Antidepressant effects of tricyclic antidepressants and selective serotonin-uptake blockers in diabetic rats.

Because it was reported that diabetic rodents were resistant to the effects of several tricyclic antidepressants in various psychopharmacological models, we decided to test the hypothesis that the serotonergic dysfunction seen in diabetes might participate in this phenomenon. The ability of three serotonin-uptake blockers to reverse the performance deficit in learning induced by previous uncontrollable stress (learned-helplessness paradigm) was investigated in streptozocin-induced diabetic rats. Three weeks after induction of diabetes, rats were subjected to a session of 60 inescapable electric foot shocks and, after 48 h, to three daily sessions of two-way shuttle-box training. Three serotonin-uptake blockers were given intraperitoneally over 5 consecutive days. As with nondiabetic rats, citalopram (1 mg.kg-1. day-1), fluoxetine (2 and 4 mg.kg-1. day-1), and fluvoxamine (4 mg.kg-1.day-1) reduced the number of escape failures in diabetic rats. From these data, we suggest that it is unlikely that the impaired response of diabetic rats to tricyclic antidepressants is caused by serotonergic dysfunction.

Hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients.

Thirty-seven insulin-dependent diabetic patients were tested for symptoms of hypoglycemia, cardiac autonomic neuropathy (i.e., heart rate variation during deep breathing, Valsalva maneuver, immediate heart rate response to standing), and isoproterenol sensitivity (defined as the dose of isoproterenol required to increase heart rate by 25 beats/min: I25). Tests of cardiac autonomic neuropathy showed no relation to hypoglycemic symptoms. On the contrary, a clear relationship could be established between isoproterenol sensitivity and adrenergic symptoms of hypoglycemia. Diabetic patients with decreased response to isoproterenol had fewer adrenergic symptoms, perceived hypoglycemia at a lower blood glucose level, and had more hypoglycemic accidents. Symptoms most related to isoproterenol sensitivity were tremor, sweaty palms, and hunger. With the isoproterenol-sensitivity test a distinction could be made between the groups at high (I25 greater than 3 micrograms) and low (I25 less than 3 micrograms) risk for hypoglycemic accidents. We suggest that the isoproterenol-sensitivity test could be used to identify diabetic patients at increased risk for hypoglycemia.

Decreased beta-adrenergic sensitivity in insulin-dependent diabetic subjects.

To study beta-adrenergic sensitivity in diabetes mellitus, we performed isoproterenol sensitivity tests in 34 insulin-dependent diabetic patients and 10 age-matched normal subjects. beta-adrenergic sensitivity [defined as the dose of isoproterenol required to increase the resting heart rate by 25 beat/min, (I25)] was significantly higher in the diabetic group (4.07 +/- 1.4 micrograms, mean +/- SD) than in the normal group (2.02 +/- 1.49 micrograms). A comparison of I25 of normal subjects and diabetic patients as a function of age showed that the latter were significantly less sensitive to beta-adrenergic stimulation at all ages (P less than 0.01). In diabetic patients, beta-adrenergic sensitivity also increased with the duration of diabetes (r = 0.64, P less than 0.0005), but the correlation was stronger when the age of the patients and the duration of the diabetes were both taken into consideration (r = 0.72, P less than 0.0005). We conclude that beta-adrenergic sensitivity is diminished in patients with type I diabetes mellitus of all ages.

Suspected postprandial hypoglycemia is associated with beta-adrenergic hypersensitivity and emotional distress.

Suspected postprandial (reactive or idiopathic) hypoglycemia is characterized by predominantly adrenergic symptoms appearing after meals rich in carbohydrates and by their rare association with low blood glucose level (< 2.77 mmol/L). We studied heart rate, blood pressure, plasma insulin, C-peptide, and catecholamine responses during a 5-h oral glucose tolerance test in eight patients with suspected postprandial hypoglycemia and eight age-, sex-, and body mass index-matched healthy controls. We also evaluated beta-adrenergic sensitivity by using the isoproterenol sensitivity test. Psychological profile was assessed by the Symptom Checklist (SCL-90R) self-report symptom inventory. Patients with suspected postprandial hypoglycemia had higher beta-adrenergic sensitivity (defined as the dose of isoproterenol required to increase the resting heart rate by 25 beats/min) than controls (mean +/- SEM, 0.8 +/- 0.13 vs. 1.86 +/- 0.25 microgram isoproterenol; P = 0.002). After administration of glucose (75 g) blood glucose, plasma C-peptide, plasma epinephrine, and plasma norepinephrine responses were identical in the two groups, but plasma insulin was higher in the patients (group effect, P = 0.02; group by time interaction, P = 0.0001). Both heart rate and systolic blood pressure were significantly higher (but remained in the normal range) after glucose administration in patients with suspected postprandial hypoglycemia than in controls (group by time interactions, P = 0.004 and 0.0007, respectively). After glucose intake, seven patients had symptoms (palpitations, headache, tremor, generalized sweating, hunger, dizziness, sweating of the palms, flush, nausea, and fatigue), whereas in the control group, one subject reported flush and another palpitations, tremor, and hunger. Analysis of the SCL-90R questionnaire revealed that patients had emotional distress and significantly higher anxiety, somatization, depression, and obsessive-compulsive scores than controls. We may conclude that patients with suspected postprandial hypoglycemia have normal glucose tolerance, increased beta-adrenergic sensitivity, and emotional distress.

Lack of hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients.

Plasma epinephrine, norepinephrine, and dopamine responses were studied in insulin-dependent diabetic patients at rest, on standing and during insulin-induced hypoglycemia. beta-Adrenergic sensitivity was evaluated by the isoproterenol sensitivity test. Five men who had adrenergic symptoms during hypoglycemia and no severe hypoglycemic accidents (coma, seizures) (group A) and five men who had repeated severe hypoglycemic accidents but lack of adrenergic symptoms of hypoglycemia (group B) were studied. The mean resting plasma epinephrine was lower in group B (147 +/- 22 pmol/L, SEM) than in group A (398 +/- 98 pmol/L, P less than 0.02). On standing plasma epinephrine increased significantly in both groups. During hypoglycemia blood glucose decreased identically in the two groups; plasma epinephrine and norepinephrine increased significantly and to the same extent in both groups; the mean maximal heart rate was significantly greater in group A than in group B. Isoproterenol sensitivity (defined as the dose of isoproterenol required to increase heart rate by 25 beats/min) was lower in group B (5.87 +/- 1.12 micrograms) than in group A (2.37 +/- 0.22 micrograms, P less than 0.01). The group B patients had significantly fewer hypoglycemic symptoms during insulin-induced hypoglycemia than did group A patients. We conclude that decreased beta-adrenergic sensitivity contributes to the lack of adrenergic symptoms of hypoglycemia in insulin-dependent diabetic patients.

Antagonism by benzodiazepines of the effects of serotonin-, but not norepinephrine-, uptake blockers in the learned helplessness paradigm in rats.

Benzodiazepines are routinely administered in combination with antidepressant drugs. Such combination can induce pharmacodynamic or pharmacokinetic interactions resulting in either a potentiation or a reduction of the effects of one of the drugs. The present study was undertaken to determine the effects of benzodiazepines alone and in combination with two classes of antidepressant drugs: "specific" norepinephrine uptake blockers (desipramine, maprotiline) and specific serotonin uptake blockers (indalpine, fluvoxamine) in the learned helplessness paradigm in rats. The present results show that daily injection of diazepam (0.2-2 mg/kg) and lorazepam (0.06-0.25 mg/kg) did not reverse the helpless behavior. The reversal of helpless behavior induced by indalpine (1 mg/kg/day) or fluvoxamine (4 mg/kg/day) was antagonized dose-dependently by daily coadministration of benzodiazepines. In contrast, the effects of desipramine (24 mg/kg/day) or maprotiline (48 mg/kg/day) were not modified.

Captopril as an antidepressant? Effects on the learned helplessness paradigm in rats.

Several clinical investigations have suggested that captopril, an angiotensin-converting enzyme inhibitor (ACEI), currently used as an antihypertensive agent, exhibited anti-depressant properties in humans. The present experiment was evaluated for potential antidepressive activity of captopril on the learned helplessness paradigm in rats. Captopril (8, 16, 32 mg/kg/day, IP) induced a reversal of escape deficits but did not affect significantly the motor activity, suggesting that this effect was not due to motor stimulation. This antidepressant-like activity was comparable to that of imipramine (16, 32 mg/kg/day, IP). Naloxone (0.5; 1 mg/kg, IP) blocked the effect of captopril (16 mg/kg, IP) in this test. These results suggest that an opioid mediation could be responsible at least in part for its behavioral effect.

Performance deficit induced by low doses of dopamine agonists in rats. Toward a model for approaching the neurobiology of negative schizophrenic symptomatology?

In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.

Tricyclic antidepressants, thyroid function, and their relationship with the behavioral responses in rats.

We first studied the effects of tricyclic antidepressants (TCAs) on thyroid function in rats in the learned helplessness paradigm. TCAs (clomipramine 32 mg/kg, desipramine 16, 24 mg/kg, or imipramine 8, 16, 32 mg/kg per day) were injected IP for 5 consecutive days. Blood samples were collected 1 hr after the last administration of the antidepressant for radioimmunoassay determination of triiodothyronine (T3) and thyrotropin. Whereas inducing helplessness did not result in any change in T3 and thyroid-stimulating hormone (TSH) levels, TCA therapy dose dependently decreased the T3 levels without changing TSH levels in helpless animals and in naive control rats. To further the investigation, the effects of TCAs on thyroid function were examined using two models of experimentation, one involving diabetes induction, the other using food deprivation; both are known to induce a resistance to TCAs that is reversible under T3 treatment. In both models, a decreased T3 level existed prior to the TCA administration. Although they had no effect on behavior, TCAs further decreased the T3 levels in diabetic and food-restricted rats. This study confirms that TCAs decrease thyroid function and suggests that the antidepressant effect of TCAs is not related to their T3 decreasing effects.

Monoamine oxidase A and B activities in heavy smokers.

There is a strong association between depression and smoking. Because monoamine oxidase (MAO) inhibition leads to antidepressant effect and in vitro studies have shown that cigarette smoke inhibits MAO activity, it is conceivable that smoking may have an antidepressant effect, if smokers have reduced MAO activity. Therefore, we assessed platelet MAO-B activity and plasma concentration of catecholamine metabolites reflecting MAO-A activity in heavy dependent smokers and nonsmokers matched for sociodemographic characteristics. Platelet MAO-B activity, plasma 3,4-dihydroxyphenylglycol, plasma 3,4-dihydroxyphenylacetic acid, and plasma 3,4-dihydroxyphenylalanine concentrations were significantly lower in smokers than in nonsmokers, whereas plasma norepinephrine did not differ. Significantly more smokers reported previous history of depression, manic episode, panic attack, agoraphobia, and simple phobia. Smokers had higher scores (p < 0.001) on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Scales. It is concluded that the activities of both forms of the MAO are reduced in heavy dependent smokers.

Whole blood serotonin content, tryptophan concentrations, and impulsivity in anorexia nervosa.

BACKGROUND: We hypothesized that anorectics with or without bulimic features would differ on impulsivity and indices of central serotoninergic function (high impulsivity being correlated with reduced serotoninergic function). METHODS: For all patients impulsivity rating scales and questionnaires detailing severity of eating disorder were assessed, and whole blood serotonin concentration (5-HT), free and total tryptophan (TT) concentrations, and large neutral amino acids (LNAA) were assayed. RESULTS: Nineteen patients with anorexia nervosa were included, 10 presented associated bulimic features and nine did not. Twelve healthy matched controls were also included. Our hypothesis was not verified. However, tryptophan concentration and the ratio of tryptophan concentration to LNAA allow us to separate controls from anorectics, whereas 5-HT concentration does not. Two significant and positive correlations were found: between impulsivity and anxiety in the total anorectic population, and between anxiety and serotonin in the impulsive group. CONCLUSIONS: All measured peripheral biologic indices except 5-HT concentration may be of interest in this pathology. Impulsivity and anxiety seem to be two personality components involved in anorexia nervosa. This study lead us to the necessity of redefining impulsivity in anorexia nervosa.

A single dose of three different ophthalmic beta-blockers antagonizes the chronotropic effect of isoproterenol in healthy volunteers.

The systemic effect of three beta-blocking eyedrops was compared in a placebo-controlled, double-blind trial in 12 healthy male volunteers. Each subject received successively each treatment in random order at weekly intervals. The eyedrops administered were as follows: 0.5% timolol, 2% carteolol, 0.6% metipranolol, and placebo. We evaluated the intraocular pressure and systemic beta-blockade 3 hours after a single administration of one eyedrop in each eye. The systemic beta-blocking effect was evaluated by the isoproterenol sensitivity test, that is the dose of isoproterenol required to increase resting heart rate by 25 bpm (I25). Each beta-blocking eyedrop antagonized the chronotropic effect of isoproterenol. I25 for placebo was 3.1 +/- 0.5 micrograms, for metipranolol 5.2 +/- 0.9 micrograms (P less than 0.005), for timolol 10.9 +/- 1.9 micrograms (P less than 0.001), and for carteolol 39.6 +/- 5.4 micrograms (P less than 0.0005). Each treatment significantly decreased the intraocular pressure: metipranolol 3.6 +/- 0.4 mm Hg (P less than 0.001), timolol 2.44 +/- 0.4 mm Hg (P less than 0.01), and carteolol 2.38 +/- 0.48 mm Hg (P less than 0.01) compared with placebo. The resting heart rate and blood pressure were not influenced by the treatments. Even though the results might be different in the case of an earlier or a later time of evaluation or chronic administration, we believe that the isoproterenol sensitivity test may be used to evaluate the systemic effect of beta-blocking eyedrops.

Blunted 5-HT1A-receptor agonist-induced corticotropin and cortisol responses after long-term ipsapirone and fluoxetine administration to healthy subjects.

OBJECTIVES: To assess whether acute 5-hydroxytryptamine-1A (5-HT1A)-receptor-mediated corticotropin, cortisol, and temperature responses are maintained after 3 weeks of treatment with controlled-release (CR) ipsapirone and fluoxetine compared with placebo and whether changes are reversible after cessation of treatment. METHODS: This was a randomized parallel-group study. Ten healthy subjects received ipsapirone CR or fluoxetine, and eight received placebo in a double-blind manner. An ipsapirone challenge test with 20 mg ipsapirone immediate-release formulation (IR) was performed before treatment (day 0) and after 20 days of treatment with placebo, 80 mg/day ipsapirone CR, or 20 mg/day fluoxetine (day 21). From day 22 to day 34 all subjects received placebo in a simple-blind manner. A third ipsapirone challenge test was performed on day 35. RESULTS: Before treatment, resting plasma corticotropin and cortisol concentrations and increases in plasma corticotropin and cortisol concentrations after challenge with 20 mg ipsapirone IR were similar for the three groups. After 20 days of treatment, plasma corticotropin and cortisol concentrations were similar before challenge, but ipsapirone IR-induced increases in plasma corticotropin and cortisol concentrations were significantly lower in both the ipsapirone CR group (corticotropin, 6.5 +/- 2 pg/ml; cortisol, 1.5 +/- 0.7 micrograms/dl) and fluoxetine group (corticotropin 4.4 +/- 2 pg/ml; cortisol 1.5 +/- 0.7 micrograms/dl) compared with placebo (corticotropin, 34 +/- 14 pg/ml; cortisol, 5.8 +/- 2 micrograms/dl, mean +/- SEM). After 2 weeks of placebo administration, plasma corticotropin and cortisol responses to ipsapirone IR again became identical in all three groups. Plasma ipsapirone concentrations were similar in all groups during each challenge. The hypothermic response to ipsapirone IR showed no difference before treatment, at the end of the treatment period, or 2 weeks after cessation of treatment. Long-term administration of antidepressants to the healthy subjects did not lead to any serious adverse effects. CONCLUSIONS: Long-term administration of fluoxetine and ipsapirone did not influence resting plasma corticotropin and cortisol concentrations in the morning. Stimulation of corticotropin and cortisol release by a selective 5-HT1A-agonist is reduced with long-term administration of these serotoninergic antidepressants. This subsensitivity of postsynaptic 5-HT1A-receptors is reversible.

Effect of yohimbine on blood pressure in patients with depression and orthostatic hypotension induced by clomipramine.

Orthostatic hypotension, one of tricyclic antidepressant treatment's side effects, is also a factor in limiting adequate antidepressant dosing. We tested in a double-blind, crossover, placebo-controlled study the effect of low doses (4 mg/t.i.d.) of yohimbine in 12 patients with depression with clomipramine-induced orthostatic hypotension. Yohimbine, a selective alpha 2-adrenoceptor antagonist, had a favorable effect in orthostatic hypotension and induced a significant increase in blood pressure. A pharmacodynamic and pharmacokinetic interaction between yohimbine and clomipramine or demethylclomipramine was discussed.

Determination and comparison of the pressor effect of tyramine during long-term moclobemide and tranylcypromine treatment in healthy volunteers.

Monoamine oxidase inhibitors can elicit increases in systolic blood pressure after tyramine ingestion (cheese effect). Moclobemide is a new, reversible, preferential monoamine oxidase A inhibitor with antidepressant properties. Its potentiation of the tyramine pressor effect during 200 mg t.i.d. chronic treatment was compared with tranylcypromine, 10 mg b.i.d., in a double-blind, parallel-group, placebo-controlled study (n = 16). Tyramine was mixed with food and ingested in increasing daily doses, during a normal meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (tyramine 30). When compared with the usual fasting oral tyramine tests performed in the same subjects, the mean tyramine 30 dose with a meal was 2.8 times higher. The mean tyramine 30 dose with a meal decreased from 1450 mg (range, 800 to 2000 mg) during placebo to 306 mg (range, 150 to 500 mg) during moclobemide (factor, 5.0) and from 1200 mg (range, 1000 to 1600 mg) during placebo to 35 mg (range, 20 to 50 mg) during tranylcypromine (factor, 38.2). The duration of the systolic blood pressure increase was longer with tranylcypromine (126 minutes) than with moclobemide (69 minutes) (p less than 0.01).

The alpha 2-adrenergic receptor antagonist yohimbine inhibits epinephrine-induced platelet aggregation in healthy subjects.

Onset of sudden death, myocardial infarction, and stroke occurs more likely in the morning hours. Similarly, a morning increase in epinephrine-induced platelet aggregation was observed accompanied by an increase in plasma catecholamines. Inhibition of the morning increase in platelet aggregation would be of therapeutic benefit. In this study the effect of the selective alpha 2-adrenergic receptor antagonist yohimbine on platelet aggregation was evaluated in healthy subjects. Yohimbine administered orally selectively antagonized epinephrine but not collagen, arachidonic acid, or adenosine diphosphate-induced ex vivo platelet aggregation. The lowest dose of yohimbine that significantly inhibited epinephrine-induced platelet aggregation was 8 mg. The inhibitory effect of yohimbine on platelet aggregation lasted 10 hours with the 12 mg dose. At the doses studied (4, 8, and 12 mg), yohimbine did not modify blood pressure, standing heart rate, or plasma catecholamine or glucose concentrations. Twelve milligrams of yohimbine moderately but significantly accelerated supine heart rate (mean maximal increase, 7 +/- 3 beats/min). Further clinical studies are needed to evaluate whether bedtime administration of 12 mg yohimbine may block the morning increase in epinephrine-induced platelet aggregation.

A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers.

OBJECTIVE: To assess the effectiveness of moclobemide on smoking cessation and abstinence in heavy, dependent smokers. There is a strong association between smoking and depression, especially in dependent smokers. It was hypothesized that smoking is a self-medication to treat depression. Cigarette smoke has monoamine oxidase (MAO)-inhibitory properties, and smokers have lower MAO activity than non-smokers. METHODS: We used a randomized, double-blind, placebo-controlled parallel-group study. Placebo or moclobemide, 400 mg/day for 2 months and 200 mg/day during the third month, was given. Main outcome measures were self-reported and biochemically verified (plasma cotinine levels, < 20 ng/ml) abstinence rate. Secondary outcome measures were withdrawal symptoms, Montgomery-Asberg Depression Rating Scale, Hamilton anxiety rating scores, platelet MAO-B activity, and plasma dihydroxyphenylglycol as a measure of MAO-A activity. RESULTS: Eighty-eight smokers were randomized to receive moclobemide (n = 44) or placebo (n = 44). The continuous self-reported abstinence rate was higher with moclobemide than with placebo (intention-to-treat analysis until the end point, 6 months: p < 0.05; until the end of follow-up, 1 year: p = 0.09). The abstinence rate according to plasma cotinine levels showed a trend to effectiveness of moclobemide (end point: p = 0.13; follow-up: p = 0.12). Platelet MAO-B activity increased after smoking cessation but without a significant difference. Plasma dihydroxyphenylglycol levels did not change in the placebo group but decreased dose dependently in the moclobemide group. No difference occurred for withdrawal symptoms, Montgomery-Asberg Depression Rating Scale, and Hamilton anxiety scores. Cessation of moclobemide had no adverse effect. More subjects reported insomnia with moclobemide (n = 16) than with placebo (n = 3). CONCLUSION: In this preliminary study, the reversible, selective MAO inhibitor moclobemide facilitated smoking cessation in highly dependent smokers. Further studies with substantially more smokers are needed to evaluate the role of MAO inhibitors in smoking cessation and abstinence in smokers with high nicotine dependence.

Reduction of hyperglycemia after oral glucose load by the new alpha 2-adrenergic receptor antagonist SL 84.0418 in healthy subjects.

OBJECTIVE: To assess the antihyperglycemic activity of a new peripherally acting alpha 2-adrenergic receptor antagonist, SL 84.0418 in healthy volunteers METHODS: This was a randomized, double-blind crossover study. The effects of 10, 50, and 100 mg SL 84.0418 on blood glucose, plasma insulin, C-peptide, glucagon, epinephrine, and norepinephrine were investigated in comparison with placebo and 5 mg glipizide before and after an oral glucose challenge (75 gm). RESULTS: Peak blood glucose and area under the blood-glucose curve were dose-dependently reduced by SL 84.0418; the extent of this reduction was similar with 100 mg SL 84.0418 and glipizide. Glipizide but not SL 84.0418 decreased nadir blood glucose. Plasma insulin and C-peptide were increased by glipizide but not by SL 84.0418. Treatments did not modify plasma glucagon. Plasma epinephrine increased during glipizide treatment and plasma norepinephrine increased during treatment with 50 and 100 mg SL 84.0418. Systolic and diastolic blood pressure were moderately enhanced by 50 and 100 mg SL 84.0418. Adverse effects reflecting alpha 2-adrenergic receptor blockade occurred more frequently with 100 mg SL 84.0418. The adverse effect profile of 50 mg SL 84.0418 was not different from that observed with glipizide. CONCLUSION: The alpha 2-adrenergic receptor antagonist SL 84.0418 dose dependently reduced the increase in blood glucose after glucose load without modification of plasma insulin. It may represent an alternative to sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus. Further studies are needed to assess its efficacy and tolerability in non-insulin-dependent patients.

Benzodiazepines reverse the anti-immobility effect of antidepressants in the forced swimming test in mice.

The present study provides evidence that, in mice subjected to the forced swimming test, the anti-immobility effect of the tricyclic antidepressants, desipramine and imipramine (16-32 mg/kg) was antagonized by the acute co-administration of a benzodiazepine, diazepam (0.25-2 mg/kg) and lorazepam (0.125 mg/kg). This effect cannot be accounted for by variations in plasma and/or brain levels of each compound since brain and plasma concentrations of desipramine and plasma levels of diazepam and desmethyldiazepam, measured immediately after the swimming test, were not significantly modified by the co-administration. Diazepam (2 mg/kg) also counteracted the reduction of time spent immobile induced by the MAO inhibitors, toloxatone (256 mg/kg) and selegiline (4 mg/kg) and the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), but not by the psychostimulant, caffeine (32 mg/kg). The sedative neuroleptic, thioridazine (4 mg/kg) was also found to reverse the anti-immobility effect of desipramine whereas the non-benzodiazepine anxiolytics, alpidem (8 mg/kg) and buspirone (0.5 mg/kg) did not. These results indicate that the observed interactions were unlikely to be accounted for by a reduction of the stressful aspect of the situation whereas the participation of some motor or sedative component could not be totally ruled out.

Involvement of a central alpha-adrenoceptor system in antidepressant potentiation of hyperthermia induced by thyrotropin releasing hormone.

Thyrotropin releasing hormone (TRH) causes hyperthermia in mice which is potentiated by tricyclic antidepressants (nortriptyline, imipramine, clomipramine, amitriptyline), the monoamine oxidase inhibitor, tranylcypromine, and various other antidepressants (maprotiline, nomifensin, viloxazine). Only iprindole is ineffective. The effect of mianserin, itself hypothermic, could not be interpreted. A property shared by the potentiating substances seems to be activation of a central adrenoceptor system. The potentiation of TRH-induced hyperthermia which seems to be specific to antidepressants might be used in the selection of antidepressants.