Behavioral effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH₃ in an immune-mediated neurodevelopmental disruption model. Int J Neuropsychopharmacol 2015 Jan 30;18(4)
Date
02/01/2015Pubmed ID
25636893Pubmed Central ID
PMC4360215DOI
10.1093/ijnp/pyu055Scopus ID
2-s2.0-84939160954 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
BACKGROUND: Impaired γ-aminobutyric acid (GABA) signaling may contribute to the emergence of cognitive deficits and subcortical dopaminergic hyperactivity in patients with schizophrenia and related psychotic disorders. Against this background, it has been proposed that pharmacological interventions targeting GABAergic dysfunctions may prove useful in correcting such cognitive impairments and dopaminergic imbalances.
METHODS: Here, we explored possible beneficial effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH₃, with partial selectivity at the α2, α3, and α5 subunits of the GABAA receptor in an immune-mediated neurodevelopmental disruption model. The model is based on prenatal administration of the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)] in mice, which is known to capture various GABAergic, dopamine-related, and cognitive abnormalities implicated in schizophrenia and related disorders.
RESULTS: Real-time polymerase chain reaction analyses confirmed the expected alterations in GABAA receptor α subunit gene expression in the medial prefrontal cortices and ventral hippocampi of adult poly(I:C) offspring relative to control offspring. Systemic administration of SH-053-2'F-S-CH₃ failed to normalize the poly(I:C)-induced deficits in working memory and social interaction, but instead impaired performance in these cognitive and behavioral domains both in control and poly(I:C) offspring. In contrast, SH-053-2'F-S-CH₃ was highly effective in mitigating the poly(I:C)-induced amphetamine hypersensitivity phenotype without causing side effects in control offspring.
CONCLUSIONS: Our preclinical data suggest that benzodiazepine-like positive allosteric modulators with activity at the α2, α3, and α5 subunits of the GABAA receptor may be particularly useful in correcting pathological overactivity of the dopaminergic system, but they may be ineffective in targeting multiple pathological domains that involve the co-existence of psychotic, social, and cognitive dysfunctions.
Author List
Richetto J, Labouesse MA, Poe MM, Cook JM, Grace AA, Riva MA, Meyer UAuthor
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AmphetamineAnimals
Benzodiazepines
Central Nervous System Stimulants
Cognition Disorders
Disease Models, Animal
Female
GABA Agents
Hippocampus
Male
Memory, Short-Term
Mice, Inbred C57BL
Motor Activity
Polynucleotides
Prefrontal Cortex
Pregnancy
Prenatal Exposure Delayed Effects
Psychotropic Drugs
Receptors, GABA-A
Social Behavior
