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PubMed1987

[3H]desipramine labels with high affinity the neuronal transporter for adrenaline in the frog heart.

Desipramine, a tricyclic antidepressant, inhibits the neuronal uptake of adrenaline and noradrenaline and, as a radioligand, labels the noradrenaline transporter in central and peripheral tissues of the rat. To study whether [3H]desipramine also labels the neuronal adrenaline transporter in vitro, its binding was evaluated in the frog heart, a tissue with a rich adrenergic innervation but virtually devoid of noradrenergic innervation. [3H]Desipramine binding to membranes from the frog heart was of high affinity (Kd = 1.94 nM) and was potently inhibited by nisoxetine and (+)oxaprotiline. Unexpectedly, [3H]desipramine binding to the transporter for adrenaline in the frog heart was also sensitive to inhibition by imipramine and the atypical antidepressants mianserin and iprindol. This is the first study to demonstrate radioligand binding to the neuronal transporter for adrenaline. The results indicate that the pharmacological profile of the transporter for adrenaline may be different from that of the noradrenergic transporter, if species differences can be excluded. It remains to be established if the affinity of imipramine, mianserin and iprindol for the adrenaline transporter contributes to their therapeutic efficacy in depression.

Animals↗

PubMed1987

Chronic desipramine treatment prevents the upregulation of cortical beta-receptors caused by a single dose of the benzodiazepine inverse agonist FG7142.

The beta-carboline FG7142 is a partial inverse agonist at benzodiazepine receptors. We have shown previously that a single dose of this drug causes an upregulation of cortical beta-adrenoceptor numbers in mouse cerebral cortex. This rise was seen seven days, but not 15-30 min or 24 h after FG7142 administration. We now report that two weeks pretreatment with the tricyclic antidepressant desipramine prevented the beta-adrenoceptor upregulation after a single dose of FG7142, although desipramine alone did not alter beta-adrenoceptor number. We also studied the effects of desipramine pretreatment on other pharmacological effects of FG7142 to see which of these effects might be related to the beta-adrenoceptor changes. Desipramine pretreatment caused a small, but significant, decrease in the depression of locomotor activity, but no change in the hypothermic action of FG7142. The possibility that upregulation of beta-adrenoceptors by FG7142 may be related to the behavioural actions of this compound is discussed.

Animals↗

PubMed1987

Further evidence that noradrenaline is not involved in the anti-immobility activity of chronic desipramine in the rat.

The effect of 10 mg/kg per day desipramine for 7 days on performance in the forced swimming test was studied in rats given various treatments aimed at reducing central noradrenergic transmission. 6-Hydroxydopamine-induced destruction of noradrenaline-containing neurons originating in the locus coeruleus or ascending in the ventral bundle had no effect on the anti-immobility activity of desipramine. Likewise, no changes in the effect of desipramine were seen with an intraperitoneal injection of DSP-4 (50 mg/kg) which destroyed brain noradrenergic neurons, particularly those of the dorsal bundle ascending to the forebrain. The results argue against a role of noradrenaline in the mechanism by which repeated treatment with desipramine reduces the immobility of rats in the forced swimming test.

Animals↗

PubMed1990

The role of the mesolimbic dopaminergic system in the desipramine effect in the forced swimming test.

The effects of sulpiride isomers injected into the nucleus accumbens on the anti-immobility activity of desipramine in rats were studied to clarify the role of dopamine receptors. (-)-Sulpiride 100 ng/0.5 microliters injected bilaterally into the nucleus accumbens 5 min before testing reduced the effect of a 7-day treatment with 10 mg/kg per day desipramine in the swimming test but 5 micrograms/0.5 microliter (+)-sulpiride injected in the same area had no effect. Fluphenazine, 5 micrograms/0.5 microliter, or 6-hydroxydopamine-induced depletion of dopamine in the nucleus accumbens also reduced the anti-immobility effect of desipramine. The data further support the hypothesis that dopamine transmission in the nucleus accumbens has a permissive role in the effect of desipramine in the forced swimming test.

Animals↗

PubMed1991

Inhibition of sympathetic nerve activity by acute administration of the tricyclic antidepressant desipramine.

In rats anesthetized with pentobarbital/chloral hydrate, the i.v. injection of desipramine (0.3 mg/kg) caused a rapid fall in mean arterial blood pressure accompanied by a reduction in efferent renal nerve integrated activity. A similar reduction in electrical activity was seen in the preganglionic splanchnic nerve. Pretreatment of the rats with yohimbine (0.3 mg/kg) increased renal nerve activity by 20%, and the decrease in blood pressure and renal nerve activity elicited by a subsequent dose of desipramine was blocked. I.v. injection of prazosin (0.05 mg/kg) caused a reduction in systemic blood pressure. The hypotensive effect of a subsequent dose of desipramine was largely blocked, whereas the fall in renal nerve activity was attenuated, but still present. The data are consistent with an action of desipramine to reduce central sympathetic tone by increasing the release of endogenous noradrenaline which acts on alpha 2-adrenoceptors at CNS sites controlling sympathetic activity. An additional involvement of central alpha 1-adrenoceptors cannot be ruled out.

Animals↗

PubMed1993

Differential effects of desipramine on direct- and sensory-evoked noradrenaline release in thalamic locus coeruleus terminals.

The effects of desipramine on sensory-evoked (sciatic nerve stimulation) activation of locus coeruleus neurones were investigated in vivo by using treated carbon-fibre electrodes in conjunction with either differential normal pulse voltammetry or differential pulse amperometry. Firstly, the amplitude of the sensory-evoked increase in extracellular noradrenaline, monitored in thalamic locus coeruleus terminals, was not modified by desipramine (10 mg/kg), whereas that evoked by direct activation of locus coeruleus neurones was greatly increased: +143% for dorsal noradrenergic bundle stimulation and +761% for glutamate ejection in the locus coeruleus. Secondly, desipramine administered at the same dose significantly reduced (-48%) the activation of locus coeruleus neurones (monitored at the somato-dendritic level) evoked by prolonged sciatic nerve stimulation. Our results indicate that acute treatment with desipramine does not potentiate overall noradrenergic transmission by locus coeruleus neurones during sensory stimulation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Triiodothyronine increases desipramine with changing the concentrations of monoamines, in the brain of rat given imipramine.

After treatment with triiodothyronine (T3) for 5 days, rats received a single i.p. injection of imipramine. The concentrations of imipramine and desipramine decreased and increased, respectively, in the brains of T3-treated rats, and the elimination half-time of desipramine was increased. In rats that had received imipramine for 7 days, cotreatment with T3 also resulted in reduced imipramine and elevated desipramine concentrations in the brain. Coadministration of T3 with imipramine appeared to accelerate the desipramine-induced changes in norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations in brain. Since T3 treatment elevated the 5-hydroxyindole acetic acid concentration in the brain, the concentration in rats receiving both drugs was equivalent to that of vehicle-treated rats.

Animals↗

PubMed1994

Chronic variable stress enhances the stimulatory action of a low dose of morphine: reversal by desipramine.

Adult male rats were exposed to a chronic variable stress treatment, an animal model of depression, with or without concurrent daily administration of desipramine. Animals given chronic and variable stress were submitted daily to a different stressor following an injection of either saline or desipramine (5 mg/kg, i.p.), whereas control animals were unmanipulated except for the injection process. One day after the last event of the chronic procedure, control and stressed animals were administered saline or morphine (0.75 or 1.5 mg/kg, i.p.) and their locomotion assessed for 90 min. In an additional experiment, 24 h after the last stressor, stressed and control rats were challenged with either saline or one of two higher doses (behaviorally suppressant) of morphine (5 and 10 mg/kg, i.p.). A significantly greater increase in locomotor activity following a low dose (1.5 mg/kg) of morphine was observed in chronically stressed rats as compared to control rats. This potentiated locomotor response to morphine in stressed rats was prevented by desipramine pretreatment. The chronic and variable stress treatment did not modify the sedative response to the high doses of morphine. These data support the suggestion that a chronic and variable stress procedure results in sensitization to the stimulant effect of opioid stimulation, and that pretreatment with the antidepressant agent desipramine blocks the development of this sensitization.

Animals↗

PubMed1996

Desipramine treatment differently down-regulates beta-adrenoceptors of freshly isolated neurons and astrocytes.

Eight days' desipramine administration (16 mg/kg per day i.p.) to rats resulted in a significant decrease in the density of beta-adrenoceptors in neuronal and astroglial cells from rat forebrain and cerebellum without modification of their corresponding affinity. beta-Adrenoceptor subtypes, beta 1 and beta 2, which coexist in neurons and astrocytes, are differently distributed in the brain and differently modified by desipramine administration which down-regulates beta 1-adrenoceptor in forebrain neurons and astrocytes and beta 2-adrenoceptor in cerebellum neurons. This down-regulation affects the predominant subtype, beta 1 or beta 2, of the relevant structure. Astroglial and neuronal beta-adrenoceptors are differently coupled to G-proteins. Only neuronal cells contain the high-affinity conformational state of the beta-adrenoceptors which is sensitive to GTP. The percentage of neuronal receptors in the high-affinity state differs according to brain area. Desipramine treatment decreases the neuronal density of both cerebellar high- and low-affinity sites and only the forebrain high-affinity site. The desipramine effects are thus subtype-dependent and differ between the two brain areas selected.

Adrenergic Uptake Inhibitors↗

PubMed1985

Effects of desipramine on cardiovascular responses of rats to stimulation of the baroreceptor reflex and of central adrenoceptors.

Phenylephrine (0.4-2.0 micrograms 300 g-1), injected intravenously, evoked similar dose-dependent increases in blood pressure in untreated rats and in rats treated with desipramine (10 mg kg-1 day-1 for 4 weeks). The (dose-dependent) reflex fall in heart rate to the blood pressure responses were smaller in the rats treated with desipramine. Treatment with desipramine did not affect the bradycardia evoked by intrahypothalamic injection of phenylephrine (10 micrograms). After treatment with desipramine, the hypotension evoked by intrahypothalamic injection of isoprenaline (10 micrograms) was enhanced whereas the evoked tachycardia was diminished.

Adenylyl Cyclases↗

PubMed1987

Desipramine and noradrenergic neurotransmission in aging: failure to respond in aged laboratory animals.

Deficiencies in noradrenergic neurotransmission have been found in the central nervous system of aged laboratory animals. The purpose of the present study was to determine if tricyclic antidepressants, such as desipramine, can overcome the diminished noradrenergic neurotransmission found in these animals. Using electrophysiological techniques, noradrenergic neurotransmission was examined in the cerebellar cortex of rats, a model system which has been used extensively to characterize the effects of norepinephrine in the central nervous system. The discharge rate of cerebellar Purkinje neurons is very sensitive to changes in the noradrenergic input from the nucleus locus coeruleus. In this model system in young rats, treatment with desipramine slowly augments noradrenergic neurotransmission over several weeks. Similar treatment in aged animals caused no increase in the age-related deficient noradrenergic neurotransmission. The decline in efficacy of desipramine with age could not be accounted for by differences between young and old rats in the distribution of the drug. Failure of desipramine to be effective in older rats may reflect the insensitivity of aged neurons to norepinephrine itself, so that treatment strategies which increase the amount of nerepinephrine released onto these neurons may be ineffective. The findings may have implications for the use of tricyclic antidepressants in aged depressed patients.

Action Potentials↗

PubMed1989

Desipramine in small doses induces antinociception in the increasing temperature hot-plate test, but not in the tail-flick test.

The data reported for the antinociceptive effect of tricyclic antidepressants are conflicting. In this investigation, the effect of acute intraperitoneal (i.p.) administration of desipramine (2 and 5 mg/kg) was studied in rats, using the tail-flick test with simultaneous measurement of tail-skin temperature, and the increasing temperature hot-plate test. A constant negative correlation between tail-flick latency and tail-skin temperature, as described earlier, was also found in this study. Different ambient temperatures influenced the results of the tail-flick test. At an ambient temperature of 24-25 degrees C, desipramine gave rise to an apparent antinociception in the tail-flick test, which was found to be caused by a relative fall in tail-skin temperature. At 21-22 degrees C, no change in tail-flick latency was found after the administration of desipramine. In the increasing temperature hot-plate test, however, a dose-dependent antinociceptive effect of desipramine was observed at both ambient temperatures. The strong influence of moderate differences in ambient temperature on the results of the tail-flick test may explain some of the conflicting results reported in the literature. Whenever this test is used, the temperature of the tail should be recorded and taken into account in the evaluation of the data.

Animals↗

PubMed1992

Desipramine desensitizes beta-adrenergic signal transduction in rat salivary glands.

The consequences of the tricyclic antidepressant drugs include sedation, orthostatic hypotension and salivary dysfunction. It was reported that administration of desipramine resulted in a decrease in the concentration of secreted salivary protein. Tricyclic antidepressants may indirectly alter salivary function as a result of their action on the central nervous system to decrease adrenergic neural transmission or, alternately, may act directly on salivary glands to modulate beta-adrenergic signal transduction. To investigate the latter possibility, the effects of administration of desipramine (DMI) for 28 days was assessed on beta-adrenergic and post-receptor signal transduction in the parotid and submandibular glands of the rat and the reversibility of this treatment following a washout period of 15 days. Both glands demonstrated desensitization of the isoproterenol-stimulated activity, and in the parotid gland treatment with DMI decreased the post-receptor signal transduction as well. The washout period of 15 days completely reversed the desensitization in the parotid gland and partially reversed the effects in the submandibular gland. These data suggest that desipramine-induced attenuation of beta-adrenergic signal transduction is not limited to the brain and that these direct effects on salivary glands may explain the salivary dysfunction observed after administration of desipramine.

Adenylyl Cyclases↗

PubMedDate not supplied

Reversal of chloroquine resistance with desipramine in isolates of Plasmodium falciparum from Central and West Africa.

Twenty freshly isolated strains of Plasmodium falciparum from non-immune and semi-immune patients infected in Central and West Africa were tested for in vitro drug sensitivity to chloroquine alone and to a combination of chloroquine and desipramine without prior adaptation to continuous culture. Combination of desipramine at 625 nmol/litre and chloroquine reversed resistance totally (IC50 less than 100 nmol/litre) in all 14 chloroquine-resistant isolates. No effect on chloroquine sensitivity was noted in the 6 chloroquine-sensitive isolates. These observations provide additional evidence that reversal of chloroquine resistance in the presence of desipramine is not a phenomenon unique to culture-adapted strains and that desipramine may exert the same potentiating effect in vivo, provided that effective plasma concentration can be attained without serious side-effects.

Animals↗

PubMed1988

Long-term effects of inescapable stress on daily running activity and antagonism by desipramine.

The behavioral consequences of exposure to stressors such as inescapable shock are usually transitory if testing is conducted in an environment different from that in which the stressor was administered. The behaviors tested have generally been motivated by discrete stimuli in the environment (e.g., activity in reaction to shock) or have been part of homeostatic regulatory mechanisms (e.g., eating). Here we investigated the effects of inescapable shock on a behavior that is not so tightly tied to motivating and reinforcing conditions, daily activity in a familiar home cage/running wheel environment. Rats lived in the wheel environment for 44-85 days before treatment. Inescapable shock produced only a transient reduction of water intake and body weight, but daily running was depressed for 14-42 days (the maximum period studied) depending on the conditions. This long-term effect on activity occurred despite the fact that shock was administered in an environment very different from the animal's home running wheel environment. The activity reduction was reversed by desipramine in a dose dependent fashion. Indeed, the activity of inescapably shocked animals treated with the optimum dose of desipramine exceeded that of control animals undergoing neither stress nor drug treatment. The maximum effect of desipramine required 7 days of treatment. Desipramine did not affect the activity of control subjects.

Animals↗

PubMed1995

Noradrenergic denervation attenuates desipramine enhancement of aggressive behavior in isolated mice.

The effects of denervation of central noradrenergic system on the desipramine-induced enhancement of aggressive behavior were examined in long-term isolated mice. Consistent with previous reports, desipramine (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice. Pretreatment of isolated mice with DSP-4, a selective noradrenaline neurotoxin, significantly attenuated the enhancing effect of desipramine on aggressive behavior without affecting the basal aggressive responses. This effect appeared concomitant with decrease of noradrenaline levels in the cortex, hippocampus, cerebellum and hypothalamus (78%, 75%, 57%, and 17%, respectively). DSP-4 did not significantly affect dopamine or 5-HT levels in these regions. These results suggest that noradrenergic terminals originating mainly from the locus coeruleus play an important role in the desipramine enhancement of aggressive behavior, but not in the basal aggressive behavior of isolated mice.

Aggression↗

PubMed1985

Modification by desipramine of the effects of alpha-adrenoceptor antagonists on the contractile responses of the trisected rat vas deferens.

Desipramine at 10(-7) M inhibited the neuronal uptake of noradrenaline and at 10(-6) M was also a alpha 1-adrenoceptor blocker. Desipramine potentiated and inhibited the responses of the epididymal and other portions to field stimulation, respectively, probably because the increased concentration of noradrenaline in the synapse was stimulating postjunctional alpha 1- and prejunctional alpha 2-adrenoceptors, respectively. Qualitatively the effects of prazosin, phentolamine and yohimbine on responses to added noradrenaline and to field stimulation were consistent with their being alpha 1-selective, nonselective and alpha 2-selective adrenoceptor antagonists. Quantitatively the effects of phentolamine and/or yohimbine on fast and slow responses to field stimulation and the modification of these effects by desipramine were dependent on the portion of vas, the response, the frequency of stimulation and the concentration of desipramine used.

Adrenergic alpha-Antagonists↗

PubMed1990

Schedule-induced oral self-administration of cocaine and ethanol solutions: lack of effect of chronic desipramine.

Groups of rats drinking either solutions of cocaine HCl (0.16 mg/ml), ethanol (2.5% v/v), or water, drank excessive, equivalent volumes in daily, 3-h sessions of food-pellet delivery under a fixed-time 1-min (FT 1-min) schedule. During single-session exposures to pellet-delivery schedules using longer inter-pellet values (FT 3- or 5-min probe sessions), the cocaine and ethanol groups, but not the water group, drank greater ml/pellet amounts, confirming previous research. Inasmuch as enhanced ml/pellet intake during the greater FT probes correlated with the abuse potential of the drinking solution in previous research, the effect of chronic desipramine HCl (2 mg/kg, i.p. daily) on this enhanced intake response was determined. For all groups, chronic desipramine treatment (2 mg/kg was judged to be the maximum dose free of non-specific, suppressive effects) affected neither FT 1-min schedule-induced polydipsia nor did it affect the enhanced ingestional response to the greater FT probes for the cocaine and ethanol groups. Chronic administration of desipramine may have therapeutic efficacy in treating cocaine abuse only in subjects attempting to refrain from cocaine who are aided in their passage through a withdrawal phase by desipramine.

Alcohol Drinking↗