H. Sowińska

Effects of MK-801 and antidepressant drugs in the forced swimming test in rats

The effects of MK-801, a non-competitive NMDA receptor antagonist, and of antidepressant drugs were studied in the forced swimming test in rats. MK-801 reduced immobility time. Combined treatment with MK-801 + imipramine induced a stronger effect in Porsolts test than administration of either drug alone. Citalopram was inactive when given alone but it potentiated the antidepressant-like effect of MK-801. Haloperidol and prazosin antagonized the effect induced by MK-801 + IMI or CIT. Mianserin interacted with MK-801 in a similar way but to a lesser extent. Its effect was antagonized by haloperidol but not by prazosin. The reduction of the immobility time was also observed in those experimental paradigms in which the locomotor activity was not increased. The results indicate that synergism may exist between antidepressants and MK-801.

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.

Repeated treatment with antidepressant drugs increases the behavioural response to apomorphine.

The effect of repeated treatment (twice a day for 14 days) with antidepressant drugs (AD): imipramine, amitriptyline, zimelidine, citalopram and mianserin on the behavioural response to apomorphine in rats (open field test) was investigated. AD studied, given alone in a single dose or repeatedly, do not change the rats behaviour. A repeated but not single-dose treatment with AD facilitates the behaviour stimulation induced by apomorphine. This facilitation is observed 2 hours after the last dose of imipramine, zimelidine, citalopram and mianserin but 72 hours after the last dose of amitriptyline. The results presented suggest that the AD given repeatedly are able to increase the responsiveness of the brain DA system, probably the mesolimbic one.

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.

Repeated treatment with antidepressant drugs potentiates the locomotor response to (+)-amphetamine

macol. 25: 2319-23f1 Buckholtz, N. S. , Boggan, W. 0. (1977) Life Sci. 20: 2093-2100 Buckholtz, N . S. (1980) Naunyn-Schmiedeberg’s Arch. Pharmacol. 314 (3): 215-221 Ho, B. T., McIsaac, W., Walker, K. E., Estevez, V. (1968) J. Pharm. Sci. 57: 269-274 Ho, B. T., Taylor, D., Walker, K. E., McIsaac, W. (1972) Xenobiotica 2: 349-362 McIsaac, W., Taylor, D., Walker, K. E., Ho, B. T. (1972) J. Nuerochem. 19: 1203-1206 Meller, E., Friedman, E., Schweitzer, J. W., Friedhoff,

Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease

SummaryBehavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4′-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinsons disease.

The effect of l-dopa and (+)-amphetamine on the locomotor activity after pimozide and phenoxybenzamine

Previous experiments with L-dopa, apomorphine and amantadine (Maj, Grabowska & Mogilnicka, 1971 ; Maj, Grabowska & Gajda, 1972; Maj, Sowiriska & Baran, 1972) showed that in the stimulation of locomotor activity induced by these compounds both central catecholamines, dopamine and noradrenaline, play a role. Experiments studying the interactions between pimozide and phenoxybenzamine, on one hand, and L-dopa and (+)-amphetamine on the other, may support this hypothesis. The former two compounds block specifically central dopamine (AndCn, Butcher & others, 1970) and noradrenaline receptors respectively (AndCn, Dahlstrom & others, 1966). L-Dopa and amphetamine stimulate both the receptors (Ernst & Smelik, 1966; AndCn, Engel & Rubenson, 1971 ; Randrup & Scheel-Kriiger, 1966; Svensson, 1970). The locomotor activity of adult Wistar rats and Albino-Swiss mice of either sex in groups of at least 10 animals was measured in a photoresistor actometer for 15 min. The drugs were given before the test as follows: pimozide (i.p.) 4 h, phenoxybenzamine (i.p.) 2 h, L-dopa (i.p.) 1 h 45 min, (+)-amphetamine sulphate (s.c.) 30 min. An inhibitor of extracerebral decarboxylase, Ro 4-4602 [N1-(~~-seryl)-N2-(2,3,4-trihydroxybenzyl) hydrazine] (50 mg/kg i.p., 30 min before L-dopa) preceded all injections of L-dopa. The control groups were treated with appropriate solvents. Pimozide, phenoxybenzamine and L-dopa were administered as suspensions in 3 % aqueous solution of Tween 80; (+)-amphetamine and Ro 4-4602 was dissolved in saline. Statistical evaluation was made using Student’s t-test. The Pimozide, 1 and 2 mg/kg, depressed the locomotor activity of rats (Table 1).

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.

Antidepressants given repeatedly increase the behavioural effect of dopamine D-2 agonist

The effects of single or repeated doses of antidepressant drugs (imipramine, amitriptyline, citalopram, mianserin) on rat locomotor hyperactivity induced by quinpirole, a dopamine D-2 receptor agonist, was investigated. Single doses of antidepressants do not change the effect of quinpirole, but enhance it when they are administered repeatedly. This enhancement is inhibited by (±)-sulpiride, a dopamine D-2 receptor antagonist. The results obtained indicate that the enhancement of dopaminergically-stimulated hyperactivity induced by repeated doses of antidepressants is mediated by dopamine D-2 receptors.

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.