Auditory P50 in Schizophrenics on Clozapine: Improved Gating Parallels Clinical Improvement and Changes in Plasma 3-Methoxy-4-Hydroxyphenylglycol

Nagamoto, Herbert T.; Adler, Lawrence E.; McRae, K.A.; Huettl, Peter; Cawthra, Ellen; Gerhardt, Greg A.; Hea, Rebecca; Griffith, Jenny

doi:10.1159/000026553

Cited by 98 publications

(71 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Normal control participants normally exhibit suppression in the range of 50-70% , while it has been demonstrated that patients with schizophrenia display significantly lower P50 suppression (Adler et al, 1982;Boutros et al, 1991;Light et al, 2000;Ward et al, 1996;Yee and White, 2001;Braff et al, 2007), which is interpreted as reflecting a deficit in 'sensory gating' (Adler et al, 1982). Analogous to the PPI findings, there is also some evidence that P50 suppression deficits in schizophrenia may be normalized with the use of atypical antipsychotic drugs (Light et al, 2000;Nagamoto et al, 1996Nagamoto et al, , 1999Adler et al, 2004;Becker et al, 2004).…”

Section: Introductionmentioning

confidence: 80%

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Mann

Croft

Scholes

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/ phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal 'gating' function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.

show abstract

Section: Introductionmentioning

confidence: 80%

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Mann

Croft

Scholes

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 86%

“…Other studies reporting gating improvements with nicotine in rodents and humans, however, have found increases in S 1 but not S 2 (Crawford et al, 2002;Cromwell and Woodward, 2007;Metzger et al, 2007;Phillips et al, 2004Phillips et al, , 2007Rudnick et al, 2010). Clozapine, the prototype of the 'atypical' antipsychotics, and one of the few medications shown to reverse auditory sensory gating impairment in both schizophrenia and animal models, appears to selectively reduce S 2 -P50 responsivity via an α7 nicotinic mechanism (Simosky et al, 2003;Adler et al, 2004;Nagamoto et al, 1996Nagamoto et al, , 1999.Nicotine influences the release of not only acetylcholine, but also of dopamine (DA) and other neurotransmitters (norepinephrine, serotonin, glutamate, GABA) but it is not clear how these noncholinergic systems participate in gating. Although there is still confusion regarding the temporal sequencing of regionally specific DA changes in schizophrenia (Kellendonck et al, 2006), negative symptoms and cognitive deficits in this disorder have been linked to prefrontal hypodopaminergia while positive symptoms have been associated with striatal hyperdopaminergia (Kapur and Malmo, 2003).…”

mentioning

confidence: 92%

The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

et al. 2011

View full text Add to dashboard Cite

Although schizophrenia has been considered primarily a disease of dopaminergic neurotransmission, the role of dopamine in auditory sensory gating deficits in this disorder and their amelioration by smoking/nicotine is unclear. Hypothesizing that individual differences in striatal dopamine levels may moderate auditory gating and its modulation by nicotine, this preliminary study used the mid-latency (P50) auditory event-related potential (ERP) to examine the single dose (6 mg) effects of nicotine (vs. placebo) gum on sensory gating in 24 healthy nonsmokers varying in the genetic expression of the dopamine transporter (DAT). Consistent with an inverted-U relationship between dopamine level and the drug effects, individuals carrying the 9R (lower gene expression) allele, which is related to greater striatal dopamine levels, tended to evidence increased baseline gating compared to 10R (higher gene expression) allele carriers and showed a reduction in gating with acute nicotine. The present results may help to understand the link between excessive smoking and sensory gating deficits in schizophrenia and to explain the potential functional implications of genetic disposition on nicotinic treatment in schizophrenia. Keywords schizophrenia; P50; gating; dopamine transporter gene; nicotine; smoking Early theoretical models of information processing in schizophrenia postulated impairment in the preattentive, automatic processing of sensory input to be a contributing factor in the appearance of psychotic symptoms, perceptual disturbances, and various cognitive deficits that characterize this disorder (Venables, 1964). Meta-analyses and reviews of event-related potential (ERP) studies probing auditory sensory gating in a paired stimulus paradigm (involving the presentation two [ CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptfound that ~90% of patients with schizophrenia as well as ~50% of their first-degree relatives exhibit insufficient inhibitory processing of repetitive, irrelevant acoustic stimuli (Bramon et al., 2004;De Wilde et al., 2007;Patterson et al., 2008). Typically assessed with the amplitude of the early (50 ms) positive ERP component, P50, abnormal auditory sensory gating has been evidenced by a relative inability to suppress P50 to S 2 , and is expressed by larger S 2 /S 1 ratio (rP50) and/or smaller S 1 minus S 2 difference (dP50) scores.Smoking and acute nicotine have transiently corrected deficient P50 processing in schizophrenia patients and their relatives, respectively (Adler et al., 1992(Adler et al., , 1993. In addition, in a rodent model of schizophrenia-like gating deficiency, studies assessing the P20-N40 ERP, which is an analogue of the human P50, have shown agonists and antagonists of the α7 nicotinic receptor to improve deficient S 2 inhibition and to block normal S 2 inhibition, respectively (Stevens et al., 1998(Stevens et al., , 1999Simosky et al., 2001). Other studies reporting gating improvements with nicotine in rodents and humans, however, have found increa...

show abstract

“…Studies have shown that the auditory gating improves in the DBA/2 mouse with nicotine administration [54], just as it does in schizophrenia patients [27]. Additionally, similar effects were found for clozapine in both the DBA/2 mouse [55] and schizophrenia patients [33]. The mechanism of auditory gating has been clarified through the use of these animal models.…”

mentioning

confidence: 90%

“…Relatives of people with schizophrenia also have poor P50 suppression without the confounds of the additional pathological effects of schizophrenia, the effects of medications or chronic smoking [29,30,31,32]. People with schizophrenia treated with clozapine exhibit normalization of their P50 ratio coincident with improvement in their clinical symptoms [33]. Clozapine, which releases acetylcholine in the hippocampus [34], may thereby indirectly act on the nicotinic cholinergic receptors to normalize the P50 ratio, as people with schizophrenia also decrease the amount of cigarettes they smoke while taking this medication [35,36].…”

mentioning

confidence: 99%

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

125

View full text Add to dashboard Cite

Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

show abstract

Auditory P50 in Schizophrenics on Clozapine: Improved Gating Parallels Clinical Improvement and Changes in Plasma 3-Methoxy-4-Hydroxyphenylglycol

Cited by 98 publications

References 41 publications

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Contact Info

Product

Resources

About