Chronic Desipramine Treatment Research Articles

Changes in Behaviour, Neurotransmitters and Neutrophil Function in Olfactory Bulbectomized Rats: Effects of Chronic Desipramine Treatment

The olfactory bulbectomized (OB) rat has been developed as an animal model of depression. In the novel ‘open field’ environment, OB rats showed a hyperactivity which was attenuated by chronic treatment with desipramine (7·5 mg/kg) for 20 days. Neutrophil phagocytosis was suppressed by the lesion, which was reversed by desipramine administration. Results from serum ‘crossover’ studies and enzyme assay showed that a factor is present in the serum, and cellular enzymes are altered in the OB rat, which may be responsible for abnormal neutrophil phagocytosis. After bulbectomy, the concentrations of noradrenaline (NA) and dopamine (DA) were decreased, and the 5-hydroxyindole-3-acetic acid (5-HIAA) was increased in the brain limbic system of OB rats. Desipramine treatment significantly increased the concentration of NA and DA, and slightly decreased the 5-HIAA. These results suggest that the change in the neutrophil function following bulbectomy is similar to that reported in the depressed patient. Thus desipramine is an effective antidepressant for reversing lesion-induced changes in neurotransmitter, behaviour and neutrophil phagocytosis. © 1997 by John Wiley & Sons, Ltd.

Effects of chronic desipramine on waiting behaviour for a food reward in olfactory bulbectomized rats

The effects of olfactory bulbectomy (OB) on the 'waiting behaviour' of rats for a food reward in a T-maze, as well as the effect of chronic treatment with desipramine (7.5 mg/kg, i.p. x 14 days) prior to and throughout testing was assessed. In the T-maze, the time spent in locating a reward was longer in OB rats during the first phase of the food reward test. However, all groups chose the larger reward in at least 80% of trials by day 5 of test. Upon imposition of a delay in acquisition of the larger reward (phase 2), sham-operated rats chose the larger reward in correspondingly fewer trials until, by day 5, only 13% (control sham group) and 29% (desipramine-treated sham group) of trials were for the larger but delayed reward. By contrast, both OB rat groups continued to choose the larger but delayed reward throughout phase 2 in the majority of trials. The typical behavioural hyperactivity of OB rats in the 'open field' apparatus was attenuated by chronic administration of DMI. The results suggest that the OB rat has a deficit in food-motivated behaviour and appears to have reduced adaptation of this learned response when the conditions of the test are altered. Chronic desipramine treatment did not attenuate this effect.

Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant

Desipramine (DMI), a tricyclic antidepressant drug used in the treatment of depression, has been shown to increase steady-state levels of glucocorticoid receptor type II (GRII) mRNA in vitro and in vivo. To determine whether this effect is secondary to norepinephrine (NE) reuptake inhibition i.e., increases in synaptic NE induced by DMI, GRII mRNA levels were assayed in rat hippocampus following neurotoxic lesioning of NE neurons with DSP4. Chronic DMI treatment significantly increased GRII mRNA levels to the same degree in lesioned and non-lesioned animals. In contrast to DMI, the non-tricyclic antidepressant fluoxetine had no effect on GRII mRNA. These results provide evidence which demonstrates that a tricyclic antidepressant can regulate steady-state mRNA levels in vivo by a mechanism which is independent of its effects on synaptic monoamine levels.

Effects of chronic desipramine treatment on thyroid hormone concentrations in rat brain: Dependency on drug dose and brain area

As we have established that the effects of desipramine on deiodinase activities are dependent on both the dose and the area investigated (Campos-Barros et al 1994), we proceeded to check the reliability of these findings by using different doses of desipramine and investigating T 4 and T 3 concentrations in different regions of the brain

Chronic desipramine treatment influences D1 stimulation and D2 inhibition (dual control) of adenylate cyclase by dopamine in rat striatum

The response of adenylate cyclase to GTP and to dopamine (DA) was investigated in striatal membranes from desipramine (DMI)- or saline-treated rats. DMI (15 mg/kg) or saline was injected i.p. once a day for 3 weeks. In saline-treated control membranes, GTP exerted a biphasic effect on basal and DA-stimulated enzyme activity; peak levels of stimulation by DA plus GTP were observed at 1 microM GTP. On the other hand, peak levels moved to the right in the GTP dose response curve in DMI-treated membranes. Therefore, D2 inhibition might be attenuated, while the D2 specific agonist, PPHT, was not observed to cause inhibition of adenylate cyclase. Furthermore, D1 stimulation of adenylate cyclase via D1 specific agonist SKF was attenuated in DMI-treated membranes. It seems, therefore, that chronic treatment of rat striatum with DMI exerts a dual influence, that is, a lessening of both D1 stimulation and D2 inhibition of adenylate cyclase, and alters specifically the overall process of the adenylate cyclase system.

Is the state of leucocyte adhesiveness/aggregation an immune marker of stress in the olfactory bulbectomized rat?

AbstractThe state of leucocyte adhesiveness/aggregation (LAA) during stress was determined in 44 rats following sham operation or olfactory bulbectomy. The effects of chronic treatment with the antidepressant desipramine, and calf thymopeptides, on the LAA state and differential white cell count were also studied and compared. In the olfactory bulbectomized rats, LAA percentages and ratios were significantly increased compared with sham operated animals. In the white cell count, the percentage of neutrophils was markedly increased while the percentage of lymphocytes was decreased. Chronic desipramine treatment has no effect on lesioned changes in the LAA and the proportion of white cell. However, thymopeptides significantly reduced LAA percentage and normalized the lymphocyte and neutrophil count in the bulbectomized rats. Such findings further help to valid the olfactory bulbectomized rats as a model of depression and support the view that the state of LAA is a sensitive marker of stress.

Desipramine reduces plasma but not brain thyroxine levels

There is a well known association between abnormalities of thyroid function and affective illness (Joffe et al 1984). A variety of abnormalities of thyroid hormone levels have been reported in patients with major depression, including blunted thyrotropin response to thyrotropin releasing hormone (Loosen 1985) and alterations in circulating thyroxine (T4) and triiodothyronine (T3) (Gold et al 1981; Joffe et al 1985). A consistent finding observed in depressed patients is that treatment with a variety of antidepressants is associated with significant but limited decreases in circulating thyroid hormone levels, particularly T4 (reviewed in Bauer and Whybrow 1988). Furthermore, in two of these studies, responders to tricyclic antidepressant treatment had significantly greater reductions in circulating T4 and free T4 as compared with nonresponders (Baumgartner et al 1988; Joffe and Singer 1990). These findings have led us to hypothesize that reductions in brain T4 are required for antidepressant response (Joffe et al 1984). Although response to antidepressants may be associated with significant changes in circulating thyroid hormone levels, the direct effect of tricyclic antidepressants on brain thyroid hormone levels have not, to our knowledge, been directly evaluated. In this study, therefore, we compared the effects of chronic desipramine treatment on levels of T3 and T4 in the plasma and brain of the rat.

Effects of acute and chronic desipramine treatment on somatostatin receptors in brain.

The effects of acute (5 mg/kg, IP twice daily for 2 days) and chronic (5 mg/kg IP twice daily for 21 days) administration of desipramine (DMI) on [125I]-Tyr11-somatostatin binding sites in brain were examined. There was no change in [125I]Tyr11-somatostatin binding in membranes prepared from the frontal cortex, striatum, and hippocampus of rats acutely or chronically treated with DMI as compared to non treated animals. [125I]Tyr11-somatostatin binding was increased in membranes prepared from the rat nucleus accumbens only after chronic DMI administration. Scatchard analysis of the binding data from the nucleus accumbens showed that [125I]Tyr11-somatostatin labels a single population of somatostatin binding sites with an affinity constant, Kd, of 1.8 +/- 0.60 nM and a Bmax of 330 +/- 90 fmol/mg protein. Chronic treatment with DMI increased the Bmax (500 +/- 140 fmol/mg protein) but had no effect on the Kd. This finding shows a regional effect of DMI on [125I]Tyr11-somatostatin binding sites in rat brain and suggests that somatostatin may play a role in the pathophysiology of depression.

Serotonergic mechanisms in the nucleus accumbens affected by chronic desipramine treatment

The effects of repeated treatment of rats with desipramine on 5-HT mechanisms within the nucleus accumbens (NAS) have been studied in a functional model. Local microinjections of 5-HT, quipazine as well as 5-HT 1A receptor agonist buspirone, 8-OH-DPAT and NDO-008, inhibited rat locomotor activity in the open-field test. The effect of 5-HT and buspirone was blocked by serotonergic receptor antagonists methysergide and cyanopindolol, respectively. Chronic, but not acute treatment of rats with desipramine (10 mg/kg, PO, twice a day for 21 days, tests were performed 24 h after the last dose) significantly attenuated behavioral depression after 5-HT and quipazine microinjections, while the effect of buspirone was left unchanged. On the basis of present data, it may be concluded that whereas both accumbens 5-HT 1A and 5-HT 2 receptors appear to be important to regulation of animals' motility, only 5-HT 2 receptors seem to be the most likely targets of antidepressive treatment. These data, along with previously reported changes in limbic noradrenergic and dopaminergic activity after antidepressive treatment, may explain the energizing influence of drugs and electroconvulsive shocks on psychomotor retardation, a part of endogenous depression.

Chronic desipramine enhances aniphetamine-induced increases in interstitial concentrations of dopamine in the nucleus accumbens

There is accumulating evidence that some antidepressant treatments can increase the functional output of the meso-aecumbens dopanunergic system. For example, chronic administration of tricyclic antidepressant drugs such as imipramme and desipramine (DMI) enhances the locomotor stimulant effects of d-amphetamine Subsensitivity of inhibitory dopamine (DA) autoreceptors and supersensitivity of postsynaptic DA receptor mechanisms are among the mechanisms that have been suggested to underlie these observations. The present experiments investigated the effects of acute and chronic DMI treatment on interstitial DA concentrations in the nucleus accumbens and striatum using in vivo microdialysis in awake freely moving rats (48 h following implantation of a microdialysis probe). Neither acute (5 mg/kg b.i.d. for 2 days followed by 72 h withdrawal) nor chronic (5 mg/kg b.i.d. for 21 days followed by 72 h withdrawal) DMI influenced the ability of apomorphine (25 μtg/kg s.c.) to decrease extracellular concentrations of DA or its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens. In contrast, d-amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the nucleus accumbens of the chronic but not the acute DMI group. This effect was at least partially regionally selective, as significant effects were not observed in the striatum. In accordance with previous reports, the locomotor stimulant effects of d-amphetamine were also enhanced in the chronic DMI groups. DMI itself failed to alter the interstitial concentrations of DA and its metabolites in the nucleus accumbens of the control and chronic DMI groups. These results provide in vivo neurochemical confirmation that chronically administered DMI does not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a selective potentiation of the effects of this stimulant on interstitial DA concentrations in the nucleus accumbens.

Chronic desipramine treatment reduces regional neuropeptide Y binding to Y 2-type receptors in rat brain

Chronic treatment of rats with desipramine and imipramine (5 mg/kg/twice daily/i.p.) for 14 days caused a significant reduction in the binding of [ 3H]proprionyl NPY to membranes prepared from frontal cortex, nucleus accumbens, hypothalamus and hippocampus. There was no change in binding of [ 3H]proprionyl NPY in the parieto-occipital cortex, striatum or amygdala. Scatchard analysis of binding data from frontal cortical and hippocampal membranes showed that [ 3H]proprionyl NPY bound to a single site with aK d of approximately 0.3 nM. The loss of [ 3H]proprionyl NPY binding in hippocampal and frontal cortical membranes revealed that chronic tricyclic antidepressant treatment produced a reduction in the number of binding sites with no change in the affinity for the ligand. Chronic desipramine treatment did not alter the ability of NPY (0.01–25 μM) to stimulate inositol phosphate accumulation in rat frontal cortical slices as compared to saline-treated animals. The lack of change of NPY-induced inositol phosphate accumulation following chronic desipramine treatment showed that there was no change to Y 1 NPY-type receptors which are linked to the hydrolysis of inositol phospholipids. However, the ability of NPY (0.05–0.5 μM) to inhibit forskolin (1 μM) stimulated adenylate cyclase via Y 2 NPY-type receptors in rat frontal cortical slices was significantly reduced following chronic desipramine treatment. This finding suggests that the reduction of [ 3H]proprionyl NPY binding in selective brain regions may be the result of an antidepressant-induced loss of Y 2-type NPY receptors which are negatively linked to adenylate cyclase.

Acute and chronic desipramine treatment effects on rewarding electrical stimulation of the lateral hypothalamus

Two weeks of chronic desipramine HCl (DMI) (10 mg/kg, IP) treatment did not alter reward or motor/performance components of intracranial self-stimulation (ICSS) as assessed with the rate-frequency method. Acute DMI treatment produced an ICSS reward decrement relative to saline control treatment, which was similar in size on Day 1 and Day 15 of chronic testing. The failure to find a chronic DMI effect on ICSS reward suggests that ICSS in normal rats may not be a valid animal model of depression. A better paradigm may be to test the ability of antidepressants to reverse a chronic reduction in ICSS reward function that is first produced by some other method.

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.

Effects of chronic exposure to ethanol alone and in combination with desipramine on β-adrenoceptors of rat brain

The effect of chronic ethanol exposure alone or in combination with desipramine on agonist and antagonist binding to β-adrenoceptors was studied in membrane preparations from rat frontal cortex and hippocampus. Ten day exposure of animals to ethanol vapor (25 mg/1) in inhalation chambers had no effect on binding properties of antagonist iodocyanopindolol (ICYP) in either brain region. However, ethanol in combination with chronic desipramine treatment prevented the reduction of β-adrenoceptor density in frontal cortex produced by desipramine administration. Similar to its effects on antagonist binding, chronic ethanol exposure did not change the agonist isoproterenol binding characteristics measured in membranes from either rat frontal cortex or hippocampus. However, the combination of ethanol plus desipramine reduced the dissociation constant of the low affinity state of the receptor (K L) in frontal cortex from 23.1±1.7 μ M in controls to 11.2±1.7 μ M . Moreover, ethanol plus desipramine produced a greater decrease in the percentage of cortical receptors in the high affinity state for agonist (%R H) than did desipramine alone. This suggests that ethanol enhances desipramine-induced desensitization of β-adrenoceptors in frontal cortex in spite of the prevention of reduction in density of the receptors. In hippocampal membranes, ethanol together with desipramine prevented desipramine-induced changes in agonist binding characteristics, i.e. the decrease in K H (dissociation constant from high affinity state of the receptor) and the consequent enhancement in K L/K H ratio. Thus, chronic exposure to relatively low concentrations of ethanol partially prevents effects of desipramine on β-adrenoceptors.

Lack of effect of chronic desipramine treatment on dopaminergic activity in the nucleus accumbens of the rat

The binding of [3H]SCH 23390 to dopamine (DA) D1-receptors was measured in the nucleus accumbens of rats treated chronically with desipramine for 14 days. DA D1- and D2-receptor binding using [3H]SCH 23390 and [3H]spiperone, respectively as ligands, was determined in rats treated for 28 days. Neither Bmax nor Kd values were influenced by chronic desipramine treatment. In addition, chronic desipramine treatment (28 days) did not influence the dose dependent, quinpirole (10-1000 nM)-mediated inhibition of the electrically stimulated release of [3H]DA release and [14C]ACh from nucleus accumbens slices or the dose dependent increase in [3H]DA release and decrease in [14C]ACh release in the presence of 1 and 10 microM nomifensine. Therefore, our results suggest that the effect of chronic antidepressant treatment cannot be attributed to changes in either DA D1- or D2-receptor binding or DA D2-receptor function in the nucleus accumbens.

Gangliosides enhance behavioral and neurochemical effects induced by chronic desipramine (DMI) treatment

Rats pretreated with gangliosides showed a significant enhancement of the anti-immobility effect of desipramine (DMI) in the forced swimming test. Accordingly, an associated treatment of gangliosides and DMI for 7 days significantly enhanced β-adrenergic down-regulation in the frontal cortex as compared with the effect of DMI alone. Gangliosides exerted an accelerating effect on the decrease of β-adrenoceptor density induced by DMI, since the down-regulation phenomenon appeared after 3 days of treatment. Gangliosides did not affect the pharmacokinetics of DMI, since associated acute or prolonged treatments did not modify the brain levels of DMI as compared to the levels of animals that had received DMI alone. These results evidence a stimulating effect of gangliosides on the development of adaptative receptor changes induced by chronic DMI treatment.

Effect of chronic desipramine treatment on neurotransmitter-thyrotropin releasing hormone--thyrotropin interactions in the rat.

Long-term administration of the antidepressant drug, desipramine (20 mg/kg/day, orally for 28 days), decreased the stimulatory effect of the alpha 2-adrenoceptor agonist, clonidine (250 micrograms/kg, i.p.) on thyrotropin (TSH) secretion in the rat, but did not alter basal TSH secretion. beta-Adrenoceptor-mediated inhibition of TSH secretion by isoproterenol (1 mg/kg, i.p.) was unaffected by chronic desipramine treatment, as were the stimulatory effect of TSH-releasing hormone (TRH, 5 micrograms/kg, i.v.) on TSH release and its inhibition by the alpha-adrenoceptor antagonist, phentolamine (2 mg/kg, i.p.). These findings suggest that chronic desipramine treatment induces subsensitivity of alpha 2-adrenoceptors which modulate TSH secretion in the rat while not affecting beta-adrenoceptor-mediated inhibition of TSH release. These findings suggest that pituitary TRH receptors are unchanged but that changes occurred at the hypothalamic level in alpha 2-adrenoceptor-mediated stimulation of TRH release. Although cerebral beta-adrenoceptors have been shown convincingly to be down-regulated after chronic desipramine treatment, their function in the hypothalamic TRH system after 28 days of treatment with desipramine appears to be unimpaired.

The modulatory effect of neurotensin on [ 3H]dopamine release from rat nucleus accumbens slices is enhanced after chronic desipramine treatment

In the presence of the reuptake blocker, nomifensine (1 μM), neurotensin caused a dose-dependent increase in the 25 mM K +-evoked release of [ 3H]dopamine ([ 3H]-DA) from rat nucleus accumbens slices. Chronic desipramine (DMI)-treatment (20 mg DMI/kg/day, orally for 28 days) caused a significant reduction in the K +-stimulated release of [ 3H]DA from rat nucleus accumbens slices. This could possibly have resulted from increased DA autoreceptor-mediated inhibition of DA release. Superfusion of the DMI-treated rat tissue with buffer-containing neurotensin (100 nM) resulted in an increase in the K +-evoked release of [ 3H]DA to a level which was higher than that observed with tissue obtained from untreated rats. A similar enhanced effect of neurotensin on DA release was observed when the DA agonist, apomorphine (APO), and ascorbate were included in the superfusion buffer. These findings are consistent with DMI treatment giving rise to impaired DA release possibly due to DA autoreceptor-mediated inhibition of DA release and cancellation of this effect by neurotensin.

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

The β-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 β-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 β-adrenoceptor upregulation after a single dose of FG7142, although desipramine alone did not alter β-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 β-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 β-adrenoceptors by FG7142 may be related to the behavioural actions of this compound is discussed.

Chronic treatment with antidepressant drugs and the analgesia induced by 5-methoxy-N,N-dimethyltryptamine: attenuation by desipramine.

The effect of chronic and acute oral or intraperitoneal treatment with the antidepressant drugs, desipramine, amitriptyline, alaproclate and iprindole, upon pain thresholds in the tail flick, hot plate and shock titration tests of nociception in saline- and 5-MeODMT-treated rats was studied. Chronic desipramine treatment increased the pre-test tail flick latencies. In the saline-treated rats, chronic oral desipramine treatment increased tail flick latencies, whereas chronic oral amitriptyline treatment decreased tail flick latencies. In 5-MeODMT-treated rats, chronic oral desipramine treatment attenuated the effects of 5-MeODMT (1 mg/kg) in all three tests of nociception, whereas chronic amitriptyline caused a potentiation in the tail flick and hot plate tests. Chronic oral iprindole treatment attenuated 5-MeODMT-induced analgesia in the hot plate test. Chronic intraperitoneal desipramine treatment attenuated 5-MeODMT analgesia in the tail flick and shock titration tests. In a different chronic treatment experiment, oral desipramine treatment attenuated 5-MeODMT analgesia in the tail flick test and zimeldine did for both the tail flick and hot plate tests, whereas mianserin potentiated 5-MeODMT-induced analgesia in both the tail flick and hot plate tests. In the saline-treated rats, acute treatment with all four drugs, desipramine, amitriptyline, iprindole and alaproclate, elevated the shock thresholds, whereas in 5-MeODMT-treated rats, desipramine and amitriptyline elevated shock thresholds. Two main conclusions can be drawn: chronic desipramine caused a quite consistent attenuation of 5-MeODMT-induced analgesia and the effects of acute treatment differed strongly from that of the chronic treatment. The effects of chronic administration with these antidepressants were compared with other findings using different measures of behavioural and receptor function.