td-5108 and 3-(piperidine-1-yl)propyl-4-amino-5-chloro-2-methoxybenzoate-hydrochloride

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear.

Topics: Aniline Compounds; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoids; Conditioning, Classical; Dose-Response Relationship, Drug; Fear; Freezing Reaction, Cataleptic; Hippocampus; Male; Memory; Mice; para-Aminobenzoates; Piperidines; Receptor, Cannabinoid, CB1; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists

In this study, the effects of 5-HT4 receptors of the CA1 on MK801-induced amnesia and hyperlocomotion were examined. One-trial step-down method was used to assess memory retention and then, the hole-board method to assess exploratory behaviors. The results showed that post-training intra-CA1 administration of RS67333 (62.5 and 625 ng/mouse) and RS23597 (1 and 10 ng/mouse) decreased memory consolidation, but it did not alter head-dip counts, head-dip latency and locomotor activity. Similarly, MK801 (0.5 and 1 μg/mouse) decreased memory consolidation, but had no effect on head-dip counts and head-dip latency. Interestingly, it increased locomotor activity. The results also showed that post-training intra-CA1 injection of a sub-threshold dose of RS67333 (6.25 ng/mouse) or RS23597 (0.1 ng/mouse) could heighten MK801 induced amnesia and decrease locomotor activity, but it did not alter head-dip counts and head-dip latency. In conclusion, our findings suggest that the CA1 5-HT4 receptors are involved in MK801-induced amnesia and hyperlocomotion.

Topics: Amnesia; Aniline Compounds; Animals; CA1 Region, Hippocampal; Dizocilpine Maleate; Drug Partial Agonism; Exploratory Behavior; Male; Memory; Mice; Motor Activity; para-Aminobenzoates; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists

Serotonin (5HT) has been shown to be a mitogenic factor in several carcinomas. Its mitogenic effect is elicited through a wide range of 5HT receptor subtypes. In this study, the effects of 5HT, 5HT3 (1-phenylbiguanide hydrochloride) and 5HT4 (cisapride) agonists in promoting the growth of the HT29 cell line and the growth-inhibition effect of the 5HT3 receptor antagonist (Y-25130 hydrochloride) and 5HT4 receptor antagonist (RS 23597-190) were investigated. The expressions of 5HT3 and 5HT4 receptors in human colon cancer tissues and the HT29 cell line were studied.. The growth-promoting and growth-inhibition effects of 5-HT, 5HT3 and 5HT4 agonists and antagonists on the HT29 cell line were studied using MTT assay. Receptor expression has been demonstrated by western blotting.. The results showed that 5HT, 5HT3, and 5HT4 agonists caused significant proliferation of HT29 cells. 5HT3 and 5HT4 receptor antagonists had an inhibitory effect on the growth of these cells. Western blot analysis gave bands from colon tissue extracts and the HT29 cell line.. The results indicate which 5HT3 and 5HT4 receptors are significantly expressed in both colon cancer tissue and the HT29 cell line. Expression for the 5HT3 receptor is more potent. Furthermore, 5HT plays a mitogenic role in colon cancer cells and antagonists of 5HT3, and 5HT4 receptors can inhibit cancer cell growth.

Topics: Adenocarcinoma; Aminobenzoates; Biguanides; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Cisapride; Colonic Neoplasms; HT29 Cells; Humans; Oxazines; para-Aminobenzoates; Piperidines; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists