Elsevier

Biological Psychiatry

Volume 59, Issue 6, 15 March 2006, Pages 508-515
Biological Psychiatry

Original article
Endocannabinoids Activate Transient Receptor Potential Vanilloid 1 Receptors to Reduce Hyperdopaminergia-Related Hyperactivity: Therapeutic Implications

https://doi.org/10.1016/j.biopsych.2005.08.019Get rights and content

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.

Section snippets

Animals

Dopamine transporter wild-type (WT), heterozygous (HZ), and KO mice of the B6xD2F1 background were used in this study. Breeding, genotyping, and maintenance of the mice were as previously described (Morice et al 2005). All experiments were carried out in accordance with the European Communities Council Directive (86/809/EEC) regarding the care and use of animals for experimental procedures and approved by the local ethical committee.

Drugs

The AM251and AM404 (both from Tocris, Illkirch, France) and

Region-Specific Modulation of Anandamide Levels in DAT KO Mice

Tissue levels of the major endocannabinoid anandamide were measured in the hippocampus, cortex, cerebellum, and striatum of DAT WT, HZ, and KO mice. We show that in DAT KO mice, anandamide levels were significantly reduced by 30%, specifically in the striatum [F(2,35) = 3.85, p < .05; Figure 1]. No difference in anandamide levels was seen in the other regions tested (Figure 1).

The Cannabinoid Antagonist AM251 Does Not Affect Locomotion in the DAT KO Mice

Cannabinoid type 1 receptor antagonists have been shown to effectively attenuate psychostimulant-induced

Discussion

In the present study, we investigated the interactions between dopamine and endocannabinoid systems using a well-established animal model of hyperdopaminergia, the DAT KO mice. The tissue levels of the major endocannabinoid anandamide were measured in the hippocampus, cortex, cerebellum, and striatum of DAT WT, HZ, and KO mice. In the DAT KO mice, anandamide levels were significantly diminished, specifically in the striatum, the forebrain dopamine nerve terminal region, which has been

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