Influence of CGS 21680, a selective adenosine A(2A) agonist, on the phencyclidine-induced sensorimotor gating deficit and motor behaviour in rats.
BACKGROUND
Recently it has been suggested that adenosine A(2A) receptor agonists may be potential antipsychotic drugs. It is, however, not clear whether these compounds may exert their antipsychotic effect without producing extrapyramidal side-effects (e.g. catalepsy, muscle rigidity, ataxia). It is known that such side-effects may be due to overactivation of the GABAergic strio-pallidal pathway, which may be estimated as an increased expression of proenkephalin (PENK) mRNA in the striatum.


OBJECTIVE
The aim of this study was to determine whether CGS 21680, a selective adenosine A(2A) receptor agonist, can reverse the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by the non-competitive antagonist of NMDA receptors phencyclidine (PCP) without producing motor side-effects in rats.


RESULTS
Systemic administration of PCP (5 mg/kg) produced profound reduction of the PPI, which was reversed by CGS 21680 (1 mg/kg). CGS 21680 (0.1 and 1 mg/kg) was without effect on catalepsy, muscle rigidity and rotarod performance in rats as well as on the PENK mRNA expression in the striatum estimated by in situ hybridization. Only after the highest dose used (5 mg/kg) were signs of catalepsy (measured using a 9-cm cork test), disturbed balance and a loss of hind limb control (measured in the rotarod test) seen. Moreover, increased muscle resistance during passive extension measured mechanomyographically after this dose of CGS 21680 was observed.


CONCLUSIONS
The present results support the hypothesis that adenosine A(2A) receptor agonists may be potentially useful antipsychotic agents with the low incidence of extrapyramidal side-effects.
Wardas
Jadwiga
J
Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland. wardas@if-pan.krakow.pl
Konieczny
Jolanta
J
Pietraszek
Małgorzata
M
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003342:Corpus Striatum / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D006213:Hallucinogens / Q000494:pharmacology; D017403:In Situ Hybridization; D007794:Lameness, Animal / Q000139:chemically induced* / Q000378:metabolism / Q000523:psychology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009127:Muscle Rigidity / Q000139:chemically induced / Q000188:drug therapy; D009714:Nucleus Accumbens / Q000378:metabolism; D010622:Phencyclidine / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects; D045442:Rotarod Performance Test
D058908:Adenosine A2 Receptor Agonists; D018491:Dopamine Agonists; D004745:Enkephalins; D006213:Hallucinogens; D010627:Phenethylamines; D011498:Protein Precursors; D012333:RNA, Messenger; C029992:proenkephalin; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D010622:Phencyclidine; D000241:Adenosine