Itriglumide

The endocannabinoid system and the cannabinoid type 1 receptor (CB1R) are required for the extinction of conditioned fear. CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation. We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that interactions between the endocannabinoid and CCKergic transmitter systems may underlie the process of extinction of conditioned fear.

Background and Aim:  Cholecystokinin (CCK) and gastrin exert their influences via CCK receptors. This research was conducted to look at the responses of the sling and clasp fibers forming the human lower esophageal sphincter (LES) to CCK and gastrin, and the role of CCK receptors in the responses.Methods:  Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing subtotal esophagectomy. Isometric tension responses of the strips to CCK‐8 and gastrin‐17 were studied, and the maximum effect (Emax) for each agonist was derived. CCK‐A receptor antagonist, CR1409 and CCK‐B antagonist, CR2945 were applied to sling and clasp fibers and their pKB values were calculated.Results:  Sling fibers produced significant contractions following exposure to CCK‐8 and gastrin‐17, while clasp fibers had less responses to the two agents. CR1409 and CR2945 inhibited responses of sling to CCK‐8 in a concentration‐dependent fashion. The inhibition effects of the two antagonists on clasp fibers were not measurable because there was a mild contraction of the fiber in response to CCK‐8.Conclusion:  The contractions generated by sling fibers following exposure to CCK and gastrin are greater than that produced by clasp fibers. CCK‐A receptors are more important for the generation of contractions by the sling fibers, whereas both CCK‐A and CCK‐B receptors are involved in the functional regulation of the clasp fibers.[Corrections added after online publication 28 April 2008: in the Background and Aims section of the preceding abstract, all instances of ‘CKK’ were corrected to ‘CCK’. In the final sentence of the abstract ‘CCKA’was corrected to ‘CCK‐A’. In the article title ‘(CKK)’ was corrected to ‘(CCK)’.]