Abstract
GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABAA α2,3 subtype-selective GABAA partial agonist and α1/5 antagonist, and the neurosteroid, pregnenolone sulfate, a GABAA antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABAA agonists may be of benefit to treat CIAS.
Highlights
Multiple GABAergic drugs have been investigated for the treatment of the cognitive impairment associated with schizophrenia (CIAS), positive and negative symptoms [1,2,3]
Acute administration of TPA-023 dose-dependently ameliorated scPCP-induced deficit in novel object recognition (NOR) An overall two-way analysis of variance (ANOVA) revealed that neither scPCP nor acute treatment with TPA-023 in either the vehicle or scPCP-treated mice produced any significant effect on object exploration time during acquisition trial (AT), [F(3,36) = 0.411, P = 0.96; Fig. 1a]
No significant effect was observed in the total exploration times between the groups
Summary
Multiple GABAergic drugs have been investigated for the treatment of the cognitive impairment associated with schizophrenia (CIAS), positive and negative symptoms [1,2,3]. Among the most compelling evidence for the roles of Glu and GABA in schizophrenia is the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists, e.g., phencyclidine (PCP) and ketamine, to produce symptoms of schizophrenia in normal controls and exacerbate psychosis and cognitive impairment in schizophrenia patients. For this reason, acute and especially subchronic (sc) administration of NMDAR antagonists such as PCP and MK-801 have been extensively studied as models of psychosis, negative symptoms, and CIAS [9,10,11,12,13,14].
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