piperidines and 2-chloro-5-hydroxyphenylglycine

Mounting evidence has shown that glutamatergic and endocannabinoid systems in the hypothalamus regulate mammalian food intake. Stimulation of hypothalamic mGluR1/5 and CB1 receptors induces hyperphagia suggesting a possible interaction between these systems to control food intake. In addition, synthesis of endocannabinoids has been reported after mGluR1/5 stimulation in the brain. The aim of this study was to examine the potential cannabinergic activity in the food intake induction by lateral hypothalamic stimulation of mGluR1/5. Wistar albino male rats received bilateral infusions in the lateral hypothalamus (LH) of: (i) vehicle; (ii) (RS)-2-Chloro-5-hidroxyphenylglycine (CHPG; mGluR1/5 agonist); (iii) 2-AG (CB1 endogenous agonist); (iv) AM251 (CB1 antagonist); (v) tetrahydrolipstatin (THL, 1.2μg; diacyl-glycerol lipase inhibitor); and (vi) combinations of CHPG + with the other aforementioned drugs. Food intake was evaluated the first two hours after drug administration. CHPG significantly increased food intake; whereas CHPG in combination with a dose of 2-AG (with no effects on food intake) greatly increased food ingestion compared to CHPG alone. The increase induced by CHPG in food intake was prevented with AM251 or THL. These results suggest that activation of mGluR1/5 in the lateral hypothalamus induces an orexigenic effect via activation of the endocannabinoid system.

Topics: Animals; Eating; Endocannabinoids; Enzyme Inhibitors; Glycine; Hypothalamic Area, Lateral; Lactones; Lipoprotein Lipase; Male; Orlistat; Phenylacetates; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

Adenosine A(2A), cannabinoid CB(1) and metabotropic glutamate 5 (mGlu(5)) receptors are all highly expressed in the striatum. The aim of the present work was to investigate whether, and by which mechanisms, the above receptors interact in the regulation of striatal synaptic transmission. By extracellular field potentials (FPs) recordings in corticostriatal slices, we demonstrated that the ability of the selective type 1 cannabinoid receptor (CB(1)R) agonist WIN55,212-2 to depress synaptic transmission was prevented by the pharmacological blockade or the genetic inactivation of A(2A)Rs. Such a permissive effect of A(2A)Rs towards CB(1)Rs does not seem to occur pre-synaptically as the ability of WIN55,212-2 to increase the R2/R1 ratio under a protocol of paired-pulse stimulation was not modified by ZM241385. Furthermore, the effects of WIN55,212-2 were reduced in slices from mice lacking post-synaptic striatal A(2A)Rs. The selective mGlu(5)R agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) potentiated the synaptic effects of WIN55,212-2, and such a potentiation was abolished by A(2A)R blockade. Unlike the synaptic effects, the ability of WIN55,212-2 to prevent NMDA-induced toxicity was not influenced by ZM241385. Altogether, these results show that the state of activation of A(2A)Rs regulates the synaptic effects of CB(1)Rs and that A(2A)Rs may control CB(1) effects also indirectly, namely through mGlu(5)Rs.

Topics: Action Potentials; Animals; Benzoxazines; Biophysics; Calcium; Calcium Channel Blockers; Cerebral Cortex; Corpus Striatum; Electric Stimulation; Embryo, Mammalian; Excitatory Amino Acid Agonists; Female; Glycine; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Mice; Mice, Knockout; Morpholines; N-Methylaspartate; Naphthalenes; Neurons; Phenylacetates; Piperidines; Pregnancy; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Adenosine A2; Synapses; Triazines; Triazoles

The stimulation of the Schaffer collateral/commissural fibers at low frequency (1 Hz) for 3-5 min can trigger a slow-onset form of low-frequency stimulation (LFS)-long-term potentiation (LTP) (LFS-LTP) in the CA1 area of the adult rat hippocampus. Here we have examined the developmental profile of this plasticity. In 9-15 day-old rats, the application of 1 Hz for 5 min induced long-term depression (LFS-LTD). In 17-21 day-old rats, 1 Hz stimulation had no effect when applied for 5 min but mediated LTD when stimulus duration was increased to 15 min. Over 25 day-old, 1 Hz stimulation mediated LFS-LTP. LFS-LTD was dependent on both N-methyl-D-aspartate (NMDA) and mGlu5 receptor activation. Antagonists of mGlu1alpha and cannabinoid type 1 receptor were ineffective to block LTD induction. LFS-LTD was not associated with a change in paired-pulse facilitation ratio, suggesting a postsynaptic locus of expression of this plasticity. Next, we examined whether LFS-LTD was related to 'chemical' LTDs obtained by the direct stimulation of mGlu5 and NMDA receptors. The saturation of LFS-LTD completely occluded NMDA- and (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG)-induced LTD. CHPG-LTD and NMDA-LTD occluded each other. In addition, we observed that NMDA-LTD was dependent on mGlu5 receptor activation in 9-12 day old rats while it was not in animals older than 15 day-old. Therefore we postulate that during LFS application, NMDA and mGlu5 receptor could interact to trigger LTD. Low-frequency-mediated synaptic plasticity is subject to a developmental switch from NMDA- and mGlu5 receptor-dependent LTD to mGlu5 receptor-dependent LTP with a transient period (17-21 day-old) during which LFS is ineffective.

Topics: Age Factors; Animals; Animals, Newborn; Benzoxazines; Calcium Channel Blockers; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glycine; Hippocampus; In Vitro Techniques; Long-Term Potentiation; Long-Term Synaptic Depression; Male; Morpholines; N-Methylaspartate; Naphthalenes; Phenylacetates; Piperidines; Pyrazoles; Rats