[To better understand drug therapy].
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Drug Interactions↗
Biomedical subjects
J Massol
Publications and source records attributed to J Massol.
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.
Animals↗
Involvement of angiotensin-converting enzyme inhibition in reversal of helpless behavior evoked by perindopril in rats.
Several clinical investigations have suggested that captopril, an angiotensin-converting enzyme inhibitor (ACEI) currently used as an anti-hypertensive agent, exhibits antidepressant properties in humans. In the present study we evaluated the action of perindopril, another ACEI, and two of its metabolites, the di-acide form perindoprilat, which possesses ACE inhibitory properties, and BDM-4, an inactive metabolite, in the learned helplessness paradigm. In order to confirm a possible action of these drugs via dipeptidyl carboxypeptidase inhibition, we also investigated two inactive analogues of perindopril and perindoprilat. Perindopril (0.06-8 mg/kg per day) and perindoprilat (0.25-8 mg/kg per day) induced a reversal of escape deficits. BMD-4 and two analogues failed to reverse helpless behavior. These results support the hypothesis that ACE inhibition is a key factor in the behavioral antidepressant-like activity of perindopril and perindoprilat.
Angiotensin-Converting Enzyme Inhibitors↗
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.
Animals↗
Arginine vasopressin response to insulin-induced hypoglycemia in insulin-dependent diabetics with asymptomatic hypoglycemia.
Insulin-induced hypoglycemia causes an increase in plasma vasopressin (AVP) in healthy subjects but the response in diabetics is not established. We investigated the effect of insulin-induced hypoglycemia on ten insulin-dependent diabetics with asymptomatic hypoglycemia, and compared the results with those for seven healthy subjects. The lack of adrenergic symptoms of hypoglycemia in insulin dependent diabetics being attributed to a diminished beta-adrenergic sensitivity, the effect of isoprenaline infusion was investigated as control. Insulin-induced hypoglycemia resulted in both populations in significant increase (P less than 0.01) in AVP in addition to significant increases in heart rate, plasma epinephrine (E), norepenephrine (NE) and cortisol (COR). Effective osmolality and mean arterial blood pressure did not vary. Diabetics showed smaller increase in AVP (P less than 0.01) and heart rate (P less than 0.05) than controls. Maximal E, NE and COR values did not differ between the two populations. Isoprenaline infusion resulted in increase in heart rate and plasma renin activity, but AVP and COR did not vary in the two populations. In conclusion, insulin-induced hypoglycemia released AVP in diabetics with asymptomatic hypoglycemia, but the response was weaker than in healthy subjects. A causal hypothalamic alteration of beta-adrenergic or glycopenia sensitivity is discussed.
Adult↗
Antidepressant profile of bupropion and three metabolites in mice.
Bupropion is a novel antidepressant, distinct from tricyclic antidepressants both neurochemically and behaviorally. Bupropion forms several metabolites in both rodents and humans. Three chemically different molecules - BW 306, BW 494, and BW 287 - were selected. Comparative assessment of antidepressant activity of bupropion and its metabolites in mice, and pharmacological analysis of possible mechanisms of action of the parent drug and its metabolites (using interaction studies with pimozide, D,L-propranolol, and prazosin) were carried out. The results obtained show that: bupropion has a pharmacological spectrum in various animal models which predicts both antidepressant and stimulatory activity in man. BW 306 is the most active of the metabolites studied and, compared to bupropion, seems more "antidepressant" and less stimulant. BW 494, compared to bupropion or BW 306, has a lower degree of activity in various tests used to evaluate antidepressants. BW 287 has no effect in any of the tests used in this study. The interaction studies with pimozide, D,L-propranolol, and prazosin in the various tests have shown that: the stimulatory effect of bupropion, BW 306, and BW 494 is antagonized by both pimozide and prazosin. in the behavioral despair test, the reduction in the duration of immobility by bupropion and BW 494 is antagonized by pimozide, but not by prazosin or D,L-propranolol. the antagonism of reserpine-induced hypothermia by bupropion and BW 306 is significantly decreased by prazosin and D,L-propranolol, but not by pimozide. These data suggest that the clinical antidepressant profile (without a major stimulatory effect) observed in man after administration of bupropion is related to metabolite BW 306 and possibly to BW 494, rather than to bupropion itself.
Animals↗
Effects of dihydropyridine drugs on reversal by imipramine of helpless behavior in rats.
The present study was undertaken in order to determine the effects of the dihydropyridine calcium channel blocker, nimodipine and the dihydropyridine calcium channel activator BAY k 8644, in the learned helplessness test in the rat. Nimodipine dose dependently (0.5-2 mg/kg per day) reversed the behavioral deficit induced by inescapable shocks. The reversal of helpless behavior by imipramine (32 mg/kg per day) was antagonized by BAY k 8644 (0.5 and 1 mg/kg per day), and the effects of imipramine 8 and 16 mg/kg per day) were potentiated by a subeffective dose (0.5 mg/kg per day) of nimodipine. These results suggest that central dihydropyridine binding sites may be specifically involved in the modulation of the imipramine reversal of helpless behavior and favor a physiological role for dihydropyridine binding sites in the brain.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Gonadotropin-releasing hormone (GnRH) as antidepressant: a psychopharmacological animal study.
Because the secretion of gonadotrophic hormones is disturbed in some depressive states, it has been hypothesized that gonadotropin-releasing hormone (GnRH) has antidepressant properties in humans, but no clear information has emerged from clinical trials. The lack of experimental psychopharmacological data prompted us to investigate the effects of GnRH on the 'learned helplessness' behavioral model of depression in rats. GnRH was injected i.p. at doses of 0.06, 0.25, 0.50, 1 and 2 mg/kg per day. GnRH significantly reduced the number of escape failures at doses of 1 mg/kg per day or higher during the first shuttle-box session and at doses of 0.25 mg/kg per day onwards during the third shuttle-box session. These antidepressant-like effects of GnRH were similar to those observed with the tricyclic antidepressants imipramine (32 mg/kg per day) or clomipramine (32 mg/kg per day) in the same model. Moreover, while the induction of learned helplessness behaviour resulted in a fall in the plasma levels of FSH and LH, normal values of these hormones could be restored by a behaviorally effective GnRH regimen. From these data it can be suggested that GnRH exhibits an interesting antidepressant-like activity in rats.
Animals↗
Attenuation of response to antidepressants in animals induced by reduction in food intake.
A salient feature of depression is eating disorders (reduced appetite and caloric intake) and/or weight loss. In the present study, reduction in food intake in rats, resulting in moderate weight loss, markedly attenuated the ability of various antidepressant drugs to reverse depressive-like behaviors: escape deficits provoked by previous exposure to uncontrollable stress. Further data support the notion that hypofunctioning of central noradrenergic processes, perhaps linked to reduced thyroid hormone levels, might contribute to such an altered response to antidepressants. These findings suggest that current nutritional status, even with marginal weight loss, could be an intervening factor in the delayed therapeutic response to antidepressants and/or in drug-resistant depression.
Animals↗
Effects of triiodothyronine (T3) on the potentiation by antidepressants of L-5-hydroxytryptophan-induced head-twitches in mice.
1. Daily injection of T3 during three consecutive days dose-dependently enhanced L-5-HTP (4 mg/kg)-induced head-twitches in mice. 2. Pretreatment with a sub-effective dose of T3 (0.06 mg/kg) markedly enhanced the ability of drugs acting mainly on noradrenergic systems (clenbuterol, desipramine, maprotiline and nomifensine) to increase the response to L-5-HTP. 3. In contrast the potentiating effects of T3 were moderate on drugs with mixed action on serotonergic and noradrenergic systems (amitriptyline, clomipramine and imipramine) and minimal on drugs acting mainly on serotonergic systems (citalopram, fluvoxamine and indalpine). 4. These data suggest that the increased responsiveness to L-5-HTP caused by T3 involves an indirect (norepinephrine-mediated) rather than a direct effect on serotonergic processes.
5-Hydroxytryptophan↗
Are antidepressant-like effects of triiodothyronine (T3) in rodents related to an hyperthyroid state?
1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied in mice. 2. On the tests performed (antagonism of apomorphine- and oxotremorine-induced hypothermia, potentiation of yohimbine toxicity, L-5-HTP-induced head twitches and the learned-helplessness paradigm), T3 was active after subchronic treatment (1 injection per day for 3 days, ending 24 hours before testing). 3. In these tests T3 exhibited the same profile as antidepressant drugs in rodents. 4. The similar activity of beta-agonists in these tests and the ability of T3 to potentiate the effect of clenbuterol agree with the hypothesis that T3 can induce beta-adrenergic hypersensitivity. 5. Under the present experimental conditions these effects were obtained with doses of T3 which did not induce hyper-triiodothyroninemia. Thus, the lowest doses significantly affecting apomorphine- and oxotremorine-induced hypothermia were respectively .008 and .032 mg/kg/day. 6. Doses as low as .032 mg/kg/day were active in the yohimbine test. 7. L-5-HTP-induced head twitches were potentiated by a dose of .25 mg/kg/day and in the learned-helpless paradigm, the lowest effective dose was .06 mg/kg/day. 8. Plasma T3 values obtained in the same conditions were not significantly different from control at doses less than .5 mg/kg/day, and increased dramatically with higher doses, suggesting an accumulation of the hormone in plasma. 9. The doses inducing an hyper-triiodothyroninemia coincided with physiological signs of hyperthyroidism in the animals (i.e. loss of weight and slight hyperthermia). Thus, the active dose range of T3 was below the lowest dose required to produce a significant hyperthyroid state. 10. This results suggest that a clinical benefit could be obtained with low doses of T3 that do not significantly induce an hyperthyroidism.
5-Hydroxytryptophan↗
Helpless behavior (escape deficits) in streptozotocin-diabetic rats: resistance to antidepressant drugs.
Using the learned helplessness model of depression in rats, the present study undertook to investigate the possibility of an impaired response to antidepressant drugs in diabetic animals. Experimental diabetes was induced by three intraperitoneal (IP) injections of streptozotocin (37.5, 37.5, 50 mg/kg, three days apart), four weeks before behavioral testing. Diabetic and non-diabetic rats were first exposed to 60 inescapable shocks. Forty-eight hours later and over three consecutive days, they were subjected to daily shuttle-box sessions for assessment of escape failures (helpless behavior). Twice daily (IP) injection of clomipramine (24 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg) or clenbuterol (0.75 mg/kg) prevented escape deficits in the non-diabetic but not in the diabetic rats. However, this prevention was made possible in the diabetic rats by increasing the duration of the antidepressant treatment. Moreover, one week of insulin therapy restored operant escape responding to both the tricyclics and a beta-agonist. The inefficacy of clenbuterol (a central beta-agonist) in reversing helpless behavior in diabetic rats, along with the observation that triiodothyronine (T3) supplementation also restored the response to imipramine in the diabetic rats, suggests that thyroid-mediated alterations of central noradrenergic function might be a critical factor in the resistance or delayed response to antidepressants in experimental diabetes. These animal findings raise the possibility of a similar resistance to conventional antidepressants in depressed diabetic patients.
Animals↗
Decreased GABA B receptors in helpless rats: reversal by tricyclic antidepressants.
Recently, sufficient evidence has accumulated to suggest that a central GABAergic dysfunction may be primarily related to the physiopathology of affective disorders and that antidepressant mechanisms have an intrinsic GABAergic component. In depressed patients GABA levels are reported to be low in the cerebral spinal fluid and plasma, and GABA synthesis is decreased in some brain areas, including the frontal cortex. GABA mimetics exhibit antidepressant-like actions in behavioral models in the olfactory bulbectomized rat and in the learned helplessness paradigm. In the olfactory bulbectomized rat, GABA B receptors are down regulated in the frontal cortex and in the learned helplessness paradigm, GABA release is diminished in the hippocampus. These decreases are reversed by antidepressants in parallel with their behavioral activities. In this study, data obtained indicate that in the learned helplessness paradigm, GABA B receptors are decreased in the frontal cortex and this decrease is reversed by imipramine and desipramine (16 mg/kg/day) in animals which are considered to be 'responders' to antidepressant treatments.
Animals↗
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.
Analysis of Variance↗
Triiodothyroacetic acid (TRIAC) potentiation of antidepressant-induced reversal of learned helplessness in rats.
The results of several clinical investigations have suggested that a special relationship exists between thyroid function and affective disorders and/or the therapeutic response to antidepressants. Animal studies have shown the possible beta-adrenergically mediated antidepressant-like properties of triiodothyroacetic acid (TRIAC) in rodents. The present experiment showed (1) that the reversal by antidepressants (clomipramine or imipramine) of escape deficits produced by previous exposure to uncontrollable shock was significantly hastened in animals given TRIAC and (2) that L-penbutolol treatment prevented the elimination of helpless behavior induced by TRIAC, suggesting a beta-adrenergic mediation of the antidepressant activity of thyroid compounds. The study confirmed that learned helplessness might be a useful model for studying in animals the neurohormonal correlates of affective disorders and the neurobiochemical basis of the enhancement of the antidepressant action produced by thyroid compounds.
Animals↗
Antidepressant-like effects of triiodothyroacetic acid in mice.
Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the properties of triiodothyronine (T3). In particular, it has an inhibitory effect on the thyreotropic axis, but its peripheral effects are reduced. Given the activity of T3 on psychopharmacological models of depression in rodents, we investigated the effects of TA3 on some pharmacological and behavioral tests in mice. TA3 antagonized apomorphine- and oxotremorine-induced hypothermia, potentiated yohimbine-induced toxicity and L-5-hydroxy-tryptophan-induced head twitches, but did not affect forced swimming-induced immobility or reserpine-induced hypothermia. Thus, TA3 was effective on the same psychopharmacological tests which have previously been used to demonstrate the antidepressant-like effects of T3. Moreover, TA3 under the same experimental conditions as T3 has little effect on the metabolic clearance rate parameters, and might, therefore, be preferable to T3 for clinical use in depression.
Animals↗
Impaired response of experimental diabetic mice to tricyclics: a possible beta-adrenergic mechanism.
Diabetes is reportedly associated with alterations in peripheral and central noradrenergic systems. The latter might be involved in the antidepressant effects of imipramine-like drugs in both humans and animals. Therefore, it is possible that diabetics show an impaired responsiveness to tricyclics. To test this possibility the effects of streptozotocin (STZ)-induced experimental diabetes in mice were assessed in two psychopharmacological tests: 1) the reversal of apomorphine- (16 mg/kg) induced hypothermia and 2) the hypoactivity induced by a direct beta-agonist (clenbuterol 0.06 mg/kg). At day 15 after STZ or vehicle treatment, imipramine (4 mg/kg) antagonized the apomorphine-induced hypothermia in diabetic (D) and nondiabetic (ND) mice and clenbuterol produced hypoactivity in both groups. At day 30 and 45, the ability of imipramine (1, 2, 4, 8, 16 mg/kg), clomipramine (8 mg/kg) and desipramine (2 mg/kg) to reverse apomorphine-induced hypothermia disappeared at the same time that clenbuterol lost its ability to induce hypomotility in D mice. These impaired responses on both tests were corrected by a short period of insulin therapy. These two tests may reflect central beta-adrenergic functions. Therefore, these data suggest that the impaired responsiveness of diabetic mice might be due at least in part to a noradrenergic dysfunction. Possibly, in diabetes, a beta-adrenoceptor desensitization identical to that observed at the peripheral level occurs in the central nervous system. The possibility that a thyroid hormone deficiency may be involved was also tested. Decreased T3 plasma levels were found in D mice concomitant with the impaired pharmacological responses and T3 supplementation turned these responses to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Decreased central GABA B receptor binding sites in diabetic rats.
Little is known about the implication of central GABAergic neurons. However, there is evidence suggesting a growing importance of GABAergic function in the action of antidepressants. Since streptozotocin (STZ)-diabetic rats have been shown to be resistant to the action of various antidepressants, we were interested in evaluating the density of GABAergic receptor binding sites in the cortex of STZ-diabetic rats on day 15 and day 30 of diabetes. A specific and marked decrease in GABA B receptor density was observed with no change in GABA A. Although no clear relationship could be demonstrated, it may be suggested that a central GABAergic dysfunction of diabetic rats may contribute to explain their resistance to antidepressants.
Animals↗