Background
Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful
animal model of neurobiological alterations associated with hyperdopaminergia relevant
to schizophrenia and attention-deficit/hyperactivity disorder (ADHD).
Methods
Because of continuously increasing evidence for a neuromodulatory role of endocannabinoids
in dopamine-related pathophysiological responses, we assessed endocannabinoid signaling
in DAT KO mice and evaluated the ability of endocannabinoid ligands to normalize behavioral
deficits, namely spontaneous hyperlocomotion in these mice.
Results
In DAT KO mice, we found markedly reduced anandamide levels, specifically in striatum,
the dopamine nerve terminal region. Furthermore, three distinct indirect endocannabinoid
agonists, the selective anandamide reuptake inhibitors AM404 and VDM11 and the fatty
acid amidohydrolase inhibitor AA5HT, attenuated spontaneous hyperlocomotion in DAT
KO mice. The hypolocomotor effects of AM404, VDM11, and AA5HT were significantly attenuated
by co-administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist
capsazepine but not the selective cannabinoid type 1 (CB1)receptor antagonist AM251.
Interestingly, TRPV1 binding was increased in the striatum of DAT KO mice, while CB1
receptor binding was unaffected.
Conclusions
These data indicate a dysregulated striatal endocannabinoid neurotransmission associated
with hyperdopaminergic state. Restoring endocannabinoid homeostasis in active synapses
might constitute an alternative therapeutic strategy for disorders associated with
hyperdopaminergia. In this process, TRPV1 receptors seem to play a key role and represent
a novel promising pharmacological target.
Key Words
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Article info
Publication history
Published online: October 04, 2005
Accepted:
August 9,
2005
Received in revised form:
July 26,
2005
Received:
May 4,
2005
Identification
Copyright
© 2005 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
