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knockout mice for both of these phenotypes, CP55,940 induces these
responses to the same extent in wild-type and b -arrestin 2 knockout animals.
7.2. Ethanol preference
Among other behaviors related to mood, emotional state, and psychiatric
diseases, b -arrestins also seem to modulate ethanol consumption. Evidence
points toward b -arrestin 2 as a positive regulator for ethanol abuse. In the
absence of b -arrestin 2, a decreased behavioral response to ethanol is
observed in rodents and, according to microarray experiments performed
on rats, genetic variations in the ARRB2 gene can influence alcohol pref-
erence. 157,158 Despite no changes in sucrose taste preference and quinine
taste aversion in b -arrestin 2 knockout mice compared to wild-type animals,
b -arrestin 2 knockout mice, as well as heterozygotes, exhibit reduced eth-
anol preference and voluntary intake. 159 b -Arrestin 2-depleted animals
exhibit decreased ethanol-induced locomotion 159 consistent with the lack
of characteristic locomotor responses induced by dopamine in b -arrestin
2 knockout mice. 45 This suggests that b -arrestins can modulate the acute
response to ethanol in the same way that they modulate response to other
psychoactive compounds, such as amphetamine and morphine.
8. CONCLUSIONS
GPCR represents the single largest group of pharmaceutical targets in
the CNS. However, their broad involvement in overall physiological pro-
cesses makes drug development free from side effects extremely difficult.
Maintaining homeostasis across the wide range of functions that depend
on GPCR-regulated pathways, GRK and arrestins depends on a fragile
equilibrium. Relatively subtle changes in the levels of protein expression
or coexpression, protein localization, or receptor function can disrupt this
balance. Despite a potential for compensatory overlap among protein
isoforms and signaling pathways, it appears that once disequilibrium occurs,
the intracellular molecular consequences as well as the physiological ones
can be dramatic. Psychiatric drugs used for clinical treatment modulate var-
ious aspects of this delicate equilibrium in an attempt to restore normal func-
tion in terms of receptor activity and protein complex formation 66 or even
transcriptionally induced changes. 160 At present, biased agonists targeting
the dopaminergic 161 and serotonergic systems appear to be the most prom-
ising field for the development of new therapeutics. Their potential to selec-
tively modulate signaling pathways, whether G protein- or arrestin-
dependent, downstream of the targeted GPCR constitutes a new field of
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