Previous findings have demonstrated a protective role for
dopamine D(3)/D(2) receptor agonists in the
convulsant and lethal effects of acutely administered
cocaine. Data are provided here to establish that the protection occurs through a D(3)-linked mechanism and that protection is extended to seizure kindling. The D(3) antagonist
SB-277011-A [4-quinolinecarboxamide,N-[trans-4-[2-(6-cyano-3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-cyclohexyl]-(9CI)] prevented the
anticonvulsant effect of the D(3)/D(2) receptor agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] on
cocaine-induced
seizures. The protection afforded by the D(3)/D(2) agonist, (+)-PD-128,907, was eliminated in D(3) receptor-deficient mice. In D(2) receptor knockout mice, the
anticonvulsant effects of (+)-PD-128,907 were preserved. (+)-PD-128,907 also prevented the acquisition and expression of
cocaine-kindled
seizures engendered by repeated daily dosing with 60 mg/kg
cocaine. (+)-PD-128,907 also blocked the
seizures induced in mice fully seizure kindled to
cocaine. Although repeated dosing with
cocaine increased the potency of
cocaine to produce
seizures and lethality (decreased ED(50) values), daily coadministration of (+)-PD-128,907 significantly prevented this potency shift. In mice treated daily with
cocaine and (+)-PD-128,907, the density, but not the affinity, of D(3) receptors was increased. The specificity with which (+)-PD-128,907 acts upon this
cocaine-driven process was demonstrated by the lack of a significant effect of (+)-PD-128,907 on seizure kindling to a
GABA(A) receptor antagonist,
pentylenetetrazol. Taken together and with literature findings, the data indicate that
dopamine D(3) receptors function in the initiation of a dampening mechanism against the toxic effects of
cocaine, a finding that might have relevance to
psychiatric disorders of
drug dependence,
schizophrenia, and
bipolar depression.