Subchronic phencyclidine in rats: alterations in locomotor activity, maze performance, and GABAA receptor binding

Abstract

Phencyclidine (PCP), an antagonist at the N-methyl-D-aspartate subtype of ionotropic glutamatergic receptors, decreases gamma-aminobutyric acid (GABA)ergic inhibition, suggesting that changes in GABAergic receptor function underlie behavioral and cognitive deficits resulting from repeated administration of PCP. To test this hypothesis, male Sprague-Dawley rats treated with PCP (4.5 mg/kg, intraperitoneal, twice a day for 7 consecutive days) or saline were tested in behavioral and cognitive tasks 7 days after injections. The PCP group showed increased amphetamine (1.5 mg/kg)-stimulated locomotor activity, and exhibited a greater number of errors in the double Y-maze memory task, when compared with controls. Subchronic PCP treatment increased [H]muscimol-binding sites and decreased affinity for [H]muscimol binding in frontal cortex, hippocampus, and striatum in comparison with controls. There were no changes in the expression of glutamic acid decarboxylase or the GABA membrane transporter protein. These data show that subchronic PCP administration induces an impaired performance of a previously learned task and an enhanced response to amphetamine in the rat. The observed changes in GABAA receptors in the rat brain are consistent with the notion that alterations in GABAergic receptor function contribute to the behavioral and cognitive impairments associated with repeated exposure to PCP.

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

“…GABAA-R expression level differences vary between receptor subtypes and brain regions in individuals with schizophrenia (Benes et al, 1996a(Benes et al, , 1996bDuncan et al, 2010). The reduction in NMDA-R and GABAA-R binding supports our two-hit modelling strategy as neither NRG1 HET mice nor chronic PCP treatment alone showed such robust impairments in the present study or in previously published experiments (Beninger et al, 2010;Bullock et al, 2009;Dean et al, 2008;Hanania et al, 1999;Lindahl and Keifer, 2004;Long et al, 2013Long et al, , 2012Newell et al, 2013;Stefansson et al, 2002;Wang et al, 2005). Cognitive and memory functions rely on balanced glutamatergic and GABAergic neurotransmission (Klausberger and Somogyi, 2008).…”

The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia

“…Adult male Sprague-Dawley rats treated subchronically with PCP (4.5 or 5 mg/kg, i.p., twice a day for 7 days, followed by 7-day washout) displayed increased locomotor activity to acute PCP (1 and 10 mg/kg, i.p.) (Shirayama et al 2007) or to acute amphetamine (1.0 or 1.5 mg/kg) (Jentsch et al 1998b;Beninger et al 2010). A challenge with a low dose of amphetamine (0.25 mg/kg) failed to show differences in locomotor responses of scPCP-treated rats and vehicle-treated rats, although in that study, the activity was overall higher in the animals treated with scPCP as compared to the scVEHtreated animals ).…”

“…There were no deficits by scPCP in the performance in a spontaneous alternation in Y-maze (Roche, inhouse data), in a delayed alternation in T-maze (Stefani and Moghaddam 2002), in a radial arm maze reference memory task (Li et al 2003) or in a temporal order task (Marquis et al 2003). Modest deficits by scPCP were found in a combined spatial discrimination-alternation task in Y-maze (Beninger et al 2010) and in a continuous alternation task in T-maze (Marquis et al 2007), but the deficits were so small that reproducibility is questionnable and there would be no roo m fo r drug t e stin g. Ind eed, a s discuss ed in Neurochemical effects underlying behavioural changes in the scPCP model section, the scPCP-induced neurochemical changes are not robust (most changes are between 10 and 30 %, few up to 50-60 %), and their reproducibility has not been broadly investigated. The association between neurochemical changes and cognitive disturbances in the scPCP model remains to be elucidated in future studies.…”

“…Jentsch et al 1997b;Jentsch et al 1998a) (Table 2). Multi-system changes in the prefrontal cortex and hippocampus have been reported, including reductions in 5-HT receptors (Steward et al 2004;Hagiwara et al 2008), glutamatergic NMDA, mGluR 2 and mGluR 4 receptors (Abe et al 2001;Newell et al 2007b;Bullock et al 2009), α 1A and α 1B adrenoceptors ) and α 7 nAChRs (Hashimoto et al 2008c), as well as increases in GABA A receptors (Bullock et al 2009;Beninger et al 2010) ( Table 2). Changes at the receptor level likely compensate for altered neurotransmission.…”

“…There is no clear evidence that the loss of parvalbumin expression and immunoreactivity after scPCP parallels to a loss of GABAergic neurons, and findings from the scPCP-induced changes in markers for GABAergic neurons vary. One study did not find any changes in the GABAergic markers in striatal or cortical regions (Beninger et al 2010), while another study reported a reduction in the GABA transporter 1 and a marker for GABAergic neurons (GAD-67) in the cerebellum (Bullock et al 2009). Hashimoto et al (2008a, b) reported reduced glycine transmission and glutamate content in the hippocampus, but not in the frontal cortex in mice (Table 2).…”