Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats

doi:10.1016/0028-3908(95)00027-4

Neuropharmacology

Volume 34, Issue 6, June 1995, Pages 669-676

https://doi.org/10.1016/0028-3908(95)00027-4 Get rights and content

Abstract

CP 55,940 is a potent synthetic bicyclic cannabinoid analog that has been used in a number of studies as a radioligand for the cannabinoid receptor. This compound shares behavioral and biochemical properties with naturally occurring cannabinoids such as Δ⁹-THC. The purpose of the present study was 3-fold: to establish the ability of CP 55,940 to serve as a discriminative stimulus, to determine whether this discriminative stimulus is identical to that of Δ⁹-THC, and to examine whether a newly developed cannabinoid antagonist, SR141716A, would antagonize the discriminative stimulus effects of CP 55,940. Rats were trained to discriminate 0.1 mg/kg CP 55,940 from vehicle in standard 2-lever operant conditioning chambers. CP 55,940 produced dose-dependent generalization from the training dose in dose-effect determinations conducted before and after testing with other drugs. The effects of the training dose of CP 55,940 were dose-dependently antagonized by co-administration of SR141716A. Results of substitution tests showed that Δ⁹-THC, WIN 55,212-2, and cannabinol substituted completely for CP 55,940 in a dose-dependent manner; however, CP 55,940 was approx 10-fold more potent than any of the other drugs in producing CP 55,940-like discriminative stimulus effects. Several drugs with CNS depressant properties (phencyclidine, haloperidol and diazepam) failed to produce reliable substitution for CP 55,940. These results demonstrate that CP 55,940 has discriminative stimulus effects and that it shares these effects with structurally dissimilar compounds that, like CP 55,940, bind to the cannabinoid receptor. Further, these effects are blocked by SR141716A, a cannabinoid receptor antagonist. The present results provide support for the use of CP 55,940 as a probe for cannabinoid receptor-mediated effects related to cannabis abuse.

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Citation Excerpt :
These changes include analgesia, catalepsy, decreased rectal temperature, and locomotor suppression and are referred to as the cannabinoid tetrad (Janoyan et al., 2002; Smith et al., 1994a). The CP-55,940 dosages used in the present study are also within the range of those employed in previously published rodent drug discrimination studies (Wiley et al., 1995). In summary, the renewed interest in SCBs as recreational drugs of abuse has raised considerable public health concern, especially in regard to women who are or may become pregnant.
Potent synthetic cannabinoids (SCBs) are illegally distributed drugs of abuse that are frequently consumed in spite of their adverse consequences. This study was designed to determine if the toxicity observed in adults also extends to the prenatal period by examining the developmental toxicity/teratogenicity of one of these SCBs, CP-55,940, in a mammalian model. First, immunohistochemistry was employed for cannabinoid receptor 1 (CB1) localization within gestational day (GD) 8 mouse embryos; this receptor was identified in the cranial neural plate, suggesting that the endogenous cannabinoid system may be involved in normal development. Based on this information and on previous avian teratogenicity studies, the current investigation focused on cannabinoid exposure during neurulation. The treatment paradigm involved acute i.p. administration of vehicle, 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg CP-55,940 to time-mated C57Bl/6J mice on their 8th day of pregnancy (n > 10 litters per treatment group). On GD 17, litters were harvested and examined for numbers of live, dead, or resorbed fetuses, as well as for fetal weight, length, and gross morphological abnormalities. No effect on litter size, fetal weight, or crown rump length was seen at any of the CP-55,940 dosages tested. Major malformations involving the craniofacies and/or eyes were noted in all drug-treated groups. Selected fetuses with craniofacial malformations were histologically sectioned and stained, allowing investigation of brain anomalies. Observed craniofacial, ocular, and brain abnormalities in drug-treated fetuses included lateral and median facial clefts, cleft palate, microphthalmia, iridial coloboma, anophthalmia, exencephaly, holoprosencephaly, and cortical dysplasia. With the most commonly observed defects involving the eyes, the incidence and severity of readily identifiable ocular malformations were utilized as a basis for dose–response analyses. Ocular malformation ratings revealed dose-dependent CP-55,940 teratogenicity within the full range of dosages tested. While examination of additional critical periods and in depth mechanistic studies is warranted, the results of this investigation clearly show the dose-dependent teratogenicity of this SCB.
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^†: Current address: Department of Psychology, University of South Carolina, Columbia, SC 29208, U.S.A.

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General paperDiscriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats

Abstract

Neurosci. Biobehav. Rev.

Neuropharmacology

Neuropharmacology

Neuropharmacology

Pharmac. Biochem. Behav.

FEBS Let.

Neuropharmacology

Brain specific benzo-diazepine receptors

Br. J. Psychiat.

Discriminative stimulus properties of Δ9-tetrahydrocannabinol: mechanistic studies

J. Clin. Pharmac.

Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from Δ9-tetrahydrocannabinol

J. Pharmac. Exp. Ther.

Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents

J. Pharmac. Exp. Ther.

Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities

J. Pharmac. Exp. Ther.

Conformationally restrained analogues of pravadoline: nanomolar potent enantioselective (aminoalkyl)indole agonists of the cannabinoid receptor

J. Med. Chem.

General paper
Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats

Discriminative stimulus properties of Δ⁹-tetrahydrocannabinol: mechanistic studies

Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from Δ⁹-tetrahydrocannabinol