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Biotech / Medical : Indications -- obesity/erectile dysfunction

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From: scaram(o)uche10/30/2019 3:26:54 PM
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Neuroscience. 2019 Sep 11. pii: S0306-4522(19)30650-5. doi: 10.1016/j.neuroscience.2019.09.005. [Epub ahead of print]

Combined Loss of Ghrelin Receptor and Cannabinoid CB1 Receptor in Mice Decreases Survival but Does Not Additively Reduce Body Weight or Eating.

Mani BK1, Castorena CM1, Vianna CR1, Lee CE1, Metzger NP1, Vijayaraghavan P1, Osborne-Lawrence S1, Elmquist JK2, Zigman JM3.

1
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
2
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
3
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States of America. Electronic address: jeffrey.zigman@utsouthwestern.edu.

Ghrelin administration increases food intake, body weight (BW), adiposity, and blood glucose. In contrast, although mouse models lacking ghrelin or its receptor (GHSR) exhibit life-threatening hypoglycemia in starvation-like states, they do not exhibit appreciable reductions in food intake, BW, adiposity, blood glucose, or survival when food availability is unrestricted. This suggests the existence of a parallel neuromodulatory system that can compensate for disruptions in the ghrelin system in certain settings. Here, we hypothesized that the cannabinoid CB1 receptor (CB1R) may encode this putative redundancy, and as such, that genetic deletion of both GHSR and CB1R would exaggerate the metabolic deficits associated with deletion of GHSR alone. To test this hypothesis, we assessed food intake, BW, blood glucose, survival, and plasma acyl-ghrelin in ad libitum-fed male wild-type mice and those that genetically lack GHSR (GHSR-nulls), CB1R (CB1R-nulls), or both GHSR and CB1R (double-nulls). BW, fat mass, and lean mass were similar in GHSR-nulls and wild-types, lower in CB1R-nulls, but not further reduced in double-nulls. Food intake, plasma acyl-ghrelin, and blood glucose were similar among genotypes. Deletion of either GHSR or CB1R alone did not have a statistically-significant effect on survival, but double-nulls demonstrated a statistical trend towards decreased survival (p?=?0.07). We conclude that CB1R is not responsible for the normal BW, adiposity, food intake, and blood glucose observed in GHSR-null mice in the setting of unrestricted food availability. Nor is CB1R required for plasma acyl-ghrelin secretion in that setting. However, GHSR may be protective against exaggerated mortality associated with CB1R deletion.

Front Behav Neurosci. 2019 Aug 14;13:184. doi: 10.3389/fnbeh.2019.00184. eCollection 2019.

Endocannabinoids Interact With the Dopaminergic System to Increase Sexual Motivation: Lessons From the Sexual Satiety Phenomenon.

Canseco-Alba A1, Rodríguez-Manzo G1.

1
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav-Sede Sur), Ciudad de México, México.

In male rats, copulation to satiety induces a long-lasting sexual inhibitory state, considered to rely on a decreased sexual motivation. Dopaminergic transmission at the mesolimbic system plays a central role in the regulation of male sexual motivation. Endocannabinoids (eCBs) modulate the activity of the mesolimbic system and both dopamine (DA) and cannabinoid receptor activation reverses the sexual inhibition that characterizes sexually satiated rats. The eCB anandamide reverses sexual satiety when systemically administered or infused into the ventral tegmental area (VTA), the region where the activity of mesolimbic dopaminergic neurons is regulated. Thus, it could be thought that sexual motivation is diminished during the long-lasting sexual inhibition of sexually satiated rats and that eCBs reverse that inhibition through the modulation of the dopaminergic system. To test this hypothesis, we assessed the motivational state of sexually satiated male rats and determined if 2-arachidonoylglycerol (2-AG), the most abundant eCB and a full cannabinoid receptor agonist, also reversed the sexual inhibitory state. To establish the possible interaction between 2-AG and anandamide with the dopaminergic system for the reversal of sexual satiety, we analyzed the effects of the co-administration of each eCB and DA receptor agonists or antagonists. Results showed that 24-h after copulation to satiety, when the sexual inhibition is well established, the males' sexual motivation is diminished as measured in the sexual incentive motivation test. 2-AG, similarly to anandamide, reverses sexual satiety through the activation of CB1 receptors and both eCBs interact with the dopaminergic system to reverse the sexual inhibitory state. 2-AG effects are mediated by the modulation of the D2-like DA receptor family, whereas anandamide's effects are clearly mediated by the modulation of the D1-like DA receptor family and the activation of D2-like DA receptors. Present results evidence that a reduced sexual motivation underlies the sexual inhibitory state of sexually satiated rats and support the notion that eCBs reverse sexual satiety by modulating dopaminergic transmission, presumably at the mesolimbic system. Anandamide and 2-AG have a different interaction with D1-like and D2-like DA receptor families. Altogether present data endorse the association of the eCB system with the regulation of the motivational tone at the mesolimbic system.

Nat Chem Biol. 2019 Oct 28. doi: 10.1038/s41589-019-0387-2. [Epub ahead of print]

Structure of an allosteric modulator bound to the CB1 cannabinoid receptor.

Shao Z1, Yan W1, Chapman K2, Ramesh K2, Ferrell AJ2, Yin J2, Wang X1, Xu Q3, Rosenbaum DM4.

1
Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
2
Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
GM/CA, Advanced Photon Source, Argonne National Laboratory, Argonne, IL, USA.
4
Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA. dan.rosenbaum@utsouthwestern.edu.

The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.
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