Chronic Desipramine Research Articles

Functional responses to baclofen and 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP) in rats repeatedly treated with desipramine

Subcutaneous chronic desipramine (DMI, 5 mg/kg once daily for 18 consecutive days) prevented subcutaneous THIP (20 mg/kg) reduction in body temperature but did not affect THIP behavioral depressant effect (open-field behavior). Repeated DMI treatment did not affect subcutaneous baclofen (2.5–10 mg/kg) reduction in body temperature and behavioral depression (open-field behavior).

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.

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.

Lack of relationship between effect of desipramine on forced swimming test and brain levels of desipramine or its demethylated metabolite in rats.

Animals were injected with 20 mg/kg desipramine (DMI) 1 h (acute) or 24, 5 and 1 h (subchronic) or once daily for 7 consecutive days (chronic) before the forced swimming test (FST). DMI was also injected at a dose of 40 mg/kg acutely. Animals were killed immediately after test for evaluation of brain concentrations of DMI and its demethylated metabolite desmethyldesipramine (DDMI). Acute and chronic DMI 20 mg/kg gave rise to similar brain concentrations but only chronic DMI was active on FST. Acute DMI 20 mg/kg and 40 mg/kg gave rise to different brain concentrations but similar effects on FST. DDMI concentrations were similar after the various DMI treatments. Results seem to indicate that no relationship exists between effect of DMI on FST and brain concentrations of either DMI or DDMI.

The effect of 5,7-DHT-induced lesions of the median raphe nucleus and chronic desipramine administration upon motor behaviour of rats given intrahippocampal clonidine injection

The role of serotonergic (5-HT) innervation of rat hippocampus in clonidine- induced behavioural effects was studied in naive and desipramine-pretreated animals. 5,7- DHT-lesions of the median raphe nucleus (MR) produced about 50 per cent decrease of serotonin and 5-hydroxyindoloacetic acid (5-HIAA) content in the rat cortex and hippocampus. Lesions of the MR also accelerated the attenuating effect of desipramine upon locomotor inhibition produced by intrahippocampal clonidine injections. In the forced swim test (FST) the MR lesion revealed the stimulatory potency of clonidine upon rat active behaviour, which was statistically significant. However, no further potentiation by MR lesions of DMI effects upon behavioural action of clonidine could be observed in this test. It is concluded that hippocampal serotonergic innervation plays a minor role in the antidepressant-induced changes in behavioural effects of clonidine, which probably occur via modulation of local alpha-adrenoceptors. It is also conceivable that the stimulatory effect of intrahippocampal clonidine injections in the forced swim test in MR-lesioned rats, may be due to the increase in the alpha-(1)-adrenoceptor function in this brain area.

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.

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

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

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.

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.

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.

The effects of desipramine, zimelidine, electroconvulsive treatment and lithium on rat brain biogenic amines: A comparison with peripheral changes

The effects of 4 common treatments for affective disorders on total body norepinephrine (NE) and dopamine (DA) turnover and metabolism were evaluated in rats. The treatments were chronic desipramine (DMI), zimelidine (ZMI), electroconvulsion (ECT) and lithium (Li). The central effects of ECT and Li were also assessed in the brain. The results obtained were compared with the effects of these 4 treatments on total NE (Sum NE) and DA (Sum DA) turnover in depressed patients. We have also evaluated central and /or peripheral effects of these treatments on phenylethylamine, p-tyramine and serotonin metabolism. The urinary changes in Sum NE and DA observed after DMI, ZMI and Li in the rat were similar to those found in depressed patients; Sum NE was significantly reduced. In contrast to its effects on depressed patients, chronic ECT significantly increased Sum NE. Similar to depressed patients, ECT reduced the fraction of NE escaping re-uptake in the rat. Sum DA was not affected by DMI, ZMI or ECT, but was significantly reduced by chronic Li treatment. All 4 treatments significantly reduced serotonin metabolism as indicated by reduced 5-hydroxyindoleacetic acid excretion rates. DMI, ZMI and Li treatments significantly reduced phenylethylamine urinary but not p-tyramine urinary outputs. The opposite effect was observed after ECT. Consistent with their efefcts on Sum NE, Li reduced while ECT increased hypothalamic NE turnover as deduced from the changes in 3-methoxy-4-hydroxyphenylglycol's rate of formation. As for Sum DA, Li had no effect on 3,4-dihydroxyphenylacetic acid or homovanillic acid's rates of formation in the caudate nucleus. Chronic ECT produced a small, but significant increase in homovanillic acid's rate of formation in the caudate nucleus.

Chronic desipramine attenuates morphine analgesia

Two experiments were conducted to explore the effects of chronic antidepressant treatment on endogenous opioid systems. In the first study, mice received desipramine for 21 days, a regimen which down-regulates beta-adrenergic receptors [13]. Subsequently, hotplate jump latencies were measured after acute saline, morphine or naloxone, to test for dynamic changes in endogenous opioid systems. Chronic desipramine treatment resulted in a significant attenuation of morphine analgesia, but had no effect on latencies of saline and naloxone treated mice. In the second experiment, naltrexone or propranolol were given with desipramine for 21 days, in an attempt to block the development of subsensitivity to morphine. Naltrexone had no effect on desipramine attenuation of morphine analgesia. Propranolol given with desipramine slightly lowered jump latencies of acute saline controls, resulting in a significant analgetic effect of morphine. These data suggest that attenuation of morphine analgesia by chronic desipramine treatment may be mediated by actions on noradrenergic systems, rather than direct effects on opioid receptors.

Potentiation of cold-water swim analgesia by acute, but not chronic desipramine administration

Like other stress responses, cold-water swim (CWS) analgesia can be altered by changes in norepinephrine (NE) availability. While clonidine pretreatment potentiates CWS analgesia, lesions placed in the noradrenergic locus coeruleus reduce this response. Desipramine (DMI) can alter both the availability and receptor function of catecholamines, particularly NE: while both acute and chronic DMI treatments decrease NE reuptake, subsensitivity of beta-adrenergic receptors occurs only after chronic DMI treatment. The present study examined whether acute and chronic DMI treatments differentially alter CWS analgesia as measured by the jump test. CWS hypothermia and basal jump thresholds. The first experiment determined that pretreatment at either 24, 5 and 1 hr or only at 1 hr with DMI doses of 20 and 5 but not 1 mg/kg potentiated CWS analgesia. The second experiment found that chronic DMI pretreatment at a dose of 10 mg/kg administered twice daily over seven days failed to alter CWS analgesia at 1, 24, 48 or 72 hr thereafter. Neither CWS hypothermia nor basal jump thresholds were affected by the acute or chronic DMI injection regimens. The selective potentiation of CWS analgesia by acute DMI pretreatment is discussed in terms of the differential actions of acute and chronic injection regimens upon NE availability, receptor function, and adaptation processes.

Modification of behavioral response to intra-hippocampal injections of noradrenaline and adrenoceptor agonists by chronic treatment with desipramine and citalopram: Functional aspects of adaptive receptor changes

The present study investigated the effects of acute and of chronic treatment with desipramine (DI) and citalopram (CT) on the alterations in rat behavior in the open field and in the forced swim tests produced by intra-hippocampal microinjections of noradrenaline (NA) and adrenoceptor agonists. Chronic but not acute treatment with DI potentiated the stimulatory effects of NA on the rats' behavior in the open field test and in the forced swim test as well as revealed the excitatory effect of microinjections of phenylephrine at a dose producing insignificant changes when given alone. The depressive effects of clonidine in the open field test were antagonized by acute DI administration and reversed by chronic DI. No characteristic changes in the isoproterenol-induced in rat locomotion were observed following chronic DI since the antagonistic interaction was found after both acute and chronic DI pretreatment. Chronic though not acute administration of CT produced effects in the forced swim test similar to those of DI, i.e. excitatory effects of phenylephrine and clonidine on behavior. The data indicate a potentiation of excitatory processes in the brain limbic structure, probably mediated via α 1-adrenoceptors.

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.

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.

Agonist interactions with beta-adrenergic receptors following chronic administration of desipramine or the atypical antidepressants, iprindole and mianserin.

Desipramine (DMI), decreased the maximum number of beta-adrenergic receptors by approximately 10, 20, 30, and 20% in groups of rats treated i.p. with 5 mg/kg for 14 days or 10 mg/kg for 7, 14, or 21 days, respectively. In studies of agonist competition for beta-adrenergic receptors labelled with [125I]-CYP, chronic DMI administration caused a selective decrease in those receptors normally found in the high affinity conformation in proportion to the dose of DMI administered. No change was observed in either the number of receptors in the agonist low affinity conformation or in the affinity of any drug for the high or low affinity conformations of the receptors. Therefore, chronic DMI caused a selective decrease in the beta-adrenergic receptors linked to adenylate cyclase but did not appear to change other properties of the receptors that would be manifested as a change in their ability to interact with adrenergic agonists. Neither iprindole (15 mg/kg i.p., 14 days) nor mianserin (10 mg/kg i.p., 14 days) decreased the number of receptors, the proportions of agonist high or low affinity receptors, or the affinity of competitor drugs for these receptors, suggesting a different mechanism for the reported loss of adenylate cyclase activity following these drugs than the down-regulation of receptors observed with chronic DMI treatment.

Hormonal responses to zimelidine and desipramine in depressed patients

Plasma prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or zimelidine (ZIM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in the depressed patients. Neither DMI nor ZIM produced changes in LH or cortisol. DMI acutely increased plasma PRL, whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models.

Behavioral evidence for α1-adrenoceptor up- and α2-adrenoceptor down-regulation in the rat hippocampus after chronic desipramine treatment

Behavioral evidence for α1-adrenoceptor up- and α2-adrenoceptor down-regulation in the rat hippocampus after chronic desipramine treatment

Reduced metabolism and turnover rates of rat brain dopamine, norepinephrine and serotonin by chronic desipramine and zimelidine treatments

As part of of an ongoing effort to compare changes in whole body turnover of catecholamines and serptonin in man with those induced by antidepressants in the rat brain, we have evaluated the chronic effects of desipramine (DMI) and zimelidine (ZMI) on brain catecholamines and serotonin in the rat. The amines and metabolites measured include norepinephrine (NE), dopamine (DA) and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenlacetic acid (DOPAC) and homovanillic acid (HVA). Three brain areas were analysed; the hypothalamus, caudate nucleus and frontal cortex. Chronic DMI and ZMI reduced hypothalamic MHPG and caudate nucleus DA metabolites, in particular HVA. Both drugs reduced NE and DA turnover rates (estimated after α-methyl-p-tyrosine injection) and the rate of MHPG formation in the hypothalamus (estimated after pargyline treatment). They did not change NE turnover rate, but reduced DA turnover rate and rate of HVA formation in the caudate nucleus. Chronic DMI but not ZMI reduced DOPAC rate of formation in the caudate nucleus. Apparently changes in DA turnover and metabolism produced by these antidepressants are better related to changes in HVA than DOPAC concentrations. Similar to their influence on hypothalamic and caudate nucleus catecholamines, both chronic DMI and ZMI produced changes in serotonin concentration in the caudate nucleus and frontal cortex serotonin that suggest a reduction in its turnover rate and metabolism. The reduction in NE turnover in hypothalamus is consistent with the effects of chronic DMI and ZMI on whole body NE turnover observed in man. In conclusion, DMI and ZMI affect all three major monoamine neurotransmitter (NE, DA and serotonin) systems in ways that suggest reduced presynaptic neuronal activity. The influence of these antidepressants on caudate nucleus DA calls for the reassessment of the role of DA in the mechanism of action of antidepressants in other brain dopaminergic regions.