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Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus.

Abstract

Marijuana impairs learning and memory through actions of its psychoactive constituent, delta-9-tetrahydrocannabinol (Delta(9)-THC), in the hippocampus, through activation of cannabinoid CB1 receptors (CB1R). CB1Rs are found on glutamate and GABA neuron axon terminals in the hippocampus where they control neurotransmitter release. Previous studies suggest that Delta(9)-THC is a partial agonist of CB1Rs on glutamate axon terminals in the hippocampus, whereas its effects on GABA terminals have not been described. Using whole-cell electrophysiology in brain slices from C57BL6/J mice, we examined Delta(9)-THC effects on synaptic GABA IPSCs and postsynaptic GABA currents elicited by laser-induced photo-uncaging (photolysis) of alpha-carboxy-2-nitrobenzyl (CNB) caged GABA. Despite robust inhibition of synaptic IPSCs in wildtype mice by the full synthetic agonist WIN55,212-2, using a Tween-80 and DMSO vehicle, Delta(9)-THC had no effects on IPSCs in this, or in a low concentration of another vehicle, randomly-methylated beta-cyclodextrin (RAMEB, 0.023%). However, IPSCs were inhibited by Delta(9)-THC in 0.1% RAMEB, but not in neurons from CB1R knockout mice. Whereas Delta(9)-THC did not affect photolysis-evoked GABA currents, these responses were prolonged by a GABA uptake inhibitor. Concentration-response curves revealed that the maximal effects of Delta(9)-THC and WIN55,212-2 were similar, indicating that Delta(9)-THC is a full agonist at CB1Rs on GABA axon terminals. These results suggest that Delta(9)-THC inhibits GABA release, but does not directly alter GABA(A) receptors or GABA uptake in the hippocampus. Furthermore, full agonist effects of Delta(9)-THC on IPSCs likely result from a much higher expression of CB1Rs on GABA versus glutamate axon terminals in the hippocampus.

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    ,

    Electrophysiology Research Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.

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    Source

    Neuropharmacology 59:1-2 pg 121-7

    MeSH

    Animals
    Axons
    Dose-Response Relationship, Drug
    Dronabinol
    Hippocampus
    In Vitro Techniques
    Inhibitory Postsynaptic Potentials
    Membrane Potentials
    Mice
    Mice, Inbred C57BL
    Mice, Knockout
    Neurons
    Psychotropic Drugs
    Receptor, Cannabinoid, CB1
    Receptors, GABA-A
    gamma-Aminobutyric Acid

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Intramural

    Language

    eng

    PubMed ID

    20417220

    Citation

    Laaris, Nora, et al. "Delta9-tetrahydrocannabinol Is a Full Agonist at CB1 Receptors On GABA Neuron Axon Terminals in the Hippocampus." Neuropharmacology, vol. 59, no. 1-2, 2010, pp. 121-7.
    Laaris N, Good CH, Lupica CR. Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology. 2010;59(1-2):121-7.
    Laaris, N., Good, C. H., & Lupica, C. R. (2010). Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology, 59(1-2), pp. 121-7. doi:10.1016/j.neuropharm.2010.04.013.
    Laaris N, Good CH, Lupica CR. Delta9-tetrahydrocannabinol Is a Full Agonist at CB1 Receptors On GABA Neuron Axon Terminals in the Hippocampus. Neuropharmacology. 2010;59(1-2):121-7. PubMed PMID: 20417220.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. AU - Laaris,Nora, AU - Good,Cameron H, AU - Lupica,Carl R, Y1 - 2010/04/22/ PY - 2009/12/09/received PY - 2010/04/12/revised PY - 2010/04/15/accepted PY - 2010/4/27/entrez PY - 2010/4/27/pubmed PY - 2010/10/21/medline SP - 121 EP - 7 JF - Neuropharmacology JO - Neuropharmacology VL - 59 IS - 1-2 N2 - Marijuana impairs learning and memory through actions of its psychoactive constituent, delta-9-tetrahydrocannabinol (Delta(9)-THC), in the hippocampus, through activation of cannabinoid CB1 receptors (CB1R). CB1Rs are found on glutamate and GABA neuron axon terminals in the hippocampus where they control neurotransmitter release. Previous studies suggest that Delta(9)-THC is a partial agonist of CB1Rs on glutamate axon terminals in the hippocampus, whereas its effects on GABA terminals have not been described. Using whole-cell electrophysiology in brain slices from C57BL6/J mice, we examined Delta(9)-THC effects on synaptic GABA IPSCs and postsynaptic GABA currents elicited by laser-induced photo-uncaging (photolysis) of alpha-carboxy-2-nitrobenzyl (CNB) caged GABA. Despite robust inhibition of synaptic IPSCs in wildtype mice by the full synthetic agonist WIN55,212-2, using a Tween-80 and DMSO vehicle, Delta(9)-THC had no effects on IPSCs in this, or in a low concentration of another vehicle, randomly-methylated beta-cyclodextrin (RAMEB, 0.023%). However, IPSCs were inhibited by Delta(9)-THC in 0.1% RAMEB, but not in neurons from CB1R knockout mice. Whereas Delta(9)-THC did not affect photolysis-evoked GABA currents, these responses were prolonged by a GABA uptake inhibitor. Concentration-response curves revealed that the maximal effects of Delta(9)-THC and WIN55,212-2 were similar, indicating that Delta(9)-THC is a full agonist at CB1Rs on GABA axon terminals. These results suggest that Delta(9)-THC inhibits GABA release, but does not directly alter GABA(A) receptors or GABA uptake in the hippocampus. Furthermore, full agonist effects of Delta(9)-THC on IPSCs likely result from a much higher expression of CB1Rs on GABA versus glutamate axon terminals in the hippocampus. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/20417220/abstract/Delta9_tetrahydrocannabinol_is_a_full_agonist_at_CB1_receptors_on_GABA_neuron_axon_terminals_in_the_hippocampus_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(10)00116-4 DB - PRIME DP - Unbound Medicine ER -