Lack of changes in beta-endorphin plasma levels after repeated treatment with fluoxetine: possible implications for the treatment of alcoholism--a pilot study.

Clinical and animal studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may help to reduce alcohol intake but investigations led to conflicting results. A few studies indicated that serotonin (5-HT) may modulate the brain beta-endorphin level, which plays an important role in the development of alcohol craving. Our study examined the influence of fluoxetine on the endogenous opioid system. We investigated plasma levels of beta-endorphin in rats with either high alcohol preference (Warsaw High-Preferring; WHP) or low alcohol preference (Warsaw Low-Preferring; WLP) after repeated treatment with fluoxetine (5 mg/kg i.p. for 21 days). We examined the rats 24 hours after fluoxetine treatment in order to determine whether chronic fluoxetine produces a long-term change in the beta-endorphin levels. The animals received either a single dose of ethanol (2 g/kg) or an identical single dose of saline one hour before blood collection. While a few studies observed an increase in the level of beta-endorphin after a single fluoxetine injection, we did not observe any increase in beta-endorphin plasma levels after repeated fluoxetine treatment. We also did not observe any changes in beta-endorphin levels of rats treated with fluoxetine and injected with ethanol. A lack of increase of beta-endorphin levels may explain why fluoxetine has a limited value in the prevention of craving for alcohol.

Anti-inflammatory capabilities of macrolides.

Macrolide antibiotics play a significant role in clinical practise due not only to their antibacterial activity, but also to their accompanying anti-inflammatory effect that is independent of their antibiotic action. Several studies reported in literature show that macrolides affect several inflammatory processes, such as migration of neutrophils, the oxidative burst in phagocytes and production of pro-inflammatory cytokines, although the precise mechanisms are not clear. They also inhibit eosinophilic inflammation and may be useful in the treatment of patients with steroid-dependent asthma. Macrolides are also effective in diffuse panbronchiolitis, chronic sinusitis and inflammatory skin diseases.

Characterization of beta-adrenergic receptors in duck cerebral cortex.

beta-adrenoceptor binding sites were characterized in duck cerebral cortex by an in vitro binding technique, using [3H]dihydroalprenolol ([3H]DHA) as a receptor-specific radioligand. The specific binding of [3H]DHA to duck cerebral cortical membranes was found to be rapid, stable, saturable, reversible, and of high affinity. Saturation analysis resulted in a linear Scatchard plot suggesting binding to a single class of receptor binding sites with high affinity (Kd = 1.18 nM) and high capacity (Bmax = 162 fmol/mg protein). Competition studies showed the following relative rank order of potency of various compounds to inhibit the [3H]DHA binding: antagonists--ICI 118,551 > S(-)-propranolol >> betaxolol, yohimbine, WB-4101, prazosin, mianserine; agonists--isoprenaline approximately equal to fenoterol > salbutamol >> clonidine, phenylephrine. The obtained data suggest that in duck cerebral cortex beta-adrenergic receptors (like those described in brains of chick and pigeon) are of the beta 2 subtype. This is in contrast to what has been reported for the mammalian brain, where--among beta-adrenoceptors--the beta 1 subtype is predominant.

The responsiveness of the endogenous inhibitor of cAMP-dependent protein kinase to isoproterenol after prolonged treatment with nifedipine.

In the present study the response of the type I inhibitor activity to isoproterenol was used as an indirect index both of cAMP generation and beta-adrenergic receptor reactivity. Our results suggest that nifedipine, after prolonged treatment, produces subsensitivity in beta-adrenergic transmission without changes in the basal level of cAMP. Administration of isoproterenol produced a dose-dependent decrease of the type I inhibitor activity (an endogenous inhibitor of cAMP-dependent protein kinase, Walsh inhibitor) in the frontal cortex and hippocampus of rats. Prolonged treatment with nifedipine (5 mg kg-1 i.p., twice daily, 21 days) did not change the basal activity of the type I inhibitor, but markedly reduced the response of the type I inhibitor activity to isoproterenol. In the treated animals a significant decrease of the type I inhibitor was seen when isoproterenol was used in much higher doses than in control rats.

The cooperation between the influx of extracellular calcium and alpha1-adrenoceptor-induced translocation of protein kinase C.

Calcium ionophore A23187 or phenylephrine injected i.p. in doses of 0.05-0 .25 mg kg-1 and 0.1-1 mg kg-1, respectively, induced translocation of protein kinase C (PKC) from the cytosol to the membrane fraction of the rat frontal cortex and hippocampus. The action of A23187 was blocked in a dose-dependent manner by nifedipine and verapamil. The phenylephrine induced translocation of PKC was blocked by prazosin and in a dose-dependent manner by nifedipine and verapamil. In contrast, pre-treatment with a small, ineffective by itself, dose of A23187 (0.02 mg kg-1) potentiated the alpha1-adrenoceptor induced translocation of PKC. Thus, it seems that the influx of calcium ions through an L-type calcium channel is probably necessary for a full alpha1-adrenoceptor mediated activation and translocation of PKC.

Cooperation between D1- and D2-dopamine receptors in the nucleus accumbens.

Apomorphine, used in small doses (20-50 micrograms/kg), induced an increase in the activity of an endogenous inhibitor of cAMP dependent protein kinases (Walsh inhibitor, type I inhibitor) in nucleus accumbens of the rat. The action of apomorphine was blocked by sulpiride and aminophylline and enhanced by SCH-23390. Pretreatment with 6-OH-dopamine resulted in a shift of the dose-response curve for apomorphine to the left, suggesting supersensitivity of D2 receptors. Moreover, stimulation of D2 receptors induced a decrease in phosphorylation of DARPP-32, a specific protein, located in neurones containing D1 receptors. Large doses of apomorphine (over 0.5 mg/kg) provoked a decrease in type I inhibitor activity, blocked by SCH-23390 and enhanced by sulpiride and aminophylline. Moreover, SCH-23390 blocked a decrease in type I inhibitor activity induced by large doses of sulpiride and sulpiride blocked an increase in type I inhibitor activity produced by large doses of SCH-23390. The results suggest that D1 and D2 receptors in the nucleus accumbens could cooperate with the same adenylate cyclase and could be located on the same neurones.