ACEA 1021, a glycine site antagonist with minor psychotomimetic and amnestic effects in rats

Antagonists of the allosteric glycine site of the NMDA receptor complex have been suggested to be beneficial in the treatment of neurodegenerative disorders. However, unwanted side effects like psychomotor stimulation and amnesia must be expected. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydroquioxaline-2,3dione) is one of the first high-selective glycine site antagonists which passes the blood–brain barrier and which has promising anticonvulsive and neuroprotective properties. In the present study the effects of ACEA 1021 (5, 7.5, 8, 10, 15 and 20 mg/kg i.p.) on sniffing stereotypy, locomotor activity, prepulse inhibition of the acoustic startle response, the anti-cataleptic properties and spatial learning were tested. Only 7.5 mg/kg ACEA 1021 induced a sniffing stereotypy which was antagonized by the partial glycine site agonist d-cycloserine ( d-4-amino-3-isoxazolidinone). ACEA 1021 had neither an effect on motor behavior measured in the open field nor on the acoustic startle response in the prepulse inhibition paradigm nor on the acquisition of spatial learning in the 8-arm-radial maze. Anti-cataleptic properties of ACEA 1021 in dopamine D 2 (haloperidol (4′fluoro-4-(1-(4-hydoxy-4- p-chlorophenyl-piperidino)-butyrophenon)) or D 1 (SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride)) receptor antagonist-pretreated rats were only minor. Thus, ACEA 1021 is a glycine site antagonist with minimal psychotomimetic side effects and with no amnesia properties. However, it has only minor anti-parkinsonian effects.