Induction of dopaminergic supersensitivity after a single dose of the neuroleptic isofloxythepin

Abstract

The development of dopaminergic supersensitivity was evaluated, after single oral administration of the long-acting neuroleptic drug isofloxythepin, in nigrostriatal and tuberoinfundibular system in the rat. Isofloxythepin (5 mg/kg orally) increased concentration homovanillic acid (HVA) in the striatum for up to 24 h after administration, whereas a significant decrease below control values was found after 4-5 days. A similar biphasic effect appeared in behavior, since there was an enhancement of apomorphine stereotypy 4-5 days after administration of isofloxythepin (5 and 10 mg/kg orally). Both findings agree with the hypothesis of development of nigrostriatal dopaminergic supersensitivity at long intervals after isofloxythepin. On the other hand, the increase in prolactin (PRL) secretion induced by isofloxythepin indicated only the blocking action of this drug on dopamine receptors in the tuberoinfundibular system, and provided no evidence for tuberoinfundibular dopaminergic supersensitivity after neuroleptic treatment. It is concluded that a single dose of isofloxythepin is capable of inducing dopaminergic supersensitivity in the nigrostriatal system, but not in the tuberoinfundibular system.

Dopamine Receptor Blocking Action of a Dibenzothiepin Derivative Isofloxythepin in Rats

“…On the other hand, prolactin secretion from mammotrophs at the anterior pituitary is tonically inhibited by dopamine released from the tuberoinfundibular IsoJoxythepin and dopaminergic nmrons dopaminergic neuron, serum prolactin levels being increased via dopamine D2-receptor blockade by haloperidol and decreased via its stimulation by bromocriptine (Macleod & Lamberts 1978;Moore & Demarest 1982;Enjalbert & Bockaert 1983). Subcutaneous injection of isofloxythepin increased serum prolactin levels in this study, as in previous studies (Valchai et a/. 1982;Yamada et a/.…”

“…In reference to biochemical investigations on effects of isofloxythepin on the central dopaminergic system (Valchai et al 1982;Lau & Runice 1985;Yamada et al 1986a), striatal dopamine and DOPAC concentrations and serum prolactin levels were measured. It has been proposed that autoreceptors regulating release and synthesis of dopamine in the striatum are dopamine Dz-receptors (Zetterstrom et al 1986;Herdon & Nahorski 1987).…”

“…It has been proposed that autoreceptors regulating release and synthesis of dopamine in the striatum are dopamine Dz-receptors (Zetterstrom et al 1986;Herdon & Nahorski 1987). Isofloxythepin increased concentrations of homovanillic acid, one of the dopamine metabolites, in the striatum (Valchai et al 1982). In this experiment, treatment with isofloxythepin or haloperidol markedly increased concentrations of DOPAC but not steady-state concentrations of dopamine in the striatum, suggesting that isofloxythepin increases the rate of turnover of dopamine in terminals of nigro-striatal dopaminergic neurons.…”

“…1985). In pharmacological studies, isofloxythepin has been reported to increase the concentrations of homovanillic acid in the striatum and the serum prolactin levels and to displace [3H]spiperone binding to striatal dopamine receptors (Valchai et al 1982;Lau & Runice 1985;Yamada et a/. 1986a;1988).…”

Sawtooth waves during REM sleep after administration of haloperidol combined with total sleep deprivation in healthy young subjects

“…The effects of neuroleptics on REM sleep have been described, but the results are controversial and depend on the dose administered (5,6). Animal experiments demonstrate that neuroleptic administration produces supersensitivity of dopaminergic receptors (6)(7)(8)(9)(10). In the rat the same is observed after sleep deprivation, and particularly after the combination of neuroleptic administration and sleep deprivation (11,12).…”