Jacques Massol

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.

Impact of physician preferences for homeopathic or conventional medicines on patients with musculoskeletal disorders: results from the EPI3‐MSD cohort

The objective of this study was to assess the effect of physician practicing preferences (PPP) in primary care for homeopathy (Ho), CAM (Complementary and alternative medicines) with conventional medicine (Mx) or exclusively conventional medicine (CM) on patients with musculoskeletal disorders (MSDs), with reference to clinical progression, drug consumption, side effects and loss of therapeutic opportunity.

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.

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.

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.

Thyroid Function and Reversal by Antidepressant Drugs of Depressive-Like Behavior (Escape Deficits) in Rats

Several investigations have suggested that a special relationship exists between thyroid function and affective disorders and/or therapeutic response to antidepressants. The present study shows that the reversal by clomipramine, desipramine, imipramine and nialamide of depressive-like behavior in rats (escape deficits produced by previous exposure to uncontrollable stress) was markedly attenuated in hypothyroid rats (propylthiouracil, 0.05% in the drinking water). Conversely, the effect of these same antidepressants was significantly hastened in euthyroid rats given daily triiodothyronine. This supports the notion of intricate thyroid/CNS interactions in the mechanisms of action of antidepressant drugs.

SCORE should be preferred to Framingham to predict cardiovascular death in French population

Background Numerous studies have examined the validity of available scores to predict the absolute cardiovascular risk. Design We developed a virtual population based on data representative of the French population and compared the performances of the two most popular risk equations to predict cardiovascular death: Framingham and SCORE. Methods A population was built based on official French demographic statistics and summarized data from representative observational studies. The 10-year coronary and cardiovascular death risk and their ratio were computed for each individual by SCORE and Framingham equations. The resulting rates were compared with those derived from national vital statistics. Results Framingham overestimated French coronary deaths by 2.8 in men and 1.9 in women, and cardiovascular deaths by 1.5 in men and 1.3 in women. SCORE overestimated coronary death by 1.6 in men and 1.7 in women, and underestimated cardiovascular death by 0.94 in men and 0.85 in women. Our results revealed an exaggerated representation of coronary among cardiovascular death predicted by Framingham, with coronary death exceeding cardiovascular death in some individual profiles. Sensitivity analyses gave some insights to explain the internal inconsistency of the Framingham equations. Conclusion Evidence is that SCORE should be preferred to Framingham to predict cardiovascular death risk in French population. This discrepancy between prediction scores is likely to be observed in other populations. To improve the validation of risk equations, specific guidelines should be issued to harmonize the outcomes definition across epidemiologic studies. Prediction models should be calibrated for risk differences in the space and time dimensions.

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.

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.

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.