Efficacy of an Hypericum perforatum (St. John's wort) extract in preventing and reverting a condition of escape deficit in rats.
(9/1011)
The treatment of unselected depressed patients with an hydro-alcoholic extract of Hypericum perforatum has been reported to have an efficacy similar to that of classical antidepressants. In the present report, the effects of H. perforatum were studied on three animal models of depression: (i) an acute form of escape deficit (ED) induced by an unavoidable stress; (ii) a chronic model of ED, which can be maintained by the administration of mild stressors on alternate days; (iii) a model of anhedonia based on the finding that repeated stressors prevent the development of an appetitive behavior induced by vanilla sugar in satiated rats fed ad libitum. H. perforatum acutely protected animals from the sequelae of unavoidable stress; such an effect was partially prevented by the administration of SCH 23390 or (-)-pindolol. Moreover, H. perforatum reverted the ED maintained by repeated stressors and preserved the animal's capacity to learn to operate for earning a positive reinforcer. It was concluded that H. perforatum contains some active principle(s) endowed with antidepressant activity. (+info)
Effects of prior fluoxetine treatment on EEG sleep in women with recurrent depression.
(10/1011)
We examined whether fluoxetine treatment has persistent effects on electroencephalographic sleep after drug discontinuation in patients with recurrent major depression. Age-matched groups of 23 women were treated with interpersonal psychotherapy alone (IPT) or fluoxetine plus interpersonal psychotherapy (IPT + FLU). Sleep studies were conducted when patients were depressed, and again at remission, at least four weeks after fluoxetine discontinuation. The groups did not differ in depression ratings pre- to post-treatment. Significant group*time interaction effects were noted for REM sleep (p = .04) and slow wave sleep (p = .02). REM percentage and phasic REM activity increased in the IPT + FLU group but decreased in the IPT group. The effects of fluoxetine treatment on electroencephalographic sleep can be observed for at least four weeks after drug discontinuation and appear to represent both drug discontinuation and neuroadaptation effects. (+info)
Modulation of dialysate levels of dopamine, noradrenaline, and serotonin (5-HT) in the frontal cortex of freely-moving rats by (-)-pindolol alone and in association with 5-HT reuptake inhibitors: comparative roles of beta-adrenergic, 5-HT1A, and 5-HT1B receptors.
(11/1011)
(-)-Pindolol, which possesses significant affinity for 5-HT1A, 5-HT1B, and beta 1/2-adrenergic receptors (AR)s, dose-dependently increased extracellular levels of dopamine (DA) and noradrenaline (NAD) versus 5-HT, in dialysates of the frontal cortex (FCX), but not accumbens and striatum, of freely-moving rats. In distinction, the preferential beta 1-AR antagonist, betaxolol, and the preferential beta 2-AR antagonist, ICI118,551, did not increase basal levels of DA, NAD, or 5-HT. Further, they both dose-dependently and markedly blunted the influence of (-)-pindolol upon DA and NAD levels. The selective 5-HT1A receptor antagonist, WAY100,635, slightly attenuated the (-)-pindolol-induced increase in DA and NAD levels, while the selective 5-HT1B antagonist, SB224,289, was ineffective. These data suggest that (-)-pindolol facilitates frontocortical dopaminergic (and adrenergic) transmission primarily by activation of beta 1/2-ARs and, to a lesser degree, by stimulation of 5-HT1A receptors, whereas 5-HT1B receptors are not involved. (-)-Pindolol potentiated the increase in FCX levels of 5-HT elicited by the 5-HT reuptake inhibitors, fluoxetine and duloxetine, and also enhanced their ability to elevate FCX levels of DA--though not of NAD. In contrast to (-)-pindolol, betaxolol and ICI118,551 did not affect the actions of fluoxetine, whereas both WAY100,635 and SB224,289 potentiated the increase in levels of 5-HT--but not DA or NAD levels--elicited by fluoxetine. In conclusion, (-)-pindolol modulates, both alone and together with 5-HT reuptake inhibitors, dopaminergic, adrenergic, and serotonergic transmission in the FCX via a complex pattern of actions at beta 1/2-ARs, 5-HT1A, and 5-HT1B receptors. These findings have important implications for clinical studies of the influence of (-)-pindolol upon the actions of antidepressant agents. (+info)
Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress.
(12/1011)
We have recently shown that priming injections of alcohol and footshock stress reinstate alcohol seeking in drug-free rats. Here we tested whether naltrexone and fluoxetine, two drugs used in the treatment of alcohol dependence, would affect reinstatement of alcohol seeking induced by these events. We also determined the effects of these drugs on alcohol self-administration during the maintenance phase. Rats were trained to press a lever for a 12% w/v alcohol solution. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished. Reinstatement of drug seeking was then determined after priming injections of alcohol (0.24-0.96 g/kg) or exposure to intermittent footshock (5 and 15 min). Rats were pretreated with naltrexone (0.2-0.4 mg/kg) or fluoxetine (2.5-5 mg/kg) during maintenance or during tests for reinstatement. Both naltrexone and fluoxetine decreased lever presses for alcohol during the maintenance phase. Naltrexone blocked alcohol-induced, but not stress-induced reinstatement. In contrast, fluoxetine blocked stress-induced reinstatement, while its effect on alcohol-induced reinstatement was less consistent. The implications of these data to the understanding of relapse to alcohol are discussed. (+info)
The promotion effect of anorectic drugs on aflatoxin B(1)-induced hepatic preneoplastic foci.
(13/1011)
The ability of three extensively used anorectic drugs, namely fenfluramine (FN), fluoxetine (FX) and amphetamine (AM), to alter the development of aflatoxin B(1) (AFB(1))-induced gamma-glutamyl-positive (GGT(+)) preneoplastic liver foci was investigated in 135 male weanling F344 rats. Following AFB(1) administration, 15 rats were killed, while the rest were divided into four groups and fed diets containing either FN, FX, AM or control diet, with half of the animals in each group subsequently being killed at 4 weeks and half at 10 weeks. All three anorectic drugs as expected suppressed initial food intake, growth rate, body weight gain and food efficiency. They also tended to suppress body fat mass and to decrease plasma levels of T(3) and T(4). FN significantly (P < 0.05) increased GGT(+) foci number/cm(2) and number/cm(3), while FX significantly increased GGT(+) foci number/cm(2) and the volume fraction of foci. Histopathological staining also revealed that FN- and FX-treated animals had more serious morphological alterations in their liver tissue. In contrast, foci development was, if anything, suppressed by AM feeding. These results indicate that serotoninergic drugs (FN and FX), as opposed to dopaminergic drugs (AM), may have tumor promoter activity, at least for liver tissue. (+info)
Fluoxetine dilates isolated small cerebral arteries of rats and attenuates constrictions to serotonin, norepinephrine, and a voltage-dependent Ca(2+) channel opener.
(14/1011)
BACKGROUND AND PURPOSE: Recent clinical observations question that the antidepressant effect of fluoxetine (Prozac) can be explained solely with serotonin reuptake inhibition in the central nervous system. We hypothesized that fluoxetine affects the tone of vessels and thereby modulates cerebral blood flow. METHODS: A small branch of rat anterior cerebral artery (195+/-15 microm in diameter at 80 mm Hg perfusion pressure) was isolated, cannulated, and pressurized (at 80 mm Hg), and changes in diameter were measured by videomicroscopy. RESULTS: Fluoxetine dilated small cerebral arteries with an EC(50) of 7.7+/-1.0x10(-6) mol/L, a response that was not affected by removal of the endothelium or application of 4-aminopyridine (an inhibitor of aminopyridine-sensitive K(+) channels), glibenclamide (an inhibitor of ATP-sensitive K(+) channels), or tetraethylammonium (a nonspecific inhibitor of K(+) channels). The presence of fluoxetine (10(-6) to 3x10(-5) mol/L) significantly attenuated constrictions to serotonin (10(-9) to 10(-5) mol/L) and norepinephrine (10(-9) to 10(-5) mol/L). Increasing concentrations of Bay K 8644 (a voltage-dependent Ca(2+) channel opener, 10(-10) to 10(-6) mol/L) elicited constrictions, which were markedly reduced by 2x10(-6) and 10(-5) mol/L fluoxetine, whereas 3x10(-5) mol/L fluoxetine practically abolished the responses. CONCLUSIONS: Fluoxetine elicits substantial dilation of isolated small cerebral arteries, a response that is not mediated by endothelium-derived dilator factors or activation of K(+) channels. The finding that fluoxetine inhibits constrictor responses to Ca(2+) channel opener, as well as serotonin and norepinephrine, suggests that fluoxetine interferes with the Ca(2+) signaling mechanisms in the vascular smooth muscle. We speculate that fluoxetine increases cerebral blood flow in vivo, which contributes to its previously described beneficial actions in the treatment of mental disorders. (+info)
Fluoxetine-resistant mutants in C. elegans define a novel family of transmembrane proteins.
(15/1011)
Fluoxetine (Prozac) is an antidepressant that is thought to act by blocking presynaptic reuptake of the neurotransmitter serotonin. Despite widespread clinical use of fluoxetine, direct evidence for this mechanism has been difficult to obtain in vivo. We have determined that fluoxetine has an additional neuromuscular effect on C. elegans that is distinct from inhibition of serotonin reuptake. By screening for mutants resistant to this effect, we have identified seven genes. We report that two of these genes are homologous to each other and define a novel gene family that encodes over a dozen multipass transmembrane proteins. Our findings may have clinical implications for the mechanism of action of fluoxetine. (+info)
Mechanism of fluoxetine block of cloned voltage-activated potassium channel Kv1.3.
(16/1011)
The effects of fluoxetine (Prozac), a widely used antidepressant drug, on Kv1.3 stably expressed in Chinese hamster ovary cells were examined using the whole-cell and excised inside-out configurations of the patch-clamp technique. In whole-cell recordings, fluoxetine accelerated the decay rate of inactivation of Kv1.3 and thus decreased the current amplitude at the end of the pulse in a concentration-dependent manner with an IC(50) value of 5.9 microM. The inhibition displayed a weak voltage dependence, increasing at more positive potentials. Neither the activation nor the steady-state inactivation curve was affected by fluoxetine. In addition, fluoxetine reduced the tail current amplitude and slowed the deactivation of the tail current, resulting in a crossover phenomenon. When applied to the internal side of the membrane in inside-out recordings, the inhibition by fluoxetine was much faster and more potent with an IC(50) value of 1.7 microM compared with whole-cell recordings. Norfluoxetine, the major metabolite of fluoxetine, also inhibited Kv1.3 in a concentration-dependent manner (IC(50) = 1.4 microM) in whole-cell recordings. To check whether the fluoxetine-induced inhibition demonstrated in cloned Kv1.3 could also be observed in native T lymphocytes, the effects of fluoxetine were investigated on human T lymphocytes. Fluoxetine also inhibited outward K(+) current in human T lymphocytes. Our results indicate that fluoxetine produced a concentration- and voltage-dependent inhibition of Kv1.3 that can be interpreted as an open channel block and that a binding site for fluoxetine is more accessible from the intracellular side. (+info)