Direct actions of cannabinoids on synaptic transmission in the nucleus accumbens: A comparison with opioids

The nucleus accumbens (NAc) represents a critical site for the rewarding an d addictive properties of several classes of abused drugs. The medium spiny GABAergic projection neurons (MSNs) in the NAc receive innervation from in trinsic GABAergic interneurons and glutamatergic innervation from extrinsic sources. Both GABA and glutamate release onto MSNs are inhibited by drugs of abuse, suggesting that this action may contribute to their rewarding pro perties. To investigate the actions of cannabinoids in the NAc, we performe d whole cell recordings from MSNs located in the shell region in rat brain slices. The cannabinoid agonist WIN 55,212-2 (1 muM) had no effect on the r esting membrane potential, input resistance, or whole cell conductance, sug gesting no direct postsynaptic effects. Evoked glutamatergic excitatory pos tsynaptic currents (EPSCs) were inhibited to a much greater extent by [Tyr- D-Ala(2), N-CH3-Phe(4), Gly-ol-enkephalin] (DAMGO, similar to 35%) than by WIN 55,212-2 (<20%), and an analysis of miniature EPSCs suggested that the effects of DAMGO were presynaptic, whereas those of WIN 55,212-2 were posts ynaptic. However, electrically evoked GABAergic inhibitory postsynaptic cur rents (evIPSCs), were reduced by WIN 55,212-2 in every neuron tested (EC50 = 123 nM; 60% maximal inhibition), and the inhibition of IPSCs by WIN 55,21 2-2 was completely antagonized by the CB1 receptor antagonist SR141716A (1 <mu>M). In contrast evIPSCs were inhibited in similar to 50% of MSNs by the mu/delta opioid agonist D-Ala(2)-methionine(2)-enkephalin-amide and were c ompletely unaffected by a selective mu -opioid receptor agonist (DAMGO). WI N 55,212-2 also increased paired-pulse facilitation of the evIPSCs and did not alter the amplitudes of tetrodotoxin-resistant miniature IPSCs, suggest ing a presynaptic action. Taken together, these data suggest that cannabino ids and opioids differentially modulate inhibitory and excitatory synaptic transmission in the NAc and that the abuse liability of marijuana may be re lated to the direct actions of cannabinoids in this structure.