Effects of cimetidine on drug metabolism in rat pups.

The effects of cimetidine on drug metabolism were studied in male and female rat pups and compared to similar effects in adult rats. As in adult rats, cimetidine 50 mg/kg/day i.p. for 7 days in the 2nd, 3rd, 4th or 5th weeks of life resulted in prolonged pentobarbitone sleeping times (diminished pentobarbitone hydroxylase activities), particularly when administered during the 3rd week. These effects of cimetidine were reversible since they continued only up to 2 weeks in males and 4 weeks in females, but by the 6th week were no longer observed. Pretreatment with cimetidine 15, 25 and 50 mg/kg/day i.p. for 7 days, resulted in a dose-dependent inhibition of aminopyrine N-demethylase and aniline hydroxylase as well as a prolongation of pentobarbitone sleeping time in both pups and adults, aniline hydroxylase being the least affected. In general, female pups were more adversely affected than male pups and adults. The therapeutic and toxicological relevance of these results in man are discussed.

Dose-related and other effects of maternal cimetidine pretreatment during lactation on drug metabolism in mouse dams and pups.

The effects of maternal cimetidine pretreatment at different dose levels during lactation, on drug metabolism, were investigated in mouse dams and recently weaned pups. Aminopyrine N-demethylase, aniline hydroxylase and pentobarbitone metabolism were inhibited in both dams and pups in a dose-dependent manner (15, 25 and 50 mg/kg/day, i.p.). Pretreatment at a dose level of 50 mg/kg/day resulted in comparable levels of inhibition of drug metabolism in dams and female pups while male pups were less affected. Of the three indices studied, aniline hydroxylase was the least influenced by cimetidine pretreatment. Thus, the effects of maternal cimetidine pretreatment on drug metabolism in the nursing pair varied with the dose, sex and substrate. The possible implications of these results for man are discussed.

Influence of acute and chronic administration of ethanol on photic-evoked response in rats.

The effect of acute and chronic administration of ethanol on photic-evoked response was studied in rats. Acute administration of ethanol (1-3 g/kg, i.p.) produced behavioural depression, EEG synchronization and a biphasic effect on the amplitude of the photic evoked responses (PER) recorded from the frontal cortex (FC) and optic cortex (OC), while a reduction in amplitude was observed in the midbrain reticular formation (MBRF). The amplitude of the averaged PER in the FC and OC was increased in chronic ethanol-treated rats, while in the MBRF, a reduction in amplitude was observed. Abrupt discontinuation of ethanol produced behavioural excitation and increase in amplitude of the averaged evoked responses recorded from the three brain areas studied. These observations suggest that the neural hyperexcitability that characterizes ethanol withdrawal may affect both cortical and subcortical structures.

Effect of some serotoninergic agents on the rectal temperature of the domestic fowl (Gallus domesticus).

The information currently available in the literature on the effects of serotonergic drugs on thermoregulation in the avian species is very scanty. Therefore, it was the objective in this project to study the influence of 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan (5-HTP), benserazide, carbidopa (Mk 486), citalopram, cyproheptadine, methysergide, xylamidine, p-chlorophenylalanine (PCPA) and lysergic acid diethylamide (LSD-25) on the rectal temperature of young chicks. 5-hydroxytryptamine (0.8 mg/kg), produced significant dose-dependent hypothermia in young chicks. Similarly, 5-HTP (16 mg/kg) profoundly lowered the rectal temperature of young chicks. The hypothermic effect of 5-HTP was potentiated by benserazide (1.25-2.5 mg/kg). Pretreatment with carbidopa (50 mg/kg) potentiated 5-HTP induced hypothermia. Citalopram (5 mg/kg) significantly potentiated hypothermia induced by 5-HT. Pretreatment with PCPA (200 mg/kg, 24 hr previously) alone resulted in hyperthermia while the hypothermic effect of 5-HTP (16 mg/kg) was antagonised by pretreatment with PCPA. Cyproheptadine (1.25 mg/kg) antagonised the hypothermic effect of 5-HT (0.1 and 0.8 mg/kg). The antagonistic effect was weak when the chicks were pretreated with larger doses of cyproheptadine (i.e. 2.5-10 mg/kg). The hypothermia induced by 5-HT (0.8 mg/kg) was antagonised by smaller doses of methysergide (0.125-1.0 mg/kg) but potentiated by larger doses of methysergide (2.0 and 4.0 mg/kg). Xylamidine (1-2 mg/kg) alone induced hyperthermia and effectively antagonised hypothermia induced by 5-HT (0.8 mg/kg). D-Lysergic acid diethylamide (2.5-10 micrograms/kg) alone induced hypothermia. The interaction between LSD and 5-HT was dose-dependent and biphasic.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of dopamine, levodopa and apomorphine on maximal electroconvulsive seizure in the domestic fowl (Gallus domesticus).

The influence of dopamine, levodopa and apomorphine on maximal electroconvulsive seizure was studied in young chicks, adult cocks and rats. The susceptibility of chicks to maximal electroshock seizure increased with age between 1 to 7 days. Low to moderate doses of dopamine (12.5-150 mg/kg, i.p.), levodopa (6.25-25 mg/kg, s.c.) and apomorphine (0.25-2.0 mg/kg, s.c.) significantly (P less than 0.005) protected chicks against electroshock seizure, while high doses (200-400 mg/kg, i.p. of dopamine, 50-200 mg/kg, s.c. of levodopa and 2.5-5 mg/kg, s.c. of apomorphine) enhanced electroshock seizure in 1 to 7 day old chicks. However, when 14 day old chicks were used, these dopaminoceptor agonists protected the chicks against maximal electroshock seizure. Noradrenaline (1-40 mg/kg, i.p.) had no significant effect on electroshock seizure in chicks. Both pimozide (4 mg/kg, i.p.) and haloperidol (0.4 mg/kg, i.p.) antagonized the effects of levodopa (12.5 and 50.0 mg/kg, i.p.) and apomorphine (0.5-5 mg/kg, s.c.) on maximal electroshock seizure. The seizure susceptibility of both adult rats and fowls to electroshock was not altered by dopamine (12.5-400 mg/kg, i.p.). Central dopamine neurotransmission might be involved in the biphasic dose-dependent effects of dopamine, levodopa and apomorphine on maximal electroshock seizure in young chicks.

Behavioural effects of beta,beta'-iminodipropionitrile (IDPN) in the domestic fowl (Gallus domesticus).

The behavioural effects of beta,beta'-iminodipropionitrile (IDPN) were studied in chicks and adult fowls. Repeated administration of IDPN (75 mg/kg) for 5 days induced behavioural changes in chicks and adult fowls characterized by excitation, choreiform head and neck movements and circling (ECC-syndrome). Both acute and chronic administration of IDPN induced EEG desynchronization, EMG activation and enhancement of photic-evoked response (PER) in the hyperstriatum and pontine reticular formation while a decrease in PER was observed in the optic tectum. d-Amphetamine (2.5-5 mg/kg), apomorphine (0.1-0.25 mg/kg), piribedil (2.5-5 mg/kg), atropine (2.5-5 mg/kg), hyoscine (2.5-5 mg/kg) and cyproheptadine (0.5 mg/kg) potentiated the circling and choreiform head and neck movements. These activities were antagonized by pimozide (1 mg/kg), physostigmine (0.5 mg/kg) and quipazine (2.5-5 mg/kg). The results suggest that dopaminergic, serotoninergic and cholinergic mechanisms may be involved in IDPN-induced behavioural effects in chicks.

Influence of levodopa, apomorphine and 3,4-dihydroxyphenylserine (DOPS) on strychnine-induced seizures in mice.

The effects of levodopa, apomorphine and 3,4-dihydroxyphenylserine (DOPS) on tonic seizures elicited by strychnine were investigated in mice. Levodopa (6.25-100 mg/kg), apomorphine (0.2-0.8 mg/kg) and FLA-63 (12.5 mg/kg) profoundly delayed the onset and reduced the incidence of strychnine seizures. In addition, these drugs decreased strychnine-induced mortality. DOPS (1-16 mg/kg) apparently shortened the onset of strychnine seizures and altered strychnine-induced mortality in a dose-dependent manner; low doses (1-2 mg/kg) enhanced while moderate doses (4-8 mg/kg) reduced the mortality rate. FLA-63 (12.5 mg/kg) potentiated the anticonvulsant effect of low doses of levodopa (6.25-12.5 mg/kg) while it had no significant influence on the anticonvulsant effect of higher doses (25-100 mg/kg) of levodopa. In addition, the onset of strychnine seizure was further delayed by FLA-63. Haloperidol (0.5 mg/kg) potentiated the convulsant effect of strychnine (1 mg/kg) as well as strychnine-induced mortality. It also antagonised the protective effect of levodopa (12.5 and 100 mg/kg) against strychnine (1 mg/kg). Phentolamine (5 mg/kg) and +/- propranolol (1 mg/kg) antagonised strychnine seizures. Strychnine-induced mortality was also reduced by these drugs. In addition, the effects of DOPS (2 mg/kg) on strychnine seizures were antagonised by phentolamine and propranolol. These results indicate that enhancement of dopaminergic and noradrenergic neurotransmission respectively attenuate and potentiate strychnine seizures in mice.

Influence of FLA-63 on pentobarbitone sleep in chicks and rats.

The influence of FLA-63 on pentobarbitone-induced sleep was studied in young chicks and adult rats. FLA-63 produced a time-dependent biphasic effect on the gross behaviour of chicks and rats; an initial sedation followed by behavioural excitation. The behavioural effects of FLA-63 were associated with an initial EEG synchronization prior to an increased activity of the EMG of the neck muscle and desynchronization of the EEG of the hyperstriatum, optic tectum and pontine reticular formation of the chick. Similarly, in rats, the EEG of the frontal cortex, optic lobe and pontine reticular formation was desynchronized while the EMG activity of the neck muscle was enhanced by FLA-63. FLA-63 delayed the onset and shortened the duration of pentobarbitone sleep. Pentobarbitone-induced EEG synchronization and decreased EMG activity in chicks was antagonized by FLA-63. Dopamine-induced antagonism of pentobarbitone sleep was potentiated by FLA-63 in chicks. Levodopa antagonized pentobarbitone-induced sleep in rats and this effect was potentiated by FLA-63. FLA-63 potentiated levodopa-induced desynchronization of the EEG of the frontal cortex, optic lobe and pontine reticular formation of the rat. Haloperidol antagonized the effect of FLA-63 on pentobarbitone-induced sleep in both rats and chicks. Noradrenaline induced behavioural sleep in young chicks dose-dependently; this effect was antagonized by phentolamine. In the rat, phentolamine shortened pentobarbitone sleeping time but did not significantly influence the effects of FLA-63 on pentobarbitone sleep. Those results suggest that an increased dopamine neurotransmission may be associated with the mechanism of wakefulness in chicks and rats.

Studies on the pharmacology of d-amphetamine on maximal electroconvulsive seizure in young chicks.

d-Amphetamine protected young chicks against electroconvulsive seizure (ECS) in a dose-dependent manner in the dose range of 1-10 mg/kg. Reserpine pretreatment reduced ECS threshold and decreased the anticonvulsant effect of d-amphetamine in chicks. FLA-63 protected chicks against ECS and potentiated the anticonvulsant effect of d-amphetamine, whereas the dopamine antagonist pimozide antagonised the protective effect of d-amphetamine against ECS. Both the alpha-adrenoceptor antagonist phentolamine, and the serotonin antagonist cyproheptadine, had no significant influence on the anticonvulsant effect of d-amphetamine. d-Amphetamine significantly increased the levels of 5-hydroxytryptamine, noradrenaline and dopamine in the hyperstriatum, brain stem and optic tectum of the chick respectively. The present data suggests that brain dopamine may be the principal monoamine involved in the protective influence of d-amphetamine against ECS in young chicks.

Histological and histometrical studies of testicular hypertrophy following hemicastration of albino rats.

This project was designed to study the effects of hemicastration in male albino rats of different ages and weights. Significant compensatory hypertrophy was seen in young rats (5 and 20 days old). The concentration of seminiferous tubules was profoundly reduced while the tubular diameter was increased in young hemicastrated rats. The weights of the kidneys were increased while the weights of the adrenal glands were not different in hemicastrated young rats. These histological and histometrical changes may be associated with specific endocrine activity.

Succinimides with oxyacetate side chain as potential anticonvulsant agents.

Two new compounds, ethyl N-succinimidoxyacetate and methyl N-succinimidoxyacetate, were prepared by reacting a solution of freshly recrystallized N-hydroxysuccinimide in tetrahydrofuran with a mixture of the corresponding halogenated ester and triethylamine. The compounds possessed some anticonvulsant properties.

Antagonism of pentobarbitone sleep by dopamine, levodopa and apomorphine in chicks.

1. The influence of dopamine, levodopa and apomorphine on sleep produced by pentobarbitone was studied in 1-14 day old chicks. 2. Pentobarbitone-induced sleep was associated with synchronization of the electroencephalogram (EEG) of the hyperstriatum, optic tectum and pontine reticular formation. 3. Dopamine desynchronized the EEG and antagonized pentobarbitone-induced EEG synchronization. 4. High doses of dopamine produced a delayed sleep which was potentiated by pimozide and antagonized by adrenoreceptor blocking agents. 5. Dopamine, levodopa and apomorphine delayed the onset and shortened the duration of pentobarbitone-induced sleep; apomorphine was the most potent. 6. Pimozide prolonged the duration of pentobarbitone-induced sleep, but had less effect when dopamine was also given.

The influence of intraperitoneally injected 6-hydroxydopamine on electroshock seizure in chicks and rats.

1. 6-Hydroxydopamine, injected intraperitoneally in rats and chicks, did not induce spontaneous seizures but produced significant alterations in the threshold to electroshock seizure in chicks; the particular effects were dose-dependent and time-dependent. 2. Administration of 6-hydroxydopamine to 3 day old chicks and rats in the first and third days after birth resulted in an increase in the proportion exhibiting tonic seizure with electroshock when tested after 10-12 weeks. 3. When 6-hydroxydopamine was injected intraperitoneally into adult rats and cocks, there was no significant alteration in seizure threshold. 4. The results suggest that 6-hydroxydopamine penetrates the central nervous system of young chicks and rats and that adrenergic mechanisms are probably involved in modulating seizure mechanisms in both the chick and rat.