The psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC), produces euphoria in humans. THC activates cannabinoid receptors that modulate ion channels and second messenger systems. In order to link molecular studies to behavioral experiments, it is essential to know the effects of these drugs on synaptic networks. Cannabimimetics inhibited glutamatergic synaptic transmission but failed to affect inhibitor neurotransmission between cultured rat hippocampal neurons. Anatomical evidence suggests that cannabinoid receptors are located on gamma- aminobutyric acid (GABA) containing striatal projections to the substantia nigra. Experiments are proposed to determine the effects of the cannabimimetic drugs on synaptic transmission between cells cultured from the rat striatum and substantia nigra. The first objective is to determine whether activation of cannabinoid receptors inhibit GABAergic neurotransmission. Neurons from striatum and substantia nigra will be grown together in primary tissue culture and synaptic activity recorded. The whole-cell configuration of the patch clamp technique will be used to record inhibitory and excitatory postsynaptic currents (IPSCs & EPSCs) evoked by stimulation of the presynaptic neuron with an extracellular electrode. The mechanism of cannabinoid-mediated effects in striatonigral co-vultures will be determined. Anatomical data, previous work with hippocampal synapses, and cannabinoid-mediated effects on ion channels, all suggest that cannabinoid receptors participate in presynaptic inhibition. A presynaptic site of action predicts that cannabinoid receptor agonists will increase the coefficient of variation of evoked postsynaptic currents, increase the number of synaptic failures, and not affect responses elicited by direct application of agonist. The pharmacology of cannabinoid-mediated effects in striatonigral co-cultures will be characterized. Pharmacologic properties to be evaluated include the potency of agonists, the intrinsic activity of partial agonists and the rate of desensitization to agonists. These studies will enhance our understanding of now cannabinoids affect synaptic transmission. Effects on inhibitory systems have not previously been examined. If the pharmacological effects of the cannabinoids are specific to particular brain regions it might be possible to separate their abuse potential from their clinically useful attributes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA011806-03
Application #
6338715
Study Section
Project Start
2000-07-22
Project End
2001-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$408,465
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2017) Phosphorylation of poly(rC) binding protein 1 (PCBP1) contributes to stabilization of mu opioid receptor (MOR) mRNA via interaction with AU-rich element RNA-binding protein 1 (AUF1) and poly A binding protein (PABP). Gene 598:113-130
Kibaly, Cherkaouia; Lin, Hong-Yiou; Loh, Horace H et al. (2017) Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus does not affect morphine tolerance in vivo. Pharmacol Res 119:153-168
Kibaly, Cherkaouia; Kam, Angel Y F; Loh, Horace H et al. (2016) Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion. Biol Psychiatry 79:906-16
Meng, Jingjing; Roy, Sabita (2016) Study of Epithelium Barrier Functions by Real-time TER Measurement. Bio Protoc 6:
Banerjee, S; Sindberg, G; Wang, F et al. (2016) Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 9:1418-1428
Banerjee, Santanu; Ninkovic, Jana; Meng, Jingjing et al. (2015) Morphine compromises bronchial epithelial TLR2/IL17R signaling crosstalk, necessary for lung IL17 homeostasis. Sci Rep 5:11384
Wang, Yan; Wang, Yan-Xia; Liu, Ting et al. (2015) ?-Opioid receptor attenuates A? oligomers-induced neurotoxicity through mTOR signaling. CNS Neurosci Ther 21:8-14
Meng, Jingjing; Banerjee, Santanu; Li, Dan et al. (2015) Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. Sci Rep 5:10918
Kotecki, Lydia; Hearing, Matthew; McCall, Nora M et al. (2015) GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner. J Neurosci 35:7131-42
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2015) Analysis of epigenetic mechanisms regulating opioid receptor gene transcription. Methods Mol Biol 1230:39-51

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