Morphine-induced catalepsy is augmented by NMDA receptor antagonists, but is partially attenuated by an AMPA receptor antagonist.
High doses of morphine produce a state of behavioural inactivity and muscular rigidity. This type of 'catalepsy' is clearly different from the state which is produced by the administration of neuroleptics, e.g. haloperidol. While haloperidol-induced catalepsy can easily be antagonised by NMDA receptor antagonists, there has been a report that the non-competitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801) potentiates morphine-induced catalepsy. The aim of this study was to further examine the role of glutamate receptors in the mediation of morphine-induced catalepsy. To this end we coadministered morphine (20, 40, 60 mg/kg i.p.) with MK-801 (0.1 and 0.3 mg/kg i.p.), the competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentoic acid (CGP 37849) (2 and 6 mg/kg i.p.), or 1-(4-aminophenyl)-4-methyl-7,8-methylen-dioxy-5H-2,3- benzodiazepine (GYKI 52466) (2 and 4 mg/kg), an antagonist of the AMPA type of glutamate receptors, respectively. The degree of catalepsy was assessed using two different methods, the 'bar/podium/grid' test which is commonly used to measure neuroleptic-induced catalepsy, and a test for the presence or absence of righting reflexes after turning the animals into a supine position. It was found that in the 'bar/podium/grid' test coadministration of both NMDA receptor antagonists significantly and dose-dependently augmented morphine-induced catalepsy. The results using the AMPA receptor antagonist were less clear since the lower dose of GYKI 52466 tended to attenuate the morphine effect whereas the higher dose augmented morphine-induced catalepsy in some cases. While placing the animals on the bar and on the podium produced essentially the same results, the grid was found to be inapplicable for the measurement of morphine-induced catalepsy since the animals did not cling to the grid and fell off almost immediately after being released from the experimenter's hand. With respect to the righting reflexes it was found that the number of animals not showing these responses increased when MK-801 or CGP 37849 was coadministered with morphine. In contrast, most of the animals treated with GYKI 52466 and morphine displayed intact righting reflexes. It is concluded that glutamatergic transmission plays an important role in the mediation of morphine-induced catalepsy, though different to that of haloperidol-induced catalepsy, and that NMDA and AMPA receptors are differentially involved in different aspects of the associated behavioural state.
Tzschentke
T M
TM
Department of Neuropharmacology, University of Tübingen, Germany. neuropha@mailserv.zdv.uni-tuebingen.de
Schmidt
W J
WJ
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000494:pharmacology; D002375:Catalepsy / Q000145:classification*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors
D014151:Anti-Anxiety Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C061950:GYKI 52466; D001569:Benzodiazepines; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine