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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014020-10
Application #
8267062
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2001-04-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$351,596
Indirect Cost
$109,887
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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
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
Brady, Anne Marie; O'Donnell, Patricio (2004) Dopaminergic modulation of prefrontal cortical input to nucleus accumbens neurons in vivo. J Neurosci 24:1040-9
Tseng, Kuei-Yuan; O'Donnell, Patricio (2003) Dopamine-glutamate interactions in the control of cell excitability in medial prefrontal cortical pyramidal neurons from adult rats. Ann N Y Acad Sci 1003:476-8
Brady, Anne Marie; Glick, Stanley D; O'Donnell, Patricio (2003) Changes in electrophysiological properties of nucleus accumbens neurons depend on the extent of behavioral sensitization to chronic methamphetamine. Ann N Y Acad Sci 1003:358-63
O'Donnell, Patricio (2003) Dopamine gating of forebrain neural ensembles. Eur J Neurosci 17:429-35