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PubMed1983

Noradrenergic and serotonergic input necessary for imipramine-induced changes in beta but not S2 receptor densities.

Chronic imipramine administration decreases the density of serotonin S2 and beta-adrenergic receptors. The mode of action is not clear but might be assumed to be a result of imipramine interacting with its high affinity binding sites on presynaptic serotonin neurons. To investigate this possibility and the role of the serotonergic and noradrenergic systems on imipramine-induced receptor down-regulations, the effects of raphe lesions and 6-hydroxydopamine lesions were examined. The theory that imipramine acts through the serotonin system to down-regulate beta-adrenergic receptors was supported by the observation that raphe lesions attenuated the imipramine-induced beta receptor denumeration. However, the effect of imipramine on the S2 site may not be a result of serotonin uptake blockade. Raphe lesions which diminish 3H-imipramine high affinity binding did not alter the imipramine-induced decrease in S2 receptor numbers. 6-Hydroxydopamine lesions prevented the reduction in beta but not S2 binding. Imipramine may exert its effect on S2 binding through a site other than the high affinity, serotonin uptake site.

Animals↗
PubMed1994

Inhibitory effect of imipramine on depolarization-induced increases in intracellular Ca2+ of rat cortical neurons.

We examined the effects of imipramine on the increase in intracellular Ca2+ concentration ([Ca2+]i) induced by elevated K+ in cultured neurons of rat cortex. Imipramine (100 nM-200 microM) produced a concentration-dependent inhibition of [Ca2+]i increases induced by 25 mM K+ with an IC50 value of 32 microM. Imipramine had no effect on resting [Ca2+]i levels. When the cells were incubated with imipramine in the presence of a voltage-sensitive Ca2+ channel (VSCC) blocker, either nicardipine (10 microM), verapamil (10 microM), or omega-conotoxin GVIA (1 microM), the combinations of imipramine and each blocker resulted in an additive inhibition of 25 mM K(+)-induced [Ca2+]i increases. The IC50 values were 44, 29 and 24 microM, respectively, which were similar to those found when incubating the cells with imipramine alone. The presence or the absence of imipramine (30 microM) in an incubation with Bay K 8644 (100 nM), a VSCC agonist, showed similar potentiation of the [Ca2+]i increases induced by 15 mM K+ (66 and 52%, respectively). On the other hand, when the cells were incubated with imipramine in the presence of Ni2+ (300 microM) or La3+ (0.3 microM), inorganic Ca(2+)-channel blockers, the IC50 values of inhibition of 25 mM K(+)-induced [Ca2+]i increases were much lower than with imipramine alone (3.2 and 16 microM, respectively). However, incubations with Ni2+ combined with nicardipine or verapamil resulted in an additive inhibition of 25 mM K(+)-induced [Ca2+]i increases.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Imipramine inhibition of transient K+ current: an external open channel blocker preventing fast inactivation.

Rapidly inactivating K+ current (KA current) is recorded from rat hippocampal neurons by whole-cell patch-clamp technique and suitable voltage protocols. It is found that imipramine, a commonly prescribed tricyclic antidepressant, is an open KA channel blocker with a binding rate constant of 5.6 x 10(6) M-1 s-1 and an apparent dissociation constant of no more than 6 microM if applied extracellularly in pH 7.4. The inhibitory effect is more pronounced in more alkaline extracellular solution, suggesting that the neutral form of imipramine is much more active than the charged form. In contrast, intracellular imipramine shows no inhibitory effect. Furthermore, the inhibitory effect of imipramine is antagonized by external but not internal K+. These findings suggest an imipramine binding site located close to the external pore mouth. It is also found that the inactivation curve of KA current is not changed by imipramine. Moreover, the recovery of KA current after a step depolarization is accelerated in the presence of imipramine. These findings suggest insignificant binding of imipramine to the fast inactivated KA channel. The selective binding of imipramine to only the activated but not the deactivated or inactivated states seems to suggest continual gating conformational changes in the external pore mouth of these neuronal KA channels during membrane depolarization.

Animals↗
PubMed1999

Block and unblock by imipramine of cloned and mutated P2X2 receptor/channel expressed in Xenopus oocytes.

Effects of imipramine on the cloned P2X2 receptor/channel and its mutants expressed in Xenopus oocytes were examined. Imipramine (100 microM) partially blocked an ionic current mediated through the wild-type P2X2 receptor/channel. With a higher concentration (300 microM) of imipramine, the current block was attenuated, suggesting that the second, lower affinity, 'unblocking' binding-site for imipramine exists in addition to the 'blocking' binding-site. These profiles of the modulation by imipramine were influenced by the substitution of negatively charged or polarized amino acid residues near the outer mouth of the channel pore (Asp315, Thr330 and Asn333) with neutral amino acid residues (Val or Ile). With the neutralization of Asp315, the current 'block' by 100 microM imipramine was attenuated. With the neutralization of Thr330, the current 'block' by 100 microM imipramine was enhanced. With the neutralization of Asn333, the 'unblock' by 300 microM imipramine disappeared. The results suggest that imipramine modulates P2X2 receptor/channels by interacting these amino acid residues.

Animals↗
PubMed1983

Antiarrhythmic plasma-concentration range of imipramine against ventricular premature depolarizations.

The antiarrhythmic plasma-concentration range of imipramine with desmethylimipramine was determined in 15 cardiac patients with ventricular arrhythmias. When more than 80% efficacy was reached, subjects' plasma concentrations of imipramine and desmethylimipramine were determined by gas chromatography. The imipramine dose required for suppression of ventricular premature depolarizations (VPDs) ranged from 50 to 400 mg a day (1.6 to 3.9 mg/kg/day). Peak plasma imipramine concentration was reached at 2.5 +/- 0.92 hr and peak plasma desmethylimipramine concentration at 4.1 +/- 2.8 hr after imipramine. At 80%, VPD suppression, mean steady-state plasma concentration of imipramine with desmethylimipramine ranged from 74 to 385 ng/ml. The ratio of plasma imipramine to desmethylimipramine ranged from 0.5 to 5.5 (median = 1.3). The elimination t1/2 for the parent compound, imipramine, ranged from 4 to 14.4 hr. Imipramine is an effective antiarrhythmic drug with sustained duration of action, although its elimination t1/2 is relatively short.

Adult↗
PubMed1999

Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline.

1 Tricyclic antidepressants (TCAs) are associated with cardiovascular side effects including prolongation of the QT interval of the ECG. In this report we studied the effects of two TCAs (imipramine and amitriptyline) on ionic current mediated by cloned HERG potassium channels. 2 Voltage clamp measurements of HERG currents were made from CHO cells transiently transfected with HERG cDNA. HERG-encoded potassium channels were inhibited in a reversible manner by both imipramine and amitriptyline. HERG tail currents (IHERG) following test pulses to +20 mV were inhibited by imipramine with an IC50 of 3.4+/-0.4 microM (mean+/-s.e.mean) and a Hill coefficient of 1.17+/-0.03 (n = 5). 3 microM amitriptyline inhibited IHERG by 34+/-6% (n = 3). The inhibition showed only weak voltage dependence. 3 Using an 'envelope of tails' comprised of pulses to +20 mV of varying durations, the tau of activation was found to be 155+/-30 ms for control and 132+/-26 ms for 3 microM imipramine (n = 5). Once maximal channel activation was achieved after 320 ms (as demonstrated by maximal tail currents), further prolongation of depolarization did not increase imipramine-mediated HERG channel inhibition. 4 Taking current measurements every second during a 10 s depolarizing pulse from -80 mV to 0 mV, block was observed during the first pulse in the presence of imipramine and the level of IHERG block was similar throughout the pulse (n=5). 5 A three pulse protocol (two depolarizing pulses to +20 mV separated by 20 ms at -80 mV) revealed that imipramine did not significantly alter the kinetics of IHERG inactivation. The tau of inactivation was 8+/-2 ms and 5.6+/-0.4 ms (n = 5) in the absence and presence of 3 microM imipramine, respectively, and currents inactivated to a similar extent. 6 Our data are consistent with TCAs causing components of block of the HERG channel in both the closed and open states. Any component of open channel block occurs rapidly upon depolarization. Inhibition of IHERG by the prototype TCAs imipramine and amitriptyline may suggest a mechanism for QT prolongation associated with risks of arrhythmia and sudden death that accompany high concentrations of TCAs following overdose.

Amitriptyline↗
PubMed2005

Urodynamics-based evidence for the beneficial effect of imipramine on valve bladders in children.

AIMS: In an era, in which valve bladder is recognised as perhaps the single most important determinant of long-term outcome in patients with posterior urethral valves (PUV), an insight into the etiopathogenesis and management of valve bladders is warranted. The present study was designed to evaluate bladder dysfunction in PUV and to assess the response to imipramine in these patients, both subjectively and objectively, by serial urodynamic studies (UDS). METHODS: From 1998-2001, 30 patients with PUV who had documented bladder dysfunction on UDS were studied. Patients with non-compliant or unstable bladders were treated with imipramine (1.5 - 2 mg/kg). All the patients in the present study were 5 years or older and hence old enough to be toilet trained. Assessment of continence and side effects of the drug was done after 3 months and repeat UDS were done at 3-6 months, 1 and 2 years. RESULTS: On the basis of initial treatment, the patients were divided into 2 groups; a fulguration group (n = 10, 33.3 %) and a vesicostomy group (n = 20, 66.6 %). Symptomatic voiding dysfunction was present in 27 of the 30 patients (90 %). Two patterns of urodynamic abnormalities were noted in the present study; 1) unstable bladders with single or multiple uninhibited contractions (18/30 patients, 60 %), and 2) small capacity, hypocompliant, hypertonic bladder (12/30 patients, 40 %). Post imipramine therapy significant symptomatic improvement was noted in 16/30 patients. On serial UDS, there was a 18-20 % increase in maximum cystometric capacity (MCC) and 30-35 % increase in pressure specific bladder volume (PSBV) following one year of imipramine therapy in 16/30 patients and 11/30 patients, respectively. 4 patients failed to show any improvement in MCC and PSBV with imipramine, they had been initially diverted with vesicostomy and later required augmentation cystoplasty. CONCLUSION: Unstable bladders and those with marginal bladder capacity and compliance showed the best response to imipramine therapy. Fibrotic, small capacity, hypertonic bladders are less responsive to imipramine. However, a trial of imipramine therapy is still warranted in these patients, as only 4/12 (33.3 %) patients with fibrotic hypertonic bladders failed to show any response and ultimately required augmentation cystoplasty. Imipramine qualifies as an effective and cheap drug for valve bladders.

Adrenergic Uptake Inhibitors↗
PubMed1983

Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites.

Imipramine inhibits the serotonin uptake by binding with high affinity to regulatory sites of this uptake located on axons that release serotonin. The number of imipramine recognition sites located on crude synaptic membrane preparations is reduced by two daily injections of imipramine or desmethylimipramine for 3 weeks. When the binding sites for [3H]imipramine are down-regulated the Vmax of the neuronal uptake of serotonin is increased. Moreover, in minces prepared from the brain hippocampus of rats receiving imipramine in a dose regimen that reduces the number of [3H]imipramine recognition sites, the efficiency of imipramine as a blocker of the serotonin uptake is diminished. Hence the high-affinity binding sites for [3H]imipramine may have a physiological role in modulation of serotonin reuptake. Probably this is mediated by an endogenous effector of these regulatory sites. A nonpeptidic constituent of rat brain capable of displacing [3H]imipramine from its high-affinity binding site and of inhibiting the serotonin uptake in a dose-related manner has been extracted and its partial purification is described.

Animals↗
PubMedDate not supplied

Clinical evidence of an interaction between imipramine and acetylsalicylic acid on protein binding in depressed patients.

The binding of imipramine to plasma proteins was studied in 20 adult patients with endogenous depression, with the purpose of assessing the effect produced by its simultaneous administration with an analgesic. Patients were administered 150 mg/day imipramine for 5 days and the binding to plasma proteins was determined. This was repeated 2 days later, after simultaneous administration of imipramine with 1,000 mg/day acetylsalicylic acid (ASA). Adverse effects for each patient were registered during both phases and were classified as mild, moderate, or severe. Results showed 84.4 +/- 7.07% of imipramine bound to plasma proteins and 72.18 +/- 6.5% when imipramine was administered with ASA (p < 0.05). When imipramine was administered alone, 1.95 mild adverse events per patient were registered. When imipramine was administered with ASA, the mild adverse events increased to 3.1 (p < 0.01) and the severe adverse events increased from 0.6 to 1.5 (p < 0.01). The levels of free imipramine increased when ASA was administered, indicating a displacement on the binding to plasma proteins. When adverse events were compared for each treatment, the accumulation of the free fraction of imipramine caused an increase in adverse events as well as in their clinical severity.

Adolescent↗
PubMed1985

5-Methoxytryptoline, a competitive endocoid acting at [3H]imipramine recognition sites in human platelets.

5-Methoxytryptoline potently inhibits [3H]imipramine binding to membranes from the cerebral cortex and platelets. Since 5-methoxytryptoline, which appears to occur endogenously with particularly high levels in the human pineal gland, also inhibits 5-hydroxytryptamine (5-HT, serotonin) uptake, it should be considered as a putative endogenous ligand modulating 5-HT transport. As the 5-HT transporter complex comprises the imipramine and the substrate recognition sites, which interact allosterically, it was essential to define the mechanism of inhibition of [3H]imipramine binding by 5-methoxytryptoline. Human platelets show an active and saturable uptake of 5-HT and tryptamine. The uptake of both substrates appears to be mediated by the same carrier and it is inhibited by 5-methoxytryptoline at submicromolar concentrations. 5-HT and tryptamine inhibit [3H]imipramine binding in human platelets with a Hill slope for inhibition close to unity and IC50 values of 3,265 and 3,475 nM, respectively. This inhibition is, however, not competitive because both 5-HT and tryptamine significantly decrease the rate of [3H]imipramine-receptor dissociation. Although 5-methoxytryptoline potently inhibits [3H]imipramine binding (IC50 = 44 nM) in human platelets with a Hill slope of unity, it does not affect the receptor-ligand dissociation rate of [3H]imipramine even at concentrations up to 100 microM. The present experiments show that 5-methoxytryptoline, in spite of its chemical similarity to the indoleamine transporter substrates, interacts with the imipramine receptor through a mechanism of competitive inhibition. This conclusion is supported by a selective effect of 5-methoxytryptoline on the Kd of [3H]imipramine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1986

Subcellular site of action of imipramine in rodent brain.

To determine the site of action of imipramine, the subcellular distribution of [3H]imipramine in rodents was followed after both in vivo administration and in vitro incubation with tissue slices under "physiological" conditions. Total [3H]imipramine (10-1,000 nM) binding was associated with all primary fractions, but in particular with the nuclear (P1) and mitochondrial (P2) pellets and the synaptosomal (P2B) and myelin (P2A) fractions. Using an excess of imipramine to define any nonspecific interactions, a specific association was observed mainly in those fractions containing isolated nerve terminals and to a lesser extent with the purified myelin fraction. Preparation of subsynaptosomal fractions by osmotic lysis indicated that [3H]imipramine was associated with the synaptic vesicle and microsomal fractions and also with synaptosomal membranes. The degree of binding to the vesicular and microsomal fractions was increased with the length of preparation time, whereas there was an inverse relationship between the length of preparation and the amount bound to the synaptosomal membrane fraction. There was no evidence of an intrasynaptosomal accumulation of [3H]imipramine at concentrations up to 1,000 nM. [3H]2-Nitroimipramine, a slowly dissociating imipramine derivative, was exclusively located in synaptic membrane fractions. Prior treatment of rats with a combination of 5,7-dihydroxytryptamine and desipramine reduced 5-hydroxytryptamine levels and the levels of [3H]imipramine associated with the synaptosomal fractions to the same extent. It is concluded that imipramine is associated with a binding site localised on 5-hydroxytryptaminergic nerve terminals and that there is a redistribution to other sites (vesicular and microsomal) during the isolation procedure.

Animals↗
PubMed1980

Electrophysiological effects of imipramine on bovine ventricular muscle and Purkinje fibres.

1 The effect of imipramine in concentrations between 0.01 microM and 50 microM has been studied on bovine Purkinje fibres and ventricular muscle transmembrane potentials. 2 In electrically stimulated fibres, imipramine had no effect on the resting membrane potential, but decreased the action potential amplitude, overshoot and maximum rate of depolarization (Vmax). 3 In Purkinje fibres, imipramine also decreased the conduction velocity and shifted the membrane responsiveness and recovery time curves downward and to the right. 4 In both Purkinje fibres and ventricular muscle, imipramine decreased the amplitude of phase 2 and prolonged phase 3. In Purkinje fibres, imipramine did not alter the action potential duration (APD) but prolonged the effective refractory period (ERP). In ventricular muscle, at concentrations higher than 1 microM imipramine shortened both the APD and the ERP and made the ERP long as compared to APD. 5 Imipramine decreased the slope of phase 4 diastolic depolarization in spontaneously beating Purkinje fibres. 6 These properties of imipramine are quite similar to those of quinidine or procainamide (class 1 antiarrhythmics). The mechanisms responsible for the cardiac effect of imipramine are discussed.

Action Potentials↗
PubMed1983

A double-blind, controlled evaluation of zimeldine, imipramine and placebo in patients with primary affective disorders.

Zimeldine, imipramine and placebo were studied in a randomized, double-blind, parallel group comparison of 119 patients with primary affective disorders. These out-patients were between 18 and 65 years of age and all received placebo single-blind during an initial 3-7-day washout period. During the subsequent 6-week double-blind period, patients were titrated from 50 mg b.d. to 150 mg b.d. with zimeldine, a potent and selective inhibitor of 5-HT reuptake, with imipramine, an inhibitor of noradrenaline and 5-HT reuptake, or with a corresponding number of placebo capsules. The zimeldine treatment group had significantly lower mean HAM-D scale total scores than the placebo and imipramine groups at week 4 and last available assessment. There was a significantly greater proportion of patients showing an improvement of 50% or more in HAM-D score, among the zimeldine group than in the placebo group at week 4, and among the imipramine group at weeks 4, 6 and last available assessment. The Clinical Global Impression (CGI) scales and the 56-item Hopkins Symptom Check-list (HSCL-56) self-rating inventory both showed significantly more improvement in the zimeldine patients than in the placebo or the imipramine patients. Fewer zimeldine patients reported adverse experiences than imipramine patients. Dry mouth was the most frequently reported adverse experience, occurring significantly more often in the imipramine group than the zimeldine or the placebo groups; significantly more zimeldine than placebo patients reported dry mouth. Headache was the only other adverse experience which occurred more often in the zimeldine than in the placebo group. The imipramine group had consistently higher mean pulse rates than the other two groups, and postural hypotension was also more common in the imipramine group.

Adolescent↗
PubMed1991

Effect of imipramine on the membrane anisotropy and on the phospholipid methylation in the central nervous system of the rat.

An ex-vivo and in-vitro study of the effects of imipramine on the membrane anisotropy and phospholipid methylation in the rat cortical membranes was carried out. A comparative study of the membrane fluidity in various brain regions indicated different basal anisotropy of the areas and different reaction of these membranes to imipramine. It was found that imipramine when given to rats chronically (14 x 10 mg kg-1, i.p.) or added externally to the cortical membranes of naive rats or rats treated with a single dose of imipramine (10 mg kg-1, i.p.) decreased the anisotropy of cortical membranes. Chronic imipramine produced some changes of the membrane architecture in the cortex, whereas imipramine in different concentrations did not fluidize these membranes in-vitro. Imipramine in concentrations corresponding to its mean concentration in the rat brain after administration at a dose of 10 mg kg-1 i.p., potentiated phospholipid methylation in the cortical membranes of naive rats and rats receiving imipramine in a single dose of 10 mg kg-1 i.p. in an in-vitro study, whereas the prolonged administration of imipramine decreased the sensitivity of phospholipid methyltransferases to the stimulating effect of the drug in-vitro.

Animals↗
PubMed2003

Imipramine-induced antinociception in the formalin test. Receptor mechanisms involved and effect of swim stress.

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10-40 mg/kg) and 0.5-3 min of swim stress (17 degrees C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through alpha(2)-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.

Animals↗
PubMed1994

Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness.

OBJECTIVE: The authors' first objective was to ascertain whether imipramine is superior to placebo in treating axis I depressive disorders in the context of HIV illness. Supplementary questions were whether severity of immunodeficiency is associated with antidepressant response and whether patients with greater immunodeficiency can tolerate standard doses of imipramine. Second, the authors sought to determine whether imipramine treatment is associated with changes in immune status. METHOD: A double-blind, randomized placebo-controlled trial of imipramine was conducted in a university-affiliated research outpatient clinic. After 6 weeks of treatment, responders were maintained double-blind for another 6 weeks and nonresponders were removed from the study and treated openly. All patients were offered 26 weeks of treatment. Of the 97 patients who were randomly assigned to placebo or imipramine, 80 completed the 6-week phase. Main outcome measures included the Clinical Global Impression, the Hamilton Depression Rating Scale, the Brief Symptom Inventory, and CD4 cell count. RESULTS: Among study completers, 31 (39%) had AIDS. The response rate to imipramine was 74% and the response rate to placebo was 26%. There was no difference in depression response between patients with more or less severe immunodeficiency, nor was there a difference in medication dose or side effects. Neither type nor duration of treatment influenced CD4 cell count during the course of treatment. CONCLUSIONS: Depressed patients with HIV illness respond to imipramine at the same rate as medically healthy depressed patients. Severity of immunosuppression is not associated with imipramine treatment outcome. There is no evidence that imipramine has negative effects on enumerative measures of immune status.

Adolescent↗
PubMed1993

Studies on cytochrome P450 responsible for oxidative metabolism of imipramine in human liver microsomes.

The activity of imipramine 2-hydroxylase highly correlated with that of desipramine 2-hydroxylase but not with that of desipramine N-demethylase. The correlation was also found between N-demethylation and 2-hydroxylation when imipramine was used as a substrate, whereas no correlation was observed between them when desipramine was used in place of imipramine. Both activities of desipramine and imipramine 2-hydroxylase were markedly inhibited by quinidine but not by quinine. Although the activity of imipramine N-demethylase was slightly inhibited by both quinidine and quinine, the activity of desipramine N-demethylase was unaffected under the same conditions. The activity of imipramine N-demethylase was roughly correlated with the amounts of P450 3A4 immunochemically determined and the activities of testosterone 6 beta-hydroxylase in human liver microsomes. The P450 3A4 catalyzed imipramine N-demethylation much more efficiently than 2-hydroxylation in a reconstituted system, whereas neither N-demethylation nor 2-hydroxylation of desipramine was catalyzed by P450 3A4. The activity of imipramine N-demethylase was inhibited, to various extents, by anti-P450 3A4 antibodies in human liver microsomes. Taking together these and other results, it is suggested that P450 3A4, other than P450 2Cmp, also partly contributes to N-demethylation of imipramine, depending on human liver microsomes.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed2003

Modulation of 8-OH-DPAT-induced hypothermia by imipramine in rats.

The effects of imipramine on 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), the 5-hydroxytryptamine (5-HT)(1A)-receptor full agonist, -induced hypothermia was examined in rats. Single administration of imipramine (30 mg/kg, i.p.) attenuated 8-OH-DPAT-induced hypothermia. This effect of imipramine was blocked by the 5-HT(2A)-receptor antagonist ketanserin. 8-OH-DPAT-induced hypothermia was not altered 24 h after repeated administration of imipramine (1 - 10 mg/kg per day) for 14 days. However, 8-OH-DPAT-induced hypothermia was significantly enhanced in repeated imipramine (10 mg/kg per day)-treated rats that received 8-OH-DPAT plus imipramine 24 h after the final imipramine administration for 14 days. The 5-HT(2A)-receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI) attenuated the 8-OH-DPAT-induced hypothermia in drug naive rats. The inhibitory effect of (+/-)-DOI (0.3 mg/kg, s.c.) on 8-OH-DPAT-induced hypothermia was attenuated by repeated administration of imipramine (10 mg/kg per day) for 14 days. These findings suggest that enhancement of the 5-HT(1A) receptors by repeated administration of imipramine may be due to reduction of the inhibitory effects from the 5-HT(2A) receptors to the 5-HT(1A) receptors.

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