Salvia divinorum increases alcohol intake and tonic immobility whilst decreasing food intake in Wistar rats.

The kappa-opioid system (KOP) is the key in drug abuse. Of all the compounds isolated from Salvia divinorum (S. divinorum), salvinorin-A (Sal-A) is predominant. Further, Sal-A is the only compound within S. divinorum which is reported to have psychoactive properties as a powerful kappa-opioid receptor (KOPr) agonist. Based on the key role of the KOP system in the consumption of drugs, S. divinorum extract (SDE) and Sal-A may modify the alcohol intake in Wistar rats. Assessing voluntary alcohol intake as a drug consummatory behavior, food intake as natural reward behavior and tonic immobility as indicative of anxiety-like behavior, the present study sought to identify the role of both SDE and Sal-A in the Wistar rat model. Forty-eight adult male rats were randomly divided into six groups: control, alcohol naive and vehicle, alcohol-naive and SDE, alcohol-naive and Sal-A, alcohol-consumption and vehicle, alcohol-consumption and SDE, and alcohol-consumption and Sal-A. Alcohol and food intake were assessed for two weeks. In the middle of these two weeks, vehicle, SDE (containing ~1 mg/kg of Sal-A) or Sal-A was injected intraperitoneally once a day for a week. Tonic immobility testing was performed once. The administration of SDE produced a significant increase in voluntary alcohol intake especially in rats with a history of forced alcohol consumption from a juvenile age, Sal-A elicited an increase in alcohol intake in animals with or without previous alcohol exposure, SDE and Sal-A prolonged the tonic immobility duration and decreased food intake. In conclusion, S. divinorum or Sal-A stimulated alcohol consumption in rats with a history of alcohol intake and independent of previous exposure respectively, also SDE or Sal-A elicited an anorexigenic effect, and increased tonic immobility as indicative of anxious-like behavior.The kappa-opioid system (KOP) is the key in drug abuse. Of all the compounds isolated from Salvia divinorum (S. divinorum), salvinorin-A (Sal-A) is predominant. Further, Sal-A is the only compound within S. divinorum which is reported to have psychoactive properties as a powerful kappa-opioid receptor (KOPr) agonist. Based on the key role of the KOP system in the consumption of drugs, S. divinorum extract (SDE) and Sal-A may modify the alcohol intake in Wistar rats. Assessing voluntary alcohol intake as a drug consummatory behavior, food intake as natural reward behavior and tonic immobility as indicative of anxiety-like behavior, the present study sought to identify the role of both SDE and Sal-A in the Wistar rat model. Forty-eight adult male rats were randomly divided into six groups: control, alcohol naive and vehicle, alcohol-naive and SDE, alcohol-naive and Sal-A, alcohol-consumption and vehicle, alcohol-consumption and SDE, and alcohol-consumption and Sal-A. Alcohol and food intake were assessed for two weeks. In the middle of these two weeks, vehicle, SDE (containing ~1 mg/kg of Sal-A) or Sal-A was injected intraperitoneally once a day for a week. Tonic immobility testing was performed once. The administration of SDE produced a significant increase in voluntary alcohol intake especially in rats with a history of forced alcohol consumption from a juvenile age, Sal-A elicited an increase in alcohol intake in animals with or without previous alcohol exposure, SDE and Sal-A prolonged the tonic immobility duration and decreased food intake. In conclusion, S. divinorum or Sal-A stimulated alcohol consumption in rats with a history of alcohol intake and independent of previous exposure respectively, also SDE or Sal-A elicited an anorexigenic effect, and increased tonic immobility as indicative of anxious-like behavior.

Forced ethanol ingestion by Wistar rats from a juvenile age increased voluntary alcohol consumption in adulthood, with the involvement of orexin-A.

Human adolescents who drink alcohol are more likely to become alcoholics in adulthood. Alcohol administration (intraperitoneally) or drinking (in a 2-bottle free choice paradigm) during the juvenile/adolescent age of rats promotes voluntary alcohol consumption in adulthood. On the other hand, there is growing evidence that the orexinergic system plays a role in several rewarded behaviors, including alcohol ingestion. Since it is unknown what effect is exerted in adulthood by forced oral ethanol intake and/or administration of orexin-A (OX-A) in juvenile rats, the present study aimed to evaluate this question. A group of male Wistar rats was forced to drink ethanol (10% v/v) as the only liquid in the diet from weaning (postnatal day 21) to postnatal day 67 (46 days), followed by a forced withdrawal period. An age-matched group was raised drinking tap water (control). OX-A or its vehicle was microinjected intracerebroventricularly (i.c.v.) (1 nmol/0.6 µL) to explore its effect as well. Locomotor activity and voluntary ethanol consumption were later assessed in all groups. The rats forced to consume ethanol early in life showed an elevated level of ambulation and alcohol ingestion in adulthood. A single injection of OX-A increased locomotor activity and acute ethanol intake in rats with or without prior exposure to alcohol at the juvenile stage. In conclusion, forced ethanol consumption in juvenile rats led to increased voluntary alcohol drinking behavior during adulthood, an effect likely facilitated by OX-A.

Analgesic and anxiolytic effects of [Leu31,Pro34]-neuropeptide Y microinjected into the periaqueductal gray in rats.

Several reports have demonstrated that neuropeptide Y (NPY) is involved in food intake, epilepsy, circadian rhythms, drug seeking, pain and anxiety, and other physiological or pathological conditions. On the other hand, periaqueductal gray (PAG) is a key brain center for modulating pain, anxiety and fear. It is the main structure implicated in integrated defensive behaviors. One such behavior, tonic immobility (TI), resembles fear and is able to induce analgesia. After microinjection of [Leu31,Pro34]-Neuropeptide Y ([Leu31,Pro34]-NPY) into the PAG dorsal (D) or ventrolateral (VL) of adult male Wistar rats, the following parameters were assessed: i) the analgesic effect by means of the tail-flick test (TF), ii) the duration of TI as a passive defensive behavioral response and as an anxiety/fear model (considering both TF and TI as single behaviors), iii) TI-induced analgesia by the combination of TF/TI, and iv) the anxious-like state through the elevated plus maze (EPM), and defensive burying behavior (DBB). The results show that the microinjection of [Leu31,Pro34]-NPY into the PAG produced an analgesic effect (increasing the TF latency); overall decreased the TI duration, which might represent an important anti-fear effect. Moreover, [Leu31,Pro34]-NPY microinjected into the PAG allows for a TI-induced analgesic effect, as well as, a substantial anxiolytic effect (evidenced by the EPM and DBB models). Hence, [Leu31,Pro34]-NPY microinjected into the PAG, especially at 0.47nmol/0.5µL produces both analgesic and anxiolytic effects, in a higher magnitude within ventrolateral area.

Vasodilator effects of bis-dihydropyridines structurally related to nifedipine.

Calcium channel blockers are widely used in therapy for hypertension and angina pectoris, and among these blockers some 1,4-dihydropyridines (e.g. amlodipine, nitrendipine and nifedipine) have had widespread clinical use. In this work we investigated the vascular effects of four bis-1,4-dihydropyridines (bis-DHPs: 01-04), structurally related to nifedipine, in which a second 1,4-dihydropyridinic moiety was incorporated in the corresponding arylic moiety in para and meta position. Of these four bis-DHPs, the meta regioisomers (bis-DHP-03 and bis-DHP-04; 0.01-3.16 mg kg(-1)) and nifedipine induced a greater decrease on diastolic and systolic blood pressure than the para isomers (bis-DHP-01 and bis-DHP-02), as shown in two experimental models: normotensive and spontaneously hypertensive rats. Complementarily, bis-DHPs action was examined in intact and endothelium-denuded rat aorta, depolarized by KCl [80 mM] in one group and stimulated by noradrenaline (1 x 10(-7) M) in another and the corresponding IC(50) values were obtained (1.5 x 10(-6)-2. 4 x 10(-7)M). Later, the relaxing action of bis-DHP-03,04 and nifedipine on the contraction evoked by Ca(2+) in K(+)-depolarized rat aorta was analyzed and the corresponding EC(50) values for the meta isomers and nifedipine were obtained. The results showed a concentration dependent vasodilating activity in both KCl precontracted and noradrenaline stimulated aorta rings. The apparent order of potency with and without endothelium in both experimental models was nifedipine >bis-DHP-04 >bis-DHP-03. The cumulative concentration-effect curves for Ca(2+) in the presence of the bis-DHPs tested show the same potency order. Unlike nifedipine, the tested compounds are not photosensitive, which makes them more attractive in therapy for hypertension related diseases.