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Sperlagh B, Windisch K, Ando RD, Sylvester Vizi E: Neurochemical evidence that stimulation of CB1 cannabinoid receptors on GABAergic nerve terminals activates the dopaminergic reward system by increasing dopamine release in the rat nucleus accumbens. Neurochem Int. 2009 Jun;54(7):452-7. Epub 2009 Feb 6.
We examined the effect of cannabinoid receptor activation on basal and electrical field simulation-evoked (25 V, 2 Hz, 240 shocks) [(3) H] dopamine efflux in the isolated rat nucleus accumbens in a preparation, in which any effect on the dendrites or somata of ventral tegmental projection neurons was excluded. The cannabinoid agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo [1,2,3-de]-1,4 -benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212-2, 100 nM) significantly enhanced stimulation-evoked [(3) H] dopamine release in the presence of the selective dopamine transporter inhibitor 1-[2-[bis-(4-fluorophenyl) methoxy] ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride (GBR12909, 100 nM). GBR12909 (100 nM-1 microM), when added alone, increased the evoked [(3) H] dopamine efflux in a concentration-dependent manner. The stimulatory effect of WIN55,212-2 on the evoked tritium efflux was inhibited by the selective CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyr azole-3-carboxamide (AM251, 100 nM) and by the GABA (A) receptor antagonist bicuculline (10 microM). Repeated application of N-methyl-d aspartate (1 mM) under Mg (2+)-free conditions, which directly acts on dopaminergic terminals, reversibly increased the tritium efflux, but WIN55,212-2 did not affect N-methyl-d aspartate-evoked [(3) H] dopamine efflux, indicating that WIN55,212-2 has no direct action on dopaminergic nerve terminals. AM251 (100 nM) alone also did not have an effect on electrical stimulation-evoked [(3) H] dopamine efflux. Likewise, the selective CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone (AM630, 0.3 microM) and the anandamide transport inhibitor (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (VDM11, 10 microM) had no significant effect on electrically evoked [(3) H] dopamine release. This is the first neurochemical evidence that the activation of CB1 cannabinoid receptors leads to the augmentation of [(3) H] dopamine efflux via a local GABA (A) receptor-mediated disinhibitory mechanism in the rat nucleus accumbens. |
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