Importance of NO/cGMP signalling via cGMP-dependent protein kinase II for controlling emotionality and neurobehavioural effects of alcohol.
Cyclic GMP is a second messenger for nitric oxide (NO) that acts as a mediator for many different physiological functions. The cGMP-dependent protein kinases (cGKs) mediate cellular signalling induced by NO and cGMP. Here, we explored the localization of cGMP-dependent protein kinase type II (cGKII) in the mouse brain. In situ hybridization revealed high levels of cGKII mRNA in cerebral cortex, thalamic nuclei, hypothalamic nuclei, and in several basal forebrain regions including medial septum, striatum and amygdala. The close link to NO and the distribution pattern of cGKII suggested that this enzyme might be involved in emotional reactions and responses to drugs of abuse. Therefore, cGKII knockout animals (cGKII-/-) were compared with littermate controls in behavioural tests (i) for emotion-linked and (ii) for acute and chronic ethanol responses. Deletion of cGKII did not influence aggressive behaviour but led to enhanced anxiety-like behaviour. In terms of acute responses to ethanol, cGKII-/- mice were hyposensitive to hypnotic doses of ethanol as measured by the loss of righting reflex, without an alteration in their blood alcohol elimination. In a two-bottle free choice test, cGKII-/- mice showed elevated alcohol consumption. No taste differences to sweet solutions were observed compared to control animals. In summary, our data show that cGKII activity modulates anxiety-like behaviour and neurobehavioural effects of alcohol.
Werner
Claudia
C
Institut für Pharmakologie und Toxikologie, Technische Universität München, Biedersteiner Strasse 29, 80802 München, Germany. pharma@ipt.med.tu-muenchen.de
Raivich
Gennadij
G
Cowen
Michael
M
Strekalova
Tatyana
T
Sillaber
Inge
I
Buters
Jeroen T
JT
Spanagel
Rainer
R
Hofmann
Franz
F
D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D001007:Anxiety / Q000201:enzymology; D001921:Brain / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology*; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004644:Emotions / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D009569:Nitric Oxide; D000431:Ethanol; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases; C569730:Prkg2 protein, mouse; D006152:Cyclic GMP