TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABAA receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia.
Lakshmi Rajagopal, Mei Huang, Eric Michael, Sunoh Kwon, Herbert Y. Meltzer
Neuropsychopharmacology November 2018 DOI: 10.1038/s41386-018-0160-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | TPA-023 lurasidone phencyclidine (PCP) |
| Measures | novel object recognition (NOR), reversal learning (RL), locomotor activity (LMA) |
| Key points | TPA-023, a GABAA α2,3 subtype-selective partial agonist, reversed subchronic PCP-induced novel object recognition and reversal learning deficits in mice, and combining sub-effective doses of TPA-023 and lurasidone potentiated the effect. TPA-023 did not blunt acute PCP-induced hyperactivity, which the authors interpret as suggesting a lack of efficacy for psychosis. The authors propose that TPA-023 and other GABAA agonists may benefit cognitive impairment associated with schizophrenia. |
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.
Citations in the library
Cites 8
- Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction. Behavioural Brain Research September 17, 2018
- GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behavioural Brain Research February 15, 2016
- Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus. Neuropharmacology January 2016
- The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia. Psychopharmacology November 2015
- Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats. Cerebral Cortex September 2014
and 3 more in the library