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Signaling Pathways:
A symposium at the 2001 annual
meeting of the Research Society on Alcoholism included,
(1) Role of endocannabinoids in ethanol tolerance, by
Appa Hungund;
(2) Modulation of cannabinoid receptor and its signal
transduction in chronic alcoholism, by B. S. Basavarajappa;
(3) Endocannabinoid involvement in the control of appetitive
behavior, by George
Kunos;
(4) Regulation of
voluntary ethanol intake by cannabinoid receptor
agonists and antagonists in alcohol-preferring sP rats, by Giancarlo Colombo; (5) Role of endogenous cannabinoid system in alcoholism, by Fernado
Rodriguez de Fonseca; and (6) Endocannabinoids and
dopamine interactions in vivo, by
Loren Parsons and George Koob. Hungund
BL, Basavarajappa BS, Vadasz
C, Kunos G, Rodriguez de Fonseca F, Colombo G, Serra S, Parsons L, Koob GF. Ethanol, endocannabinoids, and the cannabinoidergic
signaling system. Alcohol Clin
Exp Res 2002 Apr;26(4):565-74
Studies using CB1 knockout mice
support a role for endocannabinoids in retrograde
synaptic inhibition in the hippocampus, in long-term potentiation
and memory, in the development of opiate dependence, and in the control of
appetite and food intake. The use of CB2 receptor knockout mice suggested a
role for this receptor in macrophage-mediated helper T cell activation.
Kunos G, Batkai
S. Novel physiologic functions of endocannabinoids as
revealed through the use of mutant mice. Neurochem Res 2001 Sep;26(8-9):1015-21.
Endocannabinoids are retrograde messengers released by neurons, which
modulate the strength of synaptic inputs. Endocannabinoids
may mediate suppression of GABA release after depolarization of a hippocampal CA1 pyramidal neuron-termed
"depolarization-induced suppression of inhibition" (DSI). DSI is
absent in mice which lack cannabinoid receptor-1
(CB1). Endocannabinoids selectively inhibit a subclass
of synapses distinguished by fast kinetics and large unitary conductance. Endocannabinoids are highly selective, rapid modulators of hippocampal inhibition.
Cardiovascular - - Cannabinoids
are strong vasodilators, and endocannabinoids act in
hypotension in hemorrhagic and septic shock. Endocannabinoids
generated in monocytes and platelets contribute to
hypotension in acute MI. Cannabinoid(1) receptor blockade restores MAP but increases 2-h
mortality, possibly by impairing endothelial function. Wagner JA, Hu K, Bauersachs
J, Karcher J, Wiesler M, Goparaju SK, Kunos G, Ertl G. Endogenous cannabinoids mediate hypotension after experimental
myocardial infarction. J
Am Coll Cardiol 2001 Dec;38(7):2048-54
Advanced cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to
mortality. Rats with biliary cirrhosis have low blood
pressure, which is elevated by the CB1 receptor antagonist SR141716A. The low
blood pressure of rats with CCl4-induced cirrhosis was similarly reversed by
SR141716A, which also reduced the elevated mesenteric blood flow and portal
pressure. Monocytes from cirrhotic but not control
patients or rats elicited SR141716A-sensitive hypotension in normal recipient
rats and showed significantly elevated levels of anandamide.
Compared with non-cirrhotic controls, in cirrhotic human livers there was a
three-fold increase in CB1 receptors on isolated vascular endothelial cells.
These results implicate anandamide and vascular CB1
receptors in the vasodilated state in advanced
cirrhosis and indicate a novel approach for its management. Batkai S, Jarai
Z, Wagner JA, Goparaju SK, Varga
K, Liu J, Wang L, Mirshahi F, Khanolkar
AD, Makriyannis A, Urbaschek
R, Garcia N Jr, Sanyal AJ, Kunos G. Endocannabinoids acting at
vascular CB1 receptors mediate the vasodilated state
in advanced liver cirrhosis. Nat Med 2001 Jul; 7(7):827-32