Neuroscience 2002 Abstract
| Presentation Number: | 894.6 |
|---|---|
| Abstract Title: | IN VIVO EFFECTS OF THE SELECTIVE DOPAMINE D3 RECEPTOR ANTAGONIST A-437203. |
| Authors: |
Drescher, K. U.*1
; Garcia-Ladona, F. J.1
; Teschendorf, H. J.1
; Traut, M.1
; Unger, L.1
; Wicke, K. M.1
; Weddige, F. K.2
; Freeman, A. S.2
; Gross, G.1
1Abbott Lab GmbH & CoKG, 67008 Ludwigshafen, Germany 2Texas Tech Univ, Lubbock, TX |
| Primary Theme and Topics |
Neurological and Psychiatric Conditions - Psychiatric Disorders -- Schizophrenia |
| Session: |
894. Psychiatric disorders: schizophrenia--antipsychotic drug actions III Poster |
| Presentation Time: | Thursday, November 7, 2002 9:00 AM-10:00 AM |
| Location: | Hall A2-B3 Y-37 |
| Keywords: | BEHAVIOR, C-FOS, MICRODIALYSIS, ELECTROPHYSIOLOGY |
A-437203 is a potent and selective dopamine (DA) D3 receptor antagonist suited to evaluate the physiological role(s) of D3 receptors (Unger et al., this meeting). We characterized its effects in rats unless stated otherwise.
A-437203 protected D2 receptors from irreversible inactivation by EEDQ at a dose of 100 mg/kg ip, but not at 32 and 10 mg/kg, suggesting that effects observed < 10 mg/kg are D3 receptor-mediated.
A-437203 (0.1-10 mg/kg ip) inhibited the decrease in dialysate levels of DA and its metabolites induced by the DA agonists quinpirole and PD128907. This effect was pronounced in the prefrontal cortex but also detectable in n. accumbens and striatum. A dose of 10 mg/kg ip enhanced expression of c-fos (Calleja islands > n. accumbens > striatum).
A-437203 antagonized the effect of PD128907 on huddling (ED501-2 mg/kg po), a social interaction paradigm. Much higher doses were needed to antagonize apomorphine-induced climbing (ED50 25 mg/kg po) and methamphetamine-induced motor activity (82 mg/kg po) in mice. No signs of catalepsy were detectable up to 464 mg/kg po.
Chronic treatment with A-437203 (0.1-10 sc or 1-10 mg/kg/day po, 21 days) dose-dependently decreased the number of spontaneously active DA neurons in the ventral tegmental area, but not in the s. nigra.
These results demonstrate that A-437203 is a selective D3 receptor antagonist in vivo and can modulate brain DA activity regioselectively. Thus, a highly selective D3 receptor antagonist may have antipsychotic activity without inducing extrapyramidal side effects.
A-437203 protected D2 receptors from irreversible inactivation by EEDQ at a dose of 100 mg/kg ip, but not at 32 and 10 mg/kg, suggesting that effects observed < 10 mg/kg are D3 receptor-mediated.
A-437203 (0.1-10 mg/kg ip) inhibited the decrease in dialysate levels of DA and its metabolites induced by the DA agonists quinpirole and PD128907. This effect was pronounced in the prefrontal cortex but also detectable in n. accumbens and striatum. A dose of 10 mg/kg ip enhanced expression of c-fos (Calleja islands > n. accumbens > striatum).
A-437203 antagonized the effect of PD128907 on huddling (ED501-2 mg/kg po), a social interaction paradigm. Much higher doses were needed to antagonize apomorphine-induced climbing (ED50 25 mg/kg po) and methamphetamine-induced motor activity (82 mg/kg po) in mice. No signs of catalepsy were detectable up to 464 mg/kg po.
Chronic treatment with A-437203 (0.1-10 sc or 1-10 mg/kg/day po, 21 days) dose-dependently decreased the number of spontaneously active DA neurons in the ventral tegmental area, but not in the s. nigra.
These results demonstrate that A-437203 is a selective D3 receptor antagonist in vivo and can modulate brain DA activity regioselectively. Thus, a highly selective D3 receptor antagonist may have antipsychotic activity without inducing extrapyramidal side effects.
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2002 Neuroscience Meeting Planner. Orlando, FL: Society for Neuroscience, 2002. Online.
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