SR-141716A-induced stimulation of locomotor activity

Bass, Caroline E.; Griffin, Graeme; Grier, Mark C.; Mahadevan, Anu; Razdan, Raj K.; Martin, Billy R.

doi:10.1016/s0091-3057(02)00945-0

Cited by 55 publications

(38 citation statements)

References 11 publications

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“…Consistent with this hypothesis, we have previously observed stimulation induced by higher doses of THC after repeated dosing with THC or anandamide analogs in a similar tolerance/cross-tolerance paradigm (Wiley et al, 2005). On the other hand, stimulation has also been reported after administration of SR141617A, but it is not believed to be mediated via interaction with the CB 1 receptor (Bass et al, 2002). Because THC is not entirely CB 1 -selective, it is also possible that high-dose THC might have produced adaptation in the activity produced by an as-yet-unknown mechanism that does not seem to be involved in the other pharmacological measures.…”

Section: Discussionsupporting

confidence: 73%

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

McKinney

Cassidy²,

Collier³

et al. 2007

J Pharmacol Exp Ther

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Chronic treatment with ⌬ 9 -tetrahydrocannabinol (THC) produces tolerance to cannabinoid-mediated behaviors and region-specific adaptation of brain cannabinoid receptors. However, the relationship between receptor adaptation and tolerance is not well understood, and the dose-response relationship of THC-induced cannabinoid receptor adaptation is unknown. This study assessed cannabinoid receptor function in the brain and cannabinoid-mediated behaviors after chronic treatment with different dosing regimens of THC. Mice were treated twice per day for 6.5 days with the following: vehicle, 10 mg/kg THC, or escalating doses of 10 to 20 to 30 or 10 to 30 to 60 mg/kg THC. Tolerance to cannabinoid-mediated locomotor inhibition, ring immobility, antinociception, and hypothermia was produced by both ramping THC-dose paradigms. Administration of 10 mg/kg THC produced less tolerance development, the magnitude of which depended upon the particular behavior. Decreases in cannabinoid-mediated G-protein activation, which varied with treatment dose and region, were 35 S]GTP␥S binding was reduced in the hippocampus, cingulate cortex, periaqueductal gray, and cerebellum after all treatments. Decreased agonist-stimulated [35 S]GTP␥S binding in the caudate-putamen, nucleus accumbens, and preoptic area occurred only after administration of 10 to 30 to 60 mg/kg THC, and no change was found in the globus pallidus or entopeduncular nucleus after any treatment. Changes in the CB 1 receptor B max values also varied by region, with hippocampus and cerebellum showing reductions after all treatments and striatum/globus pallidus showing effects only at higher dosing regimens. These results reveal that tolerance and CB 1 receptor adaptation exhibit similar dose-dependent development, and they are consistent with previous studies demonstrating less cannabinoid receptor adaptation in striatal circuits.Cannabinoids are used for their psychoactive effects and for therapeutic treatment of nausea/emesis and cachexia. Previous studies also suggest that cannabinoids may have clinical potential for the treatment of pain and degenerative disorders (Piomelli et al., 2000;van der Stelt and Di Marzo, 2003). Acute administration of cannabinoids produces antinociception, locomotor inhibition, hypothermia, and impairment of short-term memory (Howlett et al., 2002). ⌬ 9 -Tetrahydrocannabinol (THC) and other cannabinoids produce their psychoactive and behavioral effects via activation of CB 1 receptors in the central nervous system (CNS) (Ledent et al., 1999). Recent reports indicate that CB 2 and novel cannabinoid receptors might exist in the CNS (Mackie and Stella, 2006), but their role is unclear. CB 1 receptors are widely distributed in the brain where they exhibit a predominantly presynaptic location and modulate neurotransmitter release (Schlicker and Kathmann, 2001 [2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate; GP, globus pallidus; MPE, maximal possible effect; POA, preoptic a...

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Section: Discussionsupporting

confidence: 73%

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

McKinney

Cassidy²,

Collier³

et al. 2007

J Pharmacol Exp Ther

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“…The hypoactivity produced by SR 141716A and AM 251 might be inconsistent with inverse agonism insofar as the bidirectional effects of cannabinoid agonists and inverse agonists on receptor signaling in vitro yields similar bi-directionality in vivo (i.e., hypoactivity and hyperactivity, respectively). However, even when cannabinoid antagonists produce hyperactivity, this activity is not clearly related to inverse agonism (Bass et al, 2002), and other mechanisms (i.e., inhibition of endogenous cannabinoids) could be responsible for the direct behavioral effects of SR 141716A and AM 251.…”

Section: Discussionmentioning

confidence: 99%

Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice

McMahon

Koek

2007

European Journal of Pharmacology

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Although the cannabinoid CB 1 antagonist N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide (SR 141716A) blocks many of the in vivo effects of cannabinoids, the antagonist activity of SR 141716A is limited under some conditions. The general aims of this study were to: 1) examine whether the limited antagonist activity of SR 141716A generalizes to the cannabinoidand 2) examine mechanisms by which cannabinoids produce hypothermia, catalepsy, and hypoactivity in C57BL/6J mice. SR 141716A and AM 251 were administered alone and in combination with the cannabinoid agonists Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212−2). Δ 9 -THC and WIN 55212−2 produced catalepsy, hypothermia, and hypoactivity with similar potency; WIN 55212 −2 produced greater hypothermia than Δ 9 -THC, otherwise differences in maximal effect were not detected in the other assays. When administered alone, the antagonists did not produce catalepsy or alter body temperature and they decreased locomotor activity. SR 1417167A and AM 251 blocked catalepsy and hypothermia, and partially attenuated hypoactivity, produced by Δ 9 -THC and WIN 55212−2. While the antagonists were equipotent in blocking agonist-induced hypothermia, SR 141716A was 6-fold more potent than AM 251 in blocking agonist-induced catalepsy. The results demonstrate that SR 141716A and AM 251 have strikingly similar behavioral activity, i.e., they block some and not other in vivo effects of cannabinoid agonists, and further demonstrate differences in the maximum effect of cannabinoid agonists that might be related to differences in agonist efficacy. While the results strongly suggest that cannabinoid CB 1 receptors mediate the hypothermic and cataleptic effects of cannabinoids, differences in the relative potency of antagonists suggest that mechanisms responsible for these effects are not identical.

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“…This is consistent with their in vitro binding properties, ie that AM 251 is roughly twofold more potent (K i ¼ 7.49 vs 11.5 nM) and more selective (1:306 vs 1:143) than SR141716 for CB1 over CB2 receptors (Lan et al, 1999;Krishnamurthy et al, 2004). In addition, growing evidence demonstrates that SR141716 is not as highly selective a CB1 receptor antagonist in vivo as previously believed: (1) SR141716 and its analogs significantly alter locomotion behaviors, actions that are poorly correlated to their binding affinities to the CB1 receptor (Bass et al, 2002); (2) acute or chronic administration of SR141716 produce many nonspecific 'side effects', such as grooming, intense scratching, forepaw fluttering, wet-dog shaking, ultrasonic vocalization, and in some species, emesis, which are not correlated to its action on CB1 receptors or on post-receptor intracellular G protein-mediated signaling (Rubino et al, 1998(Rubino et al, , 2000Beardsley and Thomas, 2005); (3) SR141716 produces similar biological effects in in vitro cell lines expressed with intact or mutant CB1 receptors (Pertwee, 2005); (4) SR141716 significantly elevates extracellular glutamate levels in the nucleus accumbens similarly in both wild-type and CB1-knockout mice (Xi et al, 2006c), and also reverses the inhibition of WIN55,212-2 on hippocampal glutamate transmission in both wild-type and CB1-knockout mice (Hajos et al, 2001). These data suggest that SR141716 may have nonspecific binding properties on other non-CB1 and/or non-cannabinoid receptors in vivo, which may contribute to its relative ineffectiveness in attenuating cocaine's rewarding efficacy.…”

mentioning

confidence: 95%

Cannabinoid CB1 Receptor Antagonists Attenuate Cocaine's Rewarding Effects: Experiments with Self-Administration and Brain-Stimulation Reward in Rats

Spiller

Pak

et al. 2007

Neuropsychopharmacol

105

116

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Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1-10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30-70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1-3 mg/kg) also significantly and dose-dependently inhibited (by 25-90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications.

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SR-141716A-induced stimulation of locomotor activity

Cited by 55 publications

References 11 publications

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice

Cannabinoid CB1 Receptor Antagonists Attenuate Cocaine's Rewarding Effects: Experiments with Self-Administration and Brain-Stimulation Reward in Rats

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SR-141716A-induced stimulation of locomotor activity

Cited by 55 publications

References 11 publications

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ9-Tetrahydrocannabinol

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ9-Tetrahydrocannabinol

Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice

Cannabinoid CB1 Receptor Antagonists Attenuate Cocaine's Rewarding Effects: Experiments with Self-Administration and Brain-Stimulation Reward in Rats

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Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol