Effect of the cannabinoid receptor SPECT agent, AM 281, on hippocampal acetylcholine release from rat brain slices

doi:10.1016/S0304-3940(97)00851-3

Neuroscience Letters

Volume 238, Issues 1–2, 28 November 1997, Pages 84-86

https://doi.org/10.1016/S0304-3940(97)00851-3 Get rights and content

Abstract

The SPECT ligand AM 281, a less lipophilic analog of the cannabinoid receptor antagonist SR 141716A, robustly potentiated electrically-evoked release of acetylcholine from superfused hippocampal slices and prevented the inhibition of acetylcholine release by the cannabimimetic drug WIN 55212-2. These results, similar to earlier observations with SR 141716A, indicate that AM 281 is either a cannabinoid receptor antagonist or inverse agonist. Despite showing lower affinity than SR 141716A in hippocampal membrane binding experiments, AM 281 had slightly greater potency than SR 141716A in the hippocampal slice experiments, perhaps because of reduced drug absorption to slice membranes and to the apparatus.

References (9)

G.L. Gessa et al.
Inhibition of hippocampal acetylcholine release by cannabinoids: reversal by SR 141716A
Eur. J. Pharmacol.
(1997)
P. Mailleux et al.
Distribution of neuronal cannabinoid receptor in the adult brain: a comparative receptor binding radioautography and in situ hybridization histochemistry
Neuroscience
(1992)
S.A. Deadwyler et al.
Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process
J. Pharmacol. Exp. Ther.
(1995)
Gatley, S.J., Lan, R., Volkow, N.D., Pappas, N., King, P., Wong, C.T., Gifford, A.N., Pyatt, B. and Makriyannis, A.,...

There are more references available in the full text version of this article.

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Antipyrine, first prepared in 1887, was used as antipyretic, analgesic and anti-inflammatory [16]. Pyrazole fused with benzofuran have broad spectrum of biological and pharmacological importance. [17-19]. Based on this trend and in continuation of our research work on in search of biologically active compounds [20-22], and also as our laboratory continuously investigates new analgesic and anti-inflammatory drugs, we have previously reported that the compounds bearing benzofuran nucleus exhibited good analgesic and anti-inflammatory activity [23].
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Facilitatory effect of AM281 on recognition memory in rats
2016, Pharmacological Reports
Our approach was to determine the influence of a single systemic administration of AM281, synthetic cannabinoid structurally similar to SR141716A, on recognition memory in rats.
To assess the influence of AM281 on acquisition of information the compound was given intraperitoneally once, at the doses of 0.1, 0.5, 1.0 or 2.0 mg/kg, 15 min before learning trial (T1) and in order to evaluate its influence on consolidation process AM281 was given at indicated doses, immediately after T1 trial in an object recognition test. Since cannabinoids may alter motor function and affect anxiety, the influence of AM281 on psychomotor activity and anxiety was evaluated in an open-field and elevated plus maze test, respectively.
Administration of AM281 at the doses: 0.1, 0.5 and 1.0 mg/kg significantly improved acquisition of information, while 0.1 and 0.5 mg/kg of AM281 significantly facilitated consolidation process. Not only did AM281 not affect locomotor and exploratory activity, but also anxiety.
This is the first evidence that AM281 exerts facilitatory effect on recognition memory in rats. This effect seems to be memory specific because no alterations in animals’ psychomotor activity and anxiety were observed.
Evaluation of the abuse potential of AM281, a new synthetic cannabinoid CB<inf>1</inf> receptor antagonist
2015, European Journal of Pharmacology
AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) is a new synthetic cannabinoid CB₁ receptor antagonist. Similar to other cannabinoid antagonists, AM281 has been suggested to have therapeutic indications. However, recent reports have suggested that cannabinoid CB₁ receptor antagonists may share similar behavioral effects with other drugs of abuse such as cocaine and amphetamine. These reports cast doubts on the safety profile of AM281. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of AM281 through two of the most widely used animal models for assessing the abuse potential of drugs: the conditioned place preference (CPP) and self-administration (SA) tests. Experiments were performed in Sprague–Dawley rats in various dosages [CPP (0.1, 0.5 or 2.5 mg/kg), SA (0.005, 0.025 or 0.1 mg/kg/infusion)]. We also delved into the consequences of repeated drug exposure on the subsequent response to the drug. Thus, parallel experiments were carried out in rats pretreated with AM281 for 7 or 14 days. Our findings indicated that AM281, at any dose, did not induce CPP and SA in drug-naïve rats. Interestingly, significant CPP (0.5 mg/kg of AM281), but not SA, was observed in 14 days pretreated rats. These observations suggest that AM281 per se has no or minimal rewarding and reinforcing properties, but alterations in neuronal functions and behavior due to repeated AM281 exposure may contribute in part to the abuse potential of this drug. In view of this finding, we advocate the careful use, monitoring, and dispensation of AM281.
Antidepressant-like effects of the cannabinoid receptor ligands in the forced swimming test in mice: Mechanism of action and possible interactions with cholinergic system
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The purpose of the experiments was to explore the role of the endocannabinoid system, through cannabinoid (CB) receptor ligands, nicotine and scopolamine, in the depression-related responses using the forced swimming test (FST) in mice.
Our results revealed that acute injection of oleamide (10 and 20 mg/kg), a CB1 receptor agonist, caused antidepressant-like effect in the FST, while AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist, did not provoke any effect in this test. Moreover, acute administration of both CB2 receptor agonist, JWH 133 (0.5 and 1 mg/kg) and CB2 receptor antagonist, AM 630 (0.5 mg/kg), exhibited antidepressant action.
Antidepressant effects of oleamide and JWH 133 were attenuated by acute injection of both non-effective dose of AM 251, as well as AM 630.
Among the all CB compounds used, only the combination of non-effective dose of oleamide (2.5 mg/kg) with non-effective dose of nicotine (0.5 mg/kg) caused an antidepressant effect. However, none of the CB receptor ligands, had influence on the antidepressant effects provoked by nicotine (0.2 mg/kg) injection. In turn, the combination of non-effective dose of oleamide (2.5 mg/kg); JWH (2 mg/kg) or AM 630 (2 mg/kg), but not of AM 251 (0.25 mg/kg), with non-effective dose of scopolamine (0.1 mg/kg), exhibited antidepressant properties. Indeed, all of the CB compounds used, intensified the antidepressant-like effects induced by an acute injection of scopolamine (0.3 mg/kg).
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Cannabinoid system plays a pivotal role in the seizure threshold modulation which is mainly mediated through activation of the cannabinoid CB₁ receptor. There is also several evidence of interaction between cannabinoid system and α₂-adrenoceptors in different paradigms. Using model of clonic seizure induced by intravenous pentylenetetrazole (PTZ) in male mice, we investigated whether α₂-adrenoceptors is involved in the effects of cannabinoids on the seizure threshold. Injection of the selective cannabinoid CB₁ agonist ACEA (2 mg/kg) significantly (P<0.01) increased the seizure threshold which was prevented by pretreatment with the selective CB₁ antagonist AM251 (1 mg/kg, i.p.). The highest doses of clonidine, a α₂ receptor agonist, (1 and 5 mg/kg) showed anticonvulsant effects while yohimbine, a α₂ receptor antagonist, (0.01, 0.1, 1, and 10 mg/kg) did not induce any significant effect on PTZ seizure threshold. Pretreatment with clonidine (0.1 and 0.5 mg/kg) significantly reversed the anticonvulsant effect of ACEA (2 mg/kg). Yohimbine (0.1, 1, and 10 mg/kg) pretreatment of mice enhanced the clonic seizure threshold of ACEA (1 mg/kg), significantly. Combination of non-effective doses of AM251 (0.1 mg/kg) and clonidine (0.01 mg/kg) showed additive effect in blocking the anticonvulsant effect of ACEA (2 mg/kg). In conclusion, our findings demonstrated that α₂-adrenoceptors could be involved in the anticonvulsant properties of the specific cannabinoid CB₁ agonist ACEA, suggesting that CB₁ cannabinoid and α₂ receptors have functional interactions in modulation of clonic seizure threshold.
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Endocannabinoids regulate the release of a variety of neurotransmitters in a brain regional and pathway-dependent manner. A number of studies reported inhibition of hippocampal ACh release by eCBs (Degroot et al., 2006; Gessa et al., 1998; Gifford et al., 1997, 2000; Gifford and Ashby, 1996; Tzavara et al., 2003). In contrast, ACh release in striatum does not appear to be regulated by eCB signaling (Gifford et al., 1997; Kathmann et al., 2001).
Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (−/−) mice. Mice of both genotypes (n = 5–6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82–95% at 48 h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 μM) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20–23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner.

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Effect of the cannabinoid receptor SPECT agent, AM 281, on hippocampal acetylcholine release from rat brain slices

Abstract

Eur. J. Pharmacol.

Neuroscience

Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process

J. Pharmacol. Exp. Ther.