Rhodiola rosea L. extract and its active compound salidroside antagonized both induction and reinstatement of nicotine place prefrerence in mice

Abstract RATIONALE: Conventional pharmacological treatments for drug addiction aim to reduce three most important aspects: withdrawal syndrome, craving, and relapse. Pharmacological treatments currently available for the treatment of tobacco smoking are able to alleviate withdrawal symptoms but are not sufficiently effective in reducing craving and rarely effective to prevent relapse. Rhodiola rosea L., a well-known traditional oriental medicine with anxiolytic, antidepressive, antistress, and adaptogenic properties, has been recently shown to be effective in the prevention and treatment of nicotine-withdrawal symptoms. OBJECTIVES: The present study used the conditioned place preference (CPP) model to systematically investigate, in mice, the effects of a R. rosea L. extract (RHO) and its active compound salidroside (SDS), on the reinforcing properties of nicotine and their efficacy in the vulnerability to reinstatement. METHODS: To study the effects on the rewarding properties of nicotine, RHO (10, 15, and 20 mg/kg) and SDS (0.2 mg/kg) were tested both in the acquisition and expression of CPP induced by nicotine injection (0.5 mg/kg). Moreover, the efficacy of RHO and SDS in preventing relapse induced by nicotine priming (0.1 mg/kg, s.c.) and by restraint stress was also evaluated. RESULTS: Results showed the ability of RHO and salidroside to significantly reduce the rewarding properties of nicotine at all doses tested. RHO and SDS also suppressed both priming- and stress-induced reinstatement of CPP. CONCLUSIONS: The present study showed the positive effects of R. rosea L. in reducing rewarding properties and preventing relapse to nicotine and evidenced the important role of salidroside in the effects of the extract

Effects of Brugmansia arborea Extract and Its Secondary Metabolites on Morphine Tolerance and Dependence in Mice

The aim of the present study was to investigate, in vivo, the effect of a Brugmansia arborea extract (BRU), chromatographic fractions (FA and FNA), and isolated alkaloids on the expression and the acquisition of morphine tolerance and dependence. Substances were acutely (for expression) or repeatedly (for acquisition) administered in mice treated with morphine twice daily for 5 or 6 days, in order to make them tolerant or dependent. Morphine tolerance was assessed using the tail-flick test at 1st and 5th days. Morphine dependence was evaluated through the manifestation of withdrawal symptoms induced by naloxone injection at 6th day. Results showed that BRU significantly reduced the expression of morphine tolerance, while it was ineffective to modulate its acquisition. Chromatographic fractions and pure alkaloids failed to reduce morphine tolerance. Conversely BRU, FA, and pure alkaloids administrations significantly attenuated both development and expression of morphine dependence. These data suggest that Brugmansia arborea Lagerh might have human therapeutic potential for treatment of opioid addiction

Rhodiola rosea

A novel approach to the treatment of adverse effects of drugs of abuse is one which makes use of natural products. The present study investigated the effect of Rhodiola rosea L. hydroalcoholic extract (RHO) on cocaine-induced hyperactivity and conditioned place preference (CPP) in mice. In a first experiment, mice received RHO (15, 20 or 25 mg/kg, IG), cocaine (25 mg/kg, i.p.) (COC), or a combination of both drugs (COC + RHO15, COC + RHO20, and COC + RHO25), and their locomotor activity was evaluated. In a second experiment, the effects of RHO on the acquisition, expression, and reinstatement of cocaine CPP (induced by drug priming or social defeat stress) were evaluated. RHO alone did not increase activity but potentiated the hyperactivity induced by cocaine. Rhodiola did not induce motivational effects by itself but attenuated the acquisition and expression of cocaine-induced CPP. Moreover, it was found that RHO did not block reinstatement. The results indicate that RHO is effective in reducing the rewarding properties of cocaine but is ineffective in preventing priming or stress-induced cocaine reinstatement. In light of these findings, the benefits of Rhodiola rosea L. as a treatment of cocaine addiction would seem to be limited

Favourable involvement of α2A-adrenoreceptor antagonism in the I₂-imidazoline binding sites-mediated morphine analgesia enhancement.

Aim of the present study was to obtain novel α(2)-adrenoreceptor (α(2)-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective α(2)-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole α(2A)-subtype. Moreover, 2 showed an affinity at I(2)-imidazoline binding sites (I(2)-IBS) comparable to that at α(2A)-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of α(2A)-AR antagonism in the I(2)-IBS-mediated morphine analgesia enhancement

Exploring multitarget interactions to reduce opiate withdrawal syndrome and psychiatric comorbidity

Opioid addiction is often characterized as a chronic relapsing condition due to the severe somatic and behavioral signs, associated with depressive disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major challenge, our interest has been addressed to such objective. Exploring multitarget interactions, the present investigation suggests that 3 or its (S)-enantiomer and 4, endowed with effective α2C-AR agonism/α2A-AR antagonism/5-HT1A-R agonism, or 7 and 9−11 producing efficacious α2C-AR agonism/α2A-AR antagonism/I2−IBS interaction might represent novel multifunctional tools potentially useful for reducing withdrawal syndrome and associated depression. Such agents, lacking in sedative side effects due to their α2A-AR antagonism, might afford an improvement over current therapies with clonidine-like drug

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

This study demonstrated that cyclomethyline (<b>2</b>) and the corresponding enantiomers (<i>R</i>)-(−)-<b>2</b> and (<i>S</i>)-(+)-<b>2</b>, displaying α_2C-adrenoreceptor (AR) agonism/α_2A-AR antagonism, similarly to allyphenyline (<b>1</b>) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT_1A receptor (5-HT_1A-R) activation. Indeed, <b>1</b> or the single (<i>S</i>)-(+)-<b>1</b>, <b>2</b>, or both its enantiomers, all behaving as α_2C-AR agonists/α_2A-AR antagonists/5-HT_1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction

Exploring Multitarget Interactions to Reduce Opiate Withdrawal Syndrome and Psychiatric Comorbidity

Opioid addiction is often characterized as a chronic relapsing condition due to the severe somatic and behavioral signs, associated with depressive disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major challenge, our interest has been addressed to such objective. Exploring multitarget interactions, the present investigation suggests that <b>3</b> or its (<i>S</i>)-enantiomer and <b>4</b>, endowed with effective α_2C-AR agonism/α_2A-AR antagonism/5-HT_1A-R agonism, or <b>7</b> and <b>9</b>–<b>11</b> producing efficacious α_2C-AR agonism/α_2A-AR antagonism/I₂–IBS interaction might represent novel multifunctional tools potentially useful for reducing withdrawal syndrome and associated depression. Such agents, lacking in sedative side effects due to their α_2A-AR antagonism, might afford an improvement over current therapies with clonidine-like drugs