S. Maurel

Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism.

Clinical evidence suggests that hypericum extracts (Hypericum perforatum L., St. Johns wort) have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders. In addition, hypericum extracts, as well as standard antidepressants such as the tricyclic, impramine, and the selective serotonin reuptake inhibitor, fluoxetine, have been reported to be of therapeutic benefit in the treatment of alcoholism, as these compounds may reduce alcohol craving and/or intake in particular subgroups of patients. It was the aim of the present study to compare the effects of hypericum extracts with those of imipramine and fluoxetine in the rat forced swimming test (RFST), a model of depression, as well as in cAA rats, a genetic model of alcoholism. In the RFST, triple i.p. administration of imipramine (3-30 mg/kg) and fluoxetine (3-30 mg/kg) induced a dose-dependent reduction in immobility: the minimal effective dose (MED) being 30 and 10 mg/kg, and the maximal effect being 50% and 57% immobility reduction, for imipramine and fluoxetine, respectively. In this test, the hypericum extracts Ze 117 (Remotiv) and LI 160 (Jarsin) also induced a statistically significant reduction of immobility when administered under the same application schedule (5-40 mg/kg, i.p., triple application). In the case of the hypericum extracts the dose-response relationship was inverted U-shaped with a MED value of 20 mg/kg and a maximal effect of 41% and 32% immobility reduction, for Ze 117 and LI 160, respectively. Interestingly, the anti-immobility effects tended to be more pronounced after subacute (1 week, B.I.D.) treatment with 10 mg/kg of imipramine, fluoxetine, or Ze 117, as compared with acute treatment. This phenomenon is in accordance with clinical experience and suggests that repeated treatment is required for full development of antidepressive effects. In the alcohol-preferring cAA rats, acute i.p. administration of imipramine (3-30 mg/kg), fluoxetine (1-10 mg/kg) and Ze 117 (10-40 mg/kg) dose-dependently reduced alcohol intake in a 12-h limited access two-bottle [ethanol 10% (v/v) versus water] choice procedure: with MED values of 30, 5 and 20 mg/kg, respectively. The anti-alcohol effects of fluoxetine and Ze 1-17 appeared to be specific, as reductions in alcohol intake coincided with reductions in alcohol preference. The present study suggests that hypericum extracts have antidepressant-like properties which resemble those of clinically established antidepressants, and that Remotiv may be an interesting adjunct for the treatment of alcoholism.

Comparison of the effects of the selective serotonin-reuptake inhibitors fluoxetine, paroxetine, citalopram and fluvoxamine in alcohol-preferring cAA rats

Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1-10), citalopram (3-30), fluvoxamine (3-30) and paroxetine (1-10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity, followed by citalopram and fluvoxamine, the effect of paroxetine was nonspecific. The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.

5-HT receptor ligands differentially affect operant oral self-administration of ethanol in the rat

The present study evaluated the effects of the selective serotonin (5-hydroxyhyptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT1B receptor agonist, tetrahydro-4-pyridyl[3,2-b]pyridine, CP-94,253 the preferential 5-HT2A receptor agonist, 1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane, DOI and the mixed 5-HT2C/1B receptor agonist, 1-(3-chlorophenyl)piperazine, mCPP, on oral ethanol (10% v/v) self-administration in a two-lever, fixed-ratio:1, water vs. ethanol choice procedure in the rat. All compounds affected operant behavior, with varying degrees of specificity, that is, the extent to which a reduction of ethanol-reinforced lever pressing coincided with a reduction of ethanol preference, and selectivity, that is, the extent to which a reduction of ethanol-reinforced lever pressing could be dissociated from an effect on total responding on both levers. Fluoxetine (5-20 mg/kg, i.p.) and CP-94,253 (1-10 mg/kg, i.p.) induced a nonselective disruption of operant behavior; the profile being weakly specific for CP-94,253. DOI (0.1-0.3 mg/kg, i.p.) and mCPP (0.3-1 mg/kg, i.p.) induced a specific effect; the profile being more selective for DOI. These findings suggest that operant ethanol self-administration can be suppressed in a specific manner by activation of 5-HT2A and, possibly, 5-HT2C receptors, and in a nonselective manner by activation of 5-HT1B receptors. As fluoxetine indirectly stimulates these receptors and its behavioral profile resembles more that of a 5-HT1B receptor agonist, activation of 5-HT1B receptors may underlie its effects on operant ethanol self-administration.

5-HT2A and 5-HT2C/5-HT1B receptors are differentially involved in alcohol preference and consummatory behavior in cAA rats.

The present study aimed to investigate the role of serotonin 5-HT2A and 5-HT2C receptors in the control of alcohol preference and consummatory behavior in alcohol-preferring cAA rats. Effects of the 5-HT(2A/2C) receptor agonist, DOI, the 5-HT(2C/1B) receptor agonist, mCPP, the 5-HT(2A/2C) receptor antagonist, ritanserin, and the 5-HT2A receptor antagonist, MDL 100,907, on ethanol (EtOH, 10% v/v) preference and intake, as well as total fluid and food intake were evaluated in a 12-h limited-access two-bottle paradigm. DOI (0.3-3 mg/kg, i.p.) reduced EtOH intake and preference, but not total fluid or food intake; whereas mCPP (1-10 mg/kg, s.c.) reduced EtOH, total fluid, and food intake. Therefore, it is concluded that DOI induces a specific and selective antialcohol effect, whereas mCPP rather induces a general suppressive effect on consummatory behavior. Ritanserin (1-10 mg/kg, i.p.) did not affect EtOH intake and preference, nor total fluid and food consumption. MDL 100,907 (0.1-1 mg/kg, i.p.) induced only a small reduction of food intake at the highest dose tested. Pretreatment with ritanserin (3 mg/kg, i.p.) and MDL 100,907 (0.3 mg/kg, i.p.) blocked the effects of DOI (3 mg/kg, i.p.), but not those of mCPP (10 mg/kg, i.p.). It is suggested that activation of 5-HT2C and/or 5-HT1B receptors results in a general decrease of consummatory behavior, whereas activation of 5-HT2A receptors selectively decreases EtOH intake and preference, as assessed in the cAA rat model of alcoholism.

Substitution of the selective serotonin reuptake inhibitors fluoxetine and paroxetine for the discriminative stimulus effects of ethanol in rats

Abstract Rats trained to discriminate ethanol (EtOH, 1 g/kg IP) from saline in a two-lever procedure completely generalized to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Substitution of fluoxetine was completely blocked by the selective 5-HT2A receptor antagonist MDL 100,907 and not affected by the selective 5-HT1A receptor antagonist WAY-100635. It is suggested that the previously reported effectiveness of SSRIs in reducing EtOH consumption could be based on similarities in discriminative stimulus effects of SSRIs and EtOH. Stimulation of 5-HT2A receptors may underlie these stimulus similarities and contribute to the EtOH intake-reducing effects of SSRIs.

Lack of potentiation of the anti-alcohol effects of fluoxetine by pindolol in alcohol-preferring caa rats

Abstract 1. 1. Recent clinical evidence suggests that the nonselective 5-HT 1A receptor antagonist pindolol may enhance the antidepressive efficacy of selective serotonin reuptake inhibitors (SSRIs); an effect generally ascribed to a presumed blockade of somatodendritic 5-HT 1A receptors by pindolol. 2. 2. The present study investigated whether blockade of 5-HT 1A receptors similarly potentiates the previously reported anti-alcohol effects of the SSRI fluoxetine. 3. 3. Pindolol and the selective 5-HT 1A receptor antagonist WAY-100635 were tested alone and in combination with fluoxetine in cAA rats, a genetic model of alcoholism. However, as pindolol has also a high affinity to 5-HT 1B receptors, the effects of selective 5-HT 1B receptor agonists and antagonists were evaluated as well. 4. 4. Neither pindolol (3–30 mg/kg, IP), nor WAY-100635 (1–10 mg/kg, IP) affected alcohol intake when tested alone. In contrast, the 5-HTm receptor agonists CP-94,253 and TFMPP (both 1–10 mg/kg, IP), and antagonists metergoline (1–10 mg/kg, IP) and GR 127935 (3–30 mg/kg, IP) were found to reduce alcohol intake with different degrees of selectivity (that is, the extent to which reductions in ethanol intake could be separated from reductions in food- and/or total fluid intake) and specificity (that is, the degree to which effects on ethanol intake coincided with effects on ethanol preference). 5. 5. Because the behavioral profile of pindolol resembles that of WAY-100635, and not that of the 5-HT 1B receptors ligands, combination experiments with fluoxetine were only performed with the former two compounds. Neither pindolol (30 mg/kg), nor WAY-100635 (3 mg/kg) potentiated the anti-alcohol effects of fluoxetine (10 mg/kg, IP). Moreover, WAY-100635 tended to shift the anti-alcohol effect of fluoxetine towards a less selective and specific profile. It is concluded that acute blockade of 5-HT 1A receptors does not potentiate the anti-alcohol effects of fluoxetine. In addition, it is suggested that different mechanisms underly the antidepressive and anti-alcohol effects of SSR.

Palatable fluids do not affect alcohol intake and its reduction by serotonergic compounds in alcohol-preferring cAA rats.

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) decreases alcohol intake by alcohol-preferring cAA rats more selectively than fluoxetine in a two-bottle alcohol vs. water paradigm. We report now that availability of sucrose or saccharin in a 3rd bottle does not affect (1) alcohol intake, supporting further the validity of this model of alcoholism, nor (2) the selectivity profile of the alcohol intake-reducing effects of these compounds. It is hypothesized that reduction of alcohol intake by DOI is not simply due to decreased intake of palatable fluids.