Cerebral oligemic hypoxia and iron toxicity in the mesolimbic system of rats.

60 min of bilateral clamping of the carotid arteries (BCCA) in pentobarbital anaesthetized adult Wistar rats increases the lipid peroxidation in hippocampal tissue as estimated four weeks later. 1.5 micrograms FeCl3 in 2 microliters buffer injected unilaterally in the ventrolateral striatum enforced the effect when applicated one week after the BCCA treatment.

Injection of a minuscule dose of FeCl3 within the ventrolateral striatum causes a chronic disturbance of the integrative function within the limbic part of the ventral striatum.

The present study shows that low amounts of applied iron have a potent effect on the ventrolateral striatum. This is reflected by an influence on spontaneous night activity, cognitive behaviour during the water maze navigation task, exploratory activity and in response to postsynaptic apomorphine stimulation. Such functional disturbances could be observed up to months after a single application of either 0.

The effect of imipramine on lipid peroxidation in the rat cerebral cortex.

The effect of imipramine (IMI) on lipid peroxidation in the rat cerebral cortex was investigated in ex vivo and in vitro study. It was found that IMI when given to rats chronically (14 x 10 mg/kg ip) but not acutely (10 mg/kg ip), inhibited lipid peroxidation in the cortical membranes of rat brain. When added in different concentrations (0.

Effect of transient reduction of cerebral blood flow on membrane anisotropy and lipid peroxidation in different rat brain areas.

Light-microscopical studies revealed that oligemic hypoxia for 24 and 60 min as produced by bilateral clamping of the carotid arteries (BCCA) in normotension does not produce neuronal cell necrosis in the vast majority of rat brain. Less than 5% of cases showed a pattern of mild selective neuronal necrosis as would be expected in ischemia. However, significant changes in both lipid peroxidation (as measured by MDA formation) and membrane anisotropy (measured by DPH or TMA-DPH, respectively, as a fluorescence probe) in cortical and striatal, but not in hippocampal, membrane fractions could be measured in ex vivo studies.

The effects of imipramine on the methylation of phosphatidylethanolamine (PE) in the cortical membranes of Wistar rats.

This study investigates the effect of imipramine (IMI) on the methylation of phosphatidylethanolamine (PE) in crude cortical membranes of rat brain in vitro and ex vivo. It was found that IMI enhanced the formation of phosphatidyl-N-monomethylethanolamine (PME) and phosphatidyl-N,N-dimethylethanolamine (PDE) and inhibited the formation of phosphatidylcholine (PC) in the cortical membranes of rats in vitro. The same effect i.

A comparative study on desipramine pharmacokinetics in the rat brain after administration of desipramine or imipramine.

Chronic intraperitoneal administration of desipramine led to an extensive cumulation of the drug in brain and blood compared with that after a single dose treatment, while chronic treatment with desipramine by the oral route produced a brain concentration comparable with its level after a single oral dose. Comparison of the present results with the corresponding data of published imipramine pharmacokinetics indicated that the cumulation of desipramine in the rat brain was nearly the same when rats received desipramine or imipramine twice a day for two weeks at a dose of 10 mg kg-1 orally, or imipramine, twice a day for two weeks at a dose of 10 mg kg-1 intraperitoneally. It is suggested that these three experimental paradigms may be used as models for differentiation of the pharmacological effects of imipramine and desipramine in-vivo.

Effect of imipramine on the membrane anisotropy and on the phospholipid methylation in the central nervous system of the rat.

An ex-vivo and in-vitro study of the effects of imipramine on the membrane anisotropy and phospholipid methylation in the rat cortical membranes was carried out. A comparative study of the membrane fluidity in various brain regions indicated different basal anisotropy of the areas and different reaction of these membranes to imipramine. It was found that imipramine when given to rats chronically (14 x 10 mg kg-1, i.

Effect of some cationic amphiphilic drugs on phospholipid methylation in the central nervous system of rats.

Imipramine, desipramine, citalopram and chlorpromazine in concentrations which corresponded with their concentration in the central nervous system of rats after pharmacological doses, potentiated phospholipid methylation in the synaptic cortical membranes of naive rats in-vitro. Chronic administration of imipramine, desipramine or citalopram induced changes in the activity of phospholipid methyltransferases since none of these drugs stimulated phospholipid methylation in the synaptic cortical membranes of rats treated with these antidepressants for two weeks. In contrast, chronic treatment with chlorpromazine did not change the sensitivity of phospholipid methyltransferases to the stimulating effect of chlorpromazine, whereas addition of haloperidol to the synaptic cortical membranes of rats treated chronically with haloperidol led to a decrease of phospholipid methylation.

Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment with imipramine.

Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment of rats with imipramine has been investigated. Both substances were distributed unevenly within rat brain after single and prolonged administration of imipramine. This was partly connected with the regional cerebral blood flow, lipid content in the regions and lipophilicity of the substances investigated.

Effects of two isomeric 1-aminoadamantanes on the membrane anisotropy and on alpha- and gamma-motoneurones excitability.

The structure-activity relationship of two isomeric 1-aminoadamantanes, 1-C-ethylaminoadamantane (D 174) and 1-amino-3-ethyladamantane (D 175), on membrane anisotropy and the excitability of neurons was studied in the CNS of the rat and in the decerebrated cat. Mass spectrometric analysis showed that after a single, 40 mg/kg dose, D 174 and D 175 were unevenly distributed within the CNS of the rat, moreover the distribution pattern of the two substances was different. As measured by fluorescence depolarization in controls the membrane anisotropy was found to be higher in the older parts as compared with the younger parts of the CNS.

Species differences in hepatic microsomal drug-metabolizing enzymes.

The activity of some metabolizing enzymes was assessed in the liver microsomes of Acomys cahirinus, mice and rats. The enzymatic studies were followed by the determination of cerebral level of apomorphine (APO), imipramine (IMI) and its metabolite desipramine (DMI) of animals treated with a single dose of APO or IMI. It was found that the level of cytochrome P-450 and the activity of IMI demethylase and glucuronyltransferase in the liver microsomes of rats was significantly higher than those in the liver microsomes of Acomys and mice.

A spectrophotometric method for N-nicotinoyl-tryptamine (tryptamide) assay in the blood serum of rats.

A spectrophotometric method for N-nicotinoyl-tryptamine (tryptamide) (TR) assay in the blood serum of rats has been elaborated. Sensitivity of the method is approx. 1 microgram of TR/ml of blood serum, recovery approx.

Hepatic metabolism of imipramine after prolonged administration of the drug to rats. An in vivo study.

The effect of prolonged administration of imipramine (IMI) to rats on the biliary excretion of IMI and its metabolites desipramine (DMI), 2-OH-imipramine (2-OH-IMI) and 2-OH-desipramine (2-OH-DMI) has been investigated. It was found that chronic IMI decreased the ratio DMI/IMI and 2-OH-IMI/IMI excreted with the bile and increased the ratio 2-OH-DMI/DMI. This was observed for 3 h after the last dose of chronic IMI, and suggested an inhibition of IMI demethylation and hydroxylation, and acceleration of DMI hydroxylation.

The effect of prolonged administration of imipramine on its hepatic metabolism in rats.

The effect of prolonged administration of imipramine (IMI) (20 mg/kg/day po) to rats on IMI metabolism by liver microsomes was investigated. It was found that chronic treatment of rats with IMI decreased IMI and desipramine (DMI) hydroxylase activity while IMI demethylase activity was only slightly diminished. Kinetic study of IMI hydroxylation and N-demethylation (carried out in the presence or absence of DMI) indicated that DMI inhibited competitively IMI metabolism.

The effect of neuroleptics on imipramine demethylation in rat liver microsomes and imipramine and desipramine level in the rat brain.

A study of the cytochrome P-450 level and imipramine (IMI) demethylase activity in liver microsomes of rats treated concurrently with IMI and chlorpromazine (CPZ) or IMI and chlorprothixene (CPX) for two weeks were carried out. Concomitant administration of IMI and CPZ or IMI and CPX elevated the cytochrome P-450 level and accelerated IMI demethylation in in vitro study. Kinetic study of IMI demethylation carried out in the absence or in the presence of CPZ or CPX revealed that those neuroleptics inhibited IMI demethylation via competitive mechanism.

The effect of antidepressants on ethylmorphine and imipramine N-demethylation in rat liver microsomes.

The effects of single and multiple doses of desipramine, amitriptyline or citalopram on the rat liver microsomal cytochrome P-450 level and on the rate of ethylmorphine and imipramine demethylation in-vitro have been investigated. Desipramine, amitriptyline or citalopram when given to rats as a single dose, did not affect the level of cytochrome P-450 in the liver microsomes, however, there was a tendency towards acceleration of imipramine, and particularly ethylmorphine, demethylation. Prolonged administration of desipramine and citalopram, but not amitriptyline, elevated the microsomal level of cytochrome P-450 and accelerated the rate of ethylmorphine demethylation.

N-demethylase activity in the rat liver following morphine and haloperidol treatment.

A study of the liver N-demethylase activity in rats treated with different dosage schedule of morphine, or with a single dose of haloperidol was carried out. It was found that prolonged administration of morphine to rats inhibited the rate of ethylmorphine demethylation in vitro and diminished the liver cytochrome P450 level. Therefore, it could be assumed that the changes in N-demethylase activity did not play a substantial role in altering of morphine pharmacokinetics.

Inhibition of head twitch response to quipazine in rats by chronic amitriptyline but not fluvoxamine or citalopram.

Chronic (twice daily/14 days), but not acute, treatment with 10 mg/kg PO amitriptyline reduced the number of quipazine (5 mg/kg)-induced head twitches in rats, measured 2 h (but not 72 h) after the last administration of the drug. Similar treatment with fluvoxamine or citalopram, which are more potent and much more specific serotonin uptake inhibitors than amitriptyline, did not affect the quipazine-induced response. In acute experiments, fluvoxamine (10 mg/kg PO) and citalopram (10 mg/kg PO) potentiated the head twitch reaction induced by L-5-hydroxytryptophan (50 mg/kg IP) given together with Ro 4-4602 (25 mg/kg IP), a peripheral decarboxylase inhibitor.

Pharmacokinetics of morphine in striatum and nucleus accumbens: relationship to pharmacological actions.

The pharmacokinetics of morphine was compared with its ability to increase striatal dopamine turnover (estimated by an increase in DOPAC concentration) and to produce the development of a muscular rigidity (estimated as a tonic activity in the electromyogram). After systemic administration of morphine (15 mg/kg IP), the concentration of morphine in blood plasma, striatum and substantia nigra showed a parallel time course with a maximum after 30 min; in the striatum, in addition, normorphine was found in a lower concentration, but with a similar time course. The elevation of striatal DOPAC, in contrast, commenced very rapidly and lasted for about four hours.

Chronic dosage of imipramine in animal experiment: concentrations of imipramine and desipramine in the rat brain after various modes of dosage.

Concentrations of imipramine (IMI) and desipramine (DMI) in the rat brain after administration of IMI in aqueous solution by stomach gauge twice daily, in oil solution parenterally at 48 h intervals, and with drinking water were assayed. IMI administration with the drinking water for 21 days produced a pattern of the brain concentrations of IMI and DMI similar to that observed in rats receiving IMI by stomach tube for two weeks, at 12 h intervals. When IMI was given to rats ip in an oil solution at 48 h intervals for 10 days, the brain levels of both IMI and DMI were very high and rather stable during 48 h after administration of the last dose of IMI.

The role of trazodone metabolism in its inhibitory action on avoidance response.

To assess the role of trazodone metabolism in its depressant action on conditioned avoidance response we investigated whether in the mouse brain 3-chlorophenylpiperazine (CPP) is formed from trazodone, whether trazodone metabolism is affected by a drug metabolism inhibitor, proadifen, and how trazodone, CPP and their combinations act on avoidance responses in proadifen-pretreated mice. It was found that CPP is formed from trazodone in mice, that proadifen inhibits trazodone metabolism, and that the moderate and transient inhibitory effect of trazodone on avoidance responses is dramatically potentiated and prolonged in proadifen-pretreated mice. This effect, and inhibition of unconditioned escape response observed in mice receiving lower doses of trazodone after proadifen pretreatment, were counteracted by CPP.

Effects of some antidepressant drugs on apomorphine concentration in the central nervous system of rats and apomorphine-induced stereotypy.

Pharmacokinetic aspects of interaction between antidepressant drugs (AD) and apomorphine (APO) have been studied. It was found that neither acute nor chronic AD pretreatment affected the distribution of APO-induced stereotypy was not changed. An exception was citalopram (CIT) which given in a single dose to rats significantly potentiated APO-induced gnawing.

Prolongation of thiopentone-induced sleep by trazodone and its metabolite, m-chlorophenylpiperazine.

Trazodone and its metabolite, m-chlorophenylpiperazine (CPP) prolonged significantly thiopentone-induced sleep in mice. Neither trazodone, nor CPP changed the cerebral concentrations of thiopentone. As cyproheptadine by itself did not affect thiopentone sleep and did not antagonize the effect of CPP, the effect of trazodone and CPP seems to be independent of their respective 5-HT-antagonistic and 5-HT-agonistic properties.