2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Parkinson-Disease

Current antiparkinsonian therapies focus on either replacing dopamine via precursor (L-DOPA) administration, or directly stimulating post-synaptic dopamine receptors with dopamine agonists. Unfortunately, this approach is associated with numerous side effects and these drugs lose efficacy with disease progression. This article reviews recent evidence which suggests that negative modulation of glutamatergic neurotransmission has antiparkinsonian effects in a variety of rodent and primate models of parkinsonism. The pronounced synergism between dopaminergic agents and glutamate receptor antagonists may provide a means of using very low doses of the two drug classes in concert to treat Parkinson's disease effectively and minimize dose-related drug side effects.

Topics: Animals; Antiparkinson Agents; Basal Ganglia; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Dopamine Agents; Drug Evaluation, Preclinical; Drug Synergism; Drug Tolerance; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Haplorhini; Humans; Mice; MPTP Poisoning; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Quinoxalines; Rats; Receptors, Dopamine; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

The principal neurons of the striatum, GABAergic medium spiny neurons (MSNs), are interconnected by local recurrent axon collateral synapses. Although critical to many striatal models, it is not clear whether these connections are random or whether they preferentially link functionally related groups of MSNs. To address this issue, dual whole patch-clamp recordings were made from striatal MSNs in brain slices taken from transgenic mice in which D(1) or D(2) dopamine receptor expression was reported with EGFP (enhanced green fluorescent protein). These studies revealed that unidirectional connections were common between both D(1) receptor-expressing MSN (D(1) MSN) pairs (26%) and D(2) receptor-expressing MSN (D(2) MSN) pairs (36%). D(2) MSNs also commonly formed synapses on D(1) MSNs (27% of pairs). Conversely, only 6% of the D(1) MSNs formed detectable connections with D(2) MSNs. Furthermore, synaptic connections formed by D(1) MSNs were weaker than those formed by D(2) MSNs, a difference that was attributable to fewer GABA(A) receptors at D(1) MSN synapses. The strength of detectable recurrent connections was dramatically reduced in Parkinson's disease models. The studies demonstrate that recurrent collateral connections between MSNs are not random but rather differentially couple D(1) and D(2) MSNs. Moreover, this recurrent collateral network appears to be disrupted in Parkinson's disease models, potentially contributing to pathological alterations in MSN activity patterns and psychomotor symptoms.

Topics: Animals; Animals, Newborn; Corpus Striatum; Dendritic Spines; Disease Models, Animal; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Green Fluorescent Proteins; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Medial Forebrain Bundle; Mice; Mice, Transgenic; Nerve Net; Neurons; Oxidopamine; Parkinson Disease; Patch-Clamp Techniques; Quinoxalines; Receptors, Dopamine D1; Receptors, Dopamine D2; Sympatholytics; Synapses

We studied the motor response induced by the administration of the AMPA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline(1H,4H)dione sodium salt), in two parkinsonian monkeys and its interaction with the selective D-2 dopamine receptor agonist, (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine], and the partial dopamine D-1 receptor agonist, CY 208-243 [(-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3a-b]phen anthyxidine]. NBQX treatment did not reverse the parkinsonism or change the responses previously induced by dopamine agonists. These results do not support an antiparkinsonian effect of the AMPA receptor antagonist, NBQX. In addition they indicate that there is no functional interaction between AMPA and dopamine receptors in monkeys with a substantia nigra lesion.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Dopamine Agents; Excitatory Amino Acid Antagonists; Ibotenic Acid; Indoles; Macaca fascicularis; Motor Activity; Oxazines; Parkinson Disease; Phenanthridines; Quinoxalines; Receptors, AMPA; Receptors, Glutamate