Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical γ oscillations

Abstract

Noncompetitive N-methyl-d-aspartate receptor (NMDAr) antagonists can elicit many of the symptoms observed in schizophrenia in healthy humans, and induce a behavioural phenotype in animals relevant to psychosis. These compounds also elevate the power and synchrony of gamma (γ) frequency (30-80 Hz) neural oscillations. Acute doses of antipsychotic medications have been shown to reduce ongoing γ power and to inhibit NMDAr antagonist-mediated psychosis-like behaviour in rodents. This study aimed to investigate how a chronic antipsychotic dosing regimen affects ongoing cortical γ oscillations, and the electrophysiological and behavioural responses induced by the NMDAr antagonist ketamine. Male Wistar rats were chronically treated with haloperidol (0.25 mg/kg/d), clozapine (5 mg/kg/d), LY379268 (0.3 mg/kg/d) or vehicle for 28 d, delivered by subcutaneous (s.c.) osmotic pumps. Weekly electrocorticogram (ECoG) recordings were acquired. On day 26, ketamine (5 mg/kg, s.c.) was administered, and ECoG and locomotor activity were simultaneously measured. These results were compared with data generated previously following acute treatment with these antipsychotics. Sustained and significant decreases in ongoing γ power were observed during chronic administration of haloperidol (64%) or clozapine (43%), but not of LY379268 (2% increase), compared with vehicle. Acute ketamine injection concurrently increased γ power and locomotor activity in vehicle-treated rats, and these effects were attenuated in rats chronically treated with all three antipsychotics. The ability of haloperidol or clozapine to inhibit ketamine-induced elevation in γ power was not observed following acute administration of these drugs. These results indicate that modulation of γ power may be a useful biomarker of chronic antipsychotic efficacy.

Abnormal visuomotor processing in schizophrenia

“…Because dopamine has an inhibitory effect on cortical activity (Ciccone, 2015), antipsychotics tend to shift the balance of activity towards cortical excitation. There is evidence from preclinical studies that chronic administration of antipsychotics can reduce steady state oscillatory power in the gamma frequency (Anderson et al, 2014), whilst non-invasive neuroimaging has shown enhanced steady state delta and theta but reduced alpha and beta amplitude after administration of antipsychotics in healthy volunteers (Galderisi et al, 1996; Hubl et al, 2001). The observation that taking into account patients' daily dose of psychotropic medication did not alter the results, together with evidence from other studies indicating that oscillatory abnormalities are present in unmedicated patients with schizophrenia (Boutros et al, 2008; Gallinat et al, 2004; Sun et al, 2013) and in first degree relatives (Hong et al, 2012) suggests that the abnormalities observed in our study are unlikely to be attributable to medication.…”

Evaluation of resting state gamma power as a response marker in schizophrenia

“…Animal models have studied the effect of individual antipsychotics on gamma power. Sustained and significant decreases in ongoing gamma power were found during chronic administration of haloperidol or clozapine . No study in humans, however, has studied the differing effect of individual antipsychotics on gamma oscillations in schizophrenia.…”

“…Various animal studies have shown that antipsychotics, both first‐ and second‐generation agents, have been shown to vary spontaneous high‐frequency, especially gamma oscillatory activity . Few studies specifically have investigated antipsychotic treatment effects on human gamma band activity.…”

Broad spectrum efficacy with LY2969822, an oral prodrug of metabotropic glutamate 2/3 receptor agonist LY2934747, in rodent pain models

“…once daily over 3 days at doses of 3 and 10 mg·kg À1 exhibited efficacy in the formalin assay that was indistinguishable from efficacy responses when these doses were acutely administered. The question of whether longer-term dosing of LY2969822 might lead to tachyphylaxis in rodents was not explored; however, it bears mentioning that the development of tolerance following chronic exposure to mGlu 2/3 receptor agonists in rodents is not consistently observed (see for instance Cartmell et al, 2000b;Schobel et al, 2013;Anderson et al, 2014;Battaglia et al, 2015) and may be a function of several interacting factors including species/strain, assay, dose, route of administration and specific agonist ligand. Importantly, there is no evidence that loss of efficacy on repeat dosing of mGlu 2/3 receptor agonists in rodents translates to humans.…”