Vol. 292, Issue 2, 672-683, February 2000

Induction of Spontaneous Tail-Flicks in Rats by Blockade of Transmission at N-Methyl-D-Aspartate Receptors: Roles of Multiple Monoaminergic Receptors in Relation to the Actions of Antipsychotic Agents

Mark J. Millan, Alain Gobert, Karin Bervoets, Jean-Michel Rivet, Sylvie Veiga and Mauricette Brocco

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France.

We examined the involvement of multiple monoaminergic receptors in the induction of spontaneous tail-flicks (STFs) by the open channel blocker at N-methyl-D-aspartate (NMDA) receptors, dizocilpine, and the NMDA recognition site antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). At doses eliciting a maximal STF response, dizocilpine and CPP elevated levels of norepinephrine, but not dopamine or serotonin, in dialysates of nucleus accumbens, their known locus of action in eliciting STFs. Chemically diverse ₂-adrenergic receptor (AR) antagonists atipamezole, L745,743, RX821,002, idazoxan, and desfluparoxan abolished induction of STFs by dizocilpine, whereas the preferential ₁-AR antagonists prazosin, WB4101, and ARC239 were weakly active: relative potencies in blocking STFs correlated significantly with affinity at ₂-ARs. The D₁/D₅ receptor antagonists SCH23390, SCH39166, and NNC756 potently abolished STFs, whereas the D₂ antagonist L741,626, the D₃ antagonists GR218,231 and S14297, and the D₄ antagonists S18126 and L745,870 were inactive. D₁ and ₂-AR antagonists also blocked induction of STFs by CPP. Blockade of dizocilpine-induced STFs was specific inasmuch as idazoxan and SCH 23390 did not modify induction of ataxia by dizocilpine. Antagonists at multiple 5-hydroxytryptamine receptors failed to modify induction of STFs. Finally, dizocilpine-induced STFs were blocked by clozapine and 11 other antipsychotics, the potency of which correlated significantly with affinity at ₂-ARs. In conclusion, STFs evoked by interruption of transmission at NMDA receptors are dependent on D₁ receptors and ₂-ARs for their expression. Antagonism of the ₂-ARs is involved in their blockade by antipsychotics. This model should facilitate exploration of interrelationships between glutamatergic and monoaminergic mechanisms involved in psychiatric and neurologic disorders.