Nicotinic Receptors and Schizophrenia

Nadège Ripoll; Marie Bronnec; Michel Bourin


Curr Med Res Opin. 2004;20(7) 

In This Article

Abstract and Introduction

The incidence of smoking is very high in non-schizophrenic subjects presenting various psychiatric disorders (35 to 54%). However, the incidence of smoking is extremely high in schizophrenic patients: 80% to 90%, versus 25% to 30% of the general population. Various studies have demonstrated that the use of tobacco transiently restores the schizophrenic patient's cognitive and sensory deficits. Smoking cessation also appears to exacerbate the symptoms of the disease. Post-mortem binding studies have revealed a disturbance of nicotinic receptor expression, affecting the α7 and α4β2 subunits, in various cerebral areas. Genetic linkage studies have also shown that the α7 subunit is involved in schizophrenia.

This review assesses the involvement of the nicotinic system in schizophrenia and suggests ways in which this system may participate in the pathophysiology of this disease.

Since the work by Kraepelin,[1] many studies have investigated the etiopathogenesis of schizophrenia. While these have raised numerous hypotheses and controversies, a consensus has yet to be reached. Anatomical, familial, social, biological, genetic and immunological causes have been proposed.[2,3,4] Two models are commonly accepted, based on dopaminergic and neurodevelopmental hypotheses.[5,6,7,8] The older, dopaminergic hypothesis, is based on clinical, pharmacological and biochemical arguments.[7,9,10,11,12] Andreasen et al.[13] explained the disease by an imbalance between frontal and subcortical circuits. Subcortical dopaminergic hyperactivity, responsible for positive symptoms, induces prefrontal dopaminergic hypoactivity via a negative feedback action on the cortex, responsible for negative symptoms.[7] The neurodevelopmental hypothesis, which remains a dominant hypothesis,[4] integrates morphological, biochemical and genetic factors.[3,14,15,16,17,18] It attributes a causal role to organic factors, to which are added environmental or psychological factors precipitating the onset or progression of the disease.[2,19] This theory is based on the observation of neurohistological abnormalities, suggesting an abnormal migration of neurons during the second trimester of intrauterine life of the future schizophrenic subject.[2,3,20] Apart from the classically described positive and negative symptoms,[13] the course of the disease is also marked by certain cognitive abnormalities,[21] essentially attentional disorders,[22] slow information processing,[23] working memory disorders.[24]and a lack of flexibility of adaptive strategies.[25]

Clinical and animal studies have unanimously demonstrated the primordial role played by nicotine in cognitive processes involving memory, attention and learning, either directly or by interactions with neurotransmitters, such as glutamate, dopamine, noradrenaline, serotonin and gamma-aminobutyric acid.[24] Over the last twenty years, clinicians have tried to measure the particularly high incidence of smoking in subjects suffering from mental illness. For example, Leonard et al.[26] reported an incidence of approximately 60%, compared to 25% in the general population. However, this incidence varies as a function of diagnostic categories. Leonard et al.[26] proposed a classification into schizophrenia, bipolar disorders, depression and other illnesses. The highest incidence was observed in the group of schizophrenics, with almost 70% of smokers. In an older article, Hugues et al.[27] reported that 88% of schizophrenic subjects were smokers. Poirier et al.[28] also reported that the prevalence of smoking was higher among paranoid and disorganized schizophrenics than in patients with residual and undifferentiated schizophrenia. Most schizophrenic patients are also heavy smokers (> 30 cigarettes/day),[29] who inhale more deeply to extract more nicotine per cigarette than control subjects.[30] These figures obviously raise the question of a possible attempt at self-medication, using nicotine to correct pathophysiological abnormalities of the disease.[31] De Leon et al.[29] reported that schizophrenics smoke before their first psychotic episode and that the disease therefore does not contribute to initiation of smoking, but to heavy smoking. However there are prodromal aspects of schizophrenia before the first break which could contribute to initiation. Some authors.[32,33,34]have reported that smoking cessation or reduction is associated with exacerbation of schizophrenic symptoms. Dalack et al.[34] noted that 28% of schizophrenics interviewed reported that they smoked to decrease their symptoms. Srinivasan and Thara[35] reported that smoking helped to control the schizophrenic patient's psychotic symptoms, particularly negative symptoms. The idea that smoking decreases the extrapyramidal adverse effects of neuroleptics has also been extensively reported in the literature. Two mechanisms to explain this effect have been proposed: release of dopamine after administration of nicotine, and reduction of plasma neuroleptic levels due to enzymatic induction.[33,34,36,37] Finally, nicotine appears to improve certain cognitive and sensory abnormalities associated with schizophrenia.[31,35,38,39]

The objective of this article is to provide a better understanding of the role of nicotinic receptors in schizophrenia, which may constitute an explanation for the cognitive disorders associated with this disease and of the massive use of tobacco. The review was preceded by a literature search of published material using the PubMed database, supplemented by searches on 'related articles' and pertinent related papers from those sources.