2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and 1-hydroxy-3-amino-2-pyrrolidone

Imbalances of the glutamatergic system are implicated in the pathophysiology of various basal ganglia disorders, but few is known about their role in dystonia, a common neurological syndrome in which involuntary muscle co-contractions lead to twisting movements and abnormal postures. Previous systemic administrations of glutamate receptor antagonists in dtsz hamsters, an animal model of primary paroxysmal dystonia, exerted antidystonic effects and electrophysiological experiments pointed to an enhanced corticostriatal glutamatergic activity. In order to examine the pathophysiological relevance of these findings, we performed striatal microinjections of the alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor antagonist 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) and the N-methyl-D-aspartate (NMDA) receptor antagonists D(-)-2-amino-5-phosphopentanoic acid (AP-5), (R)-(+)-3-amino-1-hydroxypyrrolidin-2-one (HA-966) and dizocilpine (MK-801). The striatal application of NBQX reduced the severity and increased the latency to onset of dystonia significantly only at a dosage of 0.08 microg per hemisphere, lower (0.03 microg) and higher dosages (0.16 microg and 0.32 microg) failed to exert comparable effects on the severity. None of the striatal injected NMDA receptor antagonists influenced the severity of the dystonic attacks in the mutant hamster. The combined application of NBQX (0.08 microg) with AP-5 (1.0 microg) failed to exert synergistic antidystonic effects, but the beneficial effect on the severity of dystonia of the single application of NBQX was reproduced. Therefore, corticostriatal glutamatergic overactivity mediated by AMPA receptors, but not by NMDA receptors, is possibly important for the manifestation of dystonic attacks in the dtsz hamster mutant.

Topics: Animals; Basal Ganglia; Caudate Nucleus; Cricetinae; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Dystonia; Excitatory Amino Acid Antagonists; Microinjections; Movement; Muscle Contraction; Mutation; Posture; Putamen; Pyrrolidinones; Quinoxalines; Reaction Time; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Severity of Illness Index; Valine

This study examined the interaction between various glutamate antagonists and selective D1 (SKF 38393) and D2 (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1-1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25-8 mg/kg) and CPP (0.2-20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4-10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2-25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D1 and D2 motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants to L-dopa in antiparkinson therapy.

Topics: 2-Amino-5-phosphonovalerate; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dizocilpine Maleate; Dopamine Agonists; Male; Mice; Mice, Inbred Strains; Motor Activity; Phenethylamines; Piperazines; Pyrrolidinones; Quinoxalines; Receptors, AMPA; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Reserpine

The relative contribution of the NMDA/glycine allosteric site and non-NMDA (AMPA) types of glutamate receptor to the acute and tonic phases of the behavioural nociceptive response to formalin has been studied in the rat. The AMPA receptor selective antagonist NBQX preferentially inhibited the acute phase indicating that AMPA receptors may be involved in mediating fast acute nociceptive transmission in the dorsal horn. In contrast, the strychnine-insensitive glycine site partial agonist (+)-HA-966 and the NMDA competitive antagonist CGS 19755 preferentially attenuated the tonic nociceptive phase. However, none of these compounds exhibited anti-inflammatory properties. Thus, both NMDA and non-NMDA antagonists can selectively block changes in neuronal excitability while tissue injury in the receptive field continues to evolve.

Topics: Analgesics; Animals; Formaldehyde; Inflammation; Male; N-Methylaspartate; Nociceptors; Pain Measurement; Pipecolic Acids; Pyrrolidinones; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Glutamate; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

The AMPA antagonist, NBQX, produced dose-dependent blockade of the locomotor stimulant effects of cocaine and methamphetamine in male, Swiss-Webster mice at doses which did not alter spontaneous locomotion. A similar finding was obtained with the competitive NMDA antagonist, NPC 12626, although blockade was only observed at the highest dose studied. The NMDA antagonists, (+)-HA-966 and 7-chlorokynurenic acid (7-CKA), which act at the strychnine-insensitive modulatory site of the NMDA receptor, only blocked the stimulatory effects of methamphetamine and with (+)-HA-966, blockade was only achieved at a dose that decreased spontaneous locomotor activity. These results provide evidence for the involvement of glutamatergic input in the control of behavior involving mesolimbic dopamine. Along with other findings these results suggest that glutamate receptors may be a target for the development of pharmacological therapies for the treatment of psychomotor stimulant abuse and for other disorders involving hyperfunction of the mesolimbic dopamine system (eg. schizophrenia).

Topics: Amino Acids; Animals; Cocaine; Excitatory Amino Acid Antagonists; Glutamic Acid; Kynurenic Acid; Male; Methamphetamine; Mice; Motor Activity; Pyrrolidinones; Quinoxalines

An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson's disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson's disease, without causing epilepsy as a side effect.

Topics: 2-Amino-5-phosphonovalerate; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dizocilpine Maleate; Dopamine Agents; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Mice; Mice, Inbred Strains; Pilocarpine; Piperazines; Pyrrolidinones; Quinoxalines; Receptors, AMPA; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Seizures