Opposite function of dopamine D1 and N-methyl-D-aspartate receptors in striatal cannabinoid-mediated signaling.
Tanya L Daigle, William C. Wetsel, Marc G. Caron
European Journal of Neuroscience November 2011 DOI: 10.1111/j.1460-9568.2011.07874.x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study using knockout mouse models Peer reviewed |
|---|---|
| Population | C57BL/6J mice and knockout mouse models (dopamine D1 receptor knockout, NMDA receptor knockdown, dopamine D2 receptor knockout, beta-arrestin-1 or -2 knockout) |
| Interventions | HU-210 AM251 |
| Key points | Cannabinoid agonists HU-210 and delta-9-THC decreased ERK1/2 phosphorylation in mouse dorsal striatum via CB1 receptors. This effect was enhanced in dopamine D1 receptor knockout mice but absent in NMDA receptor knockdown mice, while D2 receptor and beta-arrestin deletions had no effect. The authors propose that dopamine D1 and NMDA receptors oppositely regulate striatal CB1 receptor signaling. |
Abstract
It is well established that the cannabinoid and dopamine systems interact at various levels to regulate basal ganglia function. Although it is well known that acute administration of cannabinoids to mice can modify dopamine-dependent behaviors, the intraneuronal signaling pathways employed by these agents in the striatum are not well understood. Here we used knockout mouse models to examine the regulation of striatal extracellular-signal-regulated kinases 1 and 2 (ERK1/2) signaling by behaviorally relevant doses of cannabinoids. This cellular pathway has been implicated as a central mediator of drug reward and synaptic plasticity. In C57BL/6J mice, acute administration of the cannabinoid agonists, (-)-11-hydroxydimethylheptyl-Δ8-tetrahydrocannabinol (HU-210) and delta-9-tetrahydrocannabinol (Δ(9) -THC), promoted a dose- and time-dependent decrease in the phosphorylation of ERK1/2 in dorsal striatum. Co-administration of the CB1 cannabinoid receptor antagonist N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide(AM251) with HU-210 prevented ERK1/2 inactivation, indicating a requirement for activation of this receptor. In dopamine D1 receptor knockout animals treated with HU-210, the magnitude of the HU-210-dependent decrease in striatal ERK1/2 signaling was greater than in wild-type controls. In contrast, HU-210 administration to N-methyl-D-aspartate receptor knockdown mice was ineffective at promoting striatal ERK1/2 inactivation. Genetic deletion of other potential ERK1/2 mediators, the dopamine D2 receptors or β-arrestin-1 or -2, did not affect the HU-210-induced modulation of ERK1/2 signaling in the striatum. These results support the hypothesis that dopamine D1 receptors and N-methyl-D-aspartate receptors act in an opposite manner to regulate striatal CB1 cannabinoid receptor signal transduction.