RT Journal Article
SR Electronic
T1 Cannabinoid Agonists Stimulate [<sup>3</sup>H]GABA Release in the Globus Pallidus of the Rat When G<sub>i</sub> Protein-Receptor Coupling Is Restricted: Role of Dopamine D2 Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 822
OP 828
DO 10.1124/jpet.108.145425
VO 328
IS 3
A1 Brenda Gonzalez
A1 Francisco Paz
A1 Leonor Florán
A1 Jorge Aceves
A1 David Erlij
A1 Benjamín Florán
YR 2009
UL http://jpet.aspetjournals.org/content/328/3/822.abstract
AB The motor effects of cannabinoids in the globus pallidus appear to be caused by increases in interstitial GABA. To elucidate the mechanism of this response, we investigated the effect of the selective cannabinoid type 1 receptor (CB1) cannabinoid agonist arachidonyl-2-chloroethylamide (ACEA) on [3H]GABA release in slices of the rat globus pallidus. ACEA had two effects: concentrations between 10-8 and 10-6 M stimulated release, whereas higher concentrations (IC50 ≈ 10-6 M) inhibited it. Another cannabinoid agonist, WIN-55,212-2, also had bimodal effects on release. Studies of cAMP production indicate that under conditions of low Gi/o, availability the coupling of CB1 receptors with Gi/o proteins can be changed into CB1:Gs/olf coupling; therefore, we determined the effects of conditions that limit Gi/o availability on [3H]GABA release. Blockers of Gi/o protein interactions, pertussis toxin and N-ethylmaleimide, transformed the inhibitory effects of ACEA on GABA release into stimulation. It also has been suggested that stimulation of D2 receptors can reduce Gi/o availability. Blocking D2 receptors with sulpiride [(S)-5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamidersqb] or depleting dopamine with reserpine inhibited the ACEA-induced stimulation of release. Thus, the D2 dependence of stimulation is consistent with the proposal that D2 receptors reduce Gi/o proteins available for binding to the CB1 receptor. In summary, CB1 receptor activation has dual effects on GABA release in the globus pallidus. Low concentrations stimulate release through a process that depends on activation of dopamine D2 receptors that may limit Gi/o protein availability. Higher concentrations of cannabinoid inhibit GABA release through mechanisms that are independent of D2 receptor activation. The American Society for Pharmacology and Experimental Therapeutics