Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse

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Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues to focus on mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neuronal functions. Our main interest is the function of the dorsal striatum (DS), a brain region involved in action control and selection, as well as action learning. Striatal Synaptic Plasticity and Effects of Drugs of Abuse We have examined many forms of synaptic plasticity at synapses within the DS. One of the most prominent is long-term depression (LTD) at glutamatergic corticostriatal synapses produced via activation of the Gi/o class of G-protein-coupled receptors (GPCRs). In addition to LTD induced by activation of cannabinoid type 1 (CB1) and serotonin type 1B receptors, we have also observed that activation of the mu, delta and kappa receptors for opioid peptides can induce LTD. Likewise, inhibition of opioid peptide catabolism induces LTD, and this synaptic depression appears to involve actions of endogenous opioid peptides at the three receptor subtypes. The expression of the LTD induced by mu and delta opioid receptors involves decreased probability of glutamate release, resembling the mechanism of CB1-dependent LTD. Indeed, mu opioid receptor and CB1-dependent LTD can occlude on another, indicating that they share mechanisms at an overlapping population of synapses. In contrast, delta opioid receptor-dependent LTD cannot be occluded by mu-dependent LTD, indicating separate sites of action for these two opioid-mediated forms of synaptic plasticity. We have examined effects on striatal LTD of in vivo exposure to the widely-prescribed and heavily abused opioid receptor agonist oxycodone as well as ethanol. A single injection of oxycodone in vivo leads to loss of mu- and CB1-dependent LTD. The effects persist for up to 4 days following a single drug injection. The in vivo oxycodone injection has no effect on delta receptor-mediated LTD. Similar loss of mu- and CB1-dependent forms of LTD is observed following 2-4 weeks of in vivo exposure to intoxicating concentrations of ethanol. Thus, impairment of certain forms of presynaptic LTD appears to be a common impairment produced by different drugs of abuse. Loss of LTD likely alters cortical control of striatal medium spiny neurons, perhaps contributing to alterations in striatal-dependent learning produced by drugs such as ethanol, and perhaps contributing to habitual drug seeking. It will be important to figure out how mechanisms involved in LTD are impaired by in vivo drug exposure. The metabotropic glutamate receptor 2 (mGluR2) is another presynaptic receptor implicated in modulation and long-term depression of corticostriatal glutamatergic synpases. In collaboration with the laboratories of Drs. David Goldman and Markus Heilig here at NIAAA we have confirmed that a polymorphism that produces a premature stop codon in this gene (the grm2 gene) leads to loss of function of this receptor in alcohol-preferring (P) rats. Presynaptic receptor function is completely lost at corticostriatal synapses. Studies performed by the Goldman and Heilig laboratories indicate that loss of this receptor contributes to increased ethanol drinking and preference in both rat and mouse. It will be interesting to determine the contribution to these phenotypes of mGluR2 at corticostriatal synapses.