Schizophrenia and Substance Abuse Comorbidity: Nicotine Addiction and the Neonatal Quinpirole Model

Abstract

This review focuses on nicotine comorbidity in schizophrenia, and the insight into this problem provided by rodent models of schizophrenia. A particular focus is on age differences in the response to nicotine, and how this relates to the development of the disease and difficulties in treatment. Schizophrenia is a particularly difficult disease to model in rodents due to the fact that it has a plethora of symptoms ranging from paranoia and delusions of grandeur to anhedonia and negative affect. The basis of these symptoms is believed to be due to neurochemical abnormalities and neuropathology in the brain, which most models have attempted to emulate. A brief review of findings regarding nicotine use and abuse in schizophrenics is presented, with findings using rodent models that have been able to provide insight into the mechanisms of addiction. A common clinical approach to the treatment of nicotine addiction in the schizophrenic population has been that these drugs are used for self-medication purposes, and it is clear that self-medication may actually be directed at several symptoms, including cognitive impairment and anhedonia. Finally, our laboratory has reported across a series of studies that neonatal treatment with the dopamine D₂/D₃ receptor agonist quinpirole results in long-term increases in dopamine-like receptor sensitivity, consistent with data reporting increases in dopamine D₂ receptor function in schizophrenia. Across these studies, we have reported several behavioral, neurochemical, and genetic consistencies with the disease, and present a hypothesis for what we believe to be the basis of psychostimulant addiction in schizophrenia.

Association of schizotypy with striatocortical functional connectivity and its asymmetry in healthy adults

“…Given that schizophrenia spectrum disorders including schizotypy are frequently comorbid with anxiety and affective disorders [Anticevic et al, ; Buckley et al, ; Samsom and Wong, ; Zink, ] as well as substance abuse [Brown et al, ; Regier et al, ; Thoma and Daum, ], the specificity of the associations between connectivity and schizotypy observed here remains to be clarified.…”

Developmental origins of brain disorders: roles for dopamine

“…Environmental, social, and inflammatory challenges during sensitive periods of forebrain development also produce neuro(mal)adaptions in these regions and phenocopy some aspects of brain disorders (Di Forti et al, 2007; Kern et al, 2010; Han et al, 2012; Selemon and Friedman, 2013). For example, models of prenatal infection, stress, and exposure to drugs of abuse show long-lasting changes in DA receptor expression and function and have been associated with increased risk for psychiatric disorders (Alonso et al, 1994; Stanwood et al, 2001b; Berger et al, 2002; Zuckerman et al, 2003; Andersen and Teicher, 2009; Bhide, 2009; Brown et al, 2012). Taken together, these data have led our group and others to hypothesize that DAergic modulation of developmental processes produces long lasting alterations that contribute to cortical and striatal dysfunction in neuropsychiatric disorders.…”

Effects of Environmental Enrichment on Nicotine Sensitization in Rats Neonatally Treated with Quinpirole: Analyses of Glial Cell Line-Derived Neurotrophic Factor and Implications towards Schizophrenia

“…We have shown that NQ treatment in rats leads to enhanced behavioral and dopaminergic response to nicotine [4] as well as to amphetamine [5,6]. We have also validated NQ treatment as a model of psychosis in several other behavioral and neurobiological domains [7], meeting all standards of model validity [8]. Important to the present study, individuals diagnosed with schizophrenia are 3-4 times more likely to smoke cigarettes compared to the normal population [9,10], but there is no delineated mechanism for this increase.…”