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.
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 alpha(2)-adrenergic receptor (AR) antagonists atipamezole, L745,743, RX821,002, idazoxan, and desfluparoxan abolished induction of STFs by dizocilpine, whereas the preferential alpha(1)-AR antagonists prazosin, WB4101, and ARC239 were weakly active: relative potencies in blocking STFs correlated significantly with affinity at alpha(2)-ARs. The D(1)/D(5) receptor antagonists SCH23390, SCH39166, and NNC756 potently abolished STFs, whereas the D(2) antagonist L741,626, the D(3) antagonists GR218,231 and S14297, and the D(4) antagonists S18126 and L745,870 were inactive. D(1) and alpha(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 alpha(2)-ARs. In conclusion, STFs evoked by interruption of transmission at NMDA receptors are dependent on D(1) receptors and alpha(2)-ARs for their expression. Antagonism of the alpha(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.
Millan
M J
MJ
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France.
Gobert
A
A
Bervoets
K
K
Rivet
J M
JM
Veiga
S
S
Brocco
M
M
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001259:Ataxia / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013623:Tail / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D004298:Dopamine; D009638:Norepinephrine