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Maprotiline, a tetracyclic antidepressant drug, was evaluated for antidepressant and neuroleptic activity. In antidepressant tests, maprotiline antagonized reserpine-induced ptosis in rats but, unlike the tricyclic antidepressants, was found to antagonize methamphetamine stereotypy in rats, to decrease the intensity of L-dopa induced behavioural syndrome in pargyline-pretreated mice and to be ineffective in intensifying the 5-HTP induced behavioural syndrome. In neuroleptic tests, maprotiline was found to, antagonize apomorphine-induced cage climbing behaviour, induce catalepsy, inhibit the CAR and traction response, decrease the spontaneous motor activity and exploratory behaviour, and to potentiate the hypnotic effect of pentobarbitone. Our results indicate that maprotiline exhibits a profile of activity which resembles the neuroleptics and most probably exerts post-synaptic striatal DA receptor blocking activity.
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PMID:Experimental evaluation of the antidepressant and neuroleptic activity of maprotiline. 612 95

Some central effects of the tripeptides TRH (thyroliberine), MIF (melanostatine or C-terminal fragment of oxytocine) and MAF (C-terminal fragment of gastrine) have been studied in experiments on mice and rats. Upon intraperitoneal administration in mice, TRH and MIF exercise central stimulating effects: they reverse the reserpine-induced decrease in the rectal temperature, ptosis of the eyelids, hypomotility, decreased content of the cerebral homovanillic acid (HVA); they antagonize haloperidol catalepsy and the increased HVA concentration). The tripeptides potentiate apomorphine stereotypy in rats, when injected in the striatum. The results obtained characterize TRH and MIF as drugs which are capable of activating the cerebral dopaminergic receptors by antagonizing the effects of reserpine and haloperidol, MAF--as a substance acting similar to the dopaminergic receptor blockers. Consequently, the cerebral dopaminergic system is an important unit for the realization of the central effects of these low-molecular peptides.
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PMID:Effects of the tripeptides TRH, MIF and MAF on the cerebral dopaminergic system. 614 Aug 14

24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.
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PMID:Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic. 614 85

The pharmacological profile of salbutamol, an agonist of beta-adrenergic receptors and a potential antidepressant drug, and its effect on the central serotonin system were studied. It was found that salbutamol either had no effect, or, at higher doses, inhibited the spontaneous activity of mice and rats; it did not influence significantly either the produced by amphetamine locomotor stimulation (in mice and rats) or amphetamine stereotype (in rats). Salbutamol while not affecting body temperature of normal mice reversed hypothermia but not ptosis induced by reserpine, and counteracted the hypothermic action of apomorphine in mice. It neither affected the spiperone-induced catalepsy nor was active in the behavioural despair test in rats. Salbutamol had no effect either, on the fenfluramine-induced hyperthermia in rabbits, on the 5-hydroxytryptophan-induced head twitch reaction in mice, on the tryptamine-induced clonic convulsions of forepaw in rats on the flexor reflex in spinal rats, or on the quipazine- or fenfluramine-induced stimulation of this reflex. The above findings indicate that the pharmacological profile of salbutamol resembles that of classical imipramine-like antidepressant drugs to a very small extent and it does not affect the central serotonergic transmission.
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PMID:The central action of salbutamol, a beta-agonist with a potential antidepressant activity. 626 86

The behavioural and histological effects of unilateral or bilateral lesions induced by kainic acid injections into the globus pallidus were investigated in rats. Both lesions provoked a behavioural syndrome similar to those seen in animals treated systemically with neuroleptics or opiates. Animals displayed akinesia, ptosis, catalepsy, hypothermia and muscular rigidity. Also a marked hypersensitivity to touch, and a sensory neglect to touch and pain limited to hindlegs, adipsia, aphagia and high mortality of lesioned rats were observed. These symptoms were much stronger and lasted longer (catalepsy lasted over 15 days) in bilaterally lesioned animals. Subcutaneous injections of apomorphine in bilaterally lesioned rats abolished akinesia and catalepsy while rigidity and ptosis were unaffected. In unilaterally lesioned rats in which the lesion-induced spontaneous catalepsy already disappeared the spiperone-induced catalepsy was suppressed while in bilaterally lesioned animals which showed still pronounced lesion-induced catalepsy the spiperone-induced catalepsy was unchanged when compared to the sham-operated rats. Our results and the literature data suggest that the lesions of the globus pallidus produce biphasic effects: spontaneous catalepsy and unchanged neuroleptic catalepsy in the first phase and suppression of the neuroleptic catalepsy in the second phase. The role of the globus pallidus as a distal link (for neostriatum and n. accumbens) in neuronal chain forming a matrix of central patterns of catalepsy, akinesia and rigidity is discussed.
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PMID:A biphasic influence of globus pallidus lesions: spontaneous catalepsy followed by anticataleptic effect. 635 69

Male Sprague-Dawley rats were evaluated between ages 18 and 825 days for responses to doses of haloperidol (0 and 0.05-10 mg/kg, IP). Catalepsy, ptosis, and inhibition of general motor activity showed steady decreases in sensitivity to the drug with age during the first 1.5 years of maturation, while rats older than 1.5 years had strikingly increased sensitivity to the activity-inhibiting and cataleptic effects of the drug. The efficacy of haloperidol on all tests in 110-day old rats was indistinguishable whether food was available continuously, or restricted to reduce body weight by 55%, indicating that the effects of maturation are due to aging and not to increasing body weight. The effects may be due to altered drug metabolism or altered sensitivity of the central nervous system to neuroleptic agents. Clinical impressions too, indicate that immature and elderly patients are more sensitive to these and other psychotropic drugs than are young adults.
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PMID:Effects of maturation and aging on behavioral responses to haloperidol in the rat. 678 40

Circadian changes in behavioral responses to haloperidol were evaluated in rats under normal and altered lighting cycles. There was a 5.5-fold change in ED50 between the maximum (4 PM) and minimum (4 AM) cataleptic response to the drug under normal lighting (lights of 7 AM- 7 PM). The rhythm was present whether the same rats were tested repeatedly, or fresh rats were used at each time to avoid drug effects which persist for at least several days. Under normal lighting, the maximum cataleptic effect of haloperidol corresponded closely to the light-phase minimum of spontaneous motor activity in untreated rats. Measures of sedation (ptosis and motor inhibition) induced by haloperidol yielded small circadian rhythms under normal lighting and were highly dependent on the baseline level of arousal. A month of constant light or dark, or reversed dark-light cycles had small effects on the sedative actions of haloperidol, although inhibition of locomotion tended to phase-shift with general arousal; these changes did not alter the catalepsy rhythm. While the circadian rhythm of spontaneous activity underwent a complete reversal within 1 month (t 1/2 =17 days) of reversed lighting cycles, the catalepsy rhythm changed very gradually (t 1/2 = 82 days) and required nearly 6 months for complete reversal. Thus, catalepsy is a robust endogenously regulated circadian response that is only slowly influenced by altered lighting conditions which dissociate this rhythm of neuroleptic response from that of spontaneous general arousal. Endogenous neurobiologic and pharmacokinetic factors may contribute to circadian changes in neuroleptic responses.
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PMID:Circadian changes in behavioral effects of haloperidol in rats. 681 32

Minaprine (3-[2-morpholino-ethlamino]-4-methyl-6-phenyl-pyridazine dihydrochloride; 30038CM; trade name in France: Cantor) is a new psychotropic drug. The therapeutic profile of minaprine differs from that of other known psychotropic agents; in man the drug antagonizes the "inhibitory syndrome" characterized by decreased spontaneous activity, reduction in basic drives, slowed thoughts, feelings of tiredness and social withdrawal. Preliminary clinical trials have indicated that minaprine may also be effective in certain depressive states. This finding prompted us to study the effects of minaprine in animal models for depression. Like most antidepressants minaprine antagonizes behavioral despair, but the effect exhibits a slow onset and maximal activity is reached 24 h after administration. Minaprine also antagonizes reserpine-induced ptosis, this effect has a rapid onset, and is long-lasting. In contrast, minaprine poorly antagonizes reserpine-induced hypothermia. Unlike most antidepressants minaprine does not potentiate yohimbine-induced lethality. Minaprine potently antagonizes prochlorperazine-induced catalepsy in rats and potentiates amphetamine-induced stereotyped behavior, suggesting that the drug may enhance dopaminergic transmission. Finally, minaprine does not antagonize either oxotremorine-induced tremors or physiostigmine-induced lethality. Taken together the results of the present study indicate that minaprine is active on certain, but not all, animal models for depression and suggest the drug may have a potential clinical utility in the treatment of human depressions.
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PMID:Pharmacological evaluation of minaprine dihydrochloride, a new psychotropic drug. 689 Mar 59

Male Wistar rats, 35-days-old, maintained on a thiamine deficient diet for 30 days showed marked growth inhibition and a heart rate less than 70% of that of control rats. We examined the effect of thiamine deficiency on the action of drugs effecting the central nervous system at this period. In thiamine deficient rats treated with chloral hydrate 200 mg/kg, ketamine 100 mg/kg sodium pentobarbital 50 mg/kg, and hexobarbital 100 mg/kg, the sleeping time increased. Pretreatment with 15 mg/kg of the metabolic enzymes inhibitor, SKF-525A, 30 min prior to the hexobarbital administration resulted in prolongation of sleeping time in all groups. The thiamine deficient rats slept almost 3.5 times longer than did the control group. Pretreatment with 100 mg/kg of the metabolic enzyme inducer, sodium phenobarbital, 48 hours prior to hexobarbital treatment resulted in decreased sleeping time in all groups, as compared with only hexobarbital treatment. In the thiamine deficient rats the catalepsy and ptosis induced by the i.p. administration of tetrabenazine 50 mg/kg was reduced even when the control and pair-fed groups responded to this drug at the drug peak time. The spontaneous neuronal activity of lateral hypothalamus was most sensitive to the administration of 5-hydroxytryptophan in thiamine deficient rats.
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PMID:[The effect of thiamine deficiency on the actions of drugs affecting the central nervous system in rats (author's transl)]. 696 42

Behavioral pharmacological properties of mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzol[c,f]pyrazino [1.2-a]azepine monohydrochloride) were investigated in comparison with imipramine (IMP) and amitriptyline (ATP). Mianserin antagonized reserpine-induced hypothermia but to a much lesser extent than IMP or ATP, and did not block the ptosis evoked by reserpine or tetrabenazine. Amphetamine-induced stereotyped behavior was significantly enhanced by both IMP and ATP, but not by mianserin. Unlike IMP or ATP, haloperidol-induced catalepsy in the rat was not blocked by mianserin. Like IMP or ATP, mianserin did not suppress the convulsions induced by bemegride or strychnine in the mouse, and or emetic action of apomorphine in the dog, while only mianserin did not block the convulsions evoked by electric shocks. Mianserin more strongly potentiated the anesthetic action of thiopental than did IMP. ATP showed strong muscle relaxant action and the impairment of coordinated motor activities both in mice and rats, in the inclinated screen test and rotarod test, while, like IMP, these actions of mianserin were significant only in the rat. Catalepsy was not induced nor was the righting reflex suppressed by mianserin. In the low spinal cat, mianserin did not depress the amplitude of extensor MSR. Moreover, the MSR inhibition induced by conditioning stimulation of ipsilateral cutaneous afferents and the MSR potentiation evoked by conditioning stimulation of contralateral saphenous nerve were unaffected by mianserin. The curious behavior of mice and rats was significantly and dose-dependently suppressed by mianserin, and tended to be suppressed by ATP, while an enhancement was seen with IMP in large doses. Mianserin was the most potent in suppressing the fighting behavior induced by long-term isolation of the mouse, and was the weakest in suppressing electric-stimulation-induced fighting behavior, compared with IMP and ATP. Mianserin showed no significant suppression of the muricide behavior of the olfactory bulbectomized rat, while IMP significantly suppressed it. No significant differences were observed among mianserin, IMP and ATP as to their actions on the conflict behavior and the shuttle-box type conditioned avoidance behavior of the rat. These results indicate that behavioral pharmacological actions of mianserin were not always the same as those of IMP and ATP. Therefore, mianserin may be a new antidepressant with mechanisms of action which differ from that of the usual tricyclic antidepressants.
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PMID:[Behavioral pharmacology of mianserin hydrochloride, a new antidepressant (author's transl)]. 719 23


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