Mechanisms for metoclopramide-mediated sensitization and haloperidol-induced catalepsy in rats.

Abstract

Typical antipsychotics such as the dopamine D(2) receptor antagonist, haloperidol are known to cause movement disorders or catalepsy in experimental animals. Catalepsy is believed to result from blockade of dopamine D(2) receptors. In this study two drugs that differ in antipsychotic potency but are similar in blocking dopamine D(2) receptors were used to investigate the mechanism for catalepsy and its sensitization. Metoclopramide is a strong postsynaptic dopamine D(2) receptor blocker with no antipsychotic potency. At low doses of 5 or 10 mg/kg given subcutaneously (s.c.), metoclopramide did not produce catalepsy or movement disturbance for seven days after drug treatment. Also metoclopramide at 10 mg/kg given for five days, failed to induce catalepsy. Haloperidol, another potent dopamine D(2) receptor blocker at 0.5 mg/kg (s.c.) rapidly produced catalepsy and suppressed movement 1 h after a single dose of the drug. Chronic as well as acute treatment with metoclopramide caused sensitization of haloperidol-induced catalepsy. Neurochemical analyses revealed significant dopamine D(2) receptor up-regulation in both frontal cortex and striatum of rats chronically treated with metoclopramide. However, no changes in dopamine D(2) receptor numbers were noted in these areas after chronic treatment with low doses of haloperidol. Significant increases in N-methyl-D-aspartate (NMDA) receptor numbers were observed in both frontal cortex and striatum of metoclopramide treated animals, while haloperidol elicited significant decreases in NMDA receptor numbers in both brain areas. These observations plus previous reports have led us to propose a model for catalepsy and its sensitization. According to this model the increase in NMDA receptors by metoclopramide sensitizes the brain to haloperidol-induced catalepsy. Thus, catalepsy appears to be elicited by simultaneous activation of glutamatergic NMDA and dopamine D(1) receptors as well as a blockade of dopamine D(2) receptors.

• Authors: Mervan S Agovic, Elena Yablonsky-Alter, Theodore I Lidsky, Shailesh P Banerjee
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 587 Issue 1-3 Pg. 181-6 (Jun 10 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18457824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Antagonists
• Receptors, Dopamine D2
• Receptors, N-Methyl-D-Aspartate
• Spiperone
• Dizocilpine Maleate
• Haloperidol
• Metoclopramide

Topics

• Animals
• Behavior, Animal (drug effects)
• Binding, Competitive (drug effects)
• Catalepsy (chemically induced)
• Cerebral Cortex (drug effects, metabolism)
• Dizocilpine Maleate (metabolism, pharmacology)
• Dopamine Antagonists (metabolism, pharmacology)
• Haloperidol (pharmacology)
• Male
• Metoclopramide (pharmacology)
• Neostriatum (drug effects, metabolism)
• Rats
• Receptors, Dopamine D2 (drug effects, metabolism)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, metabolism)
• Spiperone (metabolism, pharmacology)