Effects of nicotine on schizophrenia-like cognitive deficits
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Schizophrenia patients exhibit increased rates of tobacco smoking, with almost 90% of schizophrenia patients smoking, compared to 25-30% in the general U.S. population. Because cognitive deficits constitute a central symptom cluster of schizophrenia that is largely resistant to current antipsychotic treatments, and because nicotine has been shown to possess some pro-cognitive properties, increased tobacco smoking in schizophrenia may represent an attempt to alleviate cognitive impairment. The proposed research will investigate the effects of nicotine on cognitive deficits and their neurochemical correlates in a rat model of schizophrenia. We hypothesize that nicotine will attenuate the cognitive deficits and normalize their neurochemical correlates in this model, supporting the concept that increased tobacco smoking in schizophrenia is due to self-medication of cognitive symptoms. The proposed studies will use phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, to model the cognitive symptoms of schizophrenia. PCP induces a psychosis-like state that mimics the various symptom clusters of schizophrenia. Similar to the negative and cognitive symptoms of schizophrenia, PCP intoxication is also resistant to typical antipsychotic treatment, while partially responding to atypical antipsychotics. Thus, PCP has become widely accepted as a model of various aspects of schizophrenia. Subchronic administration of PCP to rats produces a selective disruption of cognitive function. The proposed studies will explore the effects of nicotine on cognitive deficits and neurotransmission changes in the prefrontal cortex induced by subchronic PCP in order to investigate whether nicotine will attenuate these effects of PCP. Specific Aim 1 will investigate the effects of nicotine on PCP-induced behavioral disruptions in a range of cognitive tests. Attention will be assessed via the 5-choice serial reaction time task; a discrete paired-trial variable-delay T-maze task will be used to test working memory; and cognitive flexibility will be examined through a reversal learning task. The degree to which subchronic PCP impairs performance in these tasks, as well as the ability of chronic nicotine to attenuate or fully block the PCP-induced deficits, will be observed. Another experiment will assess whether nicotine also exerts beneficial effects on the negative symptoms of schizophrenia, such as anhedonia, which are also resistant to typical antipsychotic treatment. To this end, the effects of subchronic PCP on reward function, and their potential attenuation through chronic nicotine, will be examined via the intracranial self-stimulation threshold procedure. Specific Aim 2 will explore the neurochemical correlates of PCP-induced cognitive deficits and the attenuation of those deficits through nicotine. The actions of subchronic PCP and chronic nicotine on neurotransmitter release in the prefrontal cortex (PFC) will be assessed using in vivo microdialysis. The studies will investigate the actions of PCP on extracellular levels of dopamine, serotonin, and glutamate in the PFC after subchronic PCP administration in the presence or absence of chronic nicotine treatment. The results of the proposed studies will clarify whether nicotine ameliorates schizophrenia-like cognitive and negative symptoms, which would strengthen the hypothesis that highly increased smoking rates in schizophrenia patients are due to self-medication of these symptoms. The studies will also help elucidate the neurochemical mechanisms underlying schizophrenia-like cognitive deficits, as well as the ways in which nicotine acts to affect these deficits. A better understanding of these dynamics may lead to formulation of better treatments for cognitive impairment. These treatments may eliminate the need for self-medication through tobacco smoking, and thus help prevent the excessive smoking levels among schizophrenia patients, as well as potentially among other psychiatric populations suffering from cognitive deficits. Such medications may also aid non-mentally ill smokers experiencing mild cognitive impairment during nicotine withdrawal.