Efficacy of an Hypericum perforatum (St. John's wort) extract in preventing and reverting a condition of escape deficit in rats. 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. Rx drugs

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Neuropsychopharmacology. 1999 Aug;21(2):247-57.
Efficacy of an Hypericum perforatum (St. John's wort) extract in preventing and reverting a condition of escape deficit in rats.

Gambarana C, Ghiglieri O, Tolu P, De Montis MG, Giachetti D, Bombardelli E, Tagliamonte A.

Institute of Clinica delle Malattie Nervose e Mentali, Pharmacology Unit, Siena, Italy.

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.

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Neuropsychopharmacology. 1999 Aug;21(2):268-84.
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.

Gobert A, Millan MJ.

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France.

(-)-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.

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umich.edu

RATIONALE: Few studies have directly compared the effects of methylenedioxymethamphetamine (MDMA, "ecstasy") and its enantiomers across measures. OBJECTIVES: To investigate the capacity of MDMA and its stereoisomers to produce aggregate toxicity in mice, the influence of 5-HT(2) receptors, 5-HT transporters, and ambient temperature on this effect, and to directly compare the racemate and its enantiomers in terms of their effects on core temperature and locomotor activity with and without various serotonergic pretreatments. METHODS: Mice were injected with various doses of MDMA and its stereoisomers in various housing conditions, with and without pretreatments of serotonergic drugs, and at two distinct ambient temperatures; lethality was quantified 2 h after MDMA administration. For temperature/activity studies, mice were injected with various doses of MDMA and its enantiomers, with and without ketanserin, MDL100907, or fluoxetine pretreatments, and core temperature and locomotor activity data were collected for 24 h. RESULTS: Racemic MDMA and its isomers produced aggregate toxicity in mice. The lethal effects of racemic MDMA and its enantiomers were differentially attenuated by the various serotonergic pretreatments and manipulation of the ambient temperature across housing conditions. Racemic and S(+)-MDMA produced hyperthermic effects in mice, while R(-)-MDMA did not. The pretreatment drugs attenuated the hyperthermic effects of racemic MDMA, but were less effective in blocking S(+)-MDMA-induced hyperthermia. Racemic MDMA and both enantiomers stimulated locomotor activity, although R(-)-MDMA was least effective. The pretreatments all reduced the locomotor stimulant effects of racemic MDMA but potentiated S(+)-MDMA-induced hyperlocomotion. CONCLUSIONS: The MDMA isomers have heterogeneous effects that can be demonstrated across a wide range of endpoints.

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