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PubMed2001

Pharmacokinetics of imipramine in narcoleptic horses.

OBJECTIVE: To validate use of high-performance liquid chromatography (HPLC) in determining imipramine concentrations in equine serum and to determine pharmacokinetics of imipramine in narcoleptic horses. ANIMALS: 5 horses with adult-onset narcolepsy. PROCEDURE: Blood samples were collected before (time 0) and 3, 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 3, 4, 6, 8, 12, and 24 hours after IV administration of imipramine hydrochloride (2 or 4 mg/kg of body weight). Serum was analyzed, using HPLC, to determine imipramine concentration. The serum concentration-versus-time curve for each horse was analyzed separately to estimate pharmacokinetic values. RESULTS: Adverse effects (muscle fasciculations, tachycardia, hyperresponsiveness to sound, and hemolysis) were detected in most horses when serum imipramine concentrations were high, and these effects were most severe in horses receiving 4 mg of imipramine/kg. Residual adverse effects were not apparent. Value (mean +/- SD) for area under the curve was 3.9 +/- 0.7 h X microg/ml, whereas volume of distribution was 584 +/- 161.7 ml/kg, total body clearance was 522 +/- 102 ml/kg/h, and mean residence time was 1.8 +/- 0.6 hours. One horse had signs of narcolepsy 6 and 12 hours after imipramine administration; corrresponding serum imipramine concentrations were less than the therapeutic range. CONCLUSIONS AND CLINICAL RELEVANCE: Potentially serious adverse effects may be seen in horses administered doses of imipramine that exceed a dosage of 2 mg/kg. Total body clearance of imipramine in horses is slower than that in humans; thus, the interval between subsequent doses should be longer in horses.

Animals↗
PubMed1987

Association of [3H]-imipramine and [3H]-paroxetine binding with the 5HT transporter in brain and platelets: relevance to studies in depression.

[3H]-Imipramine and [3H]-paroxetine label with high affinity a site which is associated with the serotonergic transporter in brain and platelets. The pharmacological profile of inhibition by drugs of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of the drugs to inhibit the uptake of 5HT. Denervation of serotonergic neurons by electrolytic lesions or with 5,7-dihydroxytryptamine produces marked decreases in the density of [3H]-imipramine as well as [3H]-paroxetine binding. Dissociation kinetic experiments support the view that the substrate recognition site for 5HT is different from the modulatory site which is labelled by [3H]-imipramine or [3H]-paroxetine. The existence of an endogenous ligand acting on the [3H]-imipramine recognition site to modulate the 5HT transporter was proposed by several laboratories. [3H]-Imipramine binding in platelets appears to be a biological marker in depression. Studies carried out in several laboratories report a significant decrease in the Bmax of platelet [3H]-imipramine binding without changes in Kd, when severely depressed untreated patients are compared with healthy volunteers matched for age and sex. The Bmax of platelet [3H]-imipramine binding appears to be a state-dependent biological marker in depression. It is tempting to speculate that the endocoid of the [3H]-imipramine recognition site may play a role in the pathogenesis of depression.

Animals↗
PubMed1990

Neural adaptation in imipramine-treated rats processed in forced swim test: assessment of time course, handling, rat strain and amine uptake.

The intent of the present series of experiments was to better understand the events that produce a rapid adaptation of beta adrenergic and serotonin-2 (5-HT2) receptors when imipramine treatment and forced swim are combined in Sprague-Dawley rats. Beta adrenergic and 5-HT2 receptors were evaluated at specific stages of the forced swim test with and without imipramine treatment. Rapid changes in receptor binding were observed in saline-treated rats during specific stages of the test. The changes observed during forced swim could not be attributed to the transport-novelty that occurs during forced swim. Binding for both monoamine receptors was reduced in hippocampus and frontal cortex before the test swim in imipramine-treated rats as they were 10 min, 3 hr and 24 hr after the test swim. The increase in corticosterone induced by the second forced swim was not altered by imipramine, indicating that imipramine was not interfering with this measure of the stress response. In the Fisher-344 rat strain, imipramine did not produce a behavioral change during the test swim. In contrast to this lack of a behavioral change in the Fischer-344 rats, beta adrenergic and 5-HT2 receptor down-regulation was facilitated in this rat strain, similar to that found in imipramine-treated Sprague-Dawley rats subjected to swim. This latter finding suggests that beta adrenergic or 5-HT2 receptor adaptation alone is insufficient to cause an imipramine-induced behavioral change in the swim test. Studies with specific norepinephrine- and serotonin-uptake inhibitors, nisoxetine and fluoxetine, respectively, indicate that the behavioral effects of imipramine in the forced swim test are dependent upon norepinephrine uptake inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1990

Possible influence of carbamazepine on plasma imipramine concentrations in children with attention deficit hyperactivity disorder.

The effect of carbamazepine on the plasma concentration of imipramine and its metabolite desipramine was examined retrospectively in 36 sex- and age-matched children with attention deficit hyperactivity disorder. One-half of the children received imipramine and the other half received combined carbamazepine and imipramine for 1-6 months. The imipramine dosage was significantly higher in the combined treatment group than in the imipramine-only group. Despite receiving larger doses, the combined treatment group had significantly lower mean levels of imipramine, desipramine, and total tricyclic antidepressant compared with those children receiving imipramine alone. Lowered plasma concentrations of tricyclic antidepressants with carbamazepine coadministration have not been reported previously. Although more rigorous studies are needed to confirm these findings, our data suggest that increased imipramine doses may be necessary for adequate response in children on combined therapy. Moreover, toxicity could result upon withdrawal without imipramine dosage adjustment.

Adolescent↗
PubMed1986

Modulation of peripheral beta-1 and alpha-2 receptor sensitivities by the administration of the tricyclic antidepressant, imipramine, alone and in combination with alpha-2 antagonists to rats.

The purpose of the present investigation was to determine whether peripheral beta-1 and alpha-2 receptors are regulated by the tricyclic antidepressant, imipramine. The administration of imipramine alone decreased the sensitivity of peripheral beta-1 receptor activity in anesthetized rats (isoproterenol-induced positive chronotropy) after 11 days, but not after 4 days. The coadministration of the selective alpha-2 antagonists, yohimbine or idazoxan (RX 781094), with imipramine resulted in a decrease in beta-1 receptor sensitivity in anesthetized rats within only 4 days. In isolated spontaneously beating right atria taken from drug-treated rats, beta-1 receptor sensitivity (isoproterenol positive chronotrophy) was not affected by the administration of imipramine for 4 days; however, administration of imipramine for 11 days resulted in significant decrease in beta-1 receptor sensitivity. The coadministration of yohimbine or idazoxan with imipramine resulted in a decrease in beta-1 receptor function in only 4 days. Beta-2 receptor sensitivity (isoproterenol-induced hypotension in anesthetized rats) was not significantly altered under conditions in which beta-1 receptor sensitivity was decreased. The destruction of central catecholamine-containing neurons with 6-hydroxydopamine prevented the subsensitivity of peripheral beta-1 receptor function in anesthetized rats induced by the coadministration of imipramine plus yohimbine (4 days). The sensitivity of peripheral alpha-2 receptors (clonidine-induced inhibition of electrically stimulated rat vas deferens) was depressed after the administration of imipramine alone (4 days) and imipramine plus yohimbine or idazoxan (4 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1987

Selective labeling of serotonin uptake sites in rat brain by [3H]citalopram contrasted to labeling of multiple sites by [3H]imipramine.

Citalopram is a potent and selective inhibitor of neuronal serotonin uptake. In rat brain membranes [3H]citalopram demonstrates saturable and reversible binding with a KD of 0.8 nM and a maximal number of binding sites (Bmax) of 570 fmol/mg of protein. The drug specificity for [3H]citalopram binding and synaptosomal serotonin uptake are closely correlated. Inhibition of [3H]citalopram binding by both serotonin and imipramine is consistent with a competitive interaction in both equilibrium and kinetic analyses. The autoradiographic pattern of [3H]citalopram binding sites closely resembles the distribution of serotonin. By contrast, detailed equilibrium-saturation analysis of [3H]imipramine binding reveals two binding components, i.e., high affinity (KD = 9 nM, Bmax = 420 fmol/mg of protein) and low affinity (KD = 553 nM, Bmax = 8560 fmol/mg of protein) sites. Specific [3H]imipramine binding, defined as the binding inhibited by 100 microM desipramine, is displaced only partially by serotonin. Various studies reveal that the serotonin-sensitive portion of binding corresponds to the high affinity sites of [3H]imipramine binding whereas the serotonin-insensitive binding corresponds to the low affinity sites. Lesioning of serotonin neurons with p-chloroamphetamine causes a large decrease in [3H]citalopram and serotonin-sensitive [3H]imipramine binding with only a small effect on serotonin-insensitive [3H]imipramine binding. The dissociation rate of [3H]imipramine or [3H]citalopram is not altered by citalopram, imipramine or serotonin up to concentrations of 10 microM. The regional distribution of serotonin sensitive [3H]imipramine high affinity binding sites closely resembles that of [3H]citalopram binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[Cardiac disorders induced by mianserin in guinea pigs. Comparison with imipramine].

Infusion of mianserin to anesthetized guinea-pigs induced electrocardiographic changes (auriculo-ventricular and intraventricular conduction lenghthening, bradycardia, QRS axis and T axis rotations) quite identical to those induced by imipramine. However they appeared later and mianserin produced cardiac arrest at higher dose (133 mg/kg) than did imipramine (73 mg/kg). In vitro, increasing concentrations of mianserin suppressed the electrical response of stimulated, isolated ventricular heart strips, but this suppression was obtained by a higher concentration (172 micrograms/ml) than with imipramine (80 micrograms/ml). Transmembrane potentials were not affected by a 5 or 10 micrograms/ml mianserin or a 5 micrograms/ml imipramine perfusion. With 20 micrograms/ml mianserin or 10 micrograms/ml imipramine, only a reduced duration of the action potential was obtained. With 50 micrograms/ml mianserin or 20 micrograms/ml imipramine, the resting potential was reduced. However, with imipramine only it was preceded by a decrease in the maximal velocity of depolarisation. These results show that mianserin induces transmembrane permeability changes which appear to differ from and to be less marked than those induced by imipramine. Molar sodium bicarbonate reversed in vivo and in vitro the electrophysiologic changes elicited either by mianserin or by imipramine, but with mianserin the transient improvement was followed by an aggravation of the cardiac troubles.

Animals↗
PubMed1984

Imipramine-cimetidine interaction: impairment of clearance and enhanced absolute bioavailability.

Six healthy volunteers each received imipramine on four occasions in random sequence, i.v. (12.5 mg) and p.o. (50 mg) in a drug-free state and i.v. and p.o. while taking cimetidine 300 mg every 6 hr. After i.v. doses, elimination half-life of imipramine was increased during cimetidine treatment (22.1 vs. 15.5 hr, P less than .02) as a result of decreased total metabolic clearance (623 vs. 1048 ml/min, P less than .05) with no change in volume of distribution (17.2 vs. 19.8 liters/kg) or plasma protein binding (unbound percent, 17.7 vs. 16.5%). After single p.o. imipramine doses, peak imipramine blood levels achieved were greater during cimetidine therapy (34.4 vs. 19.3 ng/ml, P less than .05) and area under the time/concentration curve was greatly increased (569 vs. 306 ng/ml X hr, P less than .05). Desipramine, the biologically active metabolite of imipramine, was measurable only after p.o. doses. Desipramine area under the time/concentration curve was increased during cimetidine therapy after p.o. imipramine doses (274 vs. 152 ng/ml X hr, P less than .05), suggesting that desipramine clearance was inhibited as well. Comparison of i.v. and p.o. imipramine doses indicated absolute bioavailability was 40.2% in the control state and increased to 75.3% (P less than .05) during cimetidine treatment. Imipramine, with both impaired total metabolic clearance and enhanced bioavailability, in conjunction with increased accumulation of desipramine, would have marked increases in steady-state plasma concentration of both imipramine and desipramine with concurrent cimetidine therapy during chronic p.o. treatment.

Administration, Oral↗
PubMed1996

Electrophysiologic and proarrhythmogenic effects of therapeutic and toxic doses of imipramine: a study with high resolution ventricular epicardial mapping in rabbit hearts.

Electrophysiologic and proarrhythmogenic effects of imipramine were studied by use of 21 Langendorff-perfused rabbit hearts and high-resolution mapping to analyze epicardial activation of the left ventricle. In 16 hearts, a thin layer of epicardium was obtained by an endocardial cryotechnique (frozen hearts). Five hearts were kept intact (nonfrozen imipramine-treated group). Preparation stability was verified in six frozen hearts. In 10 frozen and in 5 nonfrozen hearts, 0.01, 0.1, 1.0, 2.0 and 5.0 micrograms/ml imipramine were administered. In nonfrozen imipramine-treated hearts, imipramine induced bradycardia at 5.0 micrograms/ml (291.8 +/- 40.5 vs. 495.2 +/- 54.4 msec, P = .02), one A-V block at 5.0 micrograms/ml and two monomorphic ventricular tachycardias (MVT) at 2.0 and 5.0 micrograms/ml. In 4/10 frozen hearts, three MVT were induced at 1.0 microgram/ml imipramine and one MVT at 2.0 micrograms/ml imipramine. All MVT were based on reentry around a line of functional conduction blocks. Imipramine (2.0 micrograms/ml) slowed longitudinal and transversal ventricular conduction velocities at a pacing cycle length of 1000 msec from 71.7 +/- 6.1 to 63.0 +/- 7.7 cm/sec (P = .008) and from 32.9 +/- 2.6 to 27.7 +/- 2.8 cm/sec (P = .009), respectively, and prolonged ventricular effective refractory period from 141.9 +/- 9.3 to 279.1 +/- 112.6 msec (P = .03). Imipramine induced dose- and use-dependent slowing of ventricular conduction velocity facilitating functional conduction blocks and reentrant MVT.

Animals↗
PubMed1996

Comparison of fluvoxamine, imipramine, and placebo in the treatment of outpatients with panic disorder.

Fluvoxamine and imipramine were compared to placebo in an 8-week doubleblind randomized multicentre trial comprising of 148 outpatients between 19 and 57 years of age (mean: 35) with a DSM-III-R diagnosis of Panic Disorder. mean daily dose at endpoint was: fluvoxamine, 171.4 mg; imipramine 164.7 mg. The mean number of panic attacks per week at baseline were 10.9, 14.4 and 6.5 for fluvoxamine, imipramine and placebo, respectively. The intent-to-treat analysis of the change from baseline (difference score) of the number of panic attacks at endpoint revealed: a difference of 3.3 attacks (95% CI: -0.3, 6.8) between fluvoxamine and placebo and a difference of 6.0 attacks (95% CI: 1.5, 10.5) between imipramine and placebo. Treatment was stopped prematurely in 31 (62%) on fluvoxamine, 16 (33%) on imipramine and 29 (58%) on placebo. The number of patients withdrawing due to intolerance was 13 (26%) for fluvoxamine, 10 (21%) for imipramine and 4 (8%) for placebo. The number of patients withdrawing due to lack of efficacy was 10 (20%) for fluvoxamine, 4 (8%) for imipramine and 12 (24%) for placebo. Overall, this study demonstrated that fluvoxamine was not effective in the treatment of panic disorder but did show a strong effect for imipramine. A chance occurrence of significantly fewer number of panic attacks in the placebo group at baseline may limit the conclusions of this study.

Adult↗
PubMed1992

Comparison of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine.

Twelve healthy male subjects completed this randomized, placebo controlled, four-period crossover trial to determine the effect of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. Subjects received a 7-day course of one of four treatments; verapamil (120 mg every 8 hr), diltiazem (90 mg every 8 hr), labetalol (200 mg every 12 hr), or placebo (every 12 hr) during each study period. Imipramine (100 mg) was administered orally on the morning of day 4 of each study period. Plasma and urine samples were collected periodically over the ensuing 96 hours. Samples were assayed by HPLC for imipramine, desipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine. Verapamil, diltiazem, and labetalol increased imipramine area under the plasma concentration time curve (relative bioavailability) as compared with placebo by 15%, 30%, and 53%, respectively. Verapamil and diltiazem did not demonstrate consistent changes in the formation of the measured metabolites. Labetalol caused a significant decrease in the amount of imipramine metabolized to 2-hydroxyimipramine (mean decrease: 22%) and from desipramine to 2-hydroxydesipramine (mean decrease: 8%). The molar ratios of plasma AUC of 2-hydroxyimipramine and 2-hydroxydesipramine to the parent compounds were significantly decreased. Since these metabolic processes are dependent on the cytochrome P450IID6 isozyme, these data suggest that labetalol decreases the oral clearance of imipramine by inhibiting this system. All three of these commonly used agents decreased the oral clearance of imipramine. These drug interactions could lead to elevated imipramine concentrations and have the potential for clinically important adverse events.

Administration, Oral↗
PubMed1998

Clomipramine and imipramine suppress clinical signs and T and B cell response to myelin proteins in experimental autoimmune neuritis in Lewis rats.

5-Hydroxytryptamine (5-HT) reuptake inhibitors of the zimeldine-type have induced polyneuropathies similar to Guillain-Barré syndrome (GBS) in patients with endogenous depression. Some monoamine neurotransmitters have been shown to affect immune reactions in vivo and in vitro in a concentration-dependent manner. We therefore studied the effect of the monoamine reuptake inhibitory anti-depressants, clomipramine and imipramine on specific immune response and the clinical course of experimental autoimmune neuritis (EAN), the animal model of GBS in humans. Clomipramine and imipramine both suppressed clinical signs of EAN induced by immunization with bovine peripheral nerve myelin (BPM), when given at a dose of 20 mg/kg/day intraperitoneally, via osmotic pumps. Clomipramine and imipramine reduced the numbers of Th1 cells secreting IFN-gamma in response to the neuritogenic myelin proteins BPM, P0 and P2 among lymph node mononuclear cells (MNC) from rats with EAN. The levels of cells secreting IgG antibodies to BPM, P2 and GM1 in lymph nodes were reduced at the height of EAN in clomipramine and imipramine treated animals. The action of clomipramine and imipramine on induced IFN-gamma and anti-myelin antibodies suggests that the mechanism for the suppressive effect of those substances on EAN symptoms may be due to an action on myelin T and B cell autoreactivity. Considering that the main common pharmacological principle of clomipramine and imipramine is to increase the functional activity of the nor-adrenaline (NA) and serotonin (5-HT) of the monoamines, it seems justified to postulate that the actions of clomipramine and imipramine demonstrated in this study to some extent involve NA and/or 5-HT. The immunomodulatory effects of clomipramine and imipramine call for further research on the potential role of drugs acting on the monoamine system in the treatment of autoimmune diseases, and for further studies of immunological mechanisms in the pathogenesis of depressive disorders.

Adrenergic Uptake Inhibitors↗
PubMed1982

The electrocardiographic and anticholinergic effects of trazodone and imipramine in man.

The electrocardiographic and anticholinergic effects of trazodone (150 mg) and imipramine (75 mg) were investigated in 8 healthy volunteers. Both agents increased the QTc interval and decreased T wave height, but the effects occurred earlier with trazodone (from 30 min onwards) than with imipramine (150 and 180 min after dosing). Both drugs decreased heart rate, imipramine at 30 and 60 min and trazodone at 90 min. After 120 min, heart rate began to increase with imipramine an effect which was not seen with trazodone. Salivary volume was significantly decreased by imipramine at 120 and 180 min whereas trazodone did not influence salivary volume. Plasma levels of trazodone and imipramine were significantly related to the decrease in T wave amplitude. The increase in QTc interval correlated significantly with the plasma level of imipramine. These results suggest that trazodone, like the tricyclic antidepressants prolongs ventricular repolarization; but, in contrast to imipramine, it does not have anticholinergic activity.

Adult↗
PubMed1986

The effect of ranitidine and cimetidine on imipramine disposition.

The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t 1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 micrograms X h X ml-1) or ranitidine (1.14 micrograms X h X ml-1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.

Administration, Oral↗
PubMed1976

Haemodialysis in imipramine poisoning? An experimental study.

In the last several years an increasing number of severe imipramine intoxications have been observed. Though standard principles for the treatment of acute tricyclic poisoning have been established, nonetheless there still exists doubt on the most effective method of tricyclic removal in cases of massive overdose. Haemodialysis was successfully employed until now but has not found general acceptance as only insignificant amounts of imipramine could be recovered from the dialysate. An experimental clearance study was undertaken using radiolabelled imipramine (14C-I) to obtain insight into the usefullness of haemodialysis in imipramine poisoning. 14C-I clearances which were calculated in a closed circuit dialysis system ranged between 18 ml/min and 48 ml/min depending on the constitution of the dialysate, i.e. aqueous or lipid solution. Surprisingly a rapid and significant uptake of imipramine by the plastic material (polyvinylchloride) of the extracorporeal blood line system was detected. This escape of imipramine from the blood into the tubings explains the poor recovery of tricyclics from the dialysate, which discredited haemodialysis as a therapeutical method in imipramine poisoning. The results of our experiments may offer a new method of rapid tricyclic elimination in severe imipramine intoxications.

Absorption↗
PubMed2004

Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action.

AIMS/HYPOTHESIS: Treatments with antidepressants have been associated with modifications in glucose homeostasis. The aim of this study was to assess the effect of imipramine, a tricyclic antidepressant, on insulin-secreting cells. METHODS: Insulin radioimmunoassay, radioisotopic, fluorimetric and patch-clamp methods were used to characterise the effects of imipramine on ionic and secretory events in pancreatic islet cells from Wistar albino rats. RESULTS: Imipramine induced a dose-dependent decrease in glucose-stimulated insulin output (IC(50)=5.2 micromol/l). It also provoked a concentration-dependent reduction in (45)Ca outflow from islets perifused in the presence of 16.7 mmol/l glucose. Moreover, imipramine inhibited the increase in (45)Ca outflow mediated by K(+) depolarisation. Patch-clamp recordings further revealed that imipramine provoked a marked and reversible decrease of the inward Ca(2+) current. In single islet cells, imipramine counteracted the rise in [Ca(2+)](i) evoked by glucose or high K(+) concentrations. CONCLUSIONS/INTERPRETATION: These data indicate that imipramine dose-dependently reduces the insulin secretory rate from rat pancreatic beta cells. Such an effect appears to be mediated by the inhibition of voltage-sensitive Ca(2+) channels with subsequent reduction in Ca(2+) entry. Thus, it is possible that some adverse effects of imipramine are related, at least in part, to its capacity to behave as a Ca(2+) entry blocker.

Animals↗
PubMed1997

Effect of imipramine treatments on the 5-HT1A-receptor-mediated inhibition of panic-like behaviours in rats.

The escape behaviour induced in rats by injecting D,L-homocysteic acid (DHL) into the dorsal periaqueductal grey area (DPAG) was used as an animal model of panic attacks to investigate the effect of imipramine, a drug used for the treatment of panic disorder, on the sensitivity of 5-HT1A receptors in the DPAG. Rats given imipramine (10 mg/kg per day SC for 3 weeks or IP for 2-3 days) received 250 nl saline or the 5-HT1A agonist 8-OH-DPAT (8.6 nmol) into the DPAG 10 min before inducing the escape response with DLH. As expected, 8-OH-DPAT produced a marked decrease in the average speed of the DLH-induced flight response. The short-term treatment with imipramine changed neither the DLH-induced escape behaviour nor the effect of prior 8-OH-DPAT administration on this response. In contrast, long-term treatment with imipramine enhanced the 5-HT1A-mediated inhibition, as the decrement in the amplitude of the flight response produced by 8-OH-DPAT was 96% after this treatment compared to 41% in controls. The injection of 8-OH-DPAT also significantly decreased the amplitude of the freezing behaviour observed at the end of the flight response in rats given imipramine for 3 weeks, but not in controls. The long-term imipramine treatment, however, did not significantly decrease the amplitude of DLH-induced flight and freezing behaviours in absence of prior 8-OH-DPAT administration. Finally, 8-OH-DPAT failed to inhibit the DLH-induced flight and freezing behaviours in rats withdrawn from imipramine after long-term treatment (10 mg/kg per day x 21 days). It is suggested that an alteration at the level of the DPAG-5-HT1A receptor system is implicated in the therapeutic and withdrawal effect of imipramine in panic disorder.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Effects of imipramine on raphe nuclei and prefrontal cortex extracellular serotonin levels in the rat.

The effect of acute administrations of three doses of imipramine (1, 5 and 10 mg/kg s.c.), a widely used tricyclic antidepressant, on extracellular levels of serotonin (5-HT) has been studied by intracerebral microdialysis in raphe nuclei and prefrontal cortex of conscious rats. Imipramine 1 mg/kg s.c. did not change extracellular 5-HT in either raphe nuclei and prefrontal cortex. However, with the dose of 5 mg/kg s.c. imipramine induced in raphe nuclei, a brief increase of extracellular 5-HT followed by a lowering (55-65% basal release) of the neurotransmitter. The same dose of imipramine decreased (60-70% of basal value) extracellular 5-HT in prefrontal cortex. Imipramine 10 mg/kg s.c. significantly increased 5-HT levels in both raphe nuclei (190 +/- 20% above basal value) and prefrontal cortex (280 +/- 15% above basal value). Pretreatment with (-)pindolol (5 mg/kg s.c.), a non-selective 5-HT1A subtype receptor antagonist, 30 min before imipramine 5 mg/kg, modified the effect of the antidepressant: an increase, instead of a decrease, on prefrontal cortex dialysate 5-HT was observed. (-)Pindolol (10 mg/kg s.c.) increased extracellular 5-HT in both raphe nuclei (155 +/- 20% above basal value) and prefrontal cortex (160 +/- 8% above basal value). These data show that acute administration of imipramine modifies extracellular 5-HT at the level of the raphe nuclei and prefrontal cortex. 5-HT1A autoreceptors in the raphe nuclei, which this study suggests to be tonically active, may be stimulated after systemic administration of high doses of imipramine.

Adrenergic beta-Antagonists↗