PT  - JOURNAL ARTICLE
AU  - Alexander F. Hoffman
AU  - Murat Oz
AU  - Tara Caulder
AU  - Carl R. Lupica
TI  - Functional Tolerance and Blockade of Long-Term Depression at Synapses in the Nucleus Accumbens after Chronic Cannabinoid Exposure
AID  - 10.1523/JNEUROSCI.23-12-04815.2003
DP  - 2003 Jun 15
TA  - The Journal of Neuroscience
PG  - 4815--4820
VI  - 23
IP  - 12
4099  - http://www.jneurosci.org/content/23/12/4815.short
4100  - http://www.jneurosci.org/content/23/12/4815.full
SO  - J. Neurosci.2003 Jun 15; 23
AB  - The rewarding properties of the psychoactive constituents of marijuana, termed “cannabinoids,” may reflect actions on synaptic transmission in the nucleus accumbens (NAc). Furthermore, long-term changes in these synapses may support the addictive process. Excitatory and inhibitory synapses are acutely inhibited by cannabinoids in the NAc, and endogenous cannabinoids (endocannabinoids) play a critical role in the expression of long-term depression (LTD) of excitatory cortical afferents in this structure. Because humans often use marijuana for prolonged periods, we examined the impact of long-term cannabinoid exposure on synaptic processes in an animal model. Electrophysiological recordings in rat brain slices containing the NAc were performed after chronic exposure to vehicle solution, Δ9-tetrahydrocannabinol (THC), or the cannabinoid agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2). Extracellular glutamatergic postsynaptic potentials and whole-cell GABAergic IPSCs were concentration-dependently inhibited by WIN55,212-2 in slices from naive or vehicle-treated animals. However, the sensitivity to WIN55,212-2 was diminished in chronic agonist-treated animals. In addition, cross-tolerance to the inhibitory effect of the μ-opioid agonist Tyr-d-Ala2, N-CH3-Phe4,Gly-ol-enkephalin was observed. Endocannabinoid-mediated LTD was initiated via electrical stimulation (5 min, 10 Hz) of glutamatergic afferents to the NAc and was completely blocked by the cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] in vehicle-treated animals. LTD was not observed in brain slices from rats chronically treated with Δ9-THC or WIN55,212-2. These data demonstrate that long-term exposure to the active ingredient of marijuana blocks synaptic plasticity in the NAc and reduces the sensitivity of GABAergic and glutamatergic synapses to both cannabinoids and opioids.