P50 abnormalities in schizophrenia: relationship to clinical and neuropsychological indices of attention

186

139

Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

Section: Role Of Nicotinic Receptor Subtypes In Schizophreniamentioning

confidence: 99%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

186

139

“…Deficits in two of these inhibitory measuresFprepulse inhibition of startle (PPI) and P50 event-related potential (ERP) suppression (P50 gating)Fhave been reported by several groups across the schizophrenia spectrum, including schizophrenia probands, their unaffected relatives, and schizotypal patients (Adler et al, 1982;Bolino et al, 1994;Boutros et al, 1991;Braff et al, 1978Braff et al, , 1999Braff et al, , 2001aCadenhead et al, 2000a, b;Clementz et al, 1998;Erwin et al, 1998;Freedman et al, 1983Freedman et al, , 1987Freedman et al, , 1997Judd et al, 1992;Kumari et al, 1999;Ludewig et al, 2002;Nagamoto et al, 1989;Oranje et al, 2002;Parwani et al, 2000;Siegel et al, 1984;Waldo et al, 1988;Weike et al, 2000;cf. Braff et al, 2001b;Braff and Freedman 2002).…”

Section: Introductionmentioning

confidence: 99%

Convergence and Divergence in the Neurochemical Regulation of Prepulse Inhibition of Startle and N40 Suppression in Rats

Swerdlow

Geyer

Shoemaker

et al. 2005

Prepulse inhibition of startle ('PPI'), a cross-species measure of sensorimotor gating, is impaired in schizophrenia patients. Suppression of P50 event-related potentials (ERPs) in response to the second of two clicks ('P50 gating') is also impaired in schizophrenia. Suppression of N40 ERPs to the second of two clicks ('N40 gating') is thought by some to be a rat homolog of human P50 gating. Emerging evidence suggests differences in the neurobiology of deficits detected by PPI vs P50 (or N40) gating. We recorded PPI and N40 gating contemporaneously in rats, to assess convergence and divergence in the neurochemical regulation of these measures. Dose-response studies examined the effects of apomorphine (APO), phencyclidine (PCP) or the 5HT 2A agonist DOI on PPI, and on motor responses to stimuli (S1 and S2) that elicit N40 gating. Effects of optimal drug doses on PPI and N40 gating were then assessed in other rats with implanted cortical surface electrodes. APO, PCP and DOI caused dose-dependent disruptions of both PPI and gating of motor responses to N40 stimuli. Reduced PPI reflected diminished prepulse effectiveness, demonstrated by increased startle levels on prepulse þ pulse trials. In contrast, reduced gating of motor responses to N40 stimuli reflected a reduced motor response to S1. In separate rats, robust PPI, N40 potentials and N40 gating could be detected within one test. PPI and N40 gating were disrupted by APO, PCP, and DOI. Again, drug effects on PPI reflected increased startle on prepulse þ pulse trials, while those on N40 gating reflected reduced ERP responses to S1. In conslusion, when PPI and N40 gating were studied concurrently in rats, drug effects on PPI reflected reduced inhibition of startle by the prepulse, while diminished N40 gating reflected S1 response suppression. Despite similarities in drug sensitivity, these results suggest that distinct neurobiological mechanisms underlie drug-induced deficits in PPI and N40 gating.

“…Numerous studies have demonstrated that persons with schizophrenia exhibit a blunted response to conditioning stimuli and a failure to show the characteristic reduction in ERP amplitude to the test stimulus (Adler et al, 1982;Boutros et al, 1991;Jin et al, 1997;Clementz et al, 1998a, b;Patterson et al, 2000). Notably, these deficits are strongly correlated with neuropsychological measures of attention (Erwin et al, 1998) and vigilance (Cullum et al, 1993). Abnormalities in sensory gating have been detected in unaffected family members of individuals with schizophrenia and in patients afflicted with schizotypal personality disorder, suggesting that anomalous sensory gating may represent an intermediate phenotypic marker of the illness (Siegel et al, 1984;Waldo et al, 1991;Clementz et al, 1998b;Cadenhead et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

127

Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine B /NMDA and a-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine B site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine B receptor.