BMY-14802 reversed the ? receptor agonist-induced neck dystonia in rats

Abstract

To clarify clinical roles of sigma receptor binding affinity of neuroleptics, neck dystonia induced by microinjection of sigma receptor ligands and neuroleptics into rat red nucleus was investigated. DTG and (+)-3-PPP, putative sigma receptor agonists, induced neck dystonia in dose-dependent and reversible manner. Haloperidol and perphenazine induced dystonia in the same way as sigma receptor agonists, whereas zotepine and (-)-sulpiride did not. The rank order of potency in induction of dystonia and sigma receptor affinity of these compounds showed positive correlation. Although BMY-14802 has a high affinity for sigma receptors, it never produced dystonia by itself. On the other hand, combined injection of BMY-14802 with DTG attenuated DTG-induced dystonia. Therefore, it is suggested that typical neuroleptics such as haloperidol act agonistic and atypical neuroleptics such as BMY-14802 act antagonistic at rubral sigma receptors in the induction of neck dystonia.

Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias

“…Another concern is that L-DOPA-induced rotation has sometimes been used as a marker for L-DOPA's therapeutic effects, and thus its reduction by BMY-14802 could indicate suppression of L-DOPA's therapeutic effects. This also seems unlikely since BMY-14802 has been demonstrated to counteract dystonia induced in rodents by σ agonists, including haloperidol [13]. Similarly, no parkinsonian effects were observed in clinical trials of BMY-14802 in schizophrenia [21].…”

“…Acutely, BMY-14802 and other σ antagonists block dopaminergic stimulant-induced locomotion and stereotypy [12]. Interestingly, σ-1 antagonists also block dystonic behavior produced by σ agonists and vacuous chewing produced by microinfusion of σ agonists into cranial nerve motor nuclei that control oral dyskinesias [13,14].…”

Animal models of focal dystonia

“…This dystonic head posture begins within 10 min of the injection, peaks approximately 20 min after the injection and disappears within 60 -90 min. 65 Although some data suggest that both 1 and 2 receptors play a role in acute human dystonia, 66 microinjection of ligands into the rat red nucleus shows that activation of the 2 , but not the 1 , receptor causes neck dystonia. 67 The mechanism through which agonists injected into the red nucleus produce neck dystonia is unclear.…”

Sigma binding sites identified by [3H] DTG are elevated in aged Fischer-344 � Brown Norway (F1) rats

“…Possible side effects of chronic ''typical'' neuroleptic treatment include tardive dyskinesia and dystonia. Administration of DTG or (ϩ) PPP (sigma agonists at low doses) will elicit dystonia in the rat that can be blocked by the sigma antagonist, BMY-14802, but not (-) sulpiride, a D 2 antagonist with low affinity for sigma receptors (Okumura et al, 1996). Haloperidol administration can also result in dystonia that is blocked by BMY-14802, suggesting that haloperidol may act as an agonist at sigma receptors (Okumura et al, 1996).…”

“…Administration of DTG or (ϩ) PPP (sigma agonists at low doses) will elicit dystonia in the rat that can be blocked by the sigma antagonist, BMY-14802, but not (-) sulpiride, a D 2 antagonist with low affinity for sigma receptors (Okumura et al, 1996). Haloperidol administration can also result in dystonia that is blocked by BMY-14802, suggesting that haloperidol may act as an agonist at sigma receptors (Okumura et al, 1996). Based on these findings as well as other reports, it has been postulated that sigma receptors may, at least in part, be involved in drug-induced dystonia associated with neuroleptic treatment (Jeanjean et al, 1997).…”