Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure.
Alexander F. Hoffman, Murat Oz, Tara Caulder, Carl R. Lupica
The Journal of neuroscience : the official journal of the Society for Neuroscience June 15, 2003 DOI: 10.1523/jneurosci.23-12-04815.2003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study (animal model, electrophysiology) Peer reviewed |
|---|---|
| Population | Rat brain slices containing the nucleus accumbens |
| Interventions | Delta9-tetrahydrocannabinol (THC) WIN55 212-2 |
| Topics | Depression |
| Key points | Chronic exposure to THC or WIN55,212-2 reduced the sensitivity of GABAergic and glutamatergic synapses to cannabinoids and opioids, and completely blocked endocannabinoid-mediated LTD in the nucleus accumbens. |
Abstract
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, Delta9-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 mu-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 Delta9-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.