Different brain oxidative and neuroinflammation status in rats during prolonged abstinence depending on their ethanol relapse-like drinking behavior: Effects of ethanol reintroduction.

RATIONALE: Accumulating evidence suggests that chronic alcohol consumption is associated with excessive oxidative damage and neuroinflammatory processes and these events have been associated to early alcohol withdrawal. In the present research we wonder if brain oxidative stress and neuroinflammation remains altered during prolonged withdrawal situations and whether these alterations can be correlated with relapse behavior in alcohol consumption. The effects of alcohol reintroduction were also evaluated METHODS: We have used a model based on the alcohol deprivation effect (ADE) within a cohort of wild-type male Wistar rats. Two subpopulations were identified according to the alcohol relapse-like drinking behavior displayed (ADE and NO-ADE subpopulations). Oxidized and reduced glutathione content was determined within the hippocampus and the amygdala using a mass spectrometry method. The levels of mRNA of seven different inflammatory mediators in the prefrontal cortex of rats were quantified. All the analyses were performed in two different conditions: after 21-day alcohol deprivation (prolonged abstinence) and after 24 h of ethanol reintroduction in both subpopulations. RESULTS: ADE and NO-ADE rats showed different endophenotypes. ADE rats always displayed a significant lower alcohol intake rate and ethanol preference than NO-ADE rats. The results also demonstrated the existence of altered brain redox and neuroinflammation status after prolonged abstinence exclusively in ADE rats. Moreover, when ethanol was reintroduced in the ADE subpopulation, altered oxidative stress and neuroinflammatory markers were restored. CONCLUSIONS: Present findings provide new mechanisms underlying the neurobiology of relapse behavior and suggest the development of new pharmacological approaches to treat alcohol-induced relapse.

Regional differences in mu-opioid receptor-dependent modulation of basal dopamine transmission in rat striatum.

The nigrostriatal dopamine system is implicated in the regulation of reward and motor activity. Dopamine (DA) release in dorsal striatum (DS) is controlled by the firing rate of DA neurons in substantia nigra pars compacta. However, influences at terminal level, such as those involving activation of mu opioid receptors (MORs), can play a key role in determining DA levels in striatum. Nonetheless, published data also suggest that the effect of opioid drugs on DA levels may differ depending on the DS subregion analyzed. In this study, in vivo microdialysis in rats was used to explore this regional dependence. Changes in basal DA levels induced by local retrodialysis application of DAMGO (selective MORs agonist) in three different subregions of DS along the rostro-caudal axis were studied. Our results indicate that whereas administration of 10µM DAMGO into the rostral and caudal DS significantly reduced DA levels, in medial DS an increase in DA levels was observed. These data reveal a regional-dependent MOR modulation of DA release in DS, similar to that described in the ventral striatum. Our findings may lead to a better understanding of the nigrostriatal DA system regulation.

Evidence of a flip-flop phenomenon in acamprosate pharmacokinetics: an in vivo study in rats.

The pharmacokinetics of acamprosate were examined in the rat after oral and intravenous administration in order to detect the possible presence of a flip-flop phenomenon. Rats received 9.3 or 73.3 mg/kg of the drug as an intravenous bolus. The same doses were orally administered via gastric intubation. Plasma samples were taken from the jugular vein for determination of acamprosate concentration by liquid scintillation counting. The drug content was also quantified in urine and faeces. The acamprosate bioavailability was close to 20%, the amount recovered in the faeces being around 80% of the administered dose. The terminal slope of the oral plasma curve was significantly lower than that obtained after intravenous administration of the drug at both doses tested (p<2 x 10(-6) in both cases). Moreover, the downward slope after oral administration (lambda2=0.006 +/- 0.001 min(-1)) practically coincided with the first-order absorption rate constant, previously reported by us, obtained using an in situ rat gut technique. It is concluded that the acamprosate absorption rate is considerably slower than its elimination rate so that the drug exhibits flip-flop pharmacokinetics after oral administration. The lower intrinsic first-order absorption rate constant, ka, is responsible for this phenomenon.

Quantitative in vivo microdialysis in pharmacokinetic studies: some reminders.

This paper reviews the empirical methods of quantitative microdialysis that have been used to interpret the results obtained from pharmacokinetic studies. The concept of extraction efficiency or recovery and the properties of recovery in vivo (variation with flow rate, time dependency and influence of the mode of administration) are considered. The most frequently used methods for determining recovery in vivo are described and evaluated in the light of recent theoretical studies. Specifically, we review the variation of flow rate method, the very slow flow method, the no net flux method and the delivery and retrodialysis methods. Special emphasis is placed on the description of each method, demonstrating its applicability to pharmacokinetic studies conducted under steady-state or transient conditions, and also its limitations. Finally, the more relevant studies that have compared the suitability of these methods are reviewed.

Acamprosate blocks the increase in dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

Recently, we have shown that acamprosate is able to modulate extracellular dopamine (DA) levels in the nucleus accumbens (NAc) and may act as an antagonist of N-methyl-D-aspartate (NMDA) receptors. Neurochemical studies show that chemical stimulation (using NMDA) of the ventral subiculum (vSub) of the hippocampus produces robust and sustained increases in extracellular DA levels in the NAc, an effect mediated through ionotropic glutamate (iGlu) receptors. The present study examines whether acamprosate locally infused in the NAc of rats could block or attenuate the increase in NAc extracellular DA elicited by chemical stimulation (with 5 mM NMDA) of the ventral subiculum of the hippocampus. The stimulation of the vSub during perfusion of artificial cerebrospinal fluid in NAc induced a significant and persistent increase in NAc DA levels. Reverse dialysis of 0.05 mM acamprosate in NAc blocked the increase in DA evoked by the chemical stimulation of the vSub. These data support the possibility that the antagonism at the NMDA receptors in NAc can explain, at least in part, the mechanism of action of this drug.

Local acamprosate modulates dopamine release in the rat nucleus accumbens through NMDA receptors: an in vivo microdialysis study.

The effects of acamprosate on the in vivo dopamine extracellular levels in the nucleus accumbens and the involvement of N-methyl-D-aspartate (NMDA) receptors in these effects were investigated. Microdialysis in freely moving rats was used to assess dopamine levels before and during simultaneous perfusion of acamprosate and/or different agonists or antagonists of NMDA receptors. Perfusion with acamprosate at concentrations of 0.5 and 5 mM provoked a concentration-dependent increase in extracellular dopamine in nucleus accumbens. The lowest concentration of acamprosate assayed (0.05 mM) had no effect on dopamine levels. Infusion of NMDA (25 and 500 microM) and the glutamate uptake blocker, L-trans-pyrrolidine-2,4-dicarboxilic acid (PDC) (0.5 mM) into the NAc caused a significant increase in DA, whereas acamprosate (0.05 mM) co-infusion with these compounds blocked or attenuated the NMDA and PDC-induced increases in DA levels. Co-infusion of the selective antagonist of NMDA receptors, DL-2-amino-5-phosphonopentanoic acid (AP5) (400 microM) with acamprosate (0.5 mM), did not reduce the increase of DA levels induced by acamprosate. These results demonstrate that acamprosate is able to modulate DA extracellular levels in NAc via NMDA receptors and suggest that acamprosate acts as an antagonist of NMDA receptors.

Quitosanos: usos y aplicaciones en tecnología farmacéutica / Chitosans: uses and applications in pharmaceutical technology

Se presenta una revisión de la gran diversidad de aplicaciones farmacéuticas del quitosano. Tras un breve repaso de la estructura y características fisicoquímicas de los quitosanos, se destaca el uso de este polímero en la elaboración de formas de liberación controlada, ámbito en el cual se está desarrollando una intensa investigación actualmente. Además se analiza la aplicación del quitosano para la mejora de la biodisponibilidad de diversos fármacos mediante su inclusión en formas farmacéuticas administradas a través de distintas vías, así como su capacidad promotora de la absorción intestinal y nasal, discutiendo los posibles mecanismos de acción. También se revisan las aplicaciones más novedosas de los quitosanos como son en la terapia antitumoral, en las vacunas, o incluso en la terapia génica y el transplante de células. Por último, se pone de manifiesto la baja toxicidad y la buena biocompatibilidad de este polímero, que hacen de él un excelente excipiente para la industria farmacéutica y excepcional candidato para futuras formulaciones (AU)