The endocannabinoid (eCB) system participates in behavioral adaptations that accompany chronic exposureto opiates; the cellular bases for these changes are not known. One form of eCB signaling involves thepostsynaptic production of eCBs that diffuse in a retrograde manner to act on presynaptic CB1 receptors toinhibit neurotransmitter release. In the prior funding period a cell culture model that displays robust eCBmediateddepolarization-induced suppression of excitatory synaptic transmission (DSE) was developed.Preliminary data show that this model is well suited for examining adaptive changes in retrograde eCBsignaling between hippocampal neurons.
Three specific aims will examine the effects of prolonged exposureto opiates on the eCB system. 1) Opiates exert marked effects on synaptic transmission betweenhippocampal neurons. The hypothesis that prolonged exposure to opiates will up-regulate eCB signaling willbe tested. 2) Chronic exposure to opiate agonists increases the expression of brain derived neurotrophicfactor (BDNF) and increases excitatory synaptic transmission. The hypothesis that BDNF and intensesynaptic activity will produce a long-lasting strengthening of the eCB system will be tested. 3) CB1antagonists show promise for the treatment of opiate addiction. How prolonged CB1 receptor blockadeaffects the function of the eCB system is not known. The hypothesis that removal of a CB1 receptorantagonist following prolonged blockade of presynaptic CB1 receptors will result in enhancedendocannabinoid signaling will be tested. Overall, these studies will provide insight into whether the pre- andpost-synaptic elements of the eCB system change in parallel during exposure to and withdrawal fromopiates. Understanding the plasticity of the system as a whole will aid in developing agents to modulate eCBsignaling during withdrawal and abstinence from opiates.
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