Nicotine Administration Normalizes Behavioral and Neurophysiological Perturbations in the MAM Rodent Model of Schizophrenia.

BACKGROUND: The present study utilized the methylazoxymethanol (MAM) neurodevelopmental rodent model of schizophrenia (SCZ) to evaluate the hypothesis that individuals with SCZ smoke in an attempt to "self-medicate" their symptoms through nicotine (NIC) intake. METHODS: To explore this question, we examined the effects of acute and chronic administration of NIC in 2 established behavioral tests known to be disrupted in the MAM model: prepulse inhibition of startle and novel object recognition. Additionally, we assessed the effects of acute and chronic NIC on 2 indices of the pathophysiology of SCZ modeled by MAM, elevated dopamine neuron population activity in the ventral tegmental area and neuronal activity in the ventral hippocampus, using in vivo electrophysiological recordings. RESULTS: Our findings demonstrated that both acute and chronic administration of NIC significantly improved deficits in prepulse inhibition of startle and novel object recognition among MAM rats and normalized elevated ventral tegmental area and ventral hippocampal neuronal activity in these animals. CONCLUSION: Together, these findings of NIC-induced improvement of deficits lend support for a "self-medication" hypothesis behind increased cigarette smoking in SCZ and illustrate the potential utility of nicotinic modulation in future pharmacotherapies for certain SCZ symptoms.

Nicotine Self-administration Is Not Increased in the Methylazoxymethanol Acetate Rodent Model of Schizophrenia.

INTRODUCTION: Patients with schizophrenia (SCZ) smoke at a rate of 4-5 times higher than the general population, contributing to negative health consequences in this group. One possible explanation for this increased smoking is that individuals with SCZ find nicotine (NIC) more reinforcing. However, data supporting this possibility are limited. METHODS: The present experiments examined self-administration of NIC, alone or in combination with other reinforcers, across a range of doses in the methylazoxymethanol acetate (MAM) rodent model of SCZ. RESULTS: MAM and control animals did not differ in NIC self-administration across a range of doses and schedules of reinforcement, in both standard 1-hour self-administration sessions and 23-hour extended access sessions. However, MAM animals responded less for sucrose or reinforcing visual stimuli alone or when paired with NIC. CONCLUSIONS: To the extent that MAM-treated rats are a valid model of SCZ, these results suggest that increased NIC reinforcement does not account for increased smoking in SCZ patients. IMPLICATIONS: This study is the first to utilize nicotine self-administration, the gold standard for studying nicotine reinforcement, in the methylazoxymethanol acetate model of schizophrenia, which is arguably the most comprehensive animal model of the disease currently available. Our assessment found no evidence of increased nicotine reinforcement in methylazoxymethanol acetate animals, suggesting that increased reinforcement may not perpetuate increased smoking in schizophrenia patients.

Animal Research on Nicotine Reduction: Current Evidence and Research Gaps.

A mandated reduction in the nicotine content of cigarettes may improve public health by reducing the prevalence of smoking. Animal self-administration research is an important complement to clinical research on nicotine reduction. It can fill research gaps that may be difficult to address with clinical research, guide clinical researchers about variables that are likely to be important in their own research, and provide policy makers with converging evidence between clinical and preclinical studies about the potential impact of a nicotine reduction policy. Convergence between clinical and preclinical research is important, given the ease with which clinical trial participants can access nonstudy tobacco products in the current marketplace. Herein, we review contributions of preclinical animal research, with a focus on rodent self-administration, to the science of nicotine reduction. Throughout this review, we highlight areas where clinical and preclinical research converge and areas where the two differ. Preclinical research has provided data on many important topics such as the threshold for nicotine reinforcement, the likelihood of compensation, moderators of the impact of nicotine reduction, the impact of environmental stimuli on nicotine reduction, the impact of nonnicotine cigarette smoke constituents on nicotine reduction, and the impact of nicotine reduction on vulnerable populations. Special attention is paid to current research gaps including the dramatic rise in alternative tobacco products, including electronic nicotine delivery systems (ie, e-cigarettes). The evidence reviewed here will be critical for policy makers as well as clinical researchers interested in nicotine reduction. IMPLICATIONS: This review will provide policy makers and clinical researchers interested in nicotine reduction with an overview of the preclinical animal research conducted on nicotine reduction and the regulatory implications of that research. The review also highlights the utility of preclinical research for research questions related to nicotine reduction.

Monoamine oxidase inhibition in cigarette smokers: From preclinical studies to tobacco product regulation.

Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking. Given that MAO inhibition may reduce the threshold level at which nicotine becomes reinforcing, it is important to consider this in the context of very low nicotine content (VLNC) cigarettes and potential tobacco product regulation. It is also important to consider how this interaction between MAO inhibition and the reinforcing actions of nicotine may be modified in populations that are particularly vulnerable to nicotine dependence. In the context of these issues, we show that the MAO-inhibiting action of cigarette smoke extract (CSE) is similar in VLNC cigarettes and cigarettes with a standard nicotine content. In addition, we present evidence that in a rodent model of schizophrenia the effect of MAO inhibition to enhance nicotine self-administration is absent, and speculate how this may relate to brain serotonin systems. These issues are relevant to the MAO-inhibiting effect of cigarette smoking and its implications to tobacco product regulation.

Intermittent treatment with haloperidol or quetiapine does not disrupt motor and cognitive recovery after experimental brain trauma.

Traumatic brain injury (TBI)-induced agitation and aggression pose major obstacles to clinicians in the acute hospital and rehabilitation settings. Thus, management of these symptoms is crucial. Antipsychotic drugs (APDs) are a common treatment approach for alleviating these symptoms. However, previous preclinical TBI studies have indicated that daily and chronic administration of these drugs (e.g., haloperidol; HAL) can exacerbate cognitive and motor deficits. Quetiapine (QUE) is an atypical APD that differs from many typical APDs, such as HAL, in its relatively rapid dissociation from the D2 receptor. The goal of this study was to test the hypotheses that intermittent HAL and QUE would not hinder recovery of cognitive and motor function following TBI and that daily QUE would also not impair functional recovery, which would be in contrast to HAL. Seventy anesthetized male rats received either a controlled cortical impact or sham injury and were then randomly assigned to TBI and sham groups receiving HAL (0.5mg/kg) or QUE (10mg/kg) intraperitoneally once per day or once every other day and compared to each other and vehicle (VEH) controls. Motor function was assessed by beam balance/walk tests on post-operative days 1-5 and cognitive function was evaluated with a Morris water maze task on days 14-19. No differences were revealed among the sham groups in any task, and hence the data were pooled. No overall differences were detected among the TBI groups, regardless of treatment or administration paradigm [p>0.05], but all were impaired vs. SHAM controls [p<0.05]. The SHAM controls also performed significantly better in the cognitive test vs. all TBI groups [p<0.05]. Moreover, the TBI+continuous HAL group performed worse than the TBI+continuous VEH, TBI+continuous QUE, and TBI+intermittent QUE groups [p<0.05], which did not differ from one another. Overall, the data suggest that QUE does not exacerbate TBI-induced cognitive and motor deficits, which supports the hypothesis. QUE may prove useful as an alternative APD treatment for management of agitation and aggression after clinical TBI. HAL may also be safe, but only if used sparingly.