GABAB receptors blockage modulates somatic and aversive manifestations induced by nicotine withdrawal.

There is substantial evidence that GABAB agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue vulnerabilities in humans. In this context, we explored different aspects associated with the possible mechanisms whereby the GABAB receptors might influence nicotine withdrawal. Male mice received nicotine (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. Nicotine-treated mice received the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC, 2 or 3.5 mg/kg, s.c.), to precipitate the withdrawal state. A second group of dependent mice received 2-hydroxysaclofen (GABAB receptor antagonist, 1 mg/kg, s.c.) before MEC-precipitated abstinence. Somatic signs of nicotine withdrawal were measured for 30 min. Anxiogenic-like response associated to nicotine withdrawal was assessed by the elevated plus maze test. The dysphoric/aversive effect induced by nicotine withdrawal was evaluated using conditioned place aversion paradigm. Dopamine, serotonin and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. Finally, α4ß2 nicotinic acetylcholine receptor density was determined in several brain regions using autoradiography assays. The results showed that MEC-precipitated nicotine withdrawal induced somatic manifestations, anxiogenic-like response and dysphoric/aversive effect, and 2-hydroxysaclofen potentiated these behavioral responses. Additionally, 2-hydroxysaclofen was able to change striatal dopamine levels and α4ß2 nicotinic acetylcholine receptor density, both altered by MEC-precipitated nicotine withdrawal. These findings provide important contributions to elucidate neurobiological mechanisms implicated in nicotine withdrawal. We suggest that GABAB receptor activity is necessary to control alterations induced by nicotine withdrawal, which supports the idea of targeting GABAB receptors to treat tobacco addiction in humans.

Baclofen prevents morphine withdrawal irrespective of seasonal variation.

In previous studies we have demonstrated a possible interaction between the gamma-aminobutyric acid (GABA)ergic and opioid systems involved in the antinociceptive effect of the GABAB agonist, baclofen (BAC). In addition, we have demonstrated that BAC was able to prevent the morphine (MOR) withdrawal syndrome in female, as well as male mice. On the other hand, seasonal variations have been observed in some MOR effects. In the present study, we analysed the effects of BAC on naloxone (NAL)-precipitated withdrawal, during two different seasons. The experiments were performed during two seasons: spring-summer (SS) and autumn-winter (AW) for two years, on male Swiss-Webster albino mice (27-33 g). Mice were rendered dependent by intraperitoneal (i.p.) injection of MOR (2mg/kg), twice daily for 9 days. On the tenth day the dependent animals were divided into two groups: one received NAL (6mg/kg, i.p.) 60 min after the last dose of MOR, to develop the NAL-precipitated withdrawal; the other group received BAC (2mg/kg, i.p.) followed by NAL (6mg/kg, i.p.), injected 30 and 60 min after the last dose of MOR, respectively. Behavioural signs were recorded in the open field for 30 min. Although there were seasonal variations in the MOR withdrawal syndrome, we found that BAC prevents MOR withdrawal irrespective of seasonal variation.

Lack of sex-related differences in the prevention by baclofen of the morphine withdrawal syndrome in mice.

In previous studies we have demonstrated a possible interaction between the GABAergic and opioid systems involved in the antinociceptive effect of the GABA(B) agonist, baclofen (BAC). On the other hand, sex differences have been observed for the antinociceptive effect of morphine (MOR). In the present study, we analyzed sex-related differences in the MOR abstinence syndrome and its prevention with BAC. Prepubertal male and female Swiss-Webster albino mice (27-33 g) were rendered dependent by intraperitoneal (i.p.) injection of MOR (2, 4 and 8 mg/kg), twice daily for 9 days. On the tenth day the dependent animals were divided into two groups: one received naloxone (NAL) (6 mg/kg, i.p.) 60 min after the last dose of MOR, to precipitate the abstinence syndrome; the other group received BAC (2 mg/kg, i.p.) followed by NAL (6 mg/kg, i.p.), injected 30 and 60 min after the last dose of MOR, respectively. Behavioral signs were recorded in the open field for 30 min. Although there were sex differences in the MOR withdrawal syndrome, we found a lack of sex differences in the prevention of the MOR abstinence syndrome by BAC.

Baclofen: intestinal absorption mechanism in mice.

1. The duodenal transfer of baclofen from sacs of mouse intestine was determined. 2. A linear relationship between the steady-state transfer rate of total and the initial mucosal baclofen concentration was observed, suggesting that the clearance is the same at different concentrations. 3. There was no significant difference in the amount of total drug removed between control and everted tissues. 4. The data support the idea that the principal transfer mechanism for baclofen is simple diffusion in mouse intestine.

A possible inhibitory action of baclofen on hippocampus GABAergic neurones.

1. The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat brain was investigated after baclofen treatment (30 mg/kg for 4 days). 2. Two h after the last dose of baclofen GAD activity was reduced in the hippocampus without changes in GABA levels. 24 h after baclofen, GAD activity was increased and the GABA content was decreased. 3. 48 h after the last dose both parameters returned to control values. 4. These results were not observed in any of the other areas investigated: frontal cerebral cortex, corpus striatum, olfactory bulbs, and medio basal hypothalamus. 5. In conclusion, the present study shows that baclofen 30 mg/kg for 4 days, induces an inhibitory action on hippocampus GABAergic neurones, which begins to disappear after 24 h free of drug.