Effect of benzodiazepines on central serotonergic neuron systems

Abstract

Intracerebral (i.c.) injection of serotonin (5-HT) into mice induced head twitches in a dose-dependent manner at 10 min after injection. The head twitches induced by 5-HT (i.c.) were potentiated by the pretreatment of isocarboxazid (3 mg/kg i.p.), and inhibited by cyproheptadine (0.3 mg/kg i.p.), a 5-HT antagonist. Benzodiazepines such as fludiazepam and diazepam potentiated the head twitches induced by 5-HT (i.c.) in a dose-dependent manner. Mescaline (50 mg/kg i.p.) also induced head twitches in mice at 15 and 30 min after injection. Benzodiazepines potentiated the head twitches induced by mescaline in a dose-dependent manner. Cyproheptadine blocked the potentiating effect of benzodiazepines on the head twitches induced by both 5-HT (i.c.) and mescaline. By repeated administration of fludiazepam or diazepam for 5 days, the potentiating effect of both drugs on the head twitches induced by mescaline was unchanged and their anticonvulsant effects were not modified. In contrast, the potency of both drugs on muscle relaxation was significantly decreased by repeated administration. Benzodiazepines failed to change the uptake of 5-HT into the synaptosomal fractions from the rat brain. These results suggest that the pharmacological action of benzodiazepines is derived at least in part from their activating effect on 5-HT receptors.

Modulation of 5‐hydroxytryptamine‐induced head‐twitch response by drugs acting at GABA and related receptors

“…Benzodiazepine receptor ligands showed the expected profile. Diazepam potentiated head-twitching (as reported by Nakamura & Fukushima, 1977) and the 'inverse agonist' PCCE (Polc et al, 1982) inhibited it. Rol 5-1788 is a benzodiazepine with antagonistic effects against both classic benzodiazepines and 'inverse agonists' (Hunkeler et al, 1981).…”

Central Serotonergic Mechanisms on Head Twitch Response Induced by Benzodiazepine Receptor Agonists

“…In addition, they showed that the BZs did not change the uptake of 5-HT into the synaptosomal fraction in the rat brain. From these results, Nakamura and Fukushima [19] suggested that the HTR induced by BZs might directly act on the 5-HT receptor. Furthermore, Fuxe et al [20] also reported that 5-HT uptake by a slice of cerebral cortex was largely not affected by BZs such as diazepam.…”

“…Thus, based on these results, it can be assumed that the possible mechanism of HTR induction by BZRAs is similar to the mechanism of the HTR induction by both p-hydroxyamphetamine and ·-methylated tryptamine derivatives such as 5-fluoro-·-methyl-tryptamine and 6-fluoro-·-methyl-tryptamine [16]. Nakamura and Fukushima [19] reported that BZs such as fludiazepam and nitrazepam induced HTR in mice, and that the responses of BZs were inhibited by cyproheptadine, a 5-HT receptor antagonist. In addition, they showed that the BZs did not change the uptake of 5-HT into the synaptosomal fraction in the rat brain.…”

Potentiation of 5‐methoxy‐n,n‐dimethyltryptamine‐induced head‐twitches by diazepam: Evidence for involvement of adenosine uptake inhibition

“…It has previously been shown that moderate to high doses of benzodiazepines can potentiate headtwitches induced in mice by 5-hydroxytryptamine (5-HT) receptor agonists such as 5-HT itself, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, and mescaline [Nakamura and Fukushima, 1977;Singh et al, 1986;Moser and Redfern, 19881. In ad-dition, certain benzodiazepines have been reported to induce head-twitches [ Nakamura and Fukushima, 1976;Boissier and Dumont, 19811, although this is not a consistent finding [Moser and Redfern, 19881.…”

“…It has previously been shown that moderate to high doses of benzodiazepines can potentiate headtwitches induced in mice by 5-hydroxytryptamine (5-HT) receptor agonists such as 5-HT itself, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, and mescaline [Nakamura and Fukushima, 1977;Singh et al, 1986;Moser and Redfern, 19881. In ad-dition, certain benzodiazepines have been reported to induce head-twitches [ Nakamura and Fukushima, 1976;Boissier and Dumont, 19811, although this is not a consistent finding [Moser and Redfern, 19881. The mechanisms involved in this effect of benzodiazepines remain obscure although there have been several suggestions, such as GABAergic modulation of head-twitch behavior, a direct linkage between benzodiazepine receptors and 5-HT, receptors [ Nakamura and Carney, 19831, or a direct effect of benzodiazepines on 5-HT, receptors [Nakamura and Fukushima, 19771. The modulation of head-twitch behavior by GABAergic mechanisms has been extensively studied but the results have been inconsistent, and different laboratories have reported opposite results with several compounds [e.g., Handley and Singh, 1985;Metz et al, 1985;Moser and Redfern, 19881.…”