Characterization of the selective mGluR1 antagonist, JNJ16259685, in rodent models of movement and coordination.
Metabotropic glutamate receptor 1 (mGluR1) antagonists interfere with learning and memory; however, their role in motor function is not well elucidated despite their abundance in brain areas implicated in the control of movement. Here, the effects of mGluR1 antagonism on movement, coordination, and motor learning were investigated. JNJ16259685, a selective mGluR1 antagonist (negative allosteric modulator), was tested in assays of motor skill, and motor learning in rats and mice. JNJ16259685 produced very minimal effects on locomotor activity and posture up to a dose of 30 mg/kg. Motor skill was unaffected for well-learned tasks (up to 30 mg/kg) in rats, but impaired in mice. Both rats and mice rats were profoundly impaired (0.3 mg/kg) in the acquisition of a novel motor skill (rotarod). These results implicate the mGluR1 receptor in the acquisition of novel motor skills. JNJ16259685 dramatically reduced rearing behavior, exploration of a novel environment and lever pressing for a food reward (rat: 0.3 mg/kg; mouse: 1 mg/kg). JNJ16259685 (30 mg/kg) had no effect on reflexive startle responses to loud auditory stimuli or foot shock in mice. Previous groups have proposed that mGluR1 antagonists induce a general reduction in motivation. The effects seen here to reduce exploration and reward are consistent with that hypothesis. Pharmacological inhibition of the mGluR1 receptor has a modest effect on motor function but blocks motor learning and may reduce motivation to perform simple behaviors.
Department of Neurobiology, Merck Research Labs, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Robert.Hodgson@Merck.com
Robert A
RA
Hodgson
Lynn A
LA
Hyde
Donald H
DH
Guthrie
Mary E
ME
Cohen-Williams
Prescott T
PT
Leach
Tatiana M
TM
Kazdoba
Carina J
CJ
Bleickardt
Sherry X
SX
Lu
Eric M
EM
Parker
Geoffrey B
GB
Varty
D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology
C495417:(3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone; D018691:Excitatory Amino Acid Antagonists; D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1