Effects Of Chronic Desipramine Treatment Research Articles

The effects of chronic desipramine treatment on neurotrophin-3 in the brain of mice with selective depletion of CREB and CREM in noradrenergic neurons

The disturbances in neurotrophic support are thought to be one of the main causes of depression, which depend not only on the neurotrophins themselves but also on the molecules regulating their synthesis and effector functions. One such molecule is cAMP responsive element binding protein (CREB), which role in depression and antidepressant drugs mechanism of action has been extensively studied. However, CREB’s effects vary depending on brain structure, necessitating specific transgenic models for studying its function. Moreover, deletion of CREB enhances cAMP response element modulator (CREM) expression, suspected to compensate for CREB in its absence.Previously, mice lacking CREB in noradrenergic neurons and CREM (Creb1DbhCreCrem-/-) showed to be insensitive to acute desipramine, whereas mice lacking only CREB (Creb1DbhCre) showed similar effects as wild type animals (w/t). As neurotrophic changes require chronic antidepressant treatment, in current study mice (w/t, Creb1DbhCre and Creb1DbhCreCrem-/-; both males and females) were given desipramine for 21 days, to assess the effects of the drug on CREB, neurotrophins and their receptors in the hippocampus and prefrontal cortex.Interestingly, desipramine had no effect on CREB in neither of studied groups. However, both male and female mice lacking CREB and CREM displayed alterations in neurotrophin-3 (NTF3) expression or protein levels, modulated by desipramine. These findings suggest NTF3 is connected with inhibited response to acute and probably chronic desipramine administration in Creb1DbhCreCrem–/– mice, although in w/t chronic desipramine had no effect on NTF3. Nevertheless, our findings give insight into the role of non-BDNF neurotrophins in the mechanism of antidepressant drugs.

Lithium augmentation of the effects of desipramine in a mouse model of treatment-resistant depression: A role for hippocampal cell proliferation

Approximately 50% of patients with a major depressive episode fail to achieve remission with first-line antidepressant treatments. Second-line treatment strategies for such patients include lithium augmentation of antidepressants, particularly with tricyclic antidepressants. The neurobiological mechanisms underlying the therapeutic effects of lithium augmentation are not yet fully understood. Unravelling these mechanisms could aid the development of more effective antidepressant drugs. In the present study, we investigated whether chronic treatment with a combination of lithium and the tricyclic antidepressant, desipramine, could produce antidepressant-like behaviour in a mouse strain (BALB/cOLaHsd) that exhibited reduced sensitivity to the behavioural effects of chronic desipramine treatment in the novelty-induced hypophagia test. Since chronic treatment with antidepressant drugs increases the proliferation of newly-born cells in the hippocampus, and hippocampal cell proliferation is required for the behavioural effects of at least some antidepressants in neohypophagia tests, the present study also investigated whether lithium plus desipramine increased cell proliferation in the hippocampus. Chronic treatment with lithium plus desipramine but neither drug alone, induced antidepressant-like behaviour and increased hippocampal cell proliferation, thus suggesting that increased hippocampal cell proliferation may be a mechanism underlying lithium augmentation of antidepressants. Moreover, since BALB/cOLaHsd mice respond to lithium plus desipramine but not to either drug alone, they may become useful in the development of a mouse model of treatment-refractory depression for which there is an unmet need.

Effects of chronic desipramine treatment on α 2-adrenoceptors and μ-opioid receptors in the guinea pig cortex and hippocampus

The existence of a close relation between presynaptic inhibitory α 2-adrenoceptor and μ-opioid receptor pathways is well established. Such interplay may occur during chronic conditions that give rise to neuroadaptive changes involving both receptor systems. The aim of this study was to examine the effect of chronic treatment with the tricyclic antidepressant drug, desipramine, on α 2-adrenoceptors and μ-opioid receptors in the guinea pig brain. Guinea pigs were treated with 10 mg/kg desipramine, injected i.p. for 21 days, every 24 h. The levels of expression of α 2-adrenoceptors and μ-opioid receptors, the G protein receptor regulatory kinase, GRK2/3 and signal transduction inhibitory G proteins in synaptosomes of the guinea pig hippocampus and cortex were evaluated by immunoblotting. Quantitative analysis of α 2-adrenoceptor and μ-opioid receptor mRNA levels has been carried out by competitive reverse transcriptase polymerase chain reaction. The expression levels of α 2-adrenoceptors and μ-opioid receptors and the respective mRNAs were found unchanged in the cortex, after chronic desipramine treatment. In these experimental conditions α 2-adrenoceptor and μ-opioid receptor levels decreased, while the relevant transcripts increased, in the hippocampus. GRK2/3 levels remained unchanged and increased, respectively, in the cortex and the hippocampus, after chronic exposure to desipramine. In the same experimental conditions, Gα i1, Gα i2, Gα o and Gα z levels remained unchanged, while Gα i3 levels decreased, in the cortex; whereas, Gα i1, Gα i2 and Gα i3 levels significantly increased, and Gα o and Gα z levels remained unchanged, in the hippocampus. On the whole, the present data suggest that α 2-adrenoceptor and μ-opioid receptor expression and transcription are similarly influenced by chronic treatment with desipramine, in the guinea pig cortex and hippocampus. Furthermore, alterations in the levels of regulatory GRK2/3 and of inhibitory signal transduction G proteins, relevant to activation of both receptor pathways, have been documented. The distinct pattern of adaptations of the different protein studied in response to chronic desipramine treatment in both regions is discussed.

Functional interaction between α 2-adrenoceptors, μ- and κ-opioid receptors in the guinea pig myenteric plexus: Effect of chronic desipramine treatment

The existence of a functional interplay between α 2-adrenoceptor and opioid receptor inhibitory pathways modulating neurotransmitter release has been demonstrated in the enteric nervous system by development of sensitivity changes to α 2-adrenoceptor, μ- and κ-opioid receptor agents on enteric cholinergic neurons after chronic sympathetic denervation. In the present study, to further examine this hypothesis we evaluated whether manipulation of α 2-adrenoceptor pathways by chronic treatment with the antidepressant drug, desipramine (10 mg/kg i.p. daily, for 21 days), could entail changes in enteric μ- and κ-opioid receptor pathways in the myenteric plexus of the guinea pig distal colon. In this region, subsensitivity to the inhibitory effect of both UK14,304 and U69,593, respectively α 2A-adrenoceptor and κ-opioid receptor agonist, on the peristaltic reflex developed after chronic desipramine treatment. On opposite, in these experimental conditions, supersensitivity developed to the inhibitory effect of [D-Ala, N-Me-Phe4-Gly-ol5]-enkephalin (DAMGO), μ-opioid receptor agonist, on propulsion velocity. Immunoreactive expression levels of α 2A-adrenoceptors, μ- and κ-opioid receptors significantly decreased in the myenteric plexus of the guinea pig colon after chronic desipramine treatment. In these experimental conditions, mRNA levels of α 2A-adrenoceptors, μ- and κ-opioid receptors significantly increased, excluding a direct involvement of transcription mechanisms in the regulation of receptor expression. Levels of G protein-coupled receptor kinase 2/3 and of inhibitory G i/o proteins were significantly reduced in the myenteric plexus after chronic treatment with desipramine. Such changes might represent possible molecular mechanisms involved in the development of subsensitivity to UK14,304 and U69,593 on the efficiency of peristalsis. Alternative molecular mechanisms, including a higher efficiency in the coupling between receptor activation and downstream intracellular effector systems, possibly independent from inhibitory G i/o proteins, may be accounted for the development of supersensitivity to DAMGO. Increased sensitivity to the μ-opioid agonist might compensate for the development of α 2A-adrenoceptor and κ-opioid receptor subsensitivity. On the whole, the present data further strengthen the concept that, manipulation of α 2-adrenergic inhibitory receptor pathways in the enteric nervous system entails changes in opioid inhibitory receptor pathways, which might be involved in maintaining homeostasis as suggested for μ-opioid, but not for κ-opioid receptors.

Quantitative in vitro phosphor imaging using [ 3H] and [ 18F] radioligands: the effects of chronic desipramine treatment on serotonin 5-HT 2 receptors

Traditionally, autoradiography of neuroreceptors is performed in vitro using tritiated ligands and low sensitivity X-ray film, requiring long exposure times. In vivo imaging of neuroreceptors using positron emission tomography (PET) suffers poor spatial resolution, but in vitro PET autoradiography is difficult with film due to the short half-life of the isotopes. Storage phosphor screens provide an extremely sensitive alternative to film. To demonstrate and validate quantitative in vitro phosphor imaging with PET and tritiated ligands, we treated rats chronically with the antidepressant desipramine, which results in decreased binding to serotonin 5-HT 2 receptors. Serotonin 5-HT 2 binding decreased significantly in all cortical regions examined as measured by both [ 3H]ketanserin and [ 18F]setoperone. The data from the two radioligands were not significantly different, and the distribution of the receptors was in agreement with previous reports. We also present data on the reusability of tritium-sensitive phosphor screens, and show that the use of simple corrections allows receptor binding data with PET ligands to be compared across different days. The results indicate that phosphor imaging is a valid, fast, and quantifiable technique for measuring neuroreceptor regulation, and that it provides an excellent tool to corroborate in vivo PET data in vitro at higher resolution.

Olfactory Bulbectomy Provokes a Suppression of Interleukin-1β and Tumour Necrosis Factor-α Production in Response to an in vivo Challenge with Lipopolysaccharide: Effect of Chronic Desipramine Treatment

The olfactory bulbectomized (OB) rat has been developed as an animal model of depression and exhibits several behavioural and neurochemical characteristics that are qualitatively similar to those found in clinically depressed patients. In addition to the behavioural and neurochemical abnormalities seen in OB rats, it has been reported that these animals have alterations in a number ex vivo measures of immune function many of which are reversed following chronic antidepressant treatment. In the present study we sought to examine the effects of olfactory bulbectomy on responsiveness to an in vivo immune challenge with bacterial lipopolysaccharide (LPS; 100 μg/kg, i.p.). In addition, the effect of chronic treatment with the tricyclic antidepressant desipramine (7.5 mg/kg, i.p.) on bulbectomy related behavioural changes, hypothalamic-pituitary-adrenal axis activity and immune responsiveness was evaluated. To our knowledge this is the first time that in vivo immunological responsiveness has been examined in the OB rat model of depression. OB rats exhibited a characteristic hyperactive response in a novel ‘open field’ environment, which was attenuated following chronic desipramine treatment. LPS provoked a large increase in circulating interleukin (IL)-1β and tumour necrosis factor (TNF)-α in vehicle treated sham operated animals. Vehicle treated OB rats displayed a significant impairment in LPS-induced IL-1β (54%) and TNF-α (70%) secretion compared to their sham operated controls, an effect that was potentiated following chronic desipramine treatment. Furthermore, sham animals that were chronically treated with desipramine displayed decreases in LPS-provoked IL-1β (51%) and TNF-α (49%) secretion compared to vehicle treated counterparts. In addition, LPS-induced alterations in corticosterone and adrenal ascorbic acid concentrations were also attenuated by bulbectomy, an effect that was further enhanced following chronic desipramine treatment. In conclusion, these data provide evidence that olfactory bulbectomy in the rat impairs the ability of macrophages to produce the proinflammatory cytokines IL-1β and TNF-α following an in vivo challenge with bacterial LPS. Whilst chronic treatment with desipramine normalized the behavioural hyperactivity observed in OB rats, such treatment further impaired LPS-induced IL-1β and TNF-α secretion in bulbectomized rats.

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 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

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.

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.

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.

Effect of chronic desipramine treatment on adrenoceptor modulation of [ 3H]dopamine release from rat nucleus accumbens slices

The effects of α 2- and β-adrenoceptor agonists on the 25 mM K +-induced release of [ 3H]dopamine ([ 3H]DA from nucleus accumbens slices of chronic desipramine (DMI)- and saline-treated rats were investigated using a superfusion technique. The K +-induced release of [ 3H]DA from nucleus accumbens slices was shown to be Ca 2+-dependent by ascorbic acid. In experiments with isoproterenol, ascorbic acid was added to the superfusion media in order to prevent the otherwise rapid oxidation of the drug. The K +-induced release of [ 3H]DA from nucleus accumbens slices of saline-treated rats was significantly decreased by the α 2-adrenoceptor agonist, clonidine(10 μM; 89 ± 2.4%of control values; P < 0.002), and significantly enhanced by the β-adrenoceptor agonist, isoproterenol(1 and 10 μM; 122 ± 4.3and171 ± 2.9%of control values, P < 0.002andP < 0.001, respectively). The basal release of [ 3H]DA was strongly enhanced by 10 μM but not 1 μM isoproterenol. Chronic DMI pretreatment (10 mg/kg i.p. for 28 days) did not significantly alter the K +-induced release of [ 3H]DA. Chronic DMI treatment attenuated the α-adrenoceptor-mediated inhibition of [ 3H]DA release, while the β-adrenoceptor-mediated stimulation remained unchanged. The net effect of chronic DMI treatment therefore would appear to be a facilitation of dopaminergic neurotransmission in the mesolimbic system. This is consistent with behavioural evidence which suggests that the function of the mesolimbic dopaminergic reward system is facilitated by chronic treatment with antidepressant drugs.

Effects of chronic desipramine treatment on rat brain noradrenergic responses to α-adrenergic drugs

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central β-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 μg/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic α-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic ( α 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.