Leokadia Baran

The role of nitric oxide in chemically- and electrically-induced seizures in mice

The effect of the nitric oxide synthase (NOS) inhibitors N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) on seizures induced by N-methyl-D-aspartate (NMDA), pilocarpine (PIL) and pentylenetetrazol (PTZ), as well as on the electroconvulsive threshold was studied in mice. It was found that L-NAME and 7-NI decreased the dose of NMDA necessary to produce clonic convulsions in 50% of animals (CD50). Such a proconvulsant effect was not observed in mice pretreated with N-nitro-D-arginine methyl ester (D-NAME), an inactive isomer of L-NAME. Neither L-NAME nor 7-NI affected the convulsions induced by PIL (clonic seizures) or PTZ (clonic and tonic seizures), having no effect on their CD50 values. Similarly, neither NOS inhibitor affected the electroshock threshold. These results, together with some literature data, indicate that nitric oxide (NO) may be regarded as an anticonvulsant substance in relation to seizures induced by NMDA and other excitatory amino acids, but not by other agents, in mice.

The central antiserotonergic action of mianserin

The central antiserotonergic action of mianserin (MS) was tested in mice, rats, and rabbits. MS, like cyproheptadine, to which it was compared, inhibits the head-twitch response to 5-hydroxytryptophan in mice and rats without affecting the pinna reflex. MS does not change the flexor reflex of the hind limb of the spinal rat; it antagonizes its stimulation induced by fenfluramine, LSD, and quipazine, but not that induced by clonidine. The hyperthermia in rabbits caused by the serotonergic stimulants cited above is also antagonized by pretreatment with MS. Unlike cyproheptadine, MS is not active in the oxotremorine test. The results indicate that at low doses MS is a central serotonergic-receptor blocker.

The role of nitric oxide in the kainate-induced seizures in mice

The effect of L-arginine (L-Arg), D-arginine (D-Arg), N-nitro-L-arginine methyl ester (L-NAME) and N-monomethyl-L-arginine (L-NMMA) on the kainate-induced seizures was studied in mice. It was found that the precursor of nitric oxide (NO) L-Arg (150-600 mg/kg i.p.) increased dose-dependently the dose of kinate necessary to produce clonic convulsions in 50% of the animals (CD50). Such an anticonvulsant effect was not observed in mice pretreated with D-Arg (150-600 mg/kg i.p.), the latter drug not being a substrate for NO formation. The inhibitors of NO synthase L-NAME and L-NMMA, both administered in doses of 30-30 mg/kg i.p., reduced the convulsive threshold by decreasing the CD50 of kainate. Moreover, L-NAME (3 mg/kg) antagonized the anticonvulsant effect of L-Arg (300 mg/kg). These results indicate that NO may play a role of an endogenous anticonvulsant substance in mice.

The effect of clonidine on locomotor activity in mice

Abstract Clonidine decreased the locomotor activity in mice despite marked sympathomimetic signs. It did not stimulate locomotor activity depressed by pretreatment with reserpine, alpha-methyltyrosine, FLA-63, spiroperidol or phenoxybenzamine. The combined apomorphine-clonidine treatment increased the motor activity in normal, reserpine-, alpha-methyl-tyrosine- or FLA-63-pretreated mice, but not in those mice pretreated with spiroperidol or phenoxybenzamine. Both central dopaminergic and noradrenergic receptors seem to be involved in the locomotor activity in mice.

The effects of serotonergic and antiserotonergic drugs on the flexor reflex of spinal rat: a proposed model to evaluate the action on the central serotonin receptor

The effects of serotonergic and antiserotonergic drugs on the hind limb flexor reflex (measured as a contraction of musculus tibialis anterior or as a flexion of the paw) in the spinal rat was studied. All serotonergic drugs used (L-5-hydroxytryptophan, L-tryptophan, LSD, fenfluramine, p-chloro-amphetamine) stimulate the flexor reflex. Serotonin receptor blockers (cyproheptadine, WA-335, methergoline), which given alone are inactive, inhibit the stimulation induced by serotonergic drugs but do not influence that one caused by noradrenergic agents (amphetamine, clonidine). Both types of stimulation (serotonergic and noradrenergic) are antagonized by noradrenaline receptor blockers (phenoxybenzamine, clozapine). The anti-serotonergic action of serotonin antagonists used was confirmed on the basis of the antagonism to the head twitches induced by L-5-hydroxytryptophan. The flexor reflex in the spinal rat may be a good model to evaluate the effect on the central (spinal cord) serotonin receptor and to differantiate this effect from that on the noradrenaline system.

The effect of amantadine on motor activity and catalepsy in rats

The effect of amantadine on motor activity was investigated in rats. The compound was used at doses which antagonized the catalepsy induced by spiroperidol, triperidol, chlorpromazine and reserpine. These doses moderately stimulated motor activity in normal rats; their activity was effectively antagonized by spiroperidol, chlorpromazine, phenoxybenzamine but only slightly, if at all, by α-methyltyrosine, dimethyldithiocarbamate and reserpine. The behavioral effects of amantadine in normal and reserpinized rats were potentiated by l-DOPA, nialamide, desipramine and, in particular, by cocaine. The cocaine-induced potentiation of the amantadine effect was prevented by spiroperidol. α-Methyltyrosine did not influence the antagonism of amantadine towards spiroperidol-induced catalepsy. Noradrenaline and dopamine levels in the whole brain and dopamine levels in the corpus striatum were unaltered by amantadine. The main mechanism of action of amantadine appears to be the activation of central dopamine receptors.

Activation of serotonin (5-HT)1A receptors inhibits amphetamine sensitization in mice

The effects of serotonin (5-HT)1A drugs on the development and expression of sensitization to the locomotor effect of amphetamine (AMPH) were studied in mice. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A agonist, dose-dependently reduced the expression of AMPH (2.5 mg/kg)-induced sensitization. The latter inhibitory effect of 8-OH-DPAT was reversed by (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl propamine (WAY 100135), a 5-HT1A antagonist. WAY 100135 given alone did not affect expression of AMPH sensitization. Combined injections of 8-OH-DPAT, but not WAY 100135, with AMPH (2.5 mg/kg) during the development of sensitization, protected against the expression of sensitization to a challenge dose of AMPH (2.5 mg/kg) 3 days after withdrawal. The above inhibitory effect of 8-OH-DPAT on the development of AMPH sensitization was blocked by pretreatment with WAY 100135. The AMPH-induced conditioned locomotion was unaffected by pretreatment with 8-OH-DPAT. These results indicate that 5-HT1A receptors are not involved in AMPH-induced sensitization per-se, whereas their pharmacological activation leads to the inhibition of both the development and the expression of AMPH-induced sensitization.

Pharmacological effects of 1,3-dimethyl-5-aminoadamantane, a new adamantane derivative

Abstract The pharmacological action of 1,3-dimethyl-5-aminoadamantane (D145), a new adamantane derivative, was studied in rats. It increased strongly the motor activity in normal and hypoactive (following reserpine, α-methyltyrosine or FLA-63 pretreatment) animals. Catalepsy induced by spiroperidol, haloperidol, fluphenazine and reserpine (but not by chlorpromazine) was antagonized; the flexor reflex in spinal rats was not affected. D145 had no significant effect on noradrenaline or dopamine brain levels. The body temperature was slightly raised. D145 did not antagonize the effect of oxotremorine. In contrast to amantadine, but like apomorphine, D145 evoked hypotension which was prevented by spiroperidol or haloperidol. It is concluded that D145 activates the central dopamine neurons. The compound under studies differs from amantadine and in many (but not in all) respects acts like apomorphine.

The effect of chronic treatment with antidepressant drugs on salbutamol-induced hypoactivity in rats.

Several lines of evidence (binding studies, reduced responsiveness of brain adenylate cyclase to noradrenergic stimulation, electrophysiological data) indicate that chronic treatment with antidepressant drugs induces subsensitivity of central β-adrenergic receptors. We studied the effect of acute (single dose) and chronic (14 days, twice daily) treatment with imipramine, desmethylimipramine, amitriptyline, fluvoxamine and citalopram (10 mg/kg, orally) on salbutamol-induced suppression of exploratory activity in rats. This effect of salbutamol was antagonized by chronic, but not acute treatment with antidepressants. Chronic treatment with antidepressants as a rule did not significantly affect exploratory activity. Our results may be regarded as functional evidence at the behavioural level for the subsensitivity of β-adrenergic receptors.

The central action of pizotifen

The central action of the potential antidepressant drug pizotifen (Sandomigran) was studied in mice, rats and rabbits. Pizotifen in doses up to 10 mg/kg i.p. was ineffective in classic tests for antidepressant activity. It neither antagonized the effects of reserpine in rats (hypothermia, ptosis) nor potentiated the effects of amphetamine (in mice and rats), nialamide or L-dopa (in mice) on locomotor activity. However, its antidepressant activity was found in the ‘despair test’ in rats.On the other hand, pizotifen inhibited the head twitch reaction induced by L-5-hydroxytryptophan in mice (ED50=0.009 mg/kg, i.p.) and by 5-methoxytryptamine (+tranylcypromine) in rats (ED50=0.45 mg/kg, i.p.). It also antagonized tryptamine-induced clonic convulsions of fore-paws in rats (ED50=0.35 mg/kg, i.p.), and in doses of 5–10 mg/kg s.c. inhibited hyperthermia produced by LSD in rabbits. Finally, pizotifen (0.1–0.3 mg/kg, i.v.) inhibited or abolished LSD- or quipazine-induced stimulation of the hind limb flexor reflex of spinal rats; the above effect was not due to noradrenolytic action of the drug. These results suggest that pizotifen strongly blocks the central postsynaptic serotonin receptors.