大麻酚类受体拮抗剂SR141716A减少乙醇蒸气室中大鼠的自发反应性乙醇自身给药行为(英文)

AIM: To study the potential role of dependence statuson CB_1-mediated blockade of ethanol self-administra-tion. METHODS: We examined the effects of thecannabinoid antagonist SR141716A (0, 0.03, 0.3,and 3 mg/kg) on pperant ethanol (10 ％ v/v) self-administration in male Wistar rats that were madeethanol-dependent by chronic (14 d ) exposure toethanol vapor-chambers or exposed to air in identicalvapor chambers.RESULTS: Dependent animalsresponded more for ethanol than did air controlnondependent tats. The acute administration of a 3mg/kg dose of SR141716A almost suppressed ethanolself-administration ouly in ethanol dependent animals.     

SR141716A诱导大鼠产生与CB1受体激动剂相反的行为模式

AIM: To examine the acute actions of the CB1 cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] on typical behavioral pattern of psychoactive cannabinoids in rats. METHODS: At different time after injection the tail-flick response latency, the rectal temperature, the locomotor activity, and the immobility on a ring as well as the numbers of rears, self-grooming episodes (lasting 5 s), and fecal pellets were measured. RESULTS: Acute administration of SR141716A (3 mg/kg i.p.) induced a significant increase in horizontal locomotor activity assayed by an activity meter, in stereotypic activity (such as rearing and self-grooming) and in defecation, and a decrease in nociceptive threshold recorded as tail-flick latency. This dose had no effect on ring immobility and did not change the body temperature. CONCLUSION: These results demonstrate that this cannabinoid antagonist itself was inducing behavior opposite to that of CB1 receptor agonists.     

多巴胺受体系统在诱发产生的大麻酚类戒断症状中不起主要作用

AIM: To determine the dopaminergic system involvement in precipitated cannabinoid withdrawal syndrome. METHODS: The dopamine D1 receptor antagonist SCH23390 or the dopamine D2 receptor antagonist sulpiride was administered to rats chronically treated with either delta 9-tetrahydrocannabinol (THC) or vehicle. Subjects were then injected with either SR141716A or vehicle and behavior was observed for 1 h. RESULTS: Administration of the cannabinoid receptor antagonist SR141716A to animals chronically treated with THC as described by Tsou et al (1995) produced a profound withdrawal syndrome. Treatment with dopamine antagonists did not attenuate cannabinoid precipitated withdrawal syndrome in THC tolerant animals while the agonists increased the syndrome. CONCLUSION: It is unlikely that the dopaminergic system plays a major role in mediating the behavioral aspects of the cannabinoid withdrawal syndrome.     

SR141716A诱导大鼠产生与CB1受体激动剂相反的行为模式(英文)

AIM: To examine the acute actions of the CB1cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carbowamide] on typical behavioralpattern of psychoactive cannabinoids in rats.METHODS:At different time after injection the tail-flick response latency,the rectal temperature,thelocomotor activity,and the immobility on a ring as wellas the numbers of rears,self-grooming episodes(lasting 5 s),and fecal pellets were measured.RESULTS:Achte administration of SR141716A(3 mg/kg ip) induced a significant increase inhorizontal locomotor activity assayed by an activitymeter,in stereotypic activity(such as rearing and self-     

多巴胺受体系统在诱发产生的大麻酚类戒断症状中不起主要作用(英文)

AIM: To determine the dopaminergic systeminvolvement in precipitated cannabinoid withdrawalsyndrome. METHODS: The dopamine D_1 receptorantagonist SCH23390 or the dopamine D_2 receptorantagonost sulpiride was administered to rats chronicallytreated with either △~9-tetrahydrocannabinol (THC) orvehicle. Subjects were then injected with eitherSR141716A or vehicle and behavior was observed for1 h. RESULTS: Administration of the cannabinoidreceptor antagonist SR141716A to animals chronicallytreated with THC as described by Tsou et al (1995)     

大麻酚类受体-1在脊髓、背角、背根神经节和周围神经的分布(英文)

AIM: The localization of CB1 receptors in the spinalcord, spinal roots, dorsal root ganglion (DRG), andperipheral nerve of the rat was determined.METHODS: We studied the distribution of CB1cannabinoid receptors by immunohistochemistry usingan antibody raised against the N-termina1 of thereceptor. RESULTS: The spinal cord showednumerous transverse fibers labelled for CB1 receptorsthroughout and concentrated in the dorsal horn.Lightly-stained cells were observed throughout thespinal cord gray matter. The DRG also showed cellsand fibers labelled for CB1 receptors. Labelled fiberswere observed in both dorsal and ventral roots as well as     

Partial agonist-like profile of the cannabinoid receptor antagonist SR141716A in a food-reinforced operant paradigm

Both cannabinoid CB1 receptor agonists, such as delta-tetrahydrocannabinol (delta-THC), CP 55,940 and WIN 55,212-2, and the antagonist/inverse agonist SR141716A, dose-dependently suppress operant behavior. The present study investigated to what extent combined i.p. application of SR141716A with these cannabinoids resulted in mutually antagonistic effects, in additive effects, or in no interactive effects on operant responding in rats trained in a fixed-ratio 10, food-reinforced 10-min procedure. Pretreatment with SR141716A either had no effect on (at 0.3-1mg/kg), or partially blocked (at 3 mg/kg), the inhibitory effects on responding induced by delta-THC (3-5 mg/kg) and CP 55,940 (0.03-0.2 mg/kg). Interestingly, while 3 mg/kg SR141716A induced moderate inhibitory effects on operant responding, its combination with either agonist resulted in the same level of inhibitory activity on responding as that obtained by SR141716A when tested alone. Pretreatment with a low dose of CP 55,940 (0.01 mg/kg) or WIN 55,212-2 (0.3 mg/kg) did not affect response inhibition induced by SR141716A. Combination of SR141716A (0.5 and 1mg/kg) with delta-THC (3 mg/kg) resulted in the same level of response inhibition, independently of whether SR141716A was given 5 min before or 15 min after delta-THC. Although alternative explanations are conceivable, the data may indicate that SR141716A is a partial agonist at those cannabinoid receptors mediating the response-rate suppressive effects of cannabinoids.     

Cannabinoid CB(1) antagonist SR 141716A attenuates reinstatement of heroin self-administration in heroin-abstinent rats

Rats with a previous history of heroin self-administration were studied to assess interactions occurring between cannabinoids and opioids in an animal model of reinstatement of heroin-seeking behaviour. Rats were trained to self-administer heroin and after a long-term extinction were primed with one of the following non-contingent non-reinforced drug administrations: saline (or vehicle), heroin, synthetic cannabinoid CB₁ receptor agonists (WIN 55,212-2 or CP 55,940), opioid antagonist (naloxone) or CB₁ antagonist (SR 141716A), alone or in combination. After primings, lever-pressing activity was recorded and compared to those observed during previous phases of training and extinction. Results of this study showed that (i) priming injections of heroin (0.1 mg/kg) as well as CB₁ agonists WIN 55,212-2 (0.15 or 0.30 mg/kg) and CP 55,940 (0.05 or 0.1 mg/kg) completely restore heroin-seeking behaviour; (ii) primings of naloxone (1 mg/kg) and SR 141716A (0.3 mg/kg) had no effect when administered alone; (iii) heroin-induced reinstatement was fully prevented by pre-treatment with either naloxone or SR 141716A; (iv) pre-treatment with SR 141716A significantly reduced WIN 55,212-2 and CP 55,940 priming effects. These results suggest that cannabinoid CB₁ receptors play an important role in the mechanisms underlying relapse to heroin-seeking and depict CB₁ antagonists as possible therapeutic agents for use in the prevention of relapse to heroin abuse.     

SR141716, a CB1 receptor antagonist, decreases the sensitivity to the reinforcing effects of electrical brain stimulation in rats

RATIONALE: The endogenous cannabinoid system is thought to play a role in reinforcement processes. OBJECTIVES: We tested the effects of five doses of the cannabinoid receptor 1 (CB1) antagonist SR141716 [0, 0.3, 1, 3 and 10 mg/kg intraperitoneal (IP)] on intracranial self-stimulation at the level of the median forebrain bundle (MFB). Self-stimulation was assessed 30 min and 210 min after SR141716 administration. We compared the effect of SR141716 with the effect of a decrease in the magnitude of stimulation (-100 microA) and the effects of a cocaine injection (1, 5 and 10 mg/kg IP). METHODS: a protocol of rate-frequency curve for self-stimulation was applied. Two rate-frequency curves were established daily, 3 h apart. The frequency required to produce half-maximal performance (M50) and the maximal performance (RMax) were used as the parameters to characterize the rate-frequency functions. RESULTS: SR141716 decreased the sensitivity to the electrical brain stimulation. SR141716 induced a shift to the right of the rate-frequency curve. This effect depended on the dose administered and the time after injection. Thirty minutes after the injection, 1, 3 and 10 mg/kg SR141716 induced a significant decrease in sensitivity to electrical stimulation, as shown by an elevation in the M50 value. RMax showed a tendency to decrease with increasing doses. At 210 min after administration, 3 and 10 mg/kg SR141716 maintained their decreasing effect on the sensitivity to the stimulation as shown by the significant increase of the M50, however, the maximal response was restored to the basal value. A decrease in self-stimulation intensity produced an effect comparable to the one observed 30 min after either 3 or 10 mg/kg SR141716, while cocaine (5 and 10 mg/kg) produced the opposite effect. Neither condition affected the rate-frequency curve measured 3 h later. CONCLUSIONS: In accordance with recent observations, these experiments suggest that the endogenous cannabinoid system facilitates the perception or the effects of positive reinforcers. They also suggest that this neurochemical system could be a target of interest for treating psychopathologies implicating the reinforcing system.     

The cannabinoid receptor antagonist SR 141716 prevents acquisition of drinking behavior in alcohol-preferring rats

The cannabinoid CB₁ receptor antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide) (SR 141716); 0.3–3 mg/kg, i.p., twice daily for 10 days), prevented the acquisition of alcohol drinking behavior in rats genetically selected for alcohol preference (Sardinian alcohol-preferring (sP) rats), having the free choice between alcohol (10%, v/v) and water. The results suggest that activation of cannabinoid CB₁ receptors is essential for the acquisition of alcohol drinking behavior in animals with a genetically determined alcohol preference.     

SR 141716A, a cannabinoid receptor antagonist, reverses the behavioural effects of anandamide-treated rats

We employed the CB1 cannabinoid receptor antagonist SR 141716A (3 mg/kg, i.p.) to investigate whether behavioural effects induced in rats by anandamide, an endogenous cannabinoid (20 mg/kg, i.p.), were mediated by the cannabinoid CB1 receptor. Anandamide reduced ambulatory (67%) and non-ambulatory activities (rearing and grooming, 84% and 90% respectively), with a strong cataleptic effect, produced hypothermia (about -1 degree C) and hindlimb splaying, and reduced defecation (79%). It did not significantly increase either the tail-flick or hot-plate latencies. Except for the decreased defecation, these responses were all blocked by SR 141716A. Although only single doses of the agonist and antagonist were used, the findings indicate that these behavioural effects are probably mediated by an interaction with cannabinoid CB1 receptors.     

5-HT3 receptor over-expression decreases ethanol self administration in transgenic mice

 The 5-HT₃ receptor is thought to play a role in the reward pathway and the phenomena of drug abuse by modulating dopamine release in the mesolimbic pathway. Studies involving this receptor have been hampered due to the low level of 5-HT₃ receptors in the CNS. A 5-HT₃ receptor over-expressing mouse was produced to study the role of this receptor in the rewarding properties of drugs of abuse. Over-expression was restricted to the forebrain by controlling gene expression with the Ca²⁺ calmodulin (CAM) kinase IIα promoter. No over-expression was detected in other body organs nor the cerebellum, as measured by ligand binding and Northern analysis. 5-HT₃ receptor over-expressing mice drank less alcohol than non-transgenic mice in a two-bottle free choice test. Over-expression of the 5-HT₃ receptor in these mice resulted in a decrease in ethanol consumption. These mice should prove useful in testing hypothesis regarding a common reward pathway for drugs of abuse and the role 5-HT₃ receptors play in this pathway. Received: 17 June 1998 / Final version: 14 August 1998     

Cannabinoid receptor antagonism and inverse agonism in response to SR141716A on cAMP production in human and rat brain

The effects of cannabinoid drugs on cAMP production were examined in mammalian brain. The cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3,-d,e-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone (WIN55,212-2) decreased forskolin-induced cAMP accumulation in a concentration-dependent manner (10(-8)-10(-5) M) in membranes from several rat and human brain regions, this effect being antagonized by 10(-5) M N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). Furthermore, high micromolar concentrations of SR141716A evoked a dose-dependent increase in basal cAMP in rat cerebellum and cortex, as well as in human frontal cortex. This effect was antagonized by WIN55,212-2 and abolished by N-ethylmaleimide, consistent with the involvement of cannabinoid CB(1) receptors through the activation of G(i/o) proteins. These results suggest a ligand-independent activity for cannabinoid CB(1) receptor signaling cascade in mammalian brain.     

Activity of SR141716 on post-reinforcement pauses in operant responding for sucrose reward in rats

Cannabinoids increase food intake, via CB1 receptors. The CB1 antagonist, SR141716, has been reported to decrease palatable food consumption in both operant and non-operant procedures. Similarly, CB1 receptor blockade diminished responding for normal food pellets under a fixed-ratio 15 (FR-15) schedule of reinforcement. The present experiment investigated whether the control of a continuous schedule of reinforcement (CRF) for sucrose pellets would be sensitive to the CB1 antagonist in mildly deprived rats. SR141716 dose-dependently reduced responding in a CRF procedure, by increasing post-reinforcement pauses. Together with formerly published conclusions, the data suggest that CB1 blockade reduces the rewarding efficacy of both palatable and non-palatable food.