L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests.

Abstract

This study examined the high-affinity, selective dopamine D4 receptor antagonist, L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3-b]pyridine) in rodent behavioral models used to predict antipsychotic potential and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selectively blocking D4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse, albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2 receptors in vivo. High doses also impaired motor performance; in rats L-745,870 significantly reduced spontaneous locomotor activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents. Furthermore, the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.

• Authors: L J Bristow, N Collinson, G P Cook, N Curtis, S B Freedman, J J Kulagowski, P D Leeson, S Patel, C I Ragan, M Ridgill, K L Saywell, M D Tricklebank
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 283 Issue 3 Pg. 1256-63 (Dec 1997) ISSN: 0022-3565 [Print] United States
• PMID: 9400001 (Publication Type: Journal Article)

Chemical References

• 3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine
• Antipsychotic Agents
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Drd4 protein, mouse
• Drd4 protein, rat
• Pyridines
• Pyrroles
• Receptors, Dopamine D4
• Amphetamine
• Apomorphine

Topics

• Amphetamine (pharmacology)
• Animals
• Antipsychotic Agents (pharmacology)
• Apomorphine (pharmacology)
• Avoidance Learning (drug effects)
• Behavior, Animal (drug effects)
• Dopamine Antagonists (pharmacology)
• Dopamine D2 Receptor Antagonists
• Male
• Mice
• Motor Activity (drug effects)
• Pyridines (pharmacology)
• Pyrroles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptors, Dopamine D4