Therapeutic implications of a selective alpha7 nicotinic receptor abnormality in schizophrenia.

A convergence of preclinical pharmacology, and human autopsy and genetic data support the existence of reduced expression and function of the alpha7 nicotinic receptor in patients with schizophrenia. The alpha7 nicotinic receptor is a member of a family of ligand-gated ion channels. The alpha7 nicotinic receptor may play an essential role in auditory sensory gating and voluntary smooth pursuit eye movements, two psychophysiological functions that are abnormal in patients with schizophrenia and closely related unaffected biological relatives. Diminished expression or function of the alpha7 nicotinic receptor in schizophrenia has stimulated consideration of selective full or partial alpha7 nicotinic receptor agonists as possible therapeutic interventions for this disorder. Further, the availability of positive allosteric modulators of nicotinic receptors that can improve the efficiency of transduction of the acetylcholine signal and prevent the rapid desensitization of the receptor should encourage these novel treatment approaches (e.g., galantamine).

Cocaine addicts prone to cocaine-induced psychosis have lower body mass index than cocaine addicts resistant to cocaine-induced psychosis--Implications for the cocaine model of psychosis proneness.

BACKGROUND: The specific pathogenesis of increased vulnerability to cocaine-induced paranoia/psychosis is unknown. Weight loss has been long observed in patients abusing stimulants (including cocaine and the amphetamines). In the current study, we compared Body Mass Index (calculated as weight in kilograms divided by the square of height in meters) in Cocaine-Induced Psychosis cases, referred to as "Cocaine-Induced Psychosis-prone" (n=40) and non-Cocaine-Induced Psychosis cases, referred to as "Cocaine-Induced Psychosis-resistant" (n=29) consecutively admitted to a research substance abuse unit to determine whether Body Mass Index is associated with Cocaine-Induced Psychosis. Height and weight were measured and Body Mass Index calculated by a licensed nutritionist using a standardized protocol. Cocaine-induced psychosis and cocaine use patterns were assessed using the Cocaine Experience Questionnaire. RESULTS: Body Mass Index in the Cocaine-Induced Psychosis-prone patients was significantly lower than in the Cocaine-Induced Psychosis-resistant patients (i.e., 23.1 kg/m2 +/-2.5 vs. 25.4 kg/m2 +/-3.5 (P=.003), respectively). Percentage of Ideal Body Weight also differed significantly between the two groups. CONCLUSIONS: The data suggest that lower Body Mass Index may be associated with increasing proneness to developing psychotic symptoms in the context of crack cocaine use or that higher Body Mass Index might be associated with some protection against Cocaine-Induced Psychosis in the context of similar use patterns. In the Discussion the authors speculate as to why Cocaine-Induced Psychosis is more commonly observed in the patient population with lower Body Mass Index and lower percentage of Ideal Body Weight. They evoke possible involvement of cocaine's influence on the anorexigenic cytokine Tumor Necrosis Factor, Cocaine-and-Amphetamine-Regulated Transcript, or suppression of the appetite stimulating Neuropeptide Y, or cocaine-induced deficits in nicotinic cholinergic neural-transmission, all of which have not only been linked to weight and appetite, but also to idiopathic psychosis. It could be speculated that one or more of these systems might be differentially affected by cocaine addiction in the psychosis prone Cocaine-Induced Psychosis group vs. the psychosis resistant non-Cocaine-Induced Psychosis group. Further exploration of these possible associations seem warranted. Such findings would have implications for the cocaine model of psychosis proneness and perhaps for the stimulant model of psychoses in general.

Behavioral consequences of methyllycaconitine in mice: a model of alpha7 nicotinic acetylcholine receptor deficiency.

Diminished expression of the alpha(7) nicotinic acetylcholine receptor occurs in selected brain regions of patients with schizophrenia, which may account for pathophysiological abnormalities and some of the deficits in attention and information processing. In view of this neurotransmitter receptor deficit, we wished to characterize the behavioral consequences associated with the administration of methyllycaconitine (MLA), a competitive alpha(7) nicotinic acetylcholine receptor antagonist, in mice. In this study, we injected groups of 12 outbred NIH Swiss male mice intraperitoneally with MLA (1.0, 3.2 and 10.0 mg/kg) and its saline vehicle. Thereafter, individual mice were observed over a one-hour interval and the intensity of a variety of behaviors were rated on a 4-point scale. The observed behaviors included: gnawing/chewing, rearing, grooming, sniffing, climbing, Straub tail, locomotion and ataxia. MLA produced statistically significant changes in the following observed behaviors: rearing, sniffing, climbing, and locomotion. A profile of the behavioral changes related to MLA administration in mice could lead to the development of a screening paradigm for alpha(7) nicotinic acetylcholine receptor agonist interventions. Ideally, an effective alpha(7) nicotinic acetylcholine receptor agonist intervention would target domains of psychopathology, especially cognitive symptoms that contribute to the profound functional disability that is often associated with schizophrenia.

Progressive worsening of adaptive functions in Down syndrome may be mediated by the complexing of soluble Abeta peptides with the alpha 7 nicotinic acetylcholine receptor: therapeutic implications.

In persons with Down syndrome, soluble Abeta peptides, which result from the processing of the amyloid precursor protein, appear in the brain decades before the extracellular deposition of neuritic plaques. These soluble amyloidogenic peptides accumulate intraneuronally and can be secreted extracellularly. Their appearance has been reported in the brains of fetuses with Down syndrome. The extra gene dosage effect associated with trisomy 21 results in abnormalities of the processing of amyloid precursor protein in persons with Down syndrome. Abeta peptides, especially Abeta1-42, have been shown to form tight complexes with the alpha7 nicotinic acetylcholine receptor, interfering with transduction of the acetylcholine signal by this nicotinic receptor subtype. Furthermore, the selective binding of Abeta peptides by this nicotinic acetylcholine receptor subtype is associated with cytotoxicity. The alpha7 nicotinic acetylcholine receptor has unique electrophysiologic properties and plays a prominent role in normal psychophysiologic processes (eg, sensory inhibition) and cognition. In persons with Down syndrome there is a decrease in the ability to perform instrumental activities of daily living that worsen with aging. The progressive worsening of adaptive functions and cognition in persons with Down syndrome may be, at least in part, mediated by interference with this receptor by soluble Abeta peptides. In view of this complex formed by soluble Abeta peptides and the alpha7 nicotinic acetylcholine receptor, cholinergic interventions that have been developed for Alzheimer disease, including selective nicotinic ones, should be explored in Down syndrome. Ideally, selective cholinergic interventions would slow the progression of the worsening of adaptive function and emergence of dementia in persons with Down syndrome.