW, See RE (2006) The role of the basolateral amygdala in stimulus-reward memory and extinction memory consolidation and in subsequent conditioned-cued reinstatement of cocaine seeking. European Journal of Neuroscience 23:2809-2813.
Feltenstein MW, Altar CA, See RE (2007) Aripiprazole blocks reinstatement of cocaine-seeking in an animal model of relapse. Biological Psychiatry 61(5):582-590.
Rogers JL, See RE (2007) Inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats. Neurobiology of Learning and Memory 87:688-692.
See RE, Elliott JC, Feltenstein MW (2007) The role of dorsal vs. ventral striatal pathways in cocaine-seeking behavior following prolonged abstinence in rats. Psychopharmacology 194:321–331.
Feltenstein MW, See RE (2007) NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse. Neurobiology of Learning and Memory 88:435-444.
Rogers JL, Ghee S, See RE (2008) The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151(2):579-588.
Bongiovanni M, See RE (2008) A comparison of the effects of different operant training experiences and dietary restriction on the reinstatement of cocaine-seeking in rats. Pharmacology, Biochemistry, and Behavior 89(2): 227-233.
Recent Review Papers from the NARC, Project #4.
Feltenstein MW, See RE (2008) The neurocircuitry of addiction: An overview. British Journal of Pharmacology 154(2):261-274.
See RE, Kalivas PW (2008) Neuroscience of substance abuse and dependence. In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry(Eds. Sadock BJ, Sadock VA, Ruiz P), 9th edition, Lippincott Williams & Wilkins; in press.