Mauro A. M. Carai

The endogenous brain constituent, gamma-hydroxybutyric acid (GHB), as well as its prodrug, gamma-butyrolactone (GBL), have recently gained interest in the drug addiction field due to their abuse potential and fatalities caused by overdose. It is known that GHB has two sites of actions: the gamma-aminobutyric acid(B) (GABA(B)) receptor and a specific-GHB binding site. The present study was designed to extend to GBL the investigations on the contribution of the GABA(B) receptor and the specific-GHB binding site to its in vivo effects. To this aim, DBA mice were pretreated either with GABA(B)-receptor antagonists, (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) and (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), or a putative antagonist of the specific-GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), prior to the administration of doses of GBL that induced hypothermia, motor-incoordination (measured as motor-impairment at the Rota-Rod task), and sedation/hypnosis. The capability of SCH 50911 and NCS-382 to protect against GBL-induced lethality was also investigated. Pretreatment with either GABA(B)-receptor antagonist completely prevented GBL-induced hypothermia, motor-incoordination, and sedation /hypnosis. SCH 50911 also provided complete protection against GBL-associated lethality. Vice versa, NCS-382 failed to exert any antagonistic or protective effect. These results suggest that the in vivo GBL effects tested in the present study are mediated by activation of the GABA(B) receptor.

This study investigated whether (a) cannabinoid CB₁receptor knockout (CB₁^−/−) mice displayed altered gastrointestinal transit and (b) cannabinoid CB₁and opioid receptors functionally interact in the regulation of gastrointestinal transit. Gastrointestinal transit was assessed by the Whole Gastrointestinal Transit, measuring the excretion time of an intragastrically administered marker (whole intestine), and the Upper Gastrointestinal Transit, measuring the distance covered by the marker in the small intestine. CB₁^−/−and homozygous CB₁^+/+(CB₁^+/+) mice did not differ in both whole gut and small intestine transit. CB₁^−/−and CB₁^+/+mice were equally responsive to the inhibitory effect of morphine (10 mg kg⁻¹) and loperamide (3 mg kg⁻¹) on whole gut transit. Additionally, in CD1 mice the cannabinoid CB₁receptor antagonist, rimonabant (0–0.5 mg kg⁻¹), failed to block the inhibitory effect of morphine (0–1.25 mg kg⁻¹) and loperamide (0–0.5 mg kg⁻¹) on transit in small and whole intestine. Similarly, the opioid receptor antagonists, naloxone (0–1 mg kg⁻¹) and naltrexone (0–10 mg kg⁻¹), failed to block the inhibitory effect of the cannabinoid WIN 55,212‐2 (0–3 mg kg⁻¹) on transit in small and whole intestine. These results suggest that (a) compensatory mechanisms likely developed in CB₁^−/−mice to overcome the lack of inhibitory function of endocannabinoid system; (b) cannabinoid and opioid receptor systems did not interact in regulating gastrointestinal transit in mice. British Journal of Pharmacology(2006)148, 1043–1050. doi:10.1038/sj.bjp.0706824

The present paper focuses on the different lines of evidence indicating that cannabinoid CB₁ receptor antagonists, including the prototype rimonabant, reduce food intake and body weight in laboratory animals. Recent clinical surveys demonstrated that rimonabant significantly reduced body weight also in overweight/obese humans. Treatment with rimonabant was associated with a beneficial effect on different metabolic parameters and cardiovascular risk factors linked to overweight. The data reviewed in this paper suggest that cannabinoid CB₁ receptor antagonists may constitute a novel class of drugs potentially effective in the treatment of obesity‐related disorders.