George TP, Termine A, Sacco KA, Allen TM, Reutenauer E, Vessicchio JC et al. A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: involvement of nicotinic receptor mechanisms. Schizophr Res 87: 307-315

ArticleinSchizophrenia Research 87(1-3):307-15 · November 2006with9 Reads
DOI: 10.1016/j.schres.2006.05.022 · Source: PubMed
Abstract
Schizophrenics exhibit deficits in prepulse inhibition (PPI) of the startle response, and have high rates of cigarette smoking. We evaluated the effects of cigarette smoking on PPI deficits in schizophrenia, and the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related PPI enhancement. PPI was assessed at baseline, after overnight abstinence, and after smoking reinstatement during three separate test weeks in nicotine-dependent schizophrenia (n=15) and control (n=14) smokers pre-treated with the nAChR antagonist mecamylamine (MEC; 0.0, 5.0 or 10.0 mg/day). PPI was comparable between schizophrenia and control smokers after ad lib cigarette smoking. Overnight smoking abstinence significantly reduced PPI, while smoking reinstatement reversed abstinence-induced worsening of PPI deficits in schizophrenia. However, acute abstinence and reinstatement did not alter PPI in controls. PPI enhancement by smoking reinstatement in schizophrenia was dose-dependently blocked by MEC, whereas MEC had no effect on PPI in control smokers. These results suggest that: 1) Non-deprived smokers with schizophrenia have comparable levels of PPI to non-deprived smoking controls; 2) In schizophrenia, PPI is impaired by smoking abstinence and improved by acute smoking reinstatement, and; 3) enhancement of PPI by cigarette smoking in schizophrenia is mediated by stimulation of central nAChRs. Our findings may contribute to understanding the increased vulnerability to nicotine dependence in schizophrenia, with implications for treatment of PPI deficits in this disorder.
    • "This hypothesis is supported by studies which show that nicotine improves auditory gating in the DBA/2 mouse [100] and in schizophrenic patients [101], and that a7 nAChR agonists (e.g., ABT-107, GTS-21 and tropisetron) improve auditory gating in DBA/ 2 mice [59,68,102] as well as P50 sensory gating in schizophrenic patients [60,88,103,104]. Likewise, deficits in sensorimotor gating (i.e., prepulse inhibition (PPI) of the acoustic startle) have been observed in schizophrenic patients [105,106] and nicotine has been shown to normalize these deficits [106,107], an effect blocked by the non-selective nAChR antagonist mecamylamine thus implicating nAChRs [108]. Preclinical studies of a7 nAChR agonists (e.g., tropisetron, SEN-12333) and partial agonists (e.g., RG-3487, TC- 5619) have routinely been shown to attenuate pharmacologicinduced (e.g., apomorphine and MK-801) PPI impairments [109– 112] and the effects of a7 nAChR agonists on sensorimotor gating appear to be receptor specific as the improved PPI response is attenuated by the a7 nAChR antagonist methyllycaconitine (MLA) [111]. "
    [Show abstract] [Hide abstract] ABSTRACT: The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer's disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of "multitarget-directed ligands" (MTDLs), the development and/or identification of compounds that exhibit "multifunctional" activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), "repurposing" strategies for existing compounds that have other clinical indications, and novel "adjunctive" treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, "multifunctional" properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity α4β2 nAChR and the low affinity α7 nAChR. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015
    • "Nicotine patches reversed spatial working memory impairment associated with haloperidol therapy in the delayed matching to sample test (Levin et al., 1996). Likewise, nicotine delivered via nasal spray improved delayed yes/no-recognition of visuospatial designs (Myers et al., 2004) and acute smoking re-instatement selectively enhanced PPI deficits in schizophrenic smokers (George et al., 2006). Most interestingly, as seen for strain-differences of rodents, PPI-enhancing nicotine effects were also highly genotype-dependent in humans, which demonstrates a strong genetic modulation, indicating the high predictive validity of animal PPI to model human sensorimotor gating phenomena. "
    [Show abstract] [Hide abstract] ABSTRACT: Schizophrenia patients exhibit an exceptionally high smoking prevalence, but it is not known why, although many researchers suggest that smoking constitutes a form of self-medication. Among the schizophrenia symptoms that may be improved by nicotine are cognitive deficits. We have therefore studied the effects of long-term nicotine administration on cognition in a genetic animal model of schizophrenia susceptibility, G72-transgenic (G72Tg) mice. The effect of long-term nicotine or saline administration by osmotic minipumps on different cognitive domains was assessed in G72Tg mice and controls using a battery of behavioural tests. To investigate the mechanism underlying phenotypic differences, quantitative autoradiographic mapping of nAChR subtypes was performed in forebrain structures to explore the effect of chronic nicotine exposure on nAChR density in WT and G72Tg mice. We found a striking influence of genotype on cognitive effects of chronic nicotine administration. Whereas chronic nicotine disrupted cognitive performance in WT mice, it was effective in restoring impaired prepulse inhibition, working memory, and social recognition in G72Tg mice. However, long-term spatial learning was further impaired by nicotine in transgenic animals. In contrast, associative learning was protected by G72-expression against adverse nicotine effects, as seen in WT animals. G72-expression did not decisively influence nicotine-induced up-regulation of the α4β2(*) subtype, whereas α7 nAChR density was differentially altered by genotype or by a genotype·treatment interaction in specific brain areas, most notably hippocampal subregions. Our data support the hypothesis that nicotine self-medication of schizophrenics improves cognitive symptoms, possibly by facilitating nicotine-induced α7 nAChR activation in the hippocampus.
    Full-text · Article · Jan 2014
    • "In a naturalistic experiment, individuals with schizophrenia who smoked right before having their PPI measured had greater PPI than nonsmoking individuals with schizophrenia, or individuals with schizophrenia who smoked but were abstinent immediately before the PPI measurement (Kumari et al. 2001). In a more controlled study, smoking abstinence reduced PPI, and smoking reinstated PPI, to a much greater extent in smokers with schizophrenia than in controls (George et al. 2006). Smokers with schizophrenia had PPI comparable to nonschizophrenic smokers, whereas among nonsmokers, individuals with schizophrenia exhibited a PPI deficit compared to nonschizophrenics (Woznica et al. 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Cigarette smokers smoke in part because nicotine helps regulate attention. Prepulse inhibition (PPI) of the startle reflex is a measure of early attentional gating that is reduced in abstinent smokers and in groups with attention regulation difficulties. Attention difficulties are found in people with posttraumatic stress disorder (PTSD). The aim of this study is to assess whether smoking and abstinence differentially affect the startle response and PPI in smokers with and without PTSD. Startle response and PPI (prepulses at 60, 120, or 240 ms) were measured in smokers with (N = 39) and without (N = 61) PTSD, while smoking and again while abstinent. Participants with PTSD produced both larger magnitude and faster latency startle responses than controls. Across groups, PPI was greater when smoking than when abstinent. The PTSD and control group exhibited different patterns of PPI across prepulse intervals when smoking and when abstinent. Older age was associated with reduced PPI, but only when abstinent from smoking. The effects of PTSD on startle magnitude and of smoking on PPI replicate earlier studies. The different pattern of PPI exhibited in PTSD and control groups across prepulse intervals, while smoking and abstinent suggests that previous research on smoking and PPI has been limited by not including longer prepulse intervals, and that nicotine may affect the time course as well as increasing the level of PPI. The reduced PPI among older participants during abstinence suggests that nicotine may play a role in maintaining attention in older smokers, which may motivate continued smoking in older individuals.
    Full-text · Article · Jul 2013
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