pubmed.ncbi.nlm.nih.gov

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens - PubMed

  • ️Tue Jan 01 2002

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

David Robbe et al. Proc Natl Acad Sci U S A. 2002.

Abstract

Do endocannabinoids (eCBs) participate in long-term synaptic plasticity in the brain? Using pharmacological approaches and genetically altered mice, we show that stimulation of prelimbic cortex afferents at naturally occurring frequencies causes a long-term depression of nucleus accumbens glutamatergic synapses mediated by eCB release and presynaptic CB1 receptors. Translation of glutamate synaptic transmission into eCB retrograde signaling involved metabotropic glutamate receptors and postsynaptic intracellular Ca(2+) stores. These findings unveil the role of the eCB system in activity-dependent long-term synaptic plasticity and identify a mechanism by which marijuana can alter synaptic functions in the endogenous brain reward system.

PubMed Disclaimer

Figures

Figure 1
Figure 1

eCBs mediate LTD in the NAc. (A) Typical experiment where tetanic stimulation (13 Hz during 10 min) of prelimbic cortical afferents induced a LTD of eEPSC (see Fig. 2B for averaged data). (Inset) Superimposed traces (average of 10 consecutives eEPSCs) taken at time indicated on graph. (Bar = 20 msec, 200 pA.) (B) Typical experiment showing saturation of 13-Hz LTD (as observed in four other experiments). (C) LTD is eliminated in slices perfused with the CB1 antagonist SR141716A (1 μM) (fEPSP was 96.3 ± 3.4% of baseline at 60 min in the presence of antagonist; n = 11, P <0.05 vs. control without antagonist). (D) 13-Hz LTD is eliminated in CB1−/− mice, compared with their wild-type littermates. fEPSP 60 min after tetanus measured 104.2 ± 5.1% of baseline in CB1−/− and 82.7 ± 3.8% in CB1+/+, P < 0.05.

Figure 2
Figure 2

eCB-LTD is occluded by CB1 activation and is presynaptic. (A) Typical experiment (time course) and group data (histogram) where the CB1 agonist WIN 55,212,2 (300 nM) occluded eCB-LTD. In the presence of WIN 55,512,2 fEPSP measured 106.7 ± 8.8% of baseline, 60 min after LTD-induction; n = 6, P < 0.05 vs. control without WIN 55,212,2. (B) The eCB transporter blocker AM-404 inhibits fEPSP in a SR141716A-sensitive manner (fEPSP measured 88.4 ± 2.2% of baseline 15 min after AM-404 application, n = 7, and 97.9 ± 4.2% in the presence of SR141716A, n = 5, P < 0.05) and partially occludes eCB-LTD. In the presence of AM-404, fEPSP measured 94.5 ± 3.9% of baseline 60 min after tetanus, n = 7, P < 0.06 vs. control without AM-404. (C) Representative consecutive 1-sec current sweeps from a cell where sEPSCs were recorded in control and 30 min after tetanic stimulation. (Bar = 30 pA, 200 msec.) (D) sEPSC amplitude distribution was unchanged (n = 3, Kolmogorov–Smirnof test, P > 0.001). On the contrary, the distribution of the time intervals between successive sEPSCs in these neurons shows a reduction of sEPSC frequency after tetanus (Kolmogorov–Smirnof test P < 0.0001).

Figure 3
Figure 3

Postsynaptic intracellular Ca2+ rise is necessary to eCB-LTD. (A) The membrane-permeant Ca2+-chelator BAPTA-AM markedly reduced the fEPSP (45.5 ± 7.2% of baseline in BAPTA-AM, n = 4, not shown), suggesting that this concentration effectively buffered intracellular Ca2+. Preincubation of slices with BAPTA-AM (50 μM) prevented eCB-LTD: fEPSP was 99.6 ± 7.0% of baseline at 60 min, n = 6, P < 0.05 in BAPTA-AM-treated slices vs. control without BAPTA-AM. (B) In whole-cell experiment, filling the recording pipettes with BAPTA (20 mM) also suppressed eCB-LTD: eEPSC was 153.4 ± 26.6% of baseline at 30 min in the presence of intracellular BAPTA, n = 5, P < 0.05 vs. control without BAPTA.

Figure 4
Figure 4

eCB-LTD is mediated by mGlu5 activation and rise of Ca2+ from intracellular store. (A) Antagonists of ionotropic GluR (kynurenate), NMDAR (D-AP5, 50 μM), mGlu2/3 [200 nM 2-amino-2-(2-carboxycyclopropan-1-yl)-3-(dibenzopyran-4-yl) propanoic acid and 200 μM (2S),-α-ethylglutamic acid], and D1 and D2 receptors (SCH23390 and sulpiride, 30 μM) do not affect eCB-LTD: fEPSP measured 81.1 ± 8.8% (n = 6), 84.0 ± 3.5% (n = 5), 73.1 ± 5.0% (n = 3), 86.6 ± 7.9% (n = 8) and 79.5 ± 7.2% (n = 7) of baseline, at 60 min, P = 0.8, 0.2, 0.3, 0.9, and 0.4, respectively, vs. control in the absence of antagonists. (B) The mGlu antagonist LY354740 (50 μM) and the highly specific mGlu5 antagonist 2-methyl-6-(phenylethynyl) pyridine (10 μM) suppressed eCB-LTD: fEPSP measured 109.0 ± 5.2% (n = 6) and 102.1 ± 3.0% (n = 7) of baseline at 60 min, P < 0.05 vs. control without antagonist, respectively. (C) Activation of mGlu5 with (S)-DHPG induced a form of LTD that was absent in CB1−/− mice: 30 min after (S)-DHPG, fEPSP measured 101.9 ± 4.9% of baseline in CB1−/− (n = 4, white dots) and 86.7 ± 5.2% in CB1+/+ (n = 9, black dots), P < 0.05. (D) (S)-DHPG-induced-LTD is occluded after saturation of 13-Hz/eCB-LTD: at 30 min fEPSP measured 88.7 ± 2.1% (n = 13, black dots) and 100.2 ± 3.6% (n = 6, white dots) of baseline, respectively. (E) Blockade of mGlu5/eCB-LTD after depletion of Ca2+ intracellular pools with the Ca2+-ATPase inhibitor thapsigargin. (F) Role of ryanodine-sensitive intracellular Ca2+ stores in eCB-LTD. Ryanodine (20 μM) inhibited eCB-LTD: fEPSP measured 109.7 ± 12.6% (n = 7) of baseline at 60 min after ryanodine (20 μM, 1–2 h) P = 0.03 vs. control without inhibitor.

Similar articles

Cited by

References

    1. Ameri A. Prog Neurobiol. 1999;58:315–348. - PubMed
    1. Felder C C, Glass M. Annu Rev Pharmacol Toxicol. 1998;38:179–200. - PubMed
    1. Hoffman A F, Lupica C R. J Neurosci. 2000;20:2470–2479. - PMC - PubMed
    1. Sullivan J M. J Neurophysiol. 1999;82:1286–1294. - PubMed
    1. Chan P K, Chan S C, Yung W H. NeuroReport. 1998;9:671–675. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources