s-33084 and Disease-Models--Animal

Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the hyperactive mouse mutant coloboma to identify D2-like dopamine receptor subtypes that mediate the hyperactivity and response to amphetamine; we have previously demonstrated that D1-like dopamine receptors are not involved. Targeted deletion of the D2, but not the D3 or the D4, dopamine receptor in coloboma mice eliminated the hyperactivity; depleting D2 dopamine receptors also restored the excess dopamine overflow that may drive the hyperactivity to normal concentrations. Similar to its effects on ADHD patients, amphetamine reduced the hyperactivity of coloboma mice. The D2 dopamine receptor-selective antagonist L-741,626, but not D3 or D4 dopamine receptor-selective antagonists, blocked the amphetamine-induced reduction in locomotor activity. Thus, the D2 dopamine receptor subtype mediates both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD.

Topics: Amphetamine; Animals; Attention Deficit Disorder with Hyperactivity; Benzopyrans; Corpus Striatum; Dihydroxyphenylalanine; Disease Models, Animal; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Extracellular Space; Indoles; Locomotion; Mice; Mice, Knockout; Mice, Mutant Strains; Piperidines; Pyridines; Pyrroles; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4

Development of L-DOPA-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). Sensitization to L-DOPA correlates with ectopic expression of D3 dopamine receptors in the striatum, implicating D3 receptors in development of LID. We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP-lesioned marmosets without effecting the anti-parkinsonian actions of L-DOPA. Furthermore, following a 14 day washout, when challenged with L-DOPA in the absence of S33084, these animals continued to exhibit reduced LID. In the 6-OHDA-lesioned rat, S33084 similarly attenuated development of behavioural sensitization to L-DOPA. Additionally, L-DOPA-induced elevations in striatal pre-proenkephalin-A (PPE-A) (but not PPE-B, phospho[Thr(34)]DARPP-32, D1, and D2 receptor mRNA or D3 receptor levels) were reduced in S33084 treated animals. Our data suggest a role for D3 receptors in the development of LID and suggest that initiating L-DOPA treatment with a D3 antagonist may reduce the development of LID in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Benzopyrans; Callithrix; Corpus Striatum; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists; Dyskinesia, Drug-Induced; Enkephalins; Female; Levodopa; Male; Oxidopamine; Parkinsonian Disorders; Protein Precursors; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger

To date, the lack of highly selective antagonists at the dopamine D(3) receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D(3) versus D(2) receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D(3)-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D(3) receptor stimulation. Indeed, stimulation of D(3) receptors may be detrimental to the anti-parkinsonian properties of D(2)/D(3) agonists. Selectivity for stimulation of D(2), over D(3), receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzopyrans; Brain; Callithrix; Disease Models, Animal; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Indoles; Levodopa; Parkinsonian Disorders; Pyrroles; Receptors, Dopamine D2; Receptors, Dopamine D3