title: Repeated potentiation of the metabotropic glutamate receptor 5 and the alpha 7 nicotinic acetylcholine receptor modulates behavioural and GABAergic deficits induced by early postnatal phencyclidine (PCP) treatment.
abstract: The underlying mechanism of the GABAergic deficits observed in schizophrenia has been proposed to involve NMDA receptor hypofunction. An emerging treatment strategy therefore aims at enhancing GABAergic signalling by increasing the excitatory transmission onto interneurons. We wanted to determine whether behavioural and GABAergic functional deficits induced by the NMDA receptor channel blocker, phencyclidine (PCP), could be reversed by repeated administration of two drugs known to enhance GABAergic transmission: the positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGluR5), ADX47273, and the partial agonist of the α7 nicotinic acetylcholine receptor (α7 nAChR), SSR180711. Adolescent rats (4-5 weeks) subjected to PCP treatment during the second postnatal week displayed a consistent deficit in prepulse inhibition (PPI), which was reversed by a one-week treatment with ADX47273 or SSR180711. We examined GABAergic transmission by whole cell patch-clamp recordings of miniature inhibitory postsynaptic currents (mIPSC) in pyramidal neurons in layer II/III of prefrontal cortex (PFC) and by activation of extrasynaptic δ-containing GABAA receptors by THIP. Following PCP treatment, pyramidal neurons displayed a reduced mIPSC frequency and up-regulation of extrasynaptic THIP-induced current. ADX47273 treatment restored this up-regulation of THIP-induced current. Reduced receptor function seems to be the underlying cause of the reported changes, since repeated treatment with ADX47273 and SSR180711 decreased the induction of spontaneous inhibitory current caused by acute and direct agonism of mGluR5s and α7 nAChRs in slices. These results show that repeated administration of ADX47273 or SSR180711 reverses certain behavioural and functional deficits induced by PCP, likely through down-regulation or desensitisation of mGluR5s and α7 nAChRs, respectively.
authors: Synaptic Transmission I&II, H. Lundbeck A/S, Ottiliavej 7-9, 2500 Valby, Denmark. celia.kjaerby@gmail.com
authors: Celia
authors: C
authors: Kjaerby
authors: Christoffer
authors: C
authors: Bundgaard
authors: Kim
authors: K
authors: Fejgin
authors: Uffe
authors: U
authors: Kristiansen
authors: Nils Ole
authors: NO
authors: Dalby
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects; D005260:Female; D005625:Frontal Lobe / Q000166:cytology; D059330:GABAergic Neurons / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology; D010622:Phencyclidine / Q000009:adverse effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects*; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018678:Cholinergic Agents; D018691:Excitatory Amino Acid Antagonists; D010069:Oxadiazoles; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; C533862:S-(4-fluorophenyl)-(3-(3-(4-fluorophenyl)-(1,2,4)-oxadiazol-5-yl)piperidin-1-yl)methanone; C516833:SSR180711; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010622:Phencyclidine