The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. The NAc medium spiny GABAergic neurons (MSNs) receive innervation from other intrinsic MSNs, and glutamatergic innervation from extrinsic sources. Both GABAergic and glutamatergic synapses onto MSNs are inhibited by drugs of abuse, suggesting that this action may contribute to the rewarding properties of these drugs. To investigate the actions of cannabinoids (CBs) in the NAc, we performed whole-cell recordings from MSNs in rat brain slices. The CB agonist WIN 55,212-2 (1 uM) had no effect on the resting membrane potential, input resistance, or whole cell conductance, suggesting no direct postsynaptic effects. However, electrically evoked GABAergic IPSCs (evIPSCs), were reduced by WIN 55,212-2 (EC50 = 123 nM; 60% maximal inhibition), but were unaffected by the selective u-opioid receptor agonist DAMGO. In addition, the inhibition of IPSCs was completely antagonized by the CB1 receptor antagonist SR141716A (1 uM). WIN 55,212-2 also increased paired-pulse facilitation of the evIPSCs, but did not alter the amplitudes of tetrodotoxin-resistant miniature IPSCs, suggesting a presynaptic locus of action. Evoked EPSCs were inhibited by WIN 55,212-2 by a much smaller degree (< 20%), compared to its effects on evIPSCs, or to the effects of DAMGO on evEPSCs (> 35%). Taken together, these data suggest that CBs and opioids differentially modulate inhibitory and excitatory synaptic transmission in the NAc, and that the abuse liability of marijuana may be related to the direct actions of CBs in this structure.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Intramural Research (Z01)
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National Institute on Drug Abuse
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Lupica, Carl R; Riegel, Arthur C (2005) Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 48:1105-16
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