Injection Of Desipramine Research Articles

Neuron-specific deletion of VEGF or its receptor Flk-1 occludes the antidepressant-like effects of desipramine and fluoxetine in mice.

Vascular endothelial growth factor (VEGF) signaling is known to be involved in the antidepressant-like effects of conventional antidepressants, such as desipramine (DMI), a tricyclic antidepressant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor; however, the precise role of neuronal VEGF signaling in mediating these effects remains unclear. Using mice with excitatory neuron-specific deletion of VEGF and its receptor, fetal liver kinase 1 (Flk-1) in the forebrain, we examined the effects of forebrain excitatory neuron-specific deletion of VEGF or Flk-1 on the antidepressant-like effects of repeated DMI and chronic FLX administration in the forced swim test (FST). Repeated intraperitoneal (i.p.) injections of DMI (10, 10, and 20 mg/kg at 24, 4, and 1 h before the FST, respectively) significantly decreased immobility in control mice; however, this effect was completely blocked in mice with neuron-specific VEGF or Flk-1 deletion. Although chronic treatment with FLX (18 mg/kg/day, i.p.) did not impact immobility in control mice 1 day after the 22nd injection, immobility was significantly reduced 1 day after the preswim and the 23rd FLX injection. However, in mice with neuron-specific Flk-1 deletion, chronic FLX treatment significantly increased immobility in the preswim and failed to produce antidepressant-like effects. Collectively, these findings indicate that neuronal VEGF-Flk-1 signaling contributes to the antidepressant-like actions of conventional antidepressants.

Desipramine, commonly used as a noradrenergic neuroprotectant in 6-OHDA-lesions, leads to local functional changes in the urinary bladder and gastrointestinal tract in healthy rats

The 6-hydroxydopamine (6-OHDA) rat model is one of the most common animal models of Parkinson's disease. When experimentally inducing dopaminergic neurodegeneration in the nigrostriatal pathway using 6-OHDA, the noradrenergic reuptake inhibitor desipramine is often systemically injected in order to protect against damages to the noradrenergic system in the brain. An increasing number of studies are focusing on understanding the pathophysiological changes underlying autonomic non-motor symptoms, in particular urinary bladder and gastrointestinal dysfunctions, of the disease. Several of these studies have investigated the contractile properties and the activation of smooth muscle in the 6-OHDA rat model. Since the injection of desipramine is commonly placed in close proximity to the urinary bladder and gastrointestinal tract, in the current study we wanted to understand if the drug alone has an effect. For this, we have injected a single dose (25 mg/kg) of desipramine either intraperitonially or subcutaneously and investigated smooth muscle contractility in vitro in the urinary bladder, proximal colon and distal ileum four weeks post injection. Our data show that desipramine significantly alters smooth muscle contractility of the urinary bladder and proximal colon in healthy rats. Conclusively, we suggest, based on our data, that desipramine should be omitted when using the 6-OHDA rat model to investigate smooth muscle function in Parkinson's disease research.

Stimulatory effect of desipramine on lung metastases of adenocarcinoma MADB 106 in stress highly-sensitive and stress non-reactive rats

The effect of antidepressant drugs on tumor progress is very poorly recognized. The aim of the present study was to examine the effect of individual reactivity to stress and 24-day desipramine (DES) administration on the metastatic colonization of adenocarcinoma MADB 106 cells in the lungs of Wistar rats. Wistar rats were subjected to stress procedure according to the chronic mild stress (CMS) model of depression for two weeks and stress highly-sensitive (SHS) and stress non-reactive (SNR) rats were selected. SHS rats were more prone to cancer metastasis than SNR ones and chronic DES treatment further increased the number of lung metastases by 59% and 50% in comparison to vehicle-treated appropriate control rats. The increase in lung metastases was connected with DES-induced skew macrophage activity towards M2 functional phenotype in SHS and SNR rats. Moreover, during 24h after DES injection in healthy rats, the decreased number of TCD8+ and B cells in SHS and SNR rats as well as NK cell cytotoxic activity in SNR rats could be attributed to the lowered capacity to defend against cancer metastasis observed in chronic DES treated and tumor injected rats.

Further evidence for an immediate antidepressant action of intracerebral drug administration in a model of chronic depression

This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high distress.

Age-specific effects of 6-hydroxydopamine lesions of the rat medial prefrontal cortex on stress-induced c-fos expression in subcortical areas

As adolescence is a critical period when dopaminergic neuronal maturation peaks, we hypothesized that 6-hydroxydopamine (OHDA) lesions of the medial prefrontal cortex (mPFC) in adolescent rats would have more negative effects than lesions in adult rats. Therefore, we investigated the effects of 6-OHDA lesions of the mPFC in adolescent and adult rats on stress-induced c-fos expression in the brain. Adolescent and adult Sprague–Dawley rats, aged 4 and 7 weeks on arrival, respectively, were studied. 6-OHDA (8.0 µg) for the lesion groups and ascorbic acid for the sham groups were injected bilaterally into the mPFC. All animals were pretreated with desipramine 30 min before being anesthetized. The control group did not undergo any surgery-related procedure except the desipramine injection. After recovery for 1 week, the rats were subjected to restraint stress for 1 h. Immediately after the stress, the rats were killed and c-fos immunohistochemistry was examined. The c-fos expression in the nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), CA1, CA3, dentate gyrus (DG), central amygdaloid (Ce), basolateral amygdaloid (BL), and temporal cortex (Tc) was compared. Adolescent rats with 6-OHDA lesions subjected to restraint stress had greater c-fos expression in the AcbC, AcbSh, DG, Ce, BL, and Tc, compared to the sham and control groups, whereas these differences were not observed among the adult groups. These results suggest that a hypodopaminergic state in the mPFC of adolescent rats, but not adult rats, is related to increased sensitivity to stress, suggesting that damage to or maldevelopment of dopaminergic neurons during adolescence has an age-specific effect. Further research is warranted to investigate the mechanism of the age-specific effect of 6-OHDA lesions of the mPFC.

PW01-81 - Deficits of spatial memory and oxidative stress damage following exposure to lipopolysaccharide in a rat model of Parkinson's disease

ObjectivesThe present work was undertaken in order to investigate the effects of systemic lipopolysaccharide endotoxin administration (250 μg/kg) on spatial memory formation and oxidative stress in rats subjected to right-unilateral lesion of the dopaminergic neurons of the substantia nigra by means of 6- hydroxydopamine (6-OHDA) compared to normal and lipopolysaccharide alone treated rats.MethodsThirty male Wistar rats weighing 200 ± 50 at the start of the experiment were used. The substantia nigra was right-unilateral lesioned by stereotaxic microinjections of 8 micrograms (free base) 6-OHDA. The rats were pretreated 30 min before the 6-OHDA infusion with 25 mg/kg desipramine to protect noradrenergic projections. Sham-operated rats received only an injection of desipramine, followed by vehicle in the substantia nigra. Lipopolysaccharide (LPS from Escherichia coli serotype 0111:B4, Sigma) was dissolved in pyrogen-free 0.9% NaCl at the concentration of 250 μg/kg and intraperitonealy injected in normal and 6-OHDA-lesioned rats for a period of 7 continuous days. 7 days after continuous LPS administration we assessed memory formation by means of Y-maze and radial arm-maze task, and the endogenous antioxidants activity in rat temporal cortical area.ResultsSystemic lipopolysaccharide administration significantly decreased spontaneous alternation in Y-maze task, working memory and reference memory in radial arm-maze task, suggesting impairment of both short-term memory and long term-memory, respectively. Furthermore, lipopolysaccharide administration significantly decreased activity of the biochemical markers of endogenous antioxidants in rat temporal cortical area.ConclusionsOur results further validate that lipopolysaccharide may exacerbate the development of neurological dysfunctions associated with Parkinson's disease.

Alpha-2 adrenergic-induced changes in rectal temperature in adult and 13-day old rats following acute and repeated desipramine administration

BackgroundThe effects of acute and repeated treatment with desipramine on the functional response of α2-adrenoceptors were tested in adult and 13-day old rats. The functional response measured was hypothermia that was induced by brimonidine, an α2-adrenoceptor agonist. The change in the extent of the brimonidine-induced hypothermia following pretreatment with either single or 4 twice-daily injections of desipramine was compared in 13-day old and adult (65–75 days old) male rats.ResultsBrimonidine, alone, lowered rectal temperature to a greater extent in juvenile than in adult rats, and this response was dose-dependently blocked by the selective α2-adrenoceptor antagonist, RX821002, in both groups of rats. Single desipramine administration lowered rectal temperature in the absence of brimonidine in adult but not in juvenile rats. The adult rats developed tolerance to this hypothermic effect after 4 days of desipramine treatment (10 mg/kg twice daily). Repeated desipramine treatment of adult rats also resulted in an enhancement in the brimonidine-induced hypothermic effect 24 h after the last dose, a time when above 90% of desipramine and its metabolite, desmethyldesipramine, had cleared the brain, but not at 14, 48 or 96 h after the last dose. In juvenile rats repeated injections of desipramine (3 mg/kg twice daily for 4 days) had no effect on the α2-agonist-induced hypothermia when brimonidine was given 14, 24, 63 and 96 h after the last dose of desipramine.ConclusionThe results suggest that juvenile rats response differently than adult rats to agonist stimulation of α2-adrenoceptors with and without pretreatment with the antidepressant desipramine. In the absence of desipramine pretreatment, the α2-adrenoceptor-induced hypothermic effect in juvenile rats is greater than in adult rats. Acute injections of desipramine, in the absence of agonist produced a hypothermic effect in adult but not juvenile rats. In addition, the increased α2-agonist-induced hypothermic effect following repeated injections of desipramine that is seen in adult rats is not seen in juvenile rats.

In Vivo PET Imaging of Cardiac Presynaptic Sympathoneuronal Mechanisms in the Rat

The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: (11)C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; (11)C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and (11)C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans. We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart were recorded for 60 min after radiotracer injection. A myocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determined by monoexponential fitting of myocardial time-activity curves. At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (+/- SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% +/- 0.82%/min, 3.43% +/- 0.45%/min, and 4.24% +/- 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% +/- 0.23%/min, 1.13% +/- 0.35%/min, and 0.50% +/- 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%. Kinetic profiles of HED in the rat myocardium were similar to those of HED in humans, suggesting comparable neuronal transport density. Unlike in humans, however, significant washout of EPI and faster washout of PHEN were encountered, consistent with high intraneuronal metabolic activity, high catecholamine turnover, and reduced vesicular storage. This evidence of increased neuronal activity in rodents has implications for translational studies of cardiac neuronal biology in humans.

Desipramine-induced increase in norepinephrine transporter mRNA is not mediated via α2 receptors

In situ hybridization for the norepinephrine transporter (NET) was performed in rats receiving short-term (2 days) treatment with either an alpha-2 ( α 2) receptor agonist (clonidine) or antagonist (yohimbine) followed by saline or desipramine (DMI). The ‘saline’ group received intraperitoneal injections of either clonidine, yohimbine or saline followed by an injection of saline. The ‘DMI’ group received intraperitoneal injections of either clonidine, yohimbine or saline followed by an injection of DMI. Dosages given were clonidine (0.10 mg/kg), yohimbine (0.5 mg/kg) and DMI (10 mg/kg). In the ‘saline’ group, the clonidine/saline animals had significantly less NET mRNA expression compared to the saline/saline animals. In the ‘DMI’ group an attentuation of the DMI-induced increase in NET mRNA was observed in the clonidine/DMI animals compared to the saline/DMI animals. In both treatment groups, administration of yohimbine did not alter the expression of NET mRNA compared to the appropriate control animals. These findings suggest that the DMI-induced increase in NET mRNA is not mediated via α 2 receptors for, although clonidine attenuates DMI's effect, there is no reciprocal enhancement with the α 2 antagonist yohimbine. Clonidine's attenuation of DMI's effect may occur via the imidazole receptor as clonidine is an agonist at the imidazole receptor but yohimbine has no known activity at it. Additional studies are needed to clarify the mechanism of the DMI-induced increase in NET mRNA and to correlate changes in NET mRNA with transporter expression at the synaptic membrane.

Modulation of α1‐adrenoceptors and functional consequences in the bisected rat vas deferens following chronic inhibition of neuronal noradrenaline uptake

1. The adaptational changes induced after chronic inhibition of neuronal noradrenaline uptake on both functional responsiveness of alpha 1-adrenoceptor activation and [3H]-prazosin binding were investigated in prostatic and epididymal portions of the rat vas deferens. 2. Contractile concentration-response curves to phenylephrine and saturation isotherms of [3H]-prazosin binding to homogenates of each of the portions of the bisected rat vas deferens were determined 48 h after the last injection of desipramine, nomifensine or nisoxetine (10 mg kg-1; i.p. for 14 days). 3. Treatment with both nomifensine and nisoxetine decreased the potency (pD2) of phenylephrine by about 10 and 8 fold respectively in the epididymal portion. However, administration of desipramine only reduced the potency of the alpha 1-adrenoceptor agonist by about 1.8 fold. None of the treatments modified the maximal effect (Emax) elicited by phenylephrine in this portion of the vas deferens. In the prostatic portion only the treatment with nomifensine (1.4 fold) and nisoxetine (1.8 fold) decreased the potency of phenylephrine; the maximal contraction elicited by the agonist after the treatments was also reduced. 4. Chronic treatment with either nomifensine or nisoxetine did not change the KD for [3H]-prazosin binding in either epididymal or prostatic membranes. However, these two treatments resulted in a significant decrease in the [3H]-prazosin Bmax in membranes in both portions of rat vas deferens. The reduction in density of alpha 1-adrenoceptors was higher in the epididymal than the prostatic half. Desipramine reduced the Bmax only in the epididymal portion. 5. These results indicate that differential regulation of ax-adrenoceptors in either portion of the rat vas deferens could result from a greater degree of activation of these receptors in the epididymal half after chronic inhibition of neuronal noradrenaline uptake. The different functional consequences of the loss of alpha l-adrenoceptors in each portion seems to be explained on the basis of a different relationship between the occupancy of the receptor and the response elicited.

Effects of chronic desipramine administration on the locus coeruleus neuronal activity in the learned helplessness paradigm

One week after inescapable shock (IS) exposure, animals showed an increased number of escape failures in the shuttlebox and a decreased noradrenergic (NA) transmission. The latter was assessed by electric activity of locus coeruleus (LC) neurons. Seven daily injections of desipramine (DMI) were effective in reducing the number of escapes failures in the shuttlebox, but such treatment did not modify the decreased electric activity of LC NA neurons observed 7 days after IS. These results are discussed in terms of the action of DMI on NA terminals in reversing the behavioral deficit induced by IS.

Inhibition of sympathetic nerve activity by acute administration of the tricyclic antidepressant desipramine

In rats anesthetized with pentobarbital/chloral hydrate, the i.v. injection of desipramine (0.3 mg/kg) caused a rapid fall in mean arterial blood pressure accompanied by a reduction in efferent renal nerve integrated activity. A similar reduction in electrical activity was seen in the preganglionic splanchnic nerve. Pretreatment of the rats with yohimbine (0.3 mg/kg) increased renal nerve activity by 20%, and the decrease in blood pressure and renal nerve activity elicited by a subsequent dose of desipramine was blocked. I.v. injection of prazosin (0.05 mg/kg) caused a reduction in systemic blood pressure. The hypotensive effect of a subsequent dose of desipramine was largely blocked, whereas the fall in renal nerve activity was attenuated, but still present. The data are consistent with an action of desipramine to reduce central sympathetic tone by increasing the release of endogenous noradrenaline which acts on α 2-adrenoceptors at CNS sites controlling sympathetic activity. An additional involvement of central α 1-adrenoceptors cannot be ruled out.

An investigation of the role of 5-hydroxytryptamine in the attenuation of presynapticα 2-adrenoceptor-mediated responses by antidepressant treatments

Changes in the function of presynaptic alpha 2-adrenoceptors in the brain were assessed by rating the hypoactivity (sedation) response of mice to clonidine (0.1 mg/kg). A single injection of 5,7-dihydroxytryptamine (5,7-DHT, 75 micrograms ICV) or administration of p-chlorophenylalanine (PCPA; 200 mg/kg) daily for 11-15 days produced 62-77% reductions in brain 5-HT concentrations and marked supersensitivity of 5-HT2 receptor function, as indicated by the enhancement of the head-twitch response to 5-methoxy-N,N-dimethyltryptamine (2 mg/kg). Clonidine-induced hypoactivity was moderately enhanced after 5,7-DHT lesioning, but not after repeated PCPA injection. In addition, 5,7-DHT lesioning prevented the adaptive attenuation of this alpha 2-adrenoceptor-mediated response produced by daily injection of desipramine (10 mg/kg) for 14 days, but had no effect on the reduction caused by five electroconvulsive shocks (ECS, 200 V, 2 s) spread over 10 days. In contrast, repeated PCPA treatment did not prevent the reduction of clonidine-induced hypoactivity produced by repeated desipramine or ECS administration. Together, these results indicate that 5-HT (or possibly a cotransmitter contained within 5-hydroxytryptamine neurones) influences presynaptic alpha 2-adrenoceptor function. Furthermore, an intact 5-HT neuronal input is a prerequisite for the attenuation of clonidine-induced hypoactivity by desipramine, but not ECS. The probable explanation for a contrasting requirement for a functional 5-HT input is that desipramine and ECS induce this common adaptive response by different pharmacological mechanisms.

Prepontine knife cut-induced hyperthermia in the rat. Effect of chemical sympathectomy and surgical denervation of brown adipose tissue.

The effect of brown adipose tissue (BAT) denervation on the prepontine knife cut-induced hyperthermia was studied. The knife cut has earlier been shown to induce a steady state hyperthermia of 3 to 4 degrees C, as a result of marked activation of the BAT. Before the lesion, the interscapular BAT (IBAT) temperature was lower than the colonic temperature, but the temperature gradient reversed a few minutes after the lesion and the fractional blood flow increased 12-fold. Bilateral sectioning of the 5 nerves supplying IBAT did not modify either the magnitude or the kinetics of the IBAT hyperthermic response. The IBAT fractional blood flow, which was 15 times higher in denervated than in intact tissue before the lesion, scarcely increased following the lesion despite the sharp increase in the tissue's metabolic activity. Chemical sympathectomy with 6-hydroxydopamine suppressed the hyperthermic response. Propranolol or hexamethonium injected i.v. during the steady state hyperthermia resulted in a rapid drop in IBAT temperature and in a reversal of the gradient between IBAT and colonic temperature both in denervated and in intact IBAT. Injection of desipramine, an inhibitor of noradrenaline reuptake, resulted in itself in an increase of temperature in both intact and denervated tissue, which is circumstantial evidence for the presence of a functional residual innervation in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

An increase in sensitivity of rat cingulate cortical neurones to substance P occurs following withdrawal of chronic administration of antidepressant drugs.

The sensitivity of neurones in the cingulate cortex of the rat to iontophoretically applied substance P (SP) was tested one hour after a single dose of various antidepressant drugs and also 1 day following the termination of a chronic dosing schedule (14 once daily injections) of the same agents. One hour after a single injection of desipramine (DMI), chlorimipramine (CMI), trimipramine (TMI) or zimelidine ( ZIM ) (all at 10 mg kg-1 i.p.) there was no change in the mean size of excitatory responses to SP compared to those before the injection. There was a tendency towards a decrease in the TMI group. One day following the last of 14 consecutive daily injections (10 mg kg-1 i.p.) of the above agents there was a significant increase in the size of excitatory responses to SP compared to those in rats receiving daily saline injections. However, 14 days of treatment with DMI did not alter the responses to L-glutamate. Similar chronic dosing schedules with either diazepam (5 mg kg-1) or fluphenazine (5 mg kg-1) did not affect the responses to SP. Thus chronic but not acute administration of antidepressant drugs results in an increase in the sensitivity of neurones, in the cingulate cortex of the rat, to SP.

The effect of nomifensine on the muricide induced by thiamine deficiency

We reported that the muricide response induced by thiamine deficiency was inhibited by the administration of 5-HTP and significantly enhanced by p-CPA.Therefore, it was suggested that this response may be related to the brain serotonergic system. On the other hand, the muricide responses were demonstrated to be involved in the brain dopaminergic system; methamphe-temine inhibited the muricide induced by thiamine deficiency, and the muricide response induced by tetrahydrocannabinol was reduced by 1-dopa or amantadine. So, we investigated the effect of nomifensine which inhibited selectively re-uptake of dopamine compared with other antidepressants on the muricide response induced by thiamine deficiency. Male Wister rats(75-85g) were used in this study and supplied with a thiamine deficient diet for 28 days. The occurrence of the muricide was observed between the 14th day and 28th days. Only killer rats were used in the present experiment. It was observed whether the killer rats treated with each of the drugs killed a mouse or not. When 1-dopa(i.p.) or nomifensine(i.p.) was administered for 7 days, the occurrence of muricide was significantly reduced. Furthermore, killer rats treated with nomifensine(i.p. or i.c.v.) or dopamine(i.c.v.) were converted into non-killer rats. Accordingly, it was shown that the drugs had an inhibitory effect on the muricide that was induced by the tiamine deficiency. However, the muricide behavior was not changed by the combined administration of nomifensine(i.c.v.) or dopamine (i.c.v.) after injection of desipramine(i.p.) and 6-hydroxydopamine(i.c.v.). These results indicated that this muricide response may be related to the brain dopaminergic system.

Effects of antidepressants in the forced swimming test (report 4)

Functional role of β-adrenergic mechanisms on the immobi lity-reducingaction of desipramine (DMI) in the forced swimming test was examined. Intracerebro-ventricular injections of isoproterenol (Iso) and two selective β1adrenergic blockers,atenolol (Ate) and practolol (Pra), but not a β2radrenergic blocker, IPS 339(IPS), diminished and potentiated the action of DMI(20 mg/kg,i.p.x3), respectively. The effect of Iso was almost completely blocked by pretreatment with Ate and Pra, but not by IPS. In contrast with β1adrenergic blockers,a non selective β1-adrenergic blocker,dl-propranolol,did not influence the action of DMI, but completely antagonized the effect of Iso. The potentiating effect of Ate or Pra was inhibited by IPS,but not by d-propranolol. As in the case of Iso, subcutaneous injection of clonidine(Clo) suppressed the action of DMI. The effect of do,but not that of Iso,was almost completely blocked by yohimbine. Chronic treatment(10 mg/kg,i.ρ, twice daily for 15 days) with DMI enhanced the action of the drug as compared to acute administration. The potentiation of the action of DMI by chronic treatment with the drug was inhibited by combined administration of Ate or Pra. On the other hand, a single injection of DMI,which had no effect when given alone, reduced the duration of immobility in rats treated chronically with ISO. These results suggest that β1adrenergi c mechanisms have an inhibitory effect on the immobility-reducing action of DMI in the forced swimming test, but the potentiating effect of Ate and Pra is inhibited by simul taneous blockade of both β1 and β2-adrenoceptors. It is also suggested that reduced function of the inhibitory β1adrenergic mechanisms is responsible for the potentiation of the action of DMI by chronic administration of the drug.

Effect of acute and chronic treatment with tricyclic antidepressants on 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO 4) contents in various regions of rat brain

1. Effects of acute and chronic treatment with desipramine (DMI) and amitriptyline (AMI) on 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) levels in eight brain regions were examined in rats. 2. A single injection of DMI decreased MHPG-SO4 levels in all brain regions except the midbrain, whereas the effect disappeared after the chronic treatment except in the septal area. MHPG-SO4 levels in the hippocampus and thalamus were increased after the chronic treatment with the drug. 3. A single and chronic administration of AMI decreased MHPG-SO4 levels in the thalamus and hippocampus, respectively. 4. These results indicate that the effects of acute and chronic treatment with the tricyclic antidepressants on the central noradrenergic systems differ in different regions of rat brain.