Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

Abstract

People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (α7 and α4β2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotineinduced cognitive improvement appears to be its 5HT 2 antagonist properties. The selective 5HT 2 antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia.

Nicotine-induced memory impairment by increasing brain oxidative stress

“…Some researchers have reported an ameliorating effect of nicotine on memory impairment [9][10][11][12][13][14][15] while others did not observe any effect or reported negative effects [16,17,38]. Major differences could be attributed to various methodological issues, dosage and period of treatment or animal strains.…”

“…While some researchers [9][10][11][12][13][14][15] have reported a beneficial effect of nicotine on memory, others [16,17] observed few or negative effects [18,19]. Also, recent evidence implicated medicinal nicotine as potentially harmful to neurodevelopment in children and catalyzing processes underlying neuropathology in AD [2].…”

Nicotinic acetylcholine receptors and the ascending dopamine pathways

“…nAChRs present on afferents projecting to the VTA and SNc or to the terminal fields can also influence the activity of dopaminergic neurons. The nicotinic modulation of dopamine release has generated interest in nAChRs as therapeutic targets for conditions involving dopaminergic dysfunction, including schizophrenia, attention deficit hyperactivity disorder, Parkinson's disease, Alzheimer's disease and age-related cognitive impairment [7][8][9][10].…”

The α7 Nicotinic Agonist ABT-126 in the Treatment of Cognitive Impairment Associated with Schizophrenia in Nonsmokers: Results from a Randomized Controlled Phase 2b Study

“…Of the possible nAChR targets, the α7 receptor has been one of particular interest in terms of drug development for the treatment of schizophrenia-related cognitive impairment. People with schizophrenia have decreased expression of brain α7 nAChRs, and these deficits are most prominent in the hippocampus, frontal cortex, and thalamus (Freedman et al, 1995;Guan et al, 1999;Levin and Rezvani, 2007). The decreased expression of α7 receptors has led to speculation that smoking is self-medication for cognitive impairment (Levin and Rezvani, 2007).…”