TY - JOUR
T1 - CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum
AU - Price, David A.
AU - Owens, William A.
AU - Gould, Georgianna G.
AU - Frazer, Alan
AU - Roberts, James
AU - Daws, Lynette C.
AU - Giuffrida, Andrea
PY - 2007/4
Y1 - 2007/4
N2 - Cannabinoid drugs are known to affect dopaminergic neurotransmission in the basal ganglia circuitry. In this study, we used in vitro and in vivo techniques to investigate whether cannabinoid agonists and antagonist could affect dopaminergic transmission in the striatum by acting at the dopamine transporter. Incubation of striatal synaptosomes with the cannabinoid agonists WIN55,212-2 or methanandamide decreased dopamine uptake (IC50 = 2.0 μmol/L and 3.1 μmol/L, respectively). A similar inhibitory effect was observed after application of the inactive WIN55,212-2 isomer, S(-)WIN55,212-3. The CB 1 antagonist AM251 did not reverse WIN55,212-2 effect but rather mimicked it. WIN55,212-2 and AM251 partially displaced the binding of the cocaine analog [3H]WIN35,428, thus acting as dopamine transporter pseudo-substrates in the high micromolar range. High-speed chronoamperometry measurements showed that WIN55,212-2 (4 mg/kg, i.p.) caused significant release of endogenous dopamine via activation of CB1 receptors, followed by a reduction of dopamine clearance. This reduction was CB1-independent, as it was mimicked by S(-)WIN55,212-3. Administration of AM251 (1 and 4 mg/kg, i.p.) increased the signal amplitude and reduced the clearance of dopamine pressure ejected into the striatum. These results indicate that both cannabinoid agonists and antagonists inhibit dopamine transporter activity via molecular targets other than CB1 receptors.
AB - Cannabinoid drugs are known to affect dopaminergic neurotransmission in the basal ganglia circuitry. In this study, we used in vitro and in vivo techniques to investigate whether cannabinoid agonists and antagonist could affect dopaminergic transmission in the striatum by acting at the dopamine transporter. Incubation of striatal synaptosomes with the cannabinoid agonists WIN55,212-2 or methanandamide decreased dopamine uptake (IC50 = 2.0 μmol/L and 3.1 μmol/L, respectively). A similar inhibitory effect was observed after application of the inactive WIN55,212-2 isomer, S(-)WIN55,212-3. The CB 1 antagonist AM251 did not reverse WIN55,212-2 effect but rather mimicked it. WIN55,212-2 and AM251 partially displaced the binding of the cocaine analog [3H]WIN35,428, thus acting as dopamine transporter pseudo-substrates in the high micromolar range. High-speed chronoamperometry measurements showed that WIN55,212-2 (4 mg/kg, i.p.) caused significant release of endogenous dopamine via activation of CB1 receptors, followed by a reduction of dopamine clearance. This reduction was CB1-independent, as it was mimicked by S(-)WIN55,212-3. Administration of AM251 (1 and 4 mg/kg, i.p.) increased the signal amplitude and reduced the clearance of dopamine pressure ejected into the striatum. These results indicate that both cannabinoid agonists and antagonists inhibit dopamine transporter activity via molecular targets other than CB1 receptors.
KW - Anandamide
KW - Basal ganglia
KW - Cannabinoid
KW - Chronoamperometry
KW - Dopamine transporter
KW - Striatum
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U2 - 10.1111/j.1471-4159.2006.04383.x
DO - 10.1111/j.1471-4159.2006.04383.x
M3 - Article
C2 - 17250681
AN - SCOPUS:34047181576
SN - 0022-3042
VL - 101
SP - 389
EP - 396
JO - Journal of neurochemistry
JF - Journal of neurochemistry
IS - 2
ER -