Influence of serotonin 5-HT(7) receptor blockade on the behavioral and neurochemical effects of imipramine in rats.

The aim of the present study was to examine the effect of the selective 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine (SB-269970), administered alone or in combination with imipramine, on the immobility time of rats in the forced swim test as well as on the extracellular levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex of freely moving rats. Both compounds were administered intraperitoneally (ip). Like imipramine (30 mg/kg, but not 20 mg/kg), SB-269970 (1.25 and 2.5 mg/kg, but not 0.625 mg/kg) significantly shortened the immobility time of rats without affecting their exploratory locomotor activity measured in the open field test. SB-269970 (0.625 and 1.25 mg/kg) raised the extracellular levels of DA, NA, 5-HT and their metabolites in rat prefrontal cortex. In that structure, imipramine (20 mg/kg) produced an increase in all the neurotransmitters measured, but failed to affect the levels of their metabolites. A combination of the inactive doses of SB-269970 (0.625 mg/kg) and imipramine (20 mg/kg) found in the forced swim test produced antidepressant-like effect, which did not stem from the increased exploratory locomotor activity. At the same time, that combination voked a vast increase in the output of NA - but not DA and 5-HT - compared to the effects of both those drugs given alone. These results open up a possibility that the stimulating effect of SB-269970 on DA, NA and 5-HT transmission in the prefrontal cortex plays some role in the antidepressant-like activity of this compound. Moreover, these findings suggest that the increase in cortical NA level seems to account for the anti-immobility action observed after joint administration of the selective 5-HT(7) receptor antagonist and imipramine in rats.

Down-regulation of norepinephrine transporter expression on membrane surface induced by chronic administration of desipramine and the antagonism by co-administration of local anesthetics in mice.

We have previously shown that chronic administration of the antidepressant desipramine, a norepinephrine transporter (NET) inhibitor to mice markedly enhanced convulsions induced by local anesthetics and that behavioral sensitization may be relevant to decreased [(3)H]norepinephrine uptake by the isolated hippocampus. The co-administration of local anesthetics with desipramine reversed the behavioral sensitization and down-regulation of NET function induced by desipramine. The present study aimed to elucidate whether chronic treatment with desipramine regulates the expression of NET protein examined in membrane fractions in various brain regions and whether co-administration of local anesthetics affects the desipramine-induced alteration of NET expression. Desipramine with or without local anesthetics was injected intraperitoneally once a day for 5 days. The animals were decapitated 48 h after the last administration of drugs and the whole cell fraction, membrane fraction and cell-surface protein fraction were prepared. [(3)H]nisoxetine binding was significantly reduced in the P2 fraction of the hippocampus by chronic administration of desipramine, and the reduction was overcome by co-administration of lidocaine with desipramine. Immunoreactive NET was detected by SDS-PAGE and immunoblotting in the murine hippocampus. NET protein expression in the whole cell fraction and membrane fraction was not affected by treatment with any drugs. However, administration of desipramine significantly reduced the amount of immunoreactive NET in the cell-surface protein fraction. This reduction was blocked by simultaneous injection of lidocaine, bupivacaine or tricaine. These results indicate that the NET down-regulation indicated by the reduction of [(3)H]nisoxetine binding was induced by administration of desipramine via decrease of NET localization on the cell surface. The antagonistic actions of local anesthetics against NET down-regulation by desipramine were related to alterations of the cell-surface localization of NET.

Effects of tianeptine on onset time of pentylenetetrazole-induced seizures in mice: possible role of adenosine A1 receptors.

Depression is a common psychiatric problem in epileptic patients. Thus, it is important that an antidepressant agent has anticonvulsant activity. This study was organized to investigate the effects of tianeptine, an atypical antidepressant, on pentylenetetrazole (PTZ)-induced seizure in mice. A possible contribution of adenosine receptors was also evaluated. Adult male Swiss-Webster mice (25-35 g) were subjects. PTZ (80 mg/kg, i.p.) was injected to mice 30 min after tianeptine (2.5-80 mg/kg, i.p.) or saline administration. The onset times of 'first myoclonic jerk' (FMJ) and 'generalized clonic seizures' (GCS) were recorded. Duration of 600 s was taken as a cutoff time in calculation of the onset time of the seizures. To evaluate the contribution of adenosine receptors in the effect of tianeptine, a nonspecific adenosine receptor antagonist caffeine, a specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A2A receptor antagonist 8-(3-chlorostyryl) caffeine (CSC) or their vehicles were administered to the mice 15 min before tianeptine (80 mg/kg) or saline treatments. Tianeptine (40 and 80 mg/kg) pretreatment significantly delayed the onset time of FMJ and GCS. Caffeine (10-60 mg/kg, i.p.) dose-dependently blocked the retarding effect of tianeptine (80 mg/kg) on the onset times of FMJ and GCS. DPCPX (20 mg/kg) but not CSC (1-8 mg/kg) blocked the effect of tianeptine (80 mg/kg) on FMJ. Our results suggest that tianeptine delayed the onset time of PTZ-induced seizures via adenosine A1 receptors in mice. Thus, this drug may be a useful choice for epileptic patients with depression.

Piracetam counteracts the effects of amitriptyline on inhibitory avoidance in CD1 mice.

The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30 mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Experiment 2, the same doses of amitriptyline and piracetam were chronically administered. Mice were subjected to the training phase of inhibitory avoidance on the 22nd day, and to the test phase 24 h later. Forty-five minutes after test, subjects explored the elevated plus-maze for 5 min in order to assess whether the effects of amitriptyline on avoidance performance may reflect general behavioural changes. Results obtained were that: (a) acute and chronic amitriptyline impaired inhibitory avoidance of male and female mice, (b) piracetam counteracted the effect of acutely administered amitriptyline on inhibitory avoidance, and (c) piracetam counteracted the effects of chronically administered amitriptyline in males but not females in the same learning task. These effects do not seem to be mediated by non-specific drug effects on spontaneous motor activity or anxiety.

The effect of the nitric oxide synthesis inhibitor L-NAME on amitriptyline-induced hypotension in rats.

OBJECTIVE: Hypotension induced by tricyclic antidepressants is multifactorial. Previous animal experiments suggest a contribution from nitric oxide production. Our study aimed to evaluate the role of nitric oxide in amitriptyline-induced hypotension using N-nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, and 3-morpholino sydnonimine, a nitric oxide donor, in anesthetized rats. METHODS: Amitriptyline intoxication was induced by the continuous infusion of amitriptyline 0.625 mg/kg/min throughout the experiment in anesthetized rats. Fifteen and 25 minutes after amitriptyline infusion began, two bolus doses of 10 mg/kg of N-nitro-L-arginine methyl ester (n = 8) or an equivalent volume of 5% dextrose solution (n = 8) was administered to each rat (Protocol 1). To investigate whether the effect of N-nitro-L-arginine methyl ester on blood pressure is counteracted by 3-morpholino sydnonimine, after the same protocol of amitriptyline infusion and 5 minutes after an N-nitro-L-arginine methyl ester bolus, a bolus of 3000 nmol/kg of 3-morpholino sydnonimine was administered (n = 8) to each rat (Protocol 2). To investigate the effect of N-nitro-L-arginine methyl ester on 3-morpholino sydnonimine induced hypotension, a group of rats received a continuous infusion of 0.54 mg/kg/h of 3-morpholino sydnonimine until 50% reduction was observed in mean arterial blood pressure followed by a bolus dose of 10 mg/kg of N-nitro-L-arginine methyl ester (n = 6) or 5% dextrose solution (n = 6) (Protocol 3). Outcome measures included mean arterial blood pressure, heart rate, and QRS duration in electrocardiogram. Student's t test and survival analysis were used for selected comparisons. RESULTS: For all parameters, the treatment groups were similar at baseline and at postamitriptyline periods before therapy was rendered. Amitriptyline infusion significantly reduced mean arterial blood pressure by 50.8 +/- 2.2% and prolonged QRS by 23.9 +/- 7.2% after 15 minutes. In Protocol 1, N-nitro-L-arginine methyl ester significantly increased mean arterial blood pressure compared to dextrose-treated control animals within 30 minutes (77.9 +/- 8.5% vs. 49.7 +/- 5.0% mmHg, p < 0.01, 95% CI 57.1-98.7%). QRS duration progressively increased during the amitriptyline infusion; however, there was no significant difference in QRS width between N-nitro-L-arginine methyl ester and control groups at any time point. N-nitro-L-arginine methyl ester increased survival time compared to controls (33.4 +/- 4.1 vs. 19.9 +/- 2.7 minutes, p < 0.01, 95% CI 25.4-41.3) but did not affect mortality. In Protocol 2 of continuous infusion of amitriptyline, 3-morpholino sydnonimine counteracted the N-nitro-L-arginine methyl ester-induced increase in mean arterial blood pressure. In both protocols, heart rate decreased significantly during amitriptyline infusion but there was no difference between treatment and control groups. In Protocol 3, N-nitro-L-arginine methyl ester bolus reversed 3-morpholino sydnonimine-induced hypotension compared to dextrose bolus. (83.8 +/- 5.7% vs. 54.6 +/- 4.8%, p < 0.01, 95% CI 69.2-98.4). CONCLUSION: N-nitro-L-arginine methyl ester is found to be effective in temporarily improving hypotension and prolonging survival time but does not affect overall mortality. Because this effect was antagonized by 3-morpholino sydnonimine, nitric oxide production appears to contribute to the pathophysiology of amitriptyline-induced hypotension.

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.

The antidotal effect of alpha(1)-acid glycoprotein on amitriptyline toxicity in cardiac myocytes.

Tricyclic antidepressants in overdose cause toxicity marked by prolongation of the QRS interval of the electrocardiogram. These drugs are bound to alpha(1)-acid glycoprotein (AAG) with high affinity in plasma. Animal studies have shown that the administration of AAG shortens the QRS prolongation induced by tricyclic antidepressants. In order to clarify the pharmacological mechanism involved and to obtain clinically relevant evidence at the cellular level, whole-cell patch clamp techniques were performed in single guinea-pig ventricular myocytes to elicit the time and voltage-dependent fast sodium currents using both normal and modified physiological solutions. Cells stayed viable for much longer when they were placed in normal physiological solutions, providing sufficient recording time for consistently reproducible, clinically relevant toxicological results to be obtained. Amitriptyline (AMI) produced a concentration-dependent blockade of sodium currents with an approximate IC(50) of 0.69 microM. AAG reversed this blockade in a concentration-dependent fashion at concentrations ranging from 3.2 to 12.8 microM. Using the same experimental conditions, AAG also reversed the blockade of sodium current by quinidine, a class I antiarrythmic drug. Albumin did not reverse the blockade of sodium channels by AMI. The results indicate that AAG is a potential antidote for tricyclic antidepressant overdose.

Mechanisms and surface chemical prediction of imipramine-induced hemolysis suppressed by modified cyclodextrins.

The suppression of imipramine hydrochloride (IMP)- induced hemolysis by native cyclodextrins (alpha-, beta-, and gamma-CDs) and beta-CD derivatives is measured as a function of CD concentration and is quantitatively correlated with the surface tension of the solution determined at 37.0 degrees C. The modified beta-CDs are more or less adsorbed onto the air-water interface and occupy larger areas than the wider rim of beta-CD. The surface tension data at low CD concentrations in the presence of 3 mM IMP allow us to estimate the 1:1 binding constants of IMP with CDs. Both the capabilities of hemolysis suppression and surface tension elevation for 3 mM IMP are strong in the order carboxymethyl-beta-CD (CM) > beta-CD approximately equal to 6-O-glucosyl-beta-CD (G(1)) > gamma-CD > 2-hydroxypropyl-beta-CD (HP) > alpha-CD > or = 2,6-di-O-methyl-beta-CD (DM). The suppression of IMP-induced hemolysis is ascribed to the decrease in the concentration of free IMP molecules. This concentration can be quantitatively estimated from the surface tension data determined at 37 degrees C. Therefore, the suppression of IMP-induced hemolysis by most of the CDs can be quantitatively predicted from these surface tension data, regardless of the kind and concentration of CD. However, alpha-CD, HP, and DM are outliers of this prediction. This failure for alpha-CD and HP is ascribed to their weaker competitive binding to IMP than to membrane phospholipid. Because DM has a strong hemolytic activity, it does not almost suppress the IMP-induced hemolysis.

Attenuation by nimodipine of amitriptyline-induced avoidance impairment in mice.

The effects of the dihydropyridine calcium channel blocker nimodipine on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box training and in previously trained mice of the DBA/2 strain. Nimodipine (0, 0.5, 1, 2.5, or 5 mg/kg) had no effect alone, but attenuated the avoidance impairment induced by 5 mg/kg amitriptyline on avoidance acquisition, as well as on a previously learned avoidance response. The avoidance improving action of the calcium channel blocker was less evident in mice receiving a larger dose (7.5 mg/kg) of the antidepressant drug. The effect of nimodipine did not appear to be specifically related to the avoidance impairment induced by amitriptyline, because the calcium antagonist also attenuated the avoidance impairing action of the neuroleptic chlorpromazine. The avoidance impairment induced by amitriptyline and chlorpromazine, and the related ameliorating action of nimodipine, seem imputable to drug effects on the performance of the avoidance response, rather than to interferences with learning processes. The results suggest that, in the case of concomitant administration, nimodipine could alleviate adverse side effects of tricyclic antidepressant, i.e., psychomotor disturbances.

Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo.

Pharmacokinetic drug interactions with viral protease inhibitors are of potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhibitors with substrates of cytochrome P450-2D6. Biotransformation of desipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhibitors currently used to treat human immunodeficiency virus infection were tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean Km value of 11.7 microM (range: 9.9-15.3 microM). Quinidine, a highly potent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mean inhibition constant of 0.16 microM (range: 0.13-0.18 microM). All four protease inhibitors impaired OH-DMI formation; the pattern was consistent with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were as follows: ritonavir, 4.8 microM; indinavir, 15.6 microM; saquinavir, 24.0 microM; nelfinavir, 51.9 microM. In a clinical pharmacokinetic study, coadministration of ritonavir with DMI inhibited DMI clearance by an average of 59%. The in vitro findings, together with observed plasma ritonavir concentrations, provided a reasonable quantitative forecast of this interaction, whereas estimated unbound plasma or intrahepatic ritonavir concentrations yielded poor quantitative forecasts. Thus the in vitro model correctly identifies ritonavir as a potent and clinically important inhibitor of human P450-2D6. Other protease inhibitors may also inhibit 2D6 activity in humans, but with lower potency than ritonavir.

Prevention of amitriptyline-induced avoidance impairment by tacrine in mice.

The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes.

[Chronic treatment with tween-80 (5%) or n-stearoyl glycine on the antimobility effects of imipramine in the forced swimming test in mice]. / Le traitement chronique par le Tween-80 (5%) n'affecte pas l'effect antiimmobilité de la N-stéaroyl glycine, mais supprime celui de l'Imipramine, au test de la nage forcée chez la souris.

Chronic (7 days) administration of N-stearoyl glycine (SG) or Tween-80 (5%) suppress the antiimmobility effect of Imipramine, in the forced swimming test on mice, whereas the antiimmobility effect of SG is suppressed only after chronic treatment with SG. These results suggest that chronic SG treatment could desensitize the glycinergic site of the NMDA receptors and that chronic Tween-80 (5%) administration could inactivate the glutamatergic site of the NMDA receptors or disturb some modulation, other than glycinergic, of the NMDA ionic channel. The latter could be important in an environmental or experimental viewpoint.

Antagonism of behavioral effects of electroconvulsive shock but not those of desipramine by the selective 5-HT-3 receptor antagonist, ondansetron.

The influence of ondansetron (ON) on desipramine (DMI) and electroconvulsive shock (ECS) effects in the open field (OFT) and forced swim test (FST) were studied in Wistar male rats. ON failed to influence the action of DMI but abolished stimulatory effect of ECS in the OFT and, in the lower dose (0.01 mg/kg) reduced ECS action in the FST. This result suggests that 5-HT-3 receptors are involved in behavioral effects of ECS but not DMI.

Minaprine, but not oxiracetam, prevents desipramine-induced impairment of avoidance learning in mice.

The tricyclic antidepressant desipramine impaired shuttle-box avoidance acquisition in mice of the CD-1 strain. The nootropic drug oxiracetam was unable to prevent the desipramine-induced learning impairment, while a protective action was exerted by minaprine, a psychotropic agent regarded as an atypical antidepressant drug, possessing dopaminergic and related memory-enhancing properties. It seems likely that the dopaminergic action of minaprine played a determinant role in its avoidance improving effects in desipramine treated mice, because similar effects were produced by amphetamine. However, in contrast to amphetamine, minaprine did not enhance locomotor activity and did not show signs of general behavioral stimulation.

Participation of opioid and monoaminergic mechanisms on the antinociceptive effect induced by tricyclic antidepressants in two behavioural pain tests in mice.

1. Various clinical and experimental reports indicate that tricyclic antidepressant drugs are specially useful in the treatment of chronic and acute pain conditions. The present work was aimed to study the mechanisms implicated in the antinociceptive response induced by these antidepressants on different experimental models of pain in mice, and particularly the role played by noradrenergic, serotonergic and opioidergic influences. 2. Electrical stimulation of the tail and formalin tests were used to evaluate pain perception in mice acutely treated with different antidepressants (imipramine, desipramine, amitriptyline, nortriptyline, clomipramine and desmethylclomipramine). Antinociceptive responses were more potent in formalin test than in tail electrical stimulation test. 3. These antinociceptive effects were inhibited by naloxone (2 mg/Kg, i.p.), alpha-methyl-p-tyrosine (200 mg/Kg) and p-chlorophenylalanine (600 mg/Kg). Naloxone elicited the same effectivity to inhibit antinociceptive responses induced by tricyclic antidepressants in both tail electrical stimulation and formalin tests. alpha-methyl-p-tyrosine and p-chlorophenylalanine were more effective on antinociceptive responses induced on formalin than in tail electrical stimulation test. 4. These results suggest that tricyclic antidepressants produce antinociception partly via the participation of the endogenous opioid system and partly by further activating noradrenergic and serotonergic pathways. Moreover, the analgesic responses and the mechanisms implicated were dependent of the analgesimeter test used.

Direct activation of purified Go-type GTP binding protein by tricyclic antidepressants.

A growing body of evidence suggests that tricyclic antidepressant agents (TCAs) interact with GTP binding proteins (G proteins). We have investigated if TCAs directly alter the function of the purified Go protein which is specifically expressed in neuronal tissue. Several TCAs markedly enhanced the GTPase activity of Go protein in a pertussis toxin-susceptible manner, whereas MAO-inhibitor and anxiolytic agent did not. This enhancing effect of TCAs on Go function may be due to an increase in the GDP-GTP exchange reaction occurring on Go. Thus, it is very likely that TCAs can modify various signal transduction by directly interacting with G proteins in brain cells.

Reversal of antidepressant action by dopamine antagonists in an animal model of depression.

Rats subjected chronically (12 weeks) to a variety of mild, unpredictable stressors showed a reduced consumption of sucrose or a sucrose/saccharin mixture in two-bottle consumption tests (sweet solution versus water). The deficit was apparent within 2 weeks of stress; normal behaviour was restored by chronic (7 weeks) treatment with the tricyclic antidepressants desmethylimipramine (DMI) or amitriptyline (AMI). Acute administration of the dopamine D1 receptor antagonist SCH-23390 1 week after withdrawal, or the dopamine D2 receptor antagonist sulpiride 2 weeks after withdrawal, were without effect in vehicle-treated stressed animals, and in non-stressed animals. However, the DA antagonists selectively reversed the improvement of performance in DMI- or AMI-treated stressed animals. This suggests that an increase in functional activity at DA synapses is the mechanism of action of DMI and AMI in this model.

Influence of naloxone on the antinociceptive effects of some antidepressant drugs.

The antinociceptive effects of tricyclic and atypical antidepressants were studied using the rat tail mechanical method. Clomipramine produced analgesia at the doses of 30 and 40 mg/kg, desimipramine at 10, 20 and 40 mg/kg, maprotiline at 20 and 30 mg/kg, mianserin at 30 mg/kg, nomifensine at 1, 2.5 and 5 mg/kg, indalpine at 10, 20 and 40 mg/kg, viloxazine at 60 and 80 mg/kg. Naloxone (0.8 mg/kg) abolished the antinociceptive action of these antidepressant drugs. These results suggest that the antinociceptive activity of these six antidepressant drugs in acute experimental pain could involve opiate mechanisms.

Potentiation of morphine antinociception by monoamine reuptake inhibitors in the rat spinal cord.

Potentiation of the antinociceptive effects of morphine by the tricyclic antidepressants was assayed in awake restrained rats using the tail-flick test. Intrathecally administered amitriptyline, desipramine or sertraline at doses that had no effect themselves (25-30 micrograms) potentiated a subthreshold parenteral dose of morphine (0.5 mg/kg). The morphine potentiating effect of amitriptyline was prevented by prior administration of parachlorophenylalanine (PCPA). This effect of PCPA was not restored by 5-hydroxytryptophan (5-HTP) but was restored when the animals were left for 14 days to replete. The morphine potentiating effects of amitriptyline, desipramine and sertraline were blocked by intrathecal administration of low doses of the serotonin antagonist methysergide and the alpha-adrenergic antagonists yohimbine and phentolamine but not by the beta-adrenergic antagonist propranolol. The results are consistent with the hypothesis that the potentiation of morphine's antinociceptive effect by tricyclic antidepressants depends on activation of both spinopetal serotonin and adrenergic neurons.

Reversal of tricyclic-antidepressant-induced cardiac conduction abnormalities by phenytoin.

Ten patients with cardiac conduction defects due to severe tricyclic antidepressant poisoning were successfully treated with intravenous phenytoin. Eight patients had combined first degree AV block and intraventricular conduction delay; one patient had first degree AV block alone; and one patient had intraventricular conduction delay alone. Phenytoin was injected at a rate of 50 mg/min in amounts not exceeding 500 mg (approximately 5 mg/kg to 7 mg/kg). Five patients had complete normalization within 46 min. The remaining five patients showed improvement in their conduction defects shortly after phenytoin treatment, with complete normalization occurring within 14 hr. This investigation demonstrated the effectiveness of phenytoin in reversing tricyclic-antidepressant-induced cardiac conduction abnormalities. Phenytoin is a logical drug for the treatment of severe tricyclic antidepressant poisoning signalled by first degree AV block and/or intraventricular conduction delay.