A PHP Error was encountered

Severity: Warning

Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests

Filename: helpers/my_audit_helper.php

Line Number: 143

Backtrace:

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 994
Function: getPubMedXML

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016

File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global

File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword

File: /var/www/html/index.php
Line: 316
Function: require_once

Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist. | LitMetric

Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist.

Psychopharmacology (Berl)

Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115-5000, USA,

Published: August 2015

AI Article Synopsis

  • Rimonabant's inverse agonist properties might limit its effectiveness in treating cannabinoid dependence, leading to the development of neutral antagonists to better understand withdrawal mechanisms.
  • The study introduces an animal model to examine cannabinoid dependence through distinct pharmacological profiling of novel compounds and their effects on CB1-receptor-related behavioral and physiological outcomes.
  • Results indicate that the novel cannabinoid AM2389 is more potent and longer-lasting than THC, showing that its withdrawal symptoms are linked to its interaction at the CB1 receptor and are not solely due to rimonabant's inverse agonism.

Article Abstract

Rationale: Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation, neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal.

Objective: The objective of this study is to introduce an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints.

Methods: The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test, and temperature), with some comparisons made to Δ(9)-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545.

Results: In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC.

Conclusions: These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504748PMC
http://dx.doi.org/10.1007/s00213-015-3907-0DOI Listing

Publication Analysis

Top Keywords

antagonist-precipitated withdrawal
12
inverse agonist
8
agonist neutral
8
neutral antagonist
8
inverse properties
8
cannabinoid dependence
8
centrally acting
8
rimonabant am4113
8
am2389
6
withdrawal
6

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!