Dual-diagnosis in psychiatry refers to the co-existence of drug abuse with a psychiatric condition. This is quite prevalent in schizophrenia, where more than 50% of the patients abuse some type of drug. There is no agreement in the field regarding whether this is another symptom of the disease, due to a common involvement of the brain systems that are dysfunctional in schizophrenia, or an attempt at self-medication. As animal models of schizophrenia have become more refined, incorporating a developmental origin and environmental factors, it has become apparent that many of those animals have also enhanced liability for addictive behaviors. Animals with a neonatal ventral hippocampal lesion do exhibit increased self-administration of cocaine and methamphetamine. We will use this model to explore whether those animals'increased addiction can be described as self-medication or another manifestation of their condition. Also, we will use lesioned and sham animals to explore the cellular and synaptic mechanisms associated with the increased drive for cocaine these animals exhibit, combining behavioral assessments with electrophysiological studies in slices, in anesthetized animals and in awake, freely moving animals. The experiments are expected to shed some light onto why there is propensity for addictive behaviors when mesocorticolimbic circuits are dysfunctional (as likely occurring in schizophrenia and in animals with a neonatal hippocampal lesion), and may open avenues for newer therapeutic approaches for this extremely difficult to treat dual condition This project has the potential for unveiling mechanisms by underlying the increased drive for substance abuse that exists in patients with schizophrenia. It is widely known that schizophrenia patients have increased liability for drug abuse, and this is likely to emerge from an involvement of the reward brain circuits in the disorder or alternatively as an attempt at self-medication. We will conduct a series of experiments aimed at distinguishing these two possibilities in a well-established developmental animal model of schizophrenia. To understand the cellular and synaptic mechanisms in corticolimbic circuits that could contribute to an enhanced craving for drugs in brains with a developmental alteration in these circuits would advance our understanding of why there is a strong comorbidity between drug abuse and schizophrenia, and may result in the identification of potential targets for new therapeutic approaches.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
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University of Maryland Baltimore
Anatomy/Cell Biology
Schools of Medicine
United States
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Brady, Anne Marie (2016) The Neonatal Ventral Hippocampal Lesion (NVHL) Rodent Model of Schizophrenia. Curr Protoc Neurosci 77:9.55.1-9.55.17
Brooks, Julie M; O'Donnell, Patricio; Frost, Douglas O (2016) Olanzapine Treatment of Adolescent Rats Alters Adult D2 Modulation of Cortical Inputs to the Ventral Striatum. Int J Neuropsychopharmacol :
Lopez, Juan Carlos; Karlsson, Rose-Marie; O'Donnell, Patricio (2015) Dopamine D2 Modulation of Sign and Goal Tracking in Rats. Neuropsychopharmacology 40:2096-102
Myal, S; O'Donnell, P; Counotte, D S (2015) Nucleus accumbens injections of the mGluR2/3 agonist LY379268 increase cue-induced sucrose seeking following adult, but not adolescent sucrose self-administration. Neuroscience 305:309-15
Counotte, Danielle S; Schiefer, Christopher; Shaham, Yavin et al. (2014) Time-dependent decreases in nucleus accumbens AMPA/NMDA ratio and incubation of sucrose craving in adolescent and adult rats. Psychopharmacology (Berl) 231:1675-84
Baarendse, Petra J J; Counotte, Danielle S; O'Donnell, Patricio et al. (2013) Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function. Neuropsychopharmacology 38:1485-94
Karlsson, Rose-Marie; Kircher, Daniel M; Shaham, Yavin et al. (2013) Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia. Psychopharmacology (Berl) 226:45-51
Brady, Anne Marie; McCallum, Sarah E; Glick, Stanley D et al. (2008) Enhanced methamphetamine self-administration in a neurodevelopmental rat model of schizophrenia. Psychopharmacology (Berl) 200:205-15
Benoit-Marand, Marianne; O'Donnell, Patricio (2008) D2 dopamine modulation of corticoaccumbens synaptic responses changes during adolescence. Eur J Neurosci 27:1364-72
Brady, Anne Marie; Glick, Stanley D; O'Donnell, Patricio (2005) Selective disruption of nucleus accumbens gating mechanisms in rats behaviorally sensitized to methamphetamine. J Neurosci 25:6687-95

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