Nicotinic Agonists and Psychosis

Abstract

Schizophrenia patients have insufficient inhibitory processing of identical paired auditory stimuli. This deficient "auditory gating" is thought to have physiological relevance, and its severity correlates with certain measures of both positive and negative symptoms. Schizophrenia patients also represent the heaviest smoking population subgroup. Because smoking temporarily normalizes their auditory gating deficit, this may represent a form of self-medication. Although this deficit is unresponsive to treatment with typical antipsychotic drugs, it does respond to the atypical antipsychotic clozapine. The normalization of this deficit by smoking may account for some of the intense drive to smoke that is experienced by schizophrenia patients. However, the normalizing effect of nicotine is transient and is not observed with repeated administration. Auditory gating is modulated by the alpha7 nicotinic receptor subtype, a rapidly desensitizing low-affinity nicotinic receptor. Agents that selectively activate the alpha7 receptor represent a novel class of therapeutic agents for use in the treatment of schizophrenia. Whether selective alpha7 agonists will have beneficial effects on symptoms other than the auditory gating deficit has not yet been established. The first developed alpha7-selective agonist, 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A), normalizes auditory gating in three distinct animal models of the deficit. DMXB-A is a prototype for this potential new drug class, but proof-of-concept for this type of pharmacotherapy will not be available until the completion of planned clinical trials assessing DMXB-A's effects in schizophrenia patients. Additional avenues to the potential normalization of auditory gating deficits are also discussed, focusing on the novel efficacy of clozapine and the potential utility of allosteric modulators of nicotinic receptors.

Hippocampal α4β2 Nicotinic Acetylcholine Receptor Involvement in the Enhancing Effect of Acute Nicotine on Contextual Fear Conditioning

“…This increased smoking behavior may be an attempt to self-medicate via ingestion of the psychoactive compound nicotine (Simosky et al, 2002;Kumari and Postma, 2005). Therefore, it is important to identify the nAChR subtypes and neural substrates that are critically involved in the effects of nicotine on learning and memory.…”

The pipeline and future of drug development in schizophrenia

“…117 Thus, considerable research has explored the potential use of nicotinic agents for the treatment of schizophrenia, specifically selective agonists and antagonists at various subunits of the nicotinic acetylcholine receptor. For example, the a 7 nicotinic receptor subtype modulates auditory gating, a process known to be deficient in schizophrenia 118 and agonists at a 7 receptors such as 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A) can normalize the auditory gating deficits in rodents. 119 Moreover, DMXB-A had a positive effect on a cognitive battery in a small proof-of-concept trial in humans, 120 and additional clinical trials of a 7 receptor agonists are underway.…”

“…However, long-term use of a 7 agonists may induce the desensitization of nicotinic receptors, leading to a limited duration of efficacy. 118 It has also been suggested that a 4 b 2 nicotinic receptors are involved in cognition, and agonists of a 4 b 2 receptors such as RJR 2403 can produce significant and long-lasting improvement of memory in rats. 121 Thus, nicotinic a 4 b 2 receptor agonists may be of therapeutic benefit for the treatment of the cognitive deficits in schizophrenia.…”

“…For example, galantamine is a positive allosteric modulator of nicotinic receptors in addition to being an acetylcholinesterase inhibitor. 118 The allosteric interaction of galantamine with nicotinic receptors can enhance the channel activity induced by a receptor agonist, either endogenous acetylcholine or theoretically a co-administered subtype-selective agonist.…”

Smoking during pregnancy: Postnatal effects on arousal and attentional brain systems

“…NIC has recently been reported to reduce hyperarousal and anxiety (Benowitz, 1996, Simosky et al, 2002. We recently found that the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (Phelan and Gallagher, 1992) depolarized PPN neurons early in development and later hyperpolarized them (Good et al, 2006).…”