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PubMed1995

Local 5HT3 receptors mediate fluoxetine but not desipramine-induced increase of extracellular dopamine in the prefrontal cortex.

Fluoxetine and desipramine, two antidepressants that block selectively the serotonin and the noradrenaline carrier, increase extracellular dopamine concentrations in the prefrontal cortex of freely-moving rats. This effect is calcium dependent and is prevented, in the case of fluoxetine but not desipramine, by systemic pretreatment with low doses or by low concentrations in the dialyzing Ringer of the potent 5-HT3 antagonist ICS 205930. Fluoxetine, but not desipramine, increases extracellular serotonin concentrations in the prefrontal cortex. The results indicate that selective serotonin reuptake blockers increase extracellular dopamine in the prefrontal cortex by stimulating local 5-HT3 receptors.

Animals↗

PubMed1990

Formation of cytotoxic metabolites from phenytoin, imipramine, desipramine, amitriptyline and mianserin by mouse and human hepatic microsomes.

The effects of enzyme induction on the generation of cytotoxic metabolites from phenytoin, mianserin, imipramine, desipramine and amitriptyline by mouse liver microsomes has been investigated and then compared with the bioactivation mediated by human hepatic microsomes. Cytotoxicity was assessed by co-incubation of drug and microsomes with human mononuclear leucocytes which served as target cells. Enzyme induction was assessed by measurement of hepatic cytochrome P-450 content, and determination of alkoxycoumarin O-dealkylase activity. None of the compounds investigated were metabolized to cytotoxic metabolites in the presence of control mouse microsomes. However, significant bioactivation could be observed for each drug when incubated with microsomes prepared from mice pretreated with either phenobarbitone (60 mg/kg) or beta-naphthoflavone (75 mg/kg). The rank order for metabolism-dependent cytotoxicity with phenobarbitone-induced mouse microsomes (expressed as % cell death) was phenytoin (14.6%) greater than desipramine (10.5%) greater than imipramine (7.5%) greater than mianserin (3.4%) greater than amitriptyline (3.1%). Expression of cytotoxicity with phenytoin required pre-exposure of the target cells to trichloropropane oxide, an opoxide hydrolase inhibitor. Only mianserin and desipramine were activated to cytotoxic metabolites by human liver microsomes. Analysis of stable metabolites revealed that mianserin underwent extensive (greater than 80%) metabolism by both control and induced mouse microsomes and that the principal metabolites, 8-hydroxymianserin, desmethylmianserin and mianserin N-oxide, were the same as those produced by human liver microsomes. These data suggest that mianserin is activated to a cytotoxic metabolite selectively by a constitutive form of human cytochrome P-450, whereas phenytoin, amitriptyline and imipramine are selectively activated by forms of mouse cytochrome P-450 which are induced by either phenobarbitone or beta-naphthoflavone.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1993

Noradrenergic mechanisms for the anticonvulsant effects of desipramine and yohimbine in genetically epilepsy-prone rats: studies with microdialysis.

A large body of evidence suggests that the seizure-prone state of genetically epilepsy-prone rats (GEPRs) results, in part, from deficits in central nervous system noradrenergic function. In order to link the synaptic concentration of norepinephrine (NE) to seizure behavior, we evaluated the effects of both desipramine and yohimbine on convulsions and on extracellular NE and serotonin (5-HT) concentrations in the thalamus of severe seizure GEPRs (GEPR-9s). Under anesthesia, guide cannulae were stereotaxically placed over thalami. After recovery from surgery, dialysis probes were inserted and the animals were placed individually into a plexiglass chamber where they were allowed to move about freely. Artificial CSF was perfused and samples were collected for analysis on HPLC with electrochemical detection. Either desipramine (10 and 20 mg/kg) or yohimbine (10 mg/kg) was administered i.p. after a stable baseline of NE or 5-HT was established. Significant increases in the extracellular NE concentration were seen after injection of both drugs. Temporal linkage exists between the maximum NE increase and the maximum decrease in audiogenic response score (ARS) for these two agents. No significant increases in the extracellular 5-HT concentration occurred after administration of either desipramine or yohimbine at a dose of 10 mg/kg. We conclude that these two drugs are effective anticonvulsants in GEPRs at least partially because they enhance noradrenergic transmission.

Animals↗

PubMed1996

Involvement of GABAB receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats.

Involvement of GABAergic systems in action of antidepressants was examined in the learned helplessness paradigm in rats. Rats were treated with desipramine, baclofen or muscimol for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks induced the subsequent increase in escape failures in the escape test. Desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of desipramine, although baclofen had no effects on the increased escape failures when it was injected alone. Muscimol at any dose failed to influence the increased escape failures. Therefore, it is suggested that the long-term decrease in GABAB neurotransmission may be involved in the action of antidepressants. Our present results do not support the hypothesis that activation of GABAA receptors may contribute to the action of antidepressants.

Animals↗

PubMed1978

The influence of cocaine and desipramine on the cardiac responses to exogenous and endogenous norepinephrine.

In open-chest, anesthetized dogs, cocaine and desipramine potentiated the pressor, chronotropic, inotropic and coronary sinus blood flow responses to norepinephrine (NE) infusions. The chronotropic and inotropic responses were also prolonged, the former more markedly than the later and the extraction of exogenous NE from the coronary blood stream was diminished. Cocaine and desipramine also potentiated the pressor and coronary sinus blood flow responses, but not the chronotropic or inotropic responses, to stimulation of the left ansa subclavia. The inotropic response was slightly prolonged, however, and the chronotropic response was markedly prolonged. The overflow of NE into the coronary sinus blood was not increased by either neuronal uptake blocking agent. It is proposed that cocaine and desipramine, at the doses employed, diminish the release of NE from the cardiac nerve endings at the same time that they inhibit reuptake of the neurotransmitter. Their mechanisms of action and their side effects on the circulatory system do not appear to differ significantly.

Animals↗

PubMed1985

Why is amitriptyline much weaker than desipramine at decreasing beta-adrenoceptor numbers?

Desipramine is consistently more effective than amitriptyline at causing beta-adrenoceptor down-regulation. Atropine, mepyramine, ketanserin, cyproheptadine and citalopram did not modify this action of desipramine in rats. Therefore inhibition of either muscarinic, histamine-H1, and 5-HT receptors or 5-HT uptake produced by amitriptyline is unlikely to account for its weaker effect on beta-adrenoceptors. A more likely explanation implicates noradrenaline uptake inhibition in vivo since amitriptyline was much weaker than desipramine and only effective after repeated dosing.

Amitriptyline↗

PubMed1987

A comparison of the neurochemical and behavioral effects of clenbuterol and desipramine.

Because both long-term adrenoceptor agonist administration and antidepressant treatment in animals down-regulate CNS beta-adrenoceptors and attenuate brain adenylate cyclase activity, beta-adrenoceptor agonists may also possess antidepressant properties. We compared the effects of the centrally acting beta-adrenoceptor agonist clenbuterol (5, 10 and 35 mg/kg per day), and the combination of propranolol (5 mg/kg per day) and clenbuterol (10 mg/kg per day), with desipramine (15 mg/kg per day) on forced swim test performance and on cortical beta-adrenoceptors in rats following 7 days of drug administration. Desipramine (15 mg/kg per day), and clenbuterol (10 and 35 mg/kg per day, but not 5 mg/kg per day) both significantly reduced immobility in the forced swim test. Frontal cortex beta-adrenoceptors were significantly down-regulated after desipramine and all 3 doses of clenbuterol. The co-administration of propranolol (5 mg/kg per day) blocked both the reduction in immobility and down-regulation of cortical beta-receptors induced by clenbuterol (10 mg/kg per day). Propranolol (5 mg/kg per day) alone up-regulated frontal cortex beta-adrenoceptors, but had no significant effect on swimming performance. These data suggest that the physiological consequences of beta-adrenoceptor down-regulation are important in the mechanism of action of antidepressants. The results also suggest that clenbuterol may be useful in the treatment of depression.

Animals↗

PubMed1988

Forced swimming test in rats: effect of desipramine administration and the period of exposure to the test on struggling behavior, swimming, immobility and defecation rate.

The effect of desipramine administration and the duration of the daily exposure to forced swimming on some variables has been studied in adult male rats. Desipramine administration (15 mg/kg) significantly increased struggling behavior in the first and second 5-min periods of a single exposure to forced swimming. Swimming was reduced in the first 5 min and remained unchanged thereafter. Immobility was decreased in the second and the third 5-min periods. After a pre-exposure to forced swimming for 15 min the day before, the drug was effective in increasing struggling behavior and reducing immobility during a subsequent 5-min test. Swimming was not modified. Daily exposure to forced swimming for 3 days caused a decline in struggling behavior and swimming, while increasing immobility and the defecation rate. The duration of daily exposure to forced swimming did not alter the changes in the variables measured. The present results indicate that a one-day test can be used to discriminate between saline- and desipramine-treated rats, and that struggling behavior could be a reliable measure of the positive action of antidepressants. The finding that behavioral changes over the 3 days were independent of the duration of exposure to swimming argues against the interpretation of the results which suggest that the responses are caused by the appearance of a behavioral despair state, and suggests that these behaviors might be trait-markers in the rat. In addition, the changes in struggling behavior and immobility over the 3 days cannot be attributed to a behavioral adaptation to the test because the defecation rate increased rather than decreased during successive forced swimming tests.

Animals↗

PubMed1993

Effects of clonidine on desipramine- and desmethylclomipramine-induced 3-methoxy-4-hydroxyphenylglycol levels in rat brain.

Rats received repeated i.p. administrations of desipramine (20 mg/kg) or desmethylclomipramine (10 mg/kg). The steady state concentration of each drug in the brain was attained a few days after the start of the treatment. The treatments with desipramine and desmethylclomipramine for more than 10 and 2 days, respectively, induced significant elevation of 3-methoxy-4-hydroxyphenylglycol (MHPG) level in the brain. After repeated administration of each drug, rats were given a single i.p. injection of clonidine (50 micrograms/kg). This treatment decreased the elevated MHPG level in the brain of desmethylclomipramine-treated rats, whereas it had no effect on the increased MHPG level in desipramine-treated rats.

Animals↗

PubMed1993

Effects of diazepam and desipramine in the forced swimming test: influence of previous experience with the situation.

The effects of desipramine and diazepam on the behavior of rats in the forced swimming test were studied. Desipramine significantly enhanced struggling behavior, the intensity of its effect being greater in rats previously exposed to the forced swimming test for 1 or 4 days before drug administration. The effect of desipramine on immobility was significantly only in rats previously exposed to the test. Acute diazepam administration did not modify the behavior of rats in the test. Chronic administration (6 days) of two different doses of diazepam did not alter the behavior of rats in the forced swimming test, but significantly decreased the defecation rate, suggesting that the drug was effective as an anxiolytic. The present results suggest that the behavior of rats in the forced swimming test might be related to mood states rather than to fear/anxiety and that efficacy of the test to detect antidepressant activity might be enhanced by repeated exposure of the rats to the situation.

Animals↗

PubMed1996

Effects of desipramine and maprotiline on the coeruleus-cortical noradrenergic system in anaesthetized rats.

Desipramine (1-3000 micrograms/kg i.v.) and maprotiline (1-10,000 micrograms/kg i.v.), two selective noradrenaline uptake blockers, inhibited the firing rate of noradrenergic locus coeruleus neurons and induced excitation of the prefronto-cortical neurons. The selective destruction of ascending noradrenergic pathways by intracerebroventricular injection of 6-hydroxydopamine antagonized the excitatory effect of desipramine and maprotiline on the prefronto-cortical neurons. These results suggest that desipramine and maprotiline dose dependently stimulate the electrical activity of prefronto-cortical neurons, probably by acting on noradrenergic cells of the locus coeruleus.

Animals↗

PubMed1985

Down-regulation of beta-adrenoceptors in rat cortex by repeated administration of desipramine, electroconvulsive shock and clenbuterol requires 5-HT neurones but not 5-HT.

Repeated administration to rats of desipramine (5 mg kg-1, twice daily for 14 days), clenbuterol (5 mg kg-1, twice daily for 14 days) or electroconvulsive shocks (5 ECS over 10 days) decreased the number of beta-adrenoceptors in the cortex. Injection of 5,7-dihydroxytryptamine into the lateral ventricle produced a selective depletion of cerebral 5-HT, particularly in the cortex. In confirmation of earlier studies, this lesion prevented the decrease in the number of beta-adrenoceptors produced by desipramine. However, it was found that this lesion also prevented the down-regulation of beta-adrenoceptors produced by repeated electroconvulsive shock and administration of clenbuterol. Treatment of rats with p-chlorophenylalanine (PCPA) produced a similar depletion of cerebral content of 5-HT. However, this depletion did not prevent the decrease in density of beta-adrenoceptors induced by desipramine or electroconvulsive shock. It is concluded that the modulation of the decrease in the number of beta-adrenoceptors by diverse antidepressant treatments is not by the action of 5-HT itself, but by the action of some other factor present at 5-HT terminals, which is removed by a neurotoxic lesion.

5,7-Dihydroxytryptamine↗

PubMed1986

Opioid receptors in the brain of the rat following chronic treatment with desipramine and electroconvulsive shock.

The effect of chronic administration of electroconvulsive shock and the antidepressant drug desipramine on binding to opioid receptors was studied in the cerebral cortex, the basal ganglia and the hippocampus of the forebrain of the rat. In vitro, desipramine inhibited the binding of enkephalinamide to opioid receptors through a reduction in the number of binding sites, whereas the affinity was unchanged or only slightly decreased. In vivo desipramine, injected daily (10 mg/kg) for three weeks, did not change the number of opioid binding sites in the forebrain of the rat. Chronic electroconvulsive shock, given twice a week for three weeks, had no effect on the number of opioid binding sites in the forebrain of the rat. The data do not support the hypothesis of shared effects of lithium, tricyclic antidepressants and electroconvulsive shock on the opioid peptide-opioid receptor systems.

Animals↗

PubMed1987

Evidence that dopamine mechanisms in the nucleus accumbens are selectively involved in the effect of desipramine in the forced swimming test.

Bilateral injections of 5 or 1 (but not 0.5) micrograms sulpiride into the nucleus accumbens reduced the effect of a 7-day treatment with 10 mg/kg/day desipramine in the forced swimming test. Bilateral injections of 5 or 1 micrograms sulpiride in the caudate-putamen did not modify the anti-immobility effect of desipramine. The data support the hypothesis that dopamine mechanisms in the limbic regions of the brain of the rat are involved in the effect of repeated treatment with desipramine in the forced swimming test.

Animals↗

PubMed1990

Intrathecal administration of thiorphan, bestatin, desipramine and fluoxetine differentially potentiate the antinociceptive effects induced by beta-endorphin and morphine, administered intracerebroventricularly.

The effects of the intrathecal injection of thiorphan (an inhibitor of enkephalinase inhibitor), bestatin (an inhibitor of aminopeptidase), desipramine (an inhibitor of the uptake of noradrenaline) and fluoxetine (an inhibitor of the uptake of serotonin) on the antinociception induced by beta-endorphin and morphine, administered intracerebroventricularly, were studied in male ICR mice. Antinociceptive effects were assessed by the tail-flick and hot-plate tests. Thiorphan (16 micrograms) and bestatin (16 micrograms), injected intrathecally, potentiated inhibition of the tail-flick response, induced by beta-endorphin but not by morphine administered intracerebroventricularly, whereas desipramine (6 micrograms) and fluoxetine (6 micrograms), injected intrathecally potentiated inhibition of the tail-flick response induced by morphine, but not by beta-endorphin, administered intracerebroventricularly. Thiorphan, bestatin, desipramine or fluoxetine, given intrathecally, did not antagonize inhibition of the hot-plate response, induced by beta-endorphin or morphine administered intracerebroventricularly. The results indicate that inhibition of the tail-flick response, induced by beta-endorphin administered intracerebroventricularly, is mediated by the opioid system, but not by noradrenergic and serotonergic systems in the spinal cord. On the other hand, the inhibition of the tail-flick response, induced by morphine given intracerebroventricularly, is mediated by noradrenergic and serotonergic systems, but not by the opioid system in the spinal cord. The lack of effect of enzyme inhibitors and inhibitors of the uptake of biogenic amines intrathecally on beta-endorphin- and morphine-induced inhibition of the hot-plate response, is due to the supraspinal nature of the nociceptive hot-plate response. The present results further support the hypothesis, proposed previously, that intracerebroventricularly injected beta-endorphin and morphine elicit antinociception by activating different descending inhibitory systems.

Analgesics↗

PubMedDate not supplied

Lack of effect of desipramine on the response to chloroquine of patients with chloroquine-resistant falciparum malaria.

The potential of desipramine to improve the efficacy of chloroquine against chloroquine-resistant Plasmodium falciparum in vivo in man was investigated. Fifty-three malaria patients were selected according to the criteria for the standard World Health Organization (WHO) in vivo test and were randomly divided in 2 groups. One group (n = 27) was given standard therapeutic doses of chloroquine (25 mg/kg body weight of base) and the other (n = 26) was given standard doses of chloroquine, as above, in combination with desipramine (1.3-2.8 mg/kg body weight) daily for 3 consecutive days. Standard WHO in vitro micro-tests were performed in parallel with the tests in vivo to provide chloroquine sensitivity patterns of the P. falciparum parasites. The results in vitro from both groups did not differ with regard to chloroquine sensitivity and the means of the pre-treatment parasite densities were similar. There was no apparent difference in parasite clearance in vivo between the 2 groups. This study provided no evidence for enhanced chloroquine efficacy in vivo through the use of desipramine in doses corresponding to the usual therapeutic range.

Animals↗

PubMed1986

Changes in brain catecholamine levels following olfactory bulbectomy and the effect of acute and chronic administration of desipramine in rats.

Bilateral olfactory bulbectomy of the rat caused marked changes of noradrenaline level in several brain regions accompanied with the development of mouse-killing behavior (muricide). Noradrenaline level increased in the medial amygdala, ventromedial and lateral hypothalamus in muricidal olfactory bulbectomized rats (OB rats) but not in non-muricidal OB rats, while dopamine level decreased in the lateral hypothalamus in muricidal OB rats. Acute administrations of desipramine not only suppressed muricide of OB rats but normalized noradrenaline change in ventromedial hypothalamus and dopamine change in lateral hypothalamus. Chronic administration of desipramine also suppressed muricide and normalized noradrenaline changes in ventromedial and lateral hypothalamus and medial amygdala. These findings suggest that the increase in noradrenaline levels in the medial amygdala, ventromedial and lateral hypothalamus may be important for the induction of muricide in OB rats, and muricide was suppressed by desipramine in accordance with the normalization of increased noradrenaline levels, and that the change in dopaminergic function in the lateral hypothalamus may also be important for this muricide.

Aggression↗

PubMed1987

Increased adult behavioral 'despair' in rats neonatally exposed to desipramine or zimeldine: an animal model of depression?

Occurrence of depressive behavior at mature age was studied in rats exposed neonatally to antidepressant drugs. Early antidepressant treatments have been shown to increase voluntary alcohol consumption and the percentage of rapid-eye-movement (REM) sleep relative to total sleep time in adult rats as well as to cause long-lasting reduction in the concentrations of monoamines in the forebrain. In the present study rats were daily given either 5 mg/kg desipramine or 25 mg/kg zimeldine from the 7th to the 18th postnatal days. When they were 2 months and 5 months of age behavioral 'despair' was studied by using a modified version of Porsolt's swim-test. At both ages the desipramine-treated and zimeldine-treated rats expressed lengthened immobility times in the water pail. The findings indicate that neonatal exposure of rats to desipramine or zimeldine induces behavioral 'despair' at mature age. Thus, early exposure of rats to antidepressants causes long-lasting behavioral disorders, and, moreover, may be used to devise an animal model of subsequent depression.

Animals↗