While abuse and addiction to opiates has been a long-standing problem, the recent surge in abuse of opiate analgesics foreshadows the potential for rising rates of addiction to opiates. Repeated administration of drugs of abuse, such as morphine, causes a progressive and persistent sensitization of its locomotor stimulant and positive reinforcing effects. Sensitization to morphine can be sustained for several months after drug cessation and serves as a useful animal model of plasticity and the neuroadaptations associated with repeated administration of opioids having abuse potential. Studies show that sensitization has a close relationship with relapse, compulsive drug-seeking, and drug-taking behavior. Recent evidence suggests a role for the hippocampus in controlling these long-lasting behavioral adaptations. Investigation of an opiate-induced sensitization may help us to better understand the relapse mechanisms and provide new strategies for the treatment of drug addiction. Additionally, the key role of hippocampal synapses in learning and memory suggests that an understanding of the role of its specialized subcellular compartments in addictive processes is essential. Glutamatergic systems are thought to be involved in opiate-induced neuronal and behavioral plasticity although the mechanisms underlying these effects are only beginning to be understood. We propose to analyze the role of synaptic AMPA glutamate receptors in the neuronal adaptations associated with repeated administration of morphine. The proposed experiments will test the hypothesis that repeated morphine administration modulates synaptic transmission and plasticity at hippocampal synapses by altering the expression and composition of AMPA glutamate receptors;and that these adaptive effects will persist over time leading to neuroadaptations in glutamatergic synaptic function which could be responsible for the long-term behavioral sensitization induced by repeated morphine administration.
In Specific Aim 1 we will analyze the synaptic mechanisms underlying the neuroadaptations initiated by repeated morphine administration which drive dynamic changes in the expression and composition of GluR subunits (GluR1/2/3) of AMPA glutamate receptors at hippocampal synapses and determine their correlation with long-term behavioral sensitization.
In Specific Aim 2 we will characterize the electrophysiological mechanisms contributing to GluR subunit composition at glutamatergic synapses during basal synaptic transmission and plasticity in the hippocampus following repeated morphine administration, and determine their persistence. These studies are significant because they elucidate key mechanisms underlying neuroadaptive changes in synaptic neurotransmission at hippocampal synapses and behavioral responses that occur upon repeated morphine exposure;in addition, they will provide insight into the neuronal adaptations that may lead to novel approaches for pharmacotherapeutic intervention of opiate addiction.
The long-term effects of repeated exposure to drugs of abuse are a major point of interest in the study of the pathophysiology of drug addiction. The repeated administration of a variety of potentially addictive drugs, such as morphine, produces increases in their motor-stimulant effects (called behavioral sensitization) and their incentive-motivational properties that persist many months after cessation of drug administration, thus mimicking long-term sensitivity to drugs observed in human addicts. The present proposal will analyze the mechanisms underlying morphine-induced sensitization by characterizing the modulation and alteration of hippocampus neurotransmission at the synaptic level upon repeated morphine administration.
|Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5|
|Gallo, Eduardo F; Salling, Michael C; Feng, Bo et al. (2015) Upregulation of dopamine D2 receptors in the nucleus accumbens indirect pathway increases locomotion but does not reduce alcohol consumption. Neuropsychopharmacology 40:1609-18|
|Fakira, Amanda K; Portugal, George S; Carusillo, Brianna et al. (2014) Increased small conductance calcium-activated potassium type 2 channel-mediated negative feedback on N-methyl-D-aspartate receptors impairs synaptic plasticity following context-dependent sensitization to morphine. Biol Psychiatry 75:105-14|
|Portugal, George S; Al-Hasani, Ream; Fakira, Amanda K et al. (2014) Hippocampal long-term potentiation is disrupted during expression and extinction but is restored after reinstatement of morphine place preference. J Neurosci 34:527-38|
|Cabañero, David; Baker, Alyssa; Zhou, Shengtai et al. (2013) Pain after discontinuation of morphine treatment is associated with synaptic increase of GluA4-containing AMPAR in the dorsal horn of the spinal cord. Neuropsychopharmacology 38:1472-84|
|Hogan, Dale; Baker, Alyssa L; Morón, Jose A et al. (2013) Systemic morphine treatment induces changes in firing patterns and responses of nociceptive afferent fibers in mouse glabrous skin. Pain 154:2297-309|
|Xia, Yan; Portugal, George S; Fakira, Amanda K et al. (2011) Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine. J Neurosci 31:16279-91|
|Billa, Sophie K; Xia, Yan; Moron, Jose A (2010) Disruption of morphine-conditioned place preference by a delta2-opioid receptor antagonist: study of mu-opioid and delta-opioid receptor expression at the synapse. Eur J Neurosci 32:625-31|
|Morón, Jose A; Green, Thomas A (2010) Exploring the molecular basis of addiction: drug-induced neuroadaptations. Neuropsychopharmacology 35:337-8|
|Billa, Sophie K; Liu, Jie; Bjorklund, Nicole L et al. (2010) Increased insertion of glutamate receptor 2-lacking alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors at hippocampal synapses upon repeated morphine administration. Mol Pharmacol 77:874-83|
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