Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity

Glutamatergic synaptic transmission within the striatum and prefrontal cortex regulates the neuronal synthesis of endocannabinoids. Because a primary role of dopamine is to modulate this excitatory transmission, we tested the hypothesis that dopaminergic transmission modulates endocannabinoid content in the limbic forebrain. Liquid chromatography/mass spectrometry was used to determine endogenous anandamide and 2-arachidonylglycerol (2-AG) contents within the limbic forebrain of mice after pharmacological manipulation of dopaminergic transmission. Increasing synaptic dopamine concentrations with methylphenidate significantly and dose dependently decreased both anandamide and 2-AG content. The selective dopamine reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) also significantly decreased anandamide and tended to decrease 2-AG content. The D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) increased and the D1 receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 33939) decreased anandamide content. 2-AG content was unaffected by SCH 23390 but was significantly increased by the D2 receptor antagonist eticlopride, which had no effect on anandamide content. The D2 agonist quinpirole had a biphasic effect on anandamide content with low, autoreceptor-preferring doses increasing anandamide and higher doses decreasing it back toward control. Quinpirole did not significantly affect 2-AG content. Together, these data indicate that endogenous dopamine exerts a differential, net suppressive effect upon anandamide and 2-AG content via activation of D1 and D2 receptors, respectively. These data are consistent with the hypothesis that modulation of endocannabinoid content by dopamine is secondary to changes in glutamatergic transmission, and they provide a pharmacological framework for the rational development of endocannabinoid-based therapeutic interventions for dopamine-related neuropsychiatric disorders.