Extrasynaptic GABAA receptor activation reverses recognition memory deficits in an animal model of schizophrenia.
BACKGROUND
Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication. Several neurotransmitter systems are affected in schizophrenia patients, including the γ-amino butyric acid (GABAergic) system, demonstrated by reduced parvalbumin-containing interneurons, glutamate decarboxylase (GAD) and the GABA transporter GAT-1. Furthermore, gene expression of several GABA(A) receptor sub-units, such as α1, α4 and δ is reduced in the dorsolateral prefrontal cortex of schizophrenia patients.


OBJECTIVE
The psychotomimetic NMDA receptor antagonist phencyclidine (PCP) is frequently employed to model schizophrenia in animal disease models. Sub-chronic PCP treatment of female hooded Lister rats has repeatedly been shown to induce impairments in object recognition memory, and this model was therefore chosen for the examination of the potential of positive modulation of extrasynaptic GABA(A) receptors in alleviating the PCP-induced deficit.


RESULTS
Rats treated sub-chronically with PCP showed significant impairments in recognition memory. This deficit was reversed by positive modulation of extrasynaptic GABA(A) receptors.


CONCLUSIONS
The present study shows that extrasynaptic GABA(A) receptors may present a novel target for the development of therapeutics aimed at improving cognitive deficits in schizophrenia.
Damgaard
Trine
T
H. Lundbeck A/S, In Vivo Neuropharmacology, Ottiliavej 9, Valby, 2500, Copenhagen, Denmark. trined@gmail.com
Plath
Niels
N
Neill
Jo C
JC
Hansen
Suzanne L
SL
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D030762:Estrous Cycle; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D013997:Time Factors
D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D010622:Phencyclidine; C015542:gaboxadol