Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats

Abstract

The behavioural and neurochemical effects of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine and the alpha-amino-3-hydroxy-5-methylisoxazole- 4-propionic acid (AMPA) antagonist GYKI 52466, given alone or in combination, were investigated in rats. Locomotor activity was increased by dizocilpine (0.2 mg/kg), but not by GYKI 52466 (2.4 mg/kg). Dizocilpine-induced hyperlocomotion was reduced by co-administration of GYKI 52466. In dizocilpine-treated rats dopamine (DA) metabolism (measured as DOPAC [dihydroxyphenylacetic acid] or DOPAC/DA in post mortem brain tissue) was increased in the prefrontal cortex and nucleus accumbens. In GYKI 52466-treated rats serotonin was reduced in the prefrontal cortex and nucleus accumbens while DA metabolism was not affected. In rats treated with dizocilpine plus GYKI 52466, DA metabolism was increased only in the prefrontal cortex, but not in the nucleus accumbens, when compared with vehicle-treated animals. These data confirm that AMPA and NMDA antagonists do not have synergistic effects on locomotor activity. A differential role of NMDA and AMPA antagonists in the control of mesolimbic DA neurons will be discussed here.

Role of Dopaminergic System in Core Part of Nucleus Accumbens in Hyperlocomotion and Rearing Induced by MK-801 in Rats: A Behavioral and In Vivo Microdialysis Study

“…This result indicates the possible increase of DA turnover in this area (42). Our results are consistent with those showing an increased DA metabolism, rather than DA concentration, induced by MK-801 in the ACC (43,44). However, our results are different from those reporting increased DA level by MK-801.…”

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

“…This is supported by findings that subanesthetic doses of ketamine increase Glu efflux and that AMPA /kainate receptor antagonists attenuate ketamine-induced PFC dopamine release and cognitive impairment. It is noteworthy that antagonists of AMPA /kainate receptors reverse NMDA receptor antagonistinduced neurodegeneration (Olney and Farber, 1995;Sharp et al, 1995), hyperlocomotion (Hauber and Andersen 1993;Willins et al, 1993;Bubser et al, 1995), and stereotypy (our unpublished observations). An important implication from these findings, therefore, may be that hyperactivation of non-NMDA receptors, as opposed to a "glutamatergic deficiency," may account for some of the cognitive deficits and schizophrenia-like symptoms of NMDA receptor antagonists.…”

Virally Mediated Increased Neurotensin 1 Receptor in the Nucleus Accumbens Decreases Behavioral Effects of Mesolimbic System Activation

“…Although NMDA receptor antagonists induce DA release in the NAcc (Karreman et al, 1996;Millan et al, 1999), evidence suggests that the primary site for dizocilpine behavioral effects are NMDA receptors in the amygdala and the ventral hippocampus (but not the NAcc) (Bakshi and Geyer, 1998) and non-NMDA receptors in the NAcc (Hauber and Andersen, 1993;Bubser et al, 1995). NT is known to antagonize D 2 receptor responses via receptor-receptor interactions (Fuxe and Agnati, 1985) and convergence of second-messenger systems (Binder et al, 2001b).…”