Nicotine and nicotinic system in hypoglutamatergic models of schizophrenia

Abstract

Schizophrenia is a complex neuropsychiatric disorder with devastating consequences. It is characterized by thought fragmentation, hallucination and delusion, collectively referred to as positive symptoms. In addition, mood changes or affective disorders, referred to as negative symptoms, as well as cognitive impairments can be manifested in these patients. Arguably, modeling such a disorder in its entirety in animals might not be feasible. Despite this limitation, various models with significant construct, predictive and some face validity have been developed. One such model, based on hypoglutamatergic hypothesis of schizophrenia, makes use of administering NMDA receptor antagonists and evaluating behavioral paradigms such as sensorimotor gating. Because of very high incidence of smoking among schizophrenic patients, it has been postulated that some of these patients may actually be self medicating with tobacco's nicotine. Research on nicotinic-glutamatergic interactions using various animal models has yielded conflicting results. In this review, some of these models and possible confounding factors are discussed. Overall, a therapeutic potential for nicotinic agonists in schizophrenia can be suggested. Moreover, it is evident that various experimental paradigms or models of schizophrenia symptoms need to be combined to provide a wider spectrum of the behavioral phenotype, as each model has its inherent limitations.

Effects of nicotine on sensorimotor gating impairment induced by long-term treatment with neurotoxic NMDA antagonism

“…Nonetheless, face validity of the "NMDA antagonists model" is supported by the positive, negative and cognitive impairment induced by these drugs (Javitt and Zukin, 1991;Jentsch and Roth, 1999;Geyer et al, 2001;Tsukada et al, 2005). Construct validity of the model is supported by hypoglutamatergic hypothesis of schizophrenia (Jentsch and Roth, 1999;Farber, 2003;Tamminga et al, 2003;Deutsch et al, 2006;Tizabi, 2007) as evidenced in pre-and post-mortem studies (Breese et al, 1995;Harrison et al, 2003;Laruelle et al, 2003;MeadorWoodruff et al, 2003). Finally, the predictive validity of the model is supported by examples of antipsychotic drugs reversing the behavioral effects of acute NMDA antagonists (for reviews, see Geyer et al, 2001;Swerdlow et al, 2001).…”

“…The dose of nicotine was 0.5 mg/kg, calculated as free base, administered s.c. twice daily, once in the morning (around 10:00) and the other in the afternoon (around 18:00). This dosage of nicotine was based on a number of in vivo studies where the reinforcing or other behavioral effects of nicotine were evaluated (Martinez et al, 2002;Campbell et al, 2006;2007;Tizabi et al, 1998;2007). The animals were tested for sensorimotor gating on days 17 and 22, 15 minutes after the morning nicotine injection.…”

“…Because of their implicated role in cognitive functions in general, and attentional functions in particular (see Tizabi, 2007), the densities of both high and low affinity nicotinic receptors in several brain regions were determined. This classification, based on binding affinity for nicotine and other similar compounds, also signifies the distinct anatomical, physiological and pharmacological characteristics of these receptors (see reviews by Lukas and Bencherif, 1992;Picciotto, 2003;Gotti and Clementi, 2004).…”

“…A relevant schizophrenia model for testing therapeutics is the NMDA (N-methyl-D-aspartate) receptor hypofunctional state (Farber, 2003;Domino et al, 2004;Coyle, 2006;Deutsch et al, 2006;Tizabi, 2007). Antagonists of the NMDA receptor reliably induce deficits in PPI.…”

Effects of nicotine on quinpirole- and dizocilpine (MK-801)-induced sensorimotor gating impairments in rats

“…Specifically, it is postulated that hypersensitivity of subcortical dopaminergic system, particularly the D2 receptor subtype, may play an important role in the symptomatology of this disorder as most effective antipsychotics have a D2 receptor antagonist property (see Kahn et al 1996;Deutsch et al 2006). The glutamatergic hypofunction, however, postulates that suboptimal transmission of glutamate in the frontal cortex is the primary cause of disease as the symptoms of schizophrenia may be induced by administration of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonists (see recent review by Tizabi 2007). Based on these theories, animal models have been developed where dopaminergic agonists such as quinpirole (QNP) or NMDA antagonists such as phencyclidine (PCP), ketamine, or dizocilpine (MK-801) are administrated to rodents to mimic some of the attentional or cognitive deficits observed in schizophrenic patients.…”