Odapipam

Basic research indicates a role for dopamine (DA) D1 antagonism in the treatment of schizophrenia. Clinical trials have not confirmed any role. Besides the defining second messenger (adenylyl cyclase [AC]), DA D1 receptors are linked to other effectors (e.g., phospholipase C [PLC]). Differing actions of DA D1 antagonists upon differing effectors could explain conflicting results between the lab/clinic.

In a monkey model in which behavioral effects of DA D1 antagonists/agonists have been well characterized we examined: 1) SKF 83959, biochemically, a DA D1 antagonist, behaviorally a DA D1 agonist, and 2) SKF 83822, biochemically, a DA D1 agonist, which, unlike all previously tested DA D1 agonists, does not also stimulate PLC. SKF 83959 and SKF 83822 were given alone and combined with DA D1 and D2 agonists, antagonists, and dextroamphetamine (AMP).

SKF 83959 acted as a DA D1 agonist (induced oral dyskinesia given alone, counteracted DA D1 antagonist [NNC 756], induced dystonia, and did not inhibit AMP induced behaviors). SKF 83822, unlike previously studied DA D1 agonists, did not induce dyskinesia, but resulted in a state of extreme arousal and locomotor activation without stereotypy, effectively counteracted by NNC 756, but not by SKF 83959 nor raclopride (DA D2 antagonist).

It is hypothesized that: 1) dyskinesia is linked to PLC stimulation; 2) DA D1 agonism can play a role in the induction of psychosis, via a mechanism linked neither to AC nor PLC, and 3) DA D1 antagonists differ in antipsychotic potential, possibly via this unidentified mechanism.

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.