Head twitches induced by benzodiazepines and the role of biogenic amines

Clonazepam, one of the benzodiazepines, induced head twitches in mice in a dose-dependent manner and sustained them for at least 120 min. Some of the benzodiazepines such as nitrazepam, fludiazepam, and nimetazepam also significantly induced head twitches at doses higher than 10 mg/kg, but other benzodiazepines like diazepam, flurazepam, oxazepam, medazepam, and chlordiazepoxide did not significantly induce head twitches at doses up to 60 mg/kg. The head twitches induced by clonazepam were more strongly blocked by an antiserotonin drug, cyproheptadine than catecholamine receptor blocking drugs, haloperidol, propranolol, and phentolamine, and were not blocked by GABA receptor blocking drugs, bicuculline and picrotoxin, as well as by a glycine receptor blocking drug, strychnine. Clonazepam also increased the head twitches induced by mescaline, a serotonin receptor stimulant. These results indicate that the head twitches induced by clonazepam might be mediated via serotonergic neuron systems.     

Influence of histamine on the serotonergic system of rat brain.

Both histamine and 4-methylhistamine, after intraventricular injection into normal rats, reduced the levels of serotonin and increased those of 5-hydroxyindoleacetic acid in hypothalamus; after injection into tranylcypromine-treated rats, head twitches were induced which were blocked by antiserotonin agents. 2-Pyridylethylamine, an agonist of histamine H1 receptors, neither influenced serotonin level in hypothalamus nor evoked behavioural changes. It is concluded that injected histamine may release serotonin from the hypothalamus and that this produces the behavioural changes.     

Motor depression and head twitches induced by IP injection of GABA

Influence of GABA on locomotor activity and gross behavior of mice, rats, and rabbits was studied. In mice and rats, IP GABA injection produced decreased locomotor activity, but in rats and rabbits head twitches and disturbances in body balance were seen. GABA-induced head twitches were inhibited by picrotoxin, clonidine, morphine, or cyproheptadine. Our results suggest a serotonergic component in GABA-induced head twitches, but it is not the only mechanism involved in this behavior.     

REM sleep deprivation changes behavioral response to catecholaminergic and serotonergic receptor activation in rats

The effects of REM sleep deprivation (REMD) on apomorphine-induced aggressiveness and quipazine-induced head twitches in rats were determined. Forty-eight hr of REMD increased apomorphine-induced aggressiveness, and reduced (immediately after completing of REMD) or increased (96 hr after completing of REMD) quipazine-induced head twitches. Results are discussed in terms of similarity to pharmacological effects of other antidepressive treatments.     

Separation of clonazepam-induced head twitches and muscle relaxation in mice

Stereotyped head twitches in mice were induced by clonazepam. The number of head twitches produced was directly related to the clonazepam dose. In addition to head twitches, clonazepam produced dose-related muscle relaxation. Methysergide antagonized the action of clonazepam on head twitches. However, methysergide failed to block the muscle relaxant action. In contrast to methysergide, the benzodiazepine receptor antagonists CGS 8216 and Ro 15-1788 blocked the muscle relaxant effects of clonazepam. Neither CGS 8216 nor Ro 15-1788 blocked the clonazepam-induced head twitches. These data suggest that the muscle relaxant effects of clonazepam are mediated by benzodiazepine/GABA receptor systems that can be blocked by CGS 8216 and Ro 15-1788. On the other hand, it is proposed that the benzodiazepine-induced head twitch effect is mediated by a benzodiazepine/serotonin 2 receptor system.     

Interaction of benzodiazepines with neuroleptics at central dopamine neurons

Summary Several benzodiazepines (chlordiazepoxide, clonazepam, diazepam and flunitrazepam) markedly counteracted the elevation of the homovanillic acid (HVA) content of the rat brain induced by neuroleptics (haloperidol, pimozide, chlorpromazine, and clozapine). A similar effect was obtained with the inhibitor of GABA transaminase, aminooxyacetic acid (AOAA). The interaction of benzodiazepines with the neuroleptic-induced HVA increase was similar in the striatum and in the limbic forebrain, and was antagonized by the GABA receptor-blocking agent, picrotoxin. Both the benzodiazepines used and AOAA potentiated the cataleptic effect of the four neuroleptics.It is concluded that benzodiazepines, by intensifying GABA-ergic transmission, enhance the ongoing inhibition of mesencephalic dopamine neurons exerted by the striatonigral GABA system. As a consequence, the feedback activation of dopamine neurons induced by the neuroleptic blockade of dopamine receptors in the striatum and the limbic system is attenuated. This results in a reduction of the neuroleptic-induced increase of HVA and in the potentiation of the cataleptic effect of neuroleptics.     

Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls

The acute effects of diazepam on plasma GABA were determined in 18 patients with panic disorder, 13 patients with generalized anxiety disorder and 20 healthy controls. All subjects were benzodiazepine-naive. Four logarithmically increasing doses of diazepam/placebo were administered intravenously at 15-min intervals on 2 separate days. Plasma GABA was measured at baseline and 3 min after the highest dose of diazepam/placebo. There was an overall decrease in plasma GABA that was significantly greater following diazepam compared with placebo, but no group differences in response. In a separate group of 18 panic disorder patients receiving chronic benzodiazepine treatment with alprazolam, the same diazepam infusion procedure (no placebo day) produced decreases in plasma GABA similar to those seen in the untreated panic disorder patients. The clinical and physiologic implications of these findings are discussed.     

Effects of amitriptyline and isocarboxazid on 5-hydroxytryptophan induced head twitches in mice

Effects of amitriptyline and isocarboxazid on brain 5-HT and 5-HIAA were examined in relation to their action on 5-HTP induced head twitches. Amitriptyline reduced 5-HTP induced head twitches but isocarboxazid increased them. Both amitriptyline and isocarboxazid caused a significant increase of brain 5-HT concentration in 5-HTP treated mice. Amitriptyline also caused a significant increase of 5-HIAA concentration, while isocarboxazid reduced 5-HIAA concentration in the brains of 5-HTP treated mice. Probenecid, which significantly increased 5-HIAA concentration without affecting brain 5-HT concentration in 5-HTP treated mice, reduced 5-HTP induced head twitches. These results suggest that 5-HTP induced head twitches might be induced by an increase of 5-HT concentration, and reduced by an increase of 5-HIAA or a decrease of 5-HT concentration in the brains of mice.     

The effects of benzodiazepines on aggression: Reduced or increased?

The effects of various benzodiazepines on animal models of aggression are presented. The differences in response noted after single dose or after chronic drug administrations are stressed. The implications for predicting responses to these drugs in humans are discussed.     

Effect of benzodiazepines on cyclic GMP formation in rat cerebellar slices

Cyclic 3',5' guanosine monophosphate (cGMP) levels, stimulated in brain slices by ouabain, potassium, and sodium azide depolarization, have been found to be inhibited in a dose-dependent fashion by both behaviorally active and inactive benzodiazepines. ED50's for these benzodiazepines bear no relation to potencies established from receptor membrane binding studies; however, these values do correspond to ED50's calculated for several known membrane stabilizing agents tested in this system. The concentration of [3H]flunitrazepam necessary to saturate the benzodiazepine receptor in identical slice preparations is considerably lower than that needed to initiate inhibition of depolarization-induced cGMP stimulation. Some of the reported in vivo actions of benzodiazepines on cGMP formation may be the result of membrane stabilizing actions of the benzodiazepines or mediated indirectly.     

In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain

Rationale Aripiprazole is an atypical antipsychotic drug with high in vitro affinity for 5-HT_1A, 5-HT_2A and dopamine (DA) D2 receptors. However, its in vivo actions in the brain are still poorly characterized. Objective The aim was to study the in vivo actions of aripiprazole in the rat and mouse brain. Methods Brain microdialysis and single-unit extracellular recordings were performed. Results The systemic administration of aripiprazole reduced 5-HT output in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus of the rat. Aripiprazole also reduced extracellular 5-HT in the mPFC of wild-type (WT) but not of 5-HT_1A (−/−) knockout (KO) mice. Aripiprazole reversed the elevation in extracellular 5-HT output produced by the local application of the 5-HT_2A/2C receptor agonist DOI in mPFC. Aripiprazole also increased the DA output in mPFC of WT but not of 5-HT_1A KO mice, as observed for atypical antipsychotic drugs, in contrast to haloperidol. Contrary to haloperidol, which increases the firing rate of DA neurons in the ventral tegmental area (VTA), aripiprazole induced a very moderate reduction in dopaminergic activity. Haloperidol fully reversed the inhibition in dopaminergic firing rate induced by apomorphine, whereas aripiprazole evoked a partial reversal that was significantly different from that evoked by haloperidol and from the spontaneous reversal of dopaminergic activity in rats treated with apomorphine. Conclusions These results indicate that aripiprazole modulates the in vivo 5-HT and DA release in mPFC through the activation of 5-HT_1A receptors. Moreover, aripiprazole behaves as a partial agonist at DA D2 autoreceptors in vivo, an action which clearly distinguishes it from haloperidol. A. Bortolozzi and L. Díaz-Mataix have contributed equally to this study.     

Antinociceptive action of quipazine: Relation to central serotonergic receptor stimulation

Quipazine, a serotonin receptor stimulant, inhibited the response of rats to painful stimuli in two methods currently used to measure antinociception in these animals: the hot plate and tail compression test. The antinociceptive action was observed with doses ranging from 5 to 20 mg/kg i.p. according to the test situation.The effect was significantly antagonized by a pretreatment with methergoline, a potent serotonin antagonist. An electrolytic lesion placed in the nucleus raphe medianus, which produced a marked decrease of serotonin in the forebrain did not, or only slightly, affected the effect of quipazine, depending on the method used to measure antinociception.It is suggested that quipazine can produce antinociceptive action in rats by interacting with a serotonergic mechanism. The action appears to be due mainly to a direct action on postsynaptic serotonin receptors, although a presynaptic component can also contribute to the effect of quipazine.Visiting scientist from Clinica Neurologica, UniversitàVisiting scientist from Clinica Neurologica, Università     

Effect of antidepressant drugs on serotonergic and adrenergic receptors

Summary We examined eight tricyclic antidepressants (doxepin, amitriptyline, clomipramine, imipramine, trimipramine, nortriptyline, desipramine and protriptyline) and four nontricyclic antidepressants (mianserin, nomifensin, iprindole and zimelidine) in terms of their effects on serotonergic and adrenergic receptors by direct binding assays.³H-WB-4101 (0.22 nM) served as a label for postsynaptic alpha receptors while³H-clonidine (0.2 nM) served to label presynaptic alpha receptors in the frontal cortex of the calf.³H-dihydroalprenolol (³H-DHA) (0.5 nM) was used to label the beta₁ adrenoceptors in the calf frontal cortex and beta₂ adrenoceptors in the calf cerebellar cortex.³H-d-Lysergic acid diethylamide (³H-LSD) (2 nM) and³H-serotonin (³H-5HT) (0.5 nM) were used to label the serotonergic receptors in the calf frontal cortex.The results show that at drug concentrations which occur clinically in the plasma water, most of the tertiary amine tricyclics significantly inhibited³H-WB-4101,³H-LSD and³H-5HT binding. None of the antidepressants tested had any significant effect on³H-DHA binding. The secondary amine tricyclics as a group were not potent in inhibiting the binding of all four radiolabelled ligands. The nontricyclic antidepressant mianserin was potent in inhibiting the binding of³H-WB-4101,³H-clonidine,³H-LSD and³H-5HT. We suggest that the differences between the effects of the antidepressants on adrenergic and serotonergic receptors may be responsible for the differences in their therapeutic efficacies and side effects.Supported by the Canada Medical Research Council and the Ontario Mental Health FoundationA preliminary report of this work was presented at the 9th annual meeting of the Society for Neuroscience, Atlanta, 1979     

Peripheral hormonal responses to D-fenfluramine as a probe of central serotonergic function in humans

We tested the hypothesis that D-fenfluramine (DFEN)-elicited cortisol (CORT) release in humans may be mediated by a direct effect on the adrenal gland by pretreating subjects with dexamethasone (DEX), to prevent release of ACTH from the pituitary, followed by a DFEN challenge test. Eight healthy subjects (four males; four female) (mean age = 38.1 ± 8.4 years (SD)] were studied > 1 week apart (same phase of menstrual cycle) and testing order was randomised. On the with-DEX day (DEX+), subjects took 2 mg DEX orally at 10 p.m.; 30 mg DFEN was then given orally at 9 a.m. and samples were taken at 0–5 h for PRL and CORT. Peak hormone responses (Δ values) were calculated by subtracting baseline values from the maximum levels post-DFEN administration. Peak and baseline hormonal values were compared between the two test conditions; DFEN-induced CORT and PRL responses were compared across all time points, with and without DEX. There was no significant difference in ΔPRL between the two test conditions (DEX−and DEX+), but Δ CORT values were significantly reduced after DEX: mean Δ CORT DEX− = 68.4 ± 26.3 nmol/l; DEX+ = 0.0 nmol/l (all blunted) (df 7,1; P = 0.03). The completely blunted peripheral cortisol response indicates that DFEN cortisol responses are of central origin only. Received: 20 March 1998/Final version: 15 July 1998     

Transitions in the transcriptome of the serotonergic and dopaminergic systems in the human brain during adolescence

Adolescence is a period of profound neurophysiological, behavioral, cognitive and psychological changes, but not much is known about the underlying molecular neural mechanisms. The aim of this study was to systematically analyze expression levels of the genes forming serotonergic and dopaminergic synapses during adolescence. We analyzed the mRNA expression profiles of genes that code for all components of serotonergic and dopaminergic synapses, in 16 brain areas from human and non-human primates from public domain databases, to detect genes whose expression changes during adolescence. Two serotonin receptors, HTR1E and HTR1B had expression levels that exhibit a sharp transition in the prefrontal cortex in adolescence, but we found no similar transition in the dopaminergic system. A similar but smoother rise in expression levels is observed in HTR4 and HTR5A, and in HTR1E and HTR1B in three other expression datasets published. An earlier rise is observed in HTR1A, and a smooth and significant rise with age is observed in the expression of HTR1E in microarray measurements in macaque monkeys. The expression of HTR1E and HTR1B is correlated across subjects within each age group, suggesting that they are controlled by common mechanisms. These results point to HTR1E and HTR1B as major candidate genes involved in adolescence maturation processes, and to their operation through common control mechanisms. The maturation profiles may also involve several other 5-HT receptors, including the genes HTR5A, HTR4 and HTR1A.     

Effects of benzodiazepines and pentobarbitone on the gaba-ergic recurrent inhibition of hippocampal neurons

The actions of benzodiazepines and pentobarbitone on GABA-mediated recurrent inhibition of hippocampal pyramidal neurons were investigated in the immobilized unanaesthetized cat. Extracellular action potentials of single neurons were recorded in regions CA1 or CA2 with 4 M NaCl-containing glass micropipettes. Bicuculline (0.1 mg/kg i.v.) reduced the period of inhibition induced by stimulation of the fimbria and the septum, but fludiazepam and diazepam (0.3--1.0 mg/kg i.v.) and pentobarbitone (15--30 mg/kg i.v.) prolonged the inhibition. The prolongation produced by these compounds was antagonized by the administration of bicuculline (0.3 mg/kg i.v.). The results suggest that these two classes of compounds potentiate GABA-mediated recurrent inhibition in hippocampal neurons in a similar way.     

Modification of central serotonergic and dopaminergic behaviors in the course of chronic corticosteroid administration

The effect of chronic cortisol administration (12.5 mg/kg per day p.o.) was studied in guinea pigs using two behavioral models; apomorphine-induced stereotypy (SB) and 1-5-HTP-induced myoclonus (MJB). Diurnal variations in behavioral sensitivity were evaluated by behavioral testing at five time points over a 24 h period at bi-weekly intervals. Cortisol succinate administration suppresses 1-5-HTP myoclonus in all animals and abolishes diurnal fluctuations in sensitivity during the first two weeks of therapy. At four weeks, a subgroup is observed which is behaviorally hypersensitive to 1-5-HTP. These changes occur in association with a reduction in the behavioral response to apomorphine but in the absence of major disruption in diurnal behavioral threshold variation to apomorphine. Chronic cortisol administration appears to induce major alterations in central serotonin-mediated behaviors. This observation may explain the therapeutic effect of corticosteroids in certain forms of myoclonus and the role of cortisol rhythm disturbances in the context of a variety of psychiatric disorders.     

Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy

Pretreatment with quipazine, a serotonin agonist, and clomipramine, a selective serotonin neuronal uptake blocker, was found to potentiate the cataleptic effect of haloperidol in a dose-dependent manner in rats. Pretreatment with methysergide, a serotonin antagonist, reduced the cataleptic effect of haloperidol. The results indicate that the cataleptic effect of neuroleptics depends on the balance between the dopaminergic and serotonergic systems, and that the serotonergic system exerts an inhibitory influence on the dopaminergic system.