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PubMed1987

Reserpine augmentation of desipramine in refractory depression: clinical and neurobiological effects.

Early studies showed dramatic improvement in some depressed patients when a brief course of parenteral reserpine was added to ineffective tricyclic antidepressant (TCA) treatment. We treated eight patients with DSM-III melancholic major depression with desipramine (DMI) greater than or equal to 2.5 mg/kg/day (plasma levels greater than 125 ng/ml) for at least 4 weeks. All patients failed to respond and received reserpine 5 mg IM b.i.d. over 2 days, in seven cases as a placebo-controlled, double-blind trial. One patient had dramatic resolution of depressive and psychotic symptoms within 48 h, but relapsed within 2 weeks; two other patients had transient hypomanic symptoms. Depression ratings did not significantly change for the sample as a whole, but plasma and cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) decreased and CSF levels of homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA) increased. Despite robust effects on central monoamine metabolism, reserpine augmentation appears insufficiently effective for routine use in managing refractory depression.

Adult↗
PubMed1987

The serotonin/noradrenaline-link in brain. I. The role of noradrenaline and serotonin in the regulation of density and function of beta adrenoceptors and its alteration by desipramine.

The present studies were undertaken to assess the role of noradrenaline (NA) and serotonin (5HT) in the regulation of the NA receptor coupled adenylate cyclase system and its alteration by desipramine (DMI) in brain structures with or without noradrenergic neuronal projections. In contrast to cortex and limbic forebrain, where chronic DMI administration caused subsensitivity of the NA sensitive adenylate cyclase linked to a down-regulation of beta adrenoceptors, the drug failed to alter the NA receptor coupled adenylate cyclase system in the striatum. Selective lesions of serotonergic axons with 5,7-dihydroxytryptamine caused a significant increase in the density of beta adrenoceptors in cortex, limbic forebrain and striatum and prevented the down-regulation by DMI of beta adrenoceptors in cortex and limbic forebrain while the responsiveness of the NA sensitive adenylate cyclase was reduced to the same extent as in sham-lesioned control animals. The discrepancy between beta adrenoceptor number and NA responsiveness following lesions of 5HT axons was particularly profound in the striatum. The analysis of high- and low-affinity components of agonist binding demonstrated that the increase in striatal beta adrenoceptors is due to a marked increase in receptors with low affinity while the number of receptors with high affinity is unchanged. The results lend further support to the view that the synaptic availability of NA is a prerequisite for the induction of subsensitivity of the NA sensitive adenylate cyclase and for the down-regulation of its beta adrenoceptor population by DMI and that 5HT plays a pivotal role in both the regulation of the number and the function of central beta adrenoceptors.

5,7-Dihydroxytryptamine↗
PubMed1987

Neonatal desipramine or zimeldine treatment causes long-lasting changes in brain monoaminergic systems and alcohol related behavior in rats.

To study the relationship between neonatal antidepressant administration, active (REM) sleep and adult alcohol-related behavior, rat pups were treated daily with 5 mg/kg desipramine (DMI) or 25 mg/kg zimeldine SC from the 6th to the 19th postnatal days. Movement sensitive mattress ("SCSB") measurements showed that zimeldine treatment suppressed active sleep throughout the whole treatment period, but DMI was more effective during the first 8 days than during the last treatment days. At the age of 70 days, the zimeldine-treated rats expressed a selective increase of some components of activity in the open field test, and the DMI rats had a higher defecation score compared to the controls. Furthermore, the zimeldine-rats responded with a decrease in ambulation in the open field to an alcohol dose which generally stimulates locomotion in rats. At the age of 3 months the DMI and zimeldine rats showed increased voluntary intake of 10% (v/v) alcohol. Measurement of brain monoamines revealed that the neonatal treatment with DMI or zimeldine interfered with the normal development and function of the monoamine neuronal systems: the concentrations of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), and their metabolites were altered in several brain regions. The results thus suggest that neonatal treatment with DMI or zimeldine suppresses active sleep and has an influence on later alcohol-related behavior, possibly due to a long-lasting defect in brain monoaminergic transmission.

Alcohol Drinking↗
PubMed1991

Extracellular brain cortical levels of noradrenaline in ischemia: effects of desipramine and postischemic administration of idazoxan.

Using microdialysis, extracellular noradrenaline (NA) levels in the rat cerebral cortex were studied under isoflurane/N2O anaesthesia before, during and for 6 hours following 10 min of forebrain ischemia in a 2-vessel occlusion model. A microdialysis probe was introduced into the parietal cortex and dorsal hippocampus in anaesthetized rats and continuously perfused with Krebs-Ringer-bicarbonate buffer with or without the NA uptake inhibitor desipramine (DMI, 5 microM). Twenty min fractions were collected and the extracellular NA levels were measured in the dialysates using HPLC with electrochemical detection. The basal NA concentration in the dialysate was 10.5 +/- 1.8 (mean +/- SEM) pg/20 min fraction and increased to 39.3 +/- 4.8 pg/20 min fraction after local administration of DMI. During ischemia, NA increased to 38 times the basal level without DMI, and 6 times with DMI included during two hours' perfusion prior to ischemia. After recirculation NA levels returned to, or even transiently decreased below, preischemic values. With DMI present in the dialysis buffer, administration of idazoxan immediately following ischemia delayed the return to preischemic NA levels in the recirculation phase. In the absence of DMI, no effect of idazoxan on postischemic levels of NA was found. Local administration of DMI increases basal extracellular NA levels and reduces the ischemia-induced NA release. The latter effect may be a due to inhibition of the NA uptake system working in a reversed mode, or as a result of decreased synthesis of NA due to activation of presynaptic alpha 2-receptors by the increased synaptic NA levels. Postischemic treatment with the alpha 2-adrenoceptor antagonist idazoxan in combination with DMI prolongs the period of elevated extracellular NA levels, which may be of importance for the protective properties of idazoxan against ischemic cell injury.

Adrenergic alpha-Antagonists↗
PubMed1985

Growth hormone release after desipramine in depressive illness.

The effect of i.m. administration of 75 mg of desipramine on growth hormone (GH) secretion was investigated in a sample of 87 patients with major depressive disorders and in 31 normal controls. The GH response was lower in depressed females compared to depressed males, but no such difference was present in controls. In the premenopausal female group, GH response was significantly lower in depressed patients than in controls. No significant difference was found between normal males and male depressed patients. In the premenopausal group, no difference emerged between endogenous and nonendogenous depressed women.

Adult↗
PubMed1985

Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients.

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n = 17) and amitriptyline (AT, n = 16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiles for uptake blockade and anticholinergic potency for these two compounds.

Adult↗
PubMed1984

Combined thioridazine and desipramine: early antidepressant response.

The authors examined the effect of combined thioridazine (THI) and desipramine (DMI) for an early antidepressant response in 14 patients with a DSM III diagnosis of major depressive disorder with melancholia. All 14 patients received a constant dose of 200 mg DMI/day for 21 days while 7 patients received 100 mg THI/day for only the first 7 days. A significantly greater improvement from baseline Hamilton Depression Scale (HDS) scores occurred during the first 7 days in patients receiving both drugs. Possible mechanisms for this early antidepressant action are discussed.

Adult↗
PubMed1980

Interaction of triazolam with desipramine. Effects of single and repeated treatment on certain pharmacologic responses and brain catecholamine levels.

The present study was undertaken to evaluate the effects of single and repeated doses of triazolam (1 mg/kg IP) and desipramine (DMI) (10 mg/kg IP) alone and in combination on certain pharmacologic responses and brain catecholamine levels in rats. The significant findings were: (1) triazolam and DMI given alone and in combination were synergistic with pentobarbital (PB) hypnosis; (2) repeated treatment with DMI alone repressed body weight gain; triazolam potentiated this anorectic effect; (3) triazolam induced muscle relaxation acutely, but was not affected by concomitant DMI treatment; and (4) triazolam and DMI given in combination produced hypothermia although the drugs given separately did not. Development of tolerance to hypothermia and to anorectic effects produced by triazolam and DMI significantly decreased norepinephrine (NE) levels in the hypothalamus as compared to the repeated treatment with triazolam, and significantly increased NE and dopamine (DA) levels in the striatum and DA levels in the cortex, as compared to the single treatments.

Animals↗
PubMed1985

Performance and extinction of lever press behavior following chronic administration of desipramine to rats.

The effect of repeated administration of desipramine (DMI) on the acquisition, performance, and extinction of a lever press response for food reward was studied. Chronic administration of DMI caused a reduction in pressing under a CRF schedule both in naive and well-trained rats. Responding during extinction sessions did not differ between saline-treated rats and rats given DMI chronically. In addition, chronic administration of DMI reduced the body weight and food intake of rats on either a free-feeding or a restricted-feeding schedule. Consequently, lever pressing was also studied in a group of rats whose body weight was regulated to match the body weight of rats were administered DMI chronically. In comparison to this control group, rats administered DMI chronically responded significantly less during both reinforcement and extinction sessions. These results fail to replicate earlier reports that chronic DMI administration produces increased resistance to extinction. The results also show that assessment of food-motivated performance in rats treated chronically with DMI is difficult because of long-term changes in body weight and food intake.

Animals↗
PubMed1981

A comparison of plasma and serum levels of two tricyclic antidepressants: imipramine and desipramine.

This study was performed to determine the difference, if any, between serum and plasma levels of the tricyclic antidepressant drugs imipramine and desipramine. Serum and plasma samples were drawn simultaneously from patients taking either of these drugs. Statistical analysis indicated no difference in the drug levels; that is, serum and plasma levels were identical.

Blood Chemical Analysis↗
PubMed1983

Behavioural evidence that chronic treatment with the antidepressant desipramine causes reduced functioning of brain noradrenaline systems.

A behavioral system sensitive to the net functional activity of the locus coeruleus noradrenergic system, with characteristics of a beta-adrenoceptor mediated response, has been developed based on the duration of thiopentone anaesthesia in the rat. The effects of acute and chronic treatment with the tricyclic antidepressant desipramine (DMI) were determined. Acute DMI from 5 to 25 mg/kg increased thiopentone sleeping-time in a dose-dependent fashion. This was due to an action on noradrenergic systems, since it was mimicked by treatment with the selective neurotoxin 6-hydroxydopamine, which itself increased thiopentone sleeping-time and prevented any additional effect of DMI. Chronic treatment with DMI had no effect on thiopentone sleeping-time when carried out for 2 or 5 days but markedly prolonged it when carried out for 10 or 20 days, thus paralleling the time course of clinical action of the drug.

Animals↗
PubMed1985

Biochemical and behavioral changes in rats after prolonged treatment with desipramine: interaction with p-chlorophenylalanine.

The decrease in the Bmax value of 3H-dihydroalprenolol (3H-DHA) binding to cortical membranes of rat brain induced by long-term administration of desipramine (DMI) was prevented by concomitant treatment with parachlorophenylalanine (pCPA). Acute administration of DMI significantly decreased locomotor activity in saline- and (pCPA)-pretreated rats. DMI-induced inhibition of locomotor activity was abolished in (pCPA)-pretreated rats chronically treated with DMI. Conversely, in pCPA-pretreated animals, acute DMI could still significantly decrease the locomotion of chronically DMI-treated rats. The data presented indicate that an intact serotoninergic system is required to enable antidepressant drugs to induce biochemical and behavioral changes following their chronic administration.

Animals↗
PubMed1981

3H-WB 4101 binding in the rat vas deferens. Effects of chronic treatments with desipramine and prazosin.

1. The binding of the alpha-adrenoceptor antagonist ligand, 3H-WB 4101, to membranes prepared from rat vas deferens is rapid, saturable and reversible. 2. Scatchard analyses of the data show the maximal number of binding sites (Bmax) to be 1.528 +/- 0.060 pmoles/g original wet tissue weight and a dissociation constant (Kd) of 0.84 +/- 0.07 nM. 3. Hill plots of the binding data revealed that 3H-WB 4101 binds to a single population of independent sites with no cooperative interactions. 4. The relative order of potencies of alpha-adrenoceptor antagonists for the inhibition of 3H-WB 4101 binding, prazosin greater than phentolamine greater than yohimbine, follows the pattern expected for the alpha 1-type of adrenoceptors. 5. After repeated administration of prazosin to rats (0.4 mg/kg/day for 21 days), 3H-WB 4101 binding showed a significant increase in the density of alpha 1-adrenoceptors (122% of controls). 6. Chronic treatment with desipramine (13.6 mg/Kg/day for 22 days) resulted in a significant decrease in the number of alpha 1-adrenoceptors (79% of controls).

Adrenergic alpha-Antagonists↗
PubMed1986

The significance of beta-adrenoceptor down regulation in the desipramine action in the forced swimming test.

The present studies were undertaken to clarify whether central beta-adrenoceptor down regulation is responsible for the greater effect of chronic treatment with desipramine (DMI) compared with acute treatment in the forced swimming test in rats. Repetitive administration of DMI activated the rat behaviour pattern and consequently reduced the duration of immobility. The degree of activation depended on the length of treatment, i.e. no effect when given in a single dose, moderate effect when given subchronically (3 doses) and marked activation after chronic (31 doses) treatment. Chronic treatment with DMI also produced a decrease in 3H-dihydroalprenolol (3H-DHA) binding site in the cerebral cortex. Acute stimulation of brain beta-adrenoceptors by intracerebroventricular (i.c.v.) isoprenaline significantly, though partially, attenuated the behavioural effect of chronic DMI by beta 1-adrenoceptor-related mechanisms. Similarly, chronic i.c.v. co-administration of atenolol or practolol, beta 1-adrenoceptor antagonists, together with DMI attenuated both beta-adrenoceptor down regulation and the behavioural activation by chronic DMI. On the other hand, chronic i.c.v. administration of isoprenaline, supposedly leading to down regulation of beta-adrenoceptors, facilitated the activating behavioural effect of DMI, as a single dose became effective. Changes, however, in 3H-DHA binding parameters in the cerebral cortex were not observed after chronic isoprenaline. These results suggest that down regulation of beta-adrenoceptors in brain is responsible, at least in part, for the marked activatory effect of chronic DMI in the forced swimming test, possibly by reducing an inhibitory function of beta 1-adrenoceptor mediated mechanisms.

Adrenergic beta-Antagonists↗
PubMed1989

Stimulation of Na+,K+-ATPase activity in certain membranes of the rat central nervous system (CNS) by acute administration of desipramine (DMI).

1. The activities of ATPase in rat CNS were studied 3 hr after administration of the noradrenaline uptake inhibitor, desipramine (DMI: 10 mg.kg-1, i.p.). Na+K+-ATPase activity significantly increased after DMI in the whole particulate from hypothalamus and mesencephalus but no changes in frontal cortex or in pons-medulla oblongata areas were found. This increase was prevented when the animals were pretreated with the noradrenergic neurotoxic N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). 2. Purified membrane fractions from hypothalamus were obtained by differential and sucrose gradient centrifugation (0.8-1.2 M sucrose). It was observed that after DMI, Na+,K+-ATPase activity increased only in the membranous fraction lying at 0.9 M sucrose. 3. Mg2+- or Ca2+-ATPase activities were not modified by DMI treatment. 4. Citalopram, a specific serotonergic uptake inhibitor, did not affect ATPase activities. 5. The results obtained could indicate that DMI acute administration selectively stimulates Na+,K+-ATPase activity of certain membranes of the CNS after an increase in the concentration of the noradrenergic neurotransmitter in the synaptic gap.

Animals↗
PubMed1983

Relationships between brain concentrations of desipramine and paradoxical sleep inhibition in the rat.

Desipramine (DMI), like many antidepressant drugs, inhibit the production of paradoxical sleep (PS). In the present experiment, we have investigated the relationships between brain level of DMI and PS inhibition. Groups of rats had their sleep monitored after 1, 2 or 4 mg/kg of DMI. In other animals, the brain concentration of DMI was assayed at various times after the same treatments. The results indicate that a critical threshold concentration of 300 ng/g DMI in the brain is necessary for complete PS inhibition. This stage reappears only when the DMI level falls below this value, and its production resumes at a normal rate, provided the DMI level reached initially was not largely in excess of the threshold concentration. The results are discussed with regard to the present knowledge of specific binding of tricyclics in brain and their "ex vivo" action on norepinephrine uptake resulting in enhancement of collateral inhibiton of noradrenergic cells.

Animals↗
PubMed1986

Studies on rat brain catecholamine synthesis and beta-adrenoceptor number following administration of electroconvulsive shock, desipramine and clenbuterol.

The effects of administration to rats of repeated electroconvulsive shock (ECS), clenbuterol and desipramine (DMI) on beta-adrenoceptor number in cortex, and noradrenaline (NA) and dopamine (DA) turnover in whole brain has been investigated by examining the rate of decline of NA concentration (kNA) following injection of alpha-methyl-p-tyrosine. A single injection of clenbuterol (5 mg/kg) raised brain NA content and decreased the rate constant (kNA), leaving the turnover rate unaltered. Acute DMI injection decreased kNA and turnover rate, while a single ECS did not change NA metabolic rate. Repeated treatment with either ECS (5 seizures over 10 days), clenbuterol (5 mg/kg for 14 days) or DMI (5 mg/kg twice daily for 14 days) decreased beta-adrenoceptor density in cortex. No change in NA content, rate constant or turnover rate was observed after repeated ECS or clenbuterol administration. Ninety min after the last dose of DMI brain NA content was significantly decreased but kNA was unchanged compared with control animals, possibly because of the presence of subsensitive presynaptic alpha 2-adrenoceptors. At 18 hours after the last dose brain NA content was still lower than control animals but kNA was enhanced. This presumably a "withdrawal" effect, the uptake inhibitory effect of the drug now being decreased. The treatments had little effect on DA turnover apart from DMI decreasing synthesis rate. Clearly there is no obvious relationship between the ability of antidepressant treatments to alter NA turnover and decrease beta-adrenoceptor number.

Animals↗
PubMed1994

Acceleration of desipramine-induced changes on the dopamine receptor-coupled adenylate cyclase system by pertussis toxin.

The response of adenylate cyclase to GTP and to dopamine (DA) was investigated in striatal membranes from desipramine (DMI)-treated rats (10 mg/kg, b.i.d., for 5 days). GPT exerted the same biphasic effect on basal and DA-stimulated enzyme activity in membranes from DMI-treated rats as on saline-treated rats. Rats were injected intraventricularly once with islet activating protein (IAP), pertussis toxin, and given extended treatment with DMI in order to study the effects on the inhibitory GTP-binding protein (Gi). Gi loses its function as a signal transducer on being ADP-ribosylated selectively by the IAP. D2 inhibition of adenylate cyclase by DA was attenuated by the IAP treatment in both DMI-and saline-treated rats; peak levels of DA plus GTP stimulation shifted from 1 microM to 100 microM GTP. D1 stimulation of adenylate cyclase by DA was also attenuated by the IAP in the DMI-treated rats. Since long-term treatment with DMI (15 mg/kg, once a day, for 3 weeks) resulted in suppression of D1 stimulation similar to that seen in the present findings, uncoupling between D2 receptors and Gi due to IAP treatment might accelerate DMI-induced adaptive changes of dual control of adenylate cyclase system by DA.

Adenosine Diphosphate Ribose↗