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PubMed1985

DMI, Wy-45,030, Wy-45,881 and ciramadol inhibit locus coeruleus neuronal activity.

Wy-45,030 and Wy-45,881 block the uptake of norepinephrine and serotonin in rat brain synaptosomal preparations and share several in vivo and in vitro effects with known tricyclic antidepressants. To further characterize their activity, these compounds were compared to desipramine and ciramadol in electrophysiological studies of their acute effects on noradrenergic neuronal activity. All four compounds inhibited locus coeruleus neuronal activity with a rank order of potency of desipramine greater than Wy-45,881 greater than Wy-45,030 greater than ciramadol. Administration of the alpha-adrenergic blocking drug, piperoxane, increased locus coeruleus firing rate after desipramine, Wy-45,030 and Wy-45-881. Pretreatment with naloxone prevented the reduction in locus coeruleus impulse flow observed after ciramadol administration but had no effect on the inhibition produced by Wy-45,030. Wy-45,030 and Wy-45,881, like classical antidepressants, appear to inhibit locus coeruleus neuronal firing by potentiating neuroinhibitory transmission of locus coeruleus neurons by blocking the uptake of norepinephrine into presynaptic terminals.

Animals↗
PubMed1987

Characterization of the release of neuropeptide Y (NPY) induced by tyramine from synaptosomal preparations of rabbit jejunum.

The effect of tyramine on the secretion of neuropeptide Y-like immunoreactivity (NPY-LI) was investigated in a synaptosomal fraction prepared from rabbit jejunum. In addition to evoking the release of norepinephrine (NE), tyramine induced a dose-dependent increase of NPY-LI secretion which was insensitive to tetrodotoxin and was not affected by the removal of calcium ions from the bathing medium. Desipramine reduced the effectiveness of tyramine but did not influence the basal output of NPY-LI. There was a positive correlation between the inhibitory effect of desipramine on the NPY release and on the uptake of [14C]tyramine into synaptosomes. Guanethidine, however, at a concentration insufficient to block the uptake of tyramine reduced the release of both NE and NPY. These data suggest that tyramine enters into nerve terminals through a desipramine-sensitive mechanism, resulting in the co-release of NE and NPY which can be reduced by guanethidine.

Animals↗
PubMed1988

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity.

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Effect of long-term rolipram administration on the sensitivity of alpha 2-adrenoceptors in rat brain.

The effects of single and chronic doses of rolipram on the sensitivity of alpha 2-adrenoceptors have been compared with the phosphodiesterase inhibitors, isobutylmethylxanthine (IBMX) and ICI 63,197, and the antidepressant, desipramine. While pretreatment with a single dose of rolipram, ICI 63,197 or IBMX administered either 1 or 24 h prior to clonidine (0.1 mg/kg) enhanced clonidine-induced hypothermia and hypoactivity, chronic dosing (twice daily for 14 days) with desipramine (10 mg/kg) or rolipram (5 mg/kg) antagonized these behavioural effects. In contrast, chronic dosing with IBMX or ICI 63,197 failed to antagonize clonidine-induced hypothermia and hypoactivity. In binding studies neither ICI 63,197, IBMX, rolipram nor desipramine induced changes in the binding of 3H-labelled clonidine to rat cerebral cortical membranes following chronic administration. The failure of ICI 63,107 and IBMX to antagonize clonidine-induced hypothermia and hypoactivity suggests that the antidepressant effect of rolipram is independent of its phosphodiesterase inhibitor property.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Correlative changes of serotonin and catecholamines with pharmacokinetic alterations of imipramine in rat brain.

Rats were given i.p. imipramine (20 mg/kg), acutely or chronically, and the levels of serotonin (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites in the brain at different times were compared with the concentrations of imipramine and desipramine. The levels of 5-HT, DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain did not appear to be affected by quantitative alterations in the concentrations of imipramine and desipramine. The level of 5-hydroxyindole acetic acid (5-HIAA) was reduced and the level of 3-methoxy-4-hydroxyphenylglycol (MHPG) tended to decrease 3 h after imipramine administration in acutely treated rats. The reduced level of 5-HIAA was maintained during the chronic treatment with imipramine, whereas the MHPG level increased and the NE level decreased. The decrease in 5-HIAA depended on the concentration of imipramine in the brain, whereas the changes in the levels of NE and MHPG appeared to be caused by desipramine. The present studies show that pharmacokinetic variations of imipramine in the brain might correlate with the altered levels of 5-HIAA, NE and MHPG.

Animals↗
PubMed1991

Effects of (S)-nafenodone, a new antidepressant, in isolated guinea-pig atrial and ventricular muscle fibres.

The electromechanical effects of a new antidepressant, (S)-nafenodone, were studied in isolated guinea-pig atrial and ventricular muscle fibres. In spontaneously beating right atria, (S)-nafenodone decreased the rate and amplitude of contractions and lengthened the sinus node recovery time. In electrically driven atria, the negative inotropic effect of (S)-nafenodone was less marked than that of imipramine and desipramine but similar to that of lofepramine. (S)-Nafenodone had no effect on the resting membrane potential but decreased the amplitude and maximum upstroke velocity (Vmax) both in atrial and ventricular muscle fibres; this effect was less marked than that produced by imipramine and desipramine. In atrial fibres, but not in ventricular fibres, (S)-nafenodone lengthened the action potential duration, but in both tissues it increased the duration of the effective refractory period out of proportion to the change in action potential duration. Moreover, it shifted the concentration-response curve for Ca2+ downwards and decreased the amplitude of the slow atrial contractions induced by histamine as well as the amplitude and Vmax of the slow action potentials induced by isoprenaline in papillary muscles. It is concluded that (S)-nafenodone exerted fewer cardiodepressant effects than imipramine and desipramine in isolated guinea-pig atrial and ventricular muscle fibres less.

Action Potentials↗
PubMed1992

Effects of clorgyline on the release of noradrenaline from rat vas deferens.

Release of endogenous noradrenaline (NA) and functional activity of presynaptic alpha 2-adrenoceptors were measured in isolated rat vas deferens following acute (2 mg/kg) or chronic (21 * 1 mg/kg daily, i.p.) treatment with clorgyline. Noradrenaline tissue content was higher in rats treated chronically with clorgyline than in those treated acutely. In vitro experiments done in the presence of 1 microM desipramine and 0.5 microM yohimbine showed that NA release, elicited by electrical field stimulation, was higher in chronic clorgyline rats than in controls, while no significant difference was found between acute clorgyline and control rats. Yohimbine enhanced evoked release of NA in all treatment groups, provided that desipramine was present in the Krebs solution, and the enhancement was non significantly higher in chronic clorgyline than in acute clorgyline and control rats. Efflux of 3,4-dihydroxyphenylglycol was lower in chronic clorgyline rats than in other groups. No difference was found between the treatment groups in a 1 min [3H]NA uptake into the tissue, nor in the ability of desipramine (1 microM) to block the uptake. The results indicate that following chronic treatment with clorgyline, evoked release of NA increased, and there was no reduction in the ability of the presynaptic alpha 2-adrenoceptor inhibitory mechanism to reduce nerve stimulation induced release of NA.

Animals↗
PubMed1993

Chronic antidepressant drug treatment attenuates motor-suppressant effects of apomorphine without changing [3H]GBR 12935 binding.

The effects of chronic administration (28 days s.c. via osmotic minipumps) of the antidepressants phenelzine sulphate, desipramine hydrochloride and clomipramine hydrochloride (each at 10 mg/kg per day) on dopamine function have been measured in rats. Both phenelzine and desipramine attenuated the suppression of locomotor activity induced by apomorphine hydrochloride (0.05 mg/kg s.c. 15 min). Clomipramine did not affect the behavioural response to apomorphine. Analyses of brain tissue from these animals using the radioligand [3H]GBR 12935 revealed that there were no changes in dopamine uptake site density or affinity following the administration of phenelzine, desipramine or clomipramine. Analyses of brain monoamine oxidase activity and tricyclic levels were used to confirm the efficacy of the drug administration protocol. These data indicate that changes in dopamine uptake site density do not mediate antidepressant-induced changes in behavioural responses to apomorphine.

Animals↗
PubMed1994

Early postnatal antidepressant treatment and juvenile stereotyped behaviour in rats.

The effect of antidepressants on stereotyped behaviour in rats during development was examined. Rats were injected s.c. once a day from the 6th to the 22th day after birth with 0.9% sodium chloride, with desipramine 5 mg/kg body weight, with nomifensine 10 mg/kg, or with zimelidine 25 mg/kg. Stereotyped behaviour was assessed when the rats were 1 month and 2 months of age. Desipramine intensified and prolonged apomorphine 0.5 mg/kg induced stereotyped behaviour at 1 month but not at 2 months of age. Nomifensine and zimelidine did not affect stereotyped behaviour at either 1 month or 2 months of age. Thus, 2-week treatment with desipramine during early development was shown to increase stereotyped behaviour at a juvenile age.

Animals↗
PubMed1990

Noradrenergic mechanisms appear not to be involved in cocaine-induced seizures and lethality.

In the present study we have investigated the effects of compounds which increase synaptic levels of noradrenaline on cocaine-induced seizures and lethality in mice. The noradrenaline uptake blocker desipramine (0.3, 3, 30 mg/kg i.p.; 1h pretreatment) and the alpha 2-antagonists idazoxan (0.05, 0.5, 5 mg/kg i.p.; 15 min) and RX811059A (0.01, 0.1, 1 mg/kg i.p.; 15 min) neither reduced nor increased the number of animals having convulsions in the 10 min following administration of cocaine (45, 60 mg/kg i.p.). None of these drugs increased lethality when assessed 10 minutes after 60 mg/kg cocaine and the alpha 2-antagonists did not protect against the lethal effects of a 90 mg/kg dose. On the other hand, desipramine significantly reduced the number of animals dying after this high dose of cocaine. These results suggest that noradrenergic mechanisms do not promote cocaine-induced convulsions and lethality - an important observation in light of the growing use of desipramine for initiation of abstinence in cocaine-dependent outpatients.

Adrenergic alpha-Antagonists↗
PubMed1995

Potentiation of intrathecal DAMGO antinociception, but not gastrointestinal transit inhibition, by 5-hydroxytryptamine and norepinephrine uptake blockade.

Spinally administered mu opioid agonists produce potent antinociception and inhibition of gastrointestinal transit. Blockade of 5-hydroxytryptamine (5-HT) or norepinephrine (NE) uptake potentiates intrathecal (i.t.) DAMGO antinociception. To determine whether 5-HT and NE uptake blockade will also potentiate the gastrointestinal inhibition, mice were treated with zimelidine, desipramine or saline, followed by i.t. DAMGO and tested for tailflick antinociception or inhibition of gastrointestinal transit. DAMGO produced antinociception dose-dependently (ED50 = 4.6 ng). Zimelidine (10 mg/kg, s.c., 1 hr before DAMGO) produced a 6.2-fold leftward shift in the antinociceptive dose-response curve (ED50 = 0.73 ng). Desipramine produced a 5.3-fold shift (ED50 = 1.4 ng). DAMGO also produced a dose-dependent inhibition of gastrointestinal transit (ED50 = 117 ng). However, zimelidine or desipramine treatment did not affect DAMGO inhibition of gastrointestinal transit (ED50 = 80 ng.).

Animals↗
PubMed1983

Rapid down-regulation of serotonin2 receptor binding during combined administration of tricyclic antidepressant drugs and alpha 2 antagonists.

Recent studies have shown that chronic, but not acute, treatment with several different antidepressant drugs decreases the density of serotonin2 (5HT2) receptors in the cerebral cortex (Peroutka and Snyder, 1980a). It was found that combined administration of antidepressant drugs with alpha 2 antagonists could accelerate this down-regulation of 5HT2 receptors induced by antidepressants. Amitriptyline (10 mg/kg, twice daily) in combination with yohimbine (5 mg/kg, twice daily) decreased 5HT2 receptor binding after 4 days of treatment, whereas amitriptyline alone required 10 days to decrease the density of 5HT2 receptors. Other antidepressant--alpha-antagonist combinations which rapidly decreased the density of 5HT2 receptors were desipramine-phenoxybenzamine, amitriptyline-phenoxybenzamine, iprindole-phenoxybenzamine, mianserin-phenoxybenzamine and desipramine-dihydroergotamine. Treatment with desipramine in combination with prazosin, an alpha 1 antagonist, did not accelerate the down-regulation of 5HT2 receptors induced by antidepressants. These results suggest that blockade of central alpha 2 receptors can accelerate the down-regulation of 5HT2 receptors by antidepressants. A combination of antidepressant and alpha antagonist treatment could represent a new, rapid onset antidepressant drug therapy.

Adrenergic alpha-Antagonists↗
PubMed1986

Effect of chronic administration of alprazolam and adinazolam on clonidine- or apomorphine-induced aggression in laboratory rodents.

The activity of chronic (3 weeks) treatment with the triazolobenzodiazepines, alprazolam and adinazolam, on clonidine- and apomorphine-induced aggression were studied. Adinazolam, like desipramine, potentiated aggression induced by clonidine while diazepam and alprazolam completely abolished it. In the apomorphine-induced aggression, adinazolam suppressed both aggressivity and stereotypy, while diazepam slightly potentiated it. Alprazolam did not modify the effect of aggression induced by apomorphine. On the whole, while adinazolam seemed to develop an activity closer to that of a classical antidepressant like desipramine, alprazolam appeared to be more similar to the benzodiazepines on clonidine-induced aggression in mice. Compared to desipramine and diazepam, adinazolam left these two effects induced by apomorphine almost unchanged. The experiments performed showed differences between the profiles of action of the two triazolobenzodiazepines studied.

Aggression↗
PubMed1987

Noradrenergic involvement in catalepsy induced by delta 9-tetrahydrocannabinol.

In order to elucidate the role of the catecholaminergic system in the cataleptogenic effect of delta 9-tetrahydrocannabinol (THC), the effect of pretreatment with 6-hydroxydopamine (6-OHDA) or with desipramine and 6-OHDA and lesions of the locus coeruleus were investigated in rats. The cataleptogenic effect of THC was significantly reduced in rats treated with 6-OHDA and in rats with lesions of the locus coeruleus but not in rats treated with desipramine and 6-OHDA, as compared with control rats. On the contrary, the cataleptogenic effect of haloperidol was significantly reduced in rats treated with desipramine and 6-OHDA but not in rats treated with 6-OHDA or in rats with lesions of the locus coeruleus. These results indicate that noradrenergic neurons have an important role in the manifestation of catalepsy induced by THC, whereas dopaminergic neurons are important in catalepsy induced by haloperidol.

Animals↗
PubMed1994

Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function.

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT2C/5-HT2B receptors was assessed using a putative in vivo model of 5-HT2C/5-HT2B receptor function, mCPP-induced hypolocomotion. mCPP (2, 4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily x 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily x 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o. daily x 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT2C/5-HT2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.

Animals↗
PubMed1995

Effects of monoamine reuptake inhibitors on cocaine self-administration in rats.

The objective of this study was to investigate the effects of acute administration of monoamine reuptake inhibitors on cocaine self-administration in rats. Pretreatment with GBR 12909 (1-5.6 mg/kg, IV), a dopamine-selective reuptake inhibitor, produced a dose-dependent and large reduction in the self-administration of cocaine (1 mg/kg/infusion). The 3- and 5.6-mg/kg doses of GBR 12909 produced downward shifts in the dose-response curves for cocaine (0.3-3 mg/kg/infusion) self-administration. Unlike GBR 12909, the norepinephrine-selective reuptake inhibitors, desipramine and nisoxetine, at a 10-mg/kg dose produced small, but significant, reductions in the self-administration of cocaine (1 mg/kg/infusion). The 10-mg/kg dose of fluoxetine, a serotonin-selective reuptake inhibitor, produced a small, but not significant, reduction in the self-administration of cocaine. The 10-mg/kg dose of desipramine, nisoxetine, or fluoxetine produced brief respiratory distress and motor abnormalities immediately following IV injections, thereby suggesting that this dose is close to the toxic range for all three drugs. Desipramine, nisoxetine, or fluoxetine at nontoxic doses of 1 and 3 mg/kg had no significant effects on cocaine self-administration. These data indicate that the acute enhancement of endogenous dopaminergic activity by pretreatment with dopamine reuptake inhibitor reduces the total intake of cocaine, thus supporting the hypothesis that the dopamine is critically involved in the reinforcing properties of cocaine. The data also suggest that the acute enhancements in the endogenous norepinephrine or serotonin systems by nontoxic doses of norepinephrine- or serotonin-selective reuptake inhibitors do not appear to alter the reinforcing properties of cocaine.

Animals↗
PubMed1988

Duration of the suppressive effect of tricyclic antidepressants on histamine-induced wheal-and-flare reactions in human skin.

The antihistaminic properties of the tricyclic antidepressants have been recognized since these compounds were first developed. Antidepressants, which are equally effective for treating depression or used in the treatment of chronic urticaria, have varying in vitro antihistaminic properties. We compared the duration of H1-receptor blockade by two tricyclic antidepressants, doxepin (the most potent antihistamine) and desipramine (the least potent antihistamine), in a single dose, double-blind, noncrossover study. After baseline prick test with histamine phosphate 1:1000 by Multitest (Lincoln Diagnostics, Decatur, Ill.), the suppression of cutaneous histamine-induced wheal-and-flare responses were measured daily for 7 days in 33 healthy volunteers who were randomly administered a single 25 mg dose of oral desipramine or doxepin. Significant differences in the suppression of the wheal-and-flare responses to histamine between the two drugs were noted (p less than 0.05) during the first 3 days. Desipramine suppressed the wheal for 2 days and flare for 1 day. Doxepin suppressed the wheal for 4 days and flare for 6 days. Our results suggest doxepin should be withheld for at least 7 days before allergy skin testing.

Adult↗
PubMed1989

3H-imipramine binding in the frontal cortex of suicides.

Imipramine binding (desipramine- and serotonin-sensitive) was determined in the frontal cortex of suicide victims and nonpsychiatric controls who died due to medical disease or accidents. There were no differences in Kd or Bmax of imipramine binding between controls and suicides. The Kd and Bmax values of serotonin-sensitive imipramine binding were significantly lower than desipramine-sensitive imipramine binding, both in controls and suicides. There were significant correlations between Kd and Bmax of serotonin-sensitive imipramine binding and desipramine-sensitive imipramine binding in suicides but not in controls.

Adolescent↗