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. Long-term depression at striatal GABAergic synapses We have continued our studies of long-term synaptic depression (LTD) at synapses in striatum. Previous work in the laboratory indicated that LTD occurs at GABAergic synapses intrinsic to the striatum. This LTD can be induced by afferent activation at low-moderate frequencies, and requires endocannabinoid signaling. The two predominant GABAergic inputs to striatal projection neurons (medium spiny neurons or MSNs) come from axon collaterals of other MSNs that synapse mainly on the MSN dendrites, and from the fast-spiking interneurons that synapse mainly near the MSN soma. We have used optogenetic techniques to activate the two GABAergic inputs independently, by expressing channel rhodopsin 2 selectively in the two neuronal subtypes and activating this channel with light. This approach has revealed two types of LTD at these GABAergic synapses. When the membrane potential of the postsynaptic MSN is near the normal resting potential called the """"""""down-state"""""""", LTD occurs at both sets of inputs, and does not require activation of voltage-gated calcium channels. However, when the MSN membrane potential is depolarized to values near the """"""""up-states"""""""" seen in vivo, LTD occurs exclusively at MSN-MSN synapses, and appears to involve L-type calcium channel activation. Under all conditions, LTD is mediated by endocannabinoids acting at CB1 receptors. Current experiments are exploring the different mechanisms involved in up-state versus down-state GABAergic LTD. These studies have revealed that endocannabinoids can produce differential patterns of synaptic plasticity depending on the afferent input and the state of the postsynaptic neuron. These mechanisms have the potential to shape striatal output in multiple ways by differentially affecting inhibition near excitatory synapses on the MSN dendrites, or neuronal activation controlled by GABAergic synapses near the soma. Ethanol actions at striatal GABAergic synapses We are also continuing our studies of ethanol (EtOH) effects on GABAergic synaptic transmission in dorosolateral (DLS) and dorsomedial striatum (DMS). Our observation that EtOH inhibits GABAergic synaptic transmission in DLS MSNs via a presynaptic mechanism, while potentiating transmission in DMS, suggests differential mechanisms of EtOH action in the two striatal subregions. We are currently using pharmacological approaches, as well as the optogenetic techniques described above, to determine if these differential EtOH effects occur at different afferent inputs to MSNs. These opposing effects are surprising, and may indicate that EtOH suppresses the output of the DMS that is important for goal-directed actions, while enhancing the output of DLS which is involved in habit formation. Our continuing studies of chronic EtOH effects in mice and macaque monkeys have revealed synaptic changes that could contribute to prolonged, habitual alcohol use and abuse. In both model organisms, chronic EtOH exposure leads to a maintained decrease in GABAergic synaptic transmission in DLS and DMS (roughly equivalent to putamen and caudate nucleus, respectively, in monkeys). The findings in monkey are particularly interesting, as the alcohol drinking in this model organism is heavy and prolonged, sharing many features with human drinking. One notable feature of drinking in these monkeys is that animals develop highly regular alcohol intake with increased duration of intake bouts after 2 years of drinking, and the blood alcohol levels they achieve gradually escalate over a three year period. The decreased GABAergic transmission we have observed in putamen MSNs from these monkeys is strongly correlated with the average alcohol intake for each individual monkey. We have also observed increases in glutamatergic synaptic transmission and increased numbers of dendritic spines (the sites of glutamatergic synapses) in the putamen of the chronic EtOH-drinking monkeys. Intrinsic neuronal excitability is also increased after prolong drinking in the putamen MSNs. Recent findings have extended our knowledge by showing that GABAergic synaptic changes are greater in monkeys with earlier onset of drinking, a known risk factor for human alcohol use disorders. The synaptic changes that we have observed in these monkeys appear to render the putamen nucleus hyperexcitable, due to a combination of decreased GABAergic inhibition and increased intrinsic and glutamatergic synaptic excitability. Given the role of the putamen and associated circuitry in development and production of repetitive habitual actions, we hypothesize that the hyperexcitable putamen contributes to maintained, invariant patterns of drinking with high alcohol loading observed in the monkeys. We are also continuing to study effects of fetal/early-postnatal EtOH exposure on striatal function. This project was stimulated by reports implicating altered corticostriatal function in humans with fetal alcohol spectrum disorder (FASD). We are using vapor exposure to EtOH during gestation and the early postnatal period. Electrophysiological experiments have revealed decreased GABAergic synaptic transmission in DLS MSNs examined in adult mice following fetal/early postnatal EtOH exposure. The normal decrease in GABAergic transmission produced by acute exposure to EtOH is lost in these mice, suggesting development of some sort of tolerance to EtOH actions. Interestingly, the synaptic depression normally produced by CB1 receptor activation is also lost in the fetal/early postnatal EtOH-exposed mouse DLS MSNs. Preliminary studies indicate that this effect is selective for CB1 in comparison to to other presynaptic G protein-coupled receptors, and that an abnormal tonic activation of CB1 receptors by eCBs may occur as a consequence of this early life EtOH exposure. Our parallel behavioral studies indicate that this early-life EtOH exposure also impairs habit learning in the mice, and disrupts the associated changes in striatal neuronal activity. These experiments have revealed changes in striatal synaptic transmission that could contribute to abnormalities in the corticostriatal circuitry seen in FASD.

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National Institute on Alcohol Abuse and Alcoholism
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Abrahao, Karina P; Lovinger, David M (2018) Classification of GABAergic neuron subtypes from the globus pallidus using wild-type and transgenic mice. J Physiol 596:4219-4235
Davis, Margaret I; Crittenden, Jill R; Feng, Austin Y et al. (2018) The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra. PLoS One 13:e0191436
Newton, Jamila; Suman, Shubhankar; Akinfiresoye, Luli R et al. (2018) Alcohol withdrawal upregulates mRNA encoding for CaV2.1-?1 subunit in the rat inferior colliculus. Alcohol 66:21-26
Cuzon Carlson, Verginia C; Grant, Kathleen A; Lovinger, David M (2018) Synaptic adaptations to chronic ethanol intake in male rhesus monkey dorsal striatum depend on age of drinking onset. Neuropharmacology 131:128-142
Lovinger, David M; Alvarez, Veronica A (2017) Alcohol and basal ganglia circuitry: Animal models. Neuropharmacology 122:46-55
Hawes, Sarah L; Salinas, Armando G; Lovinger, David M et al. (2017) Long-term plasticity of corticostriatal synapses is modulated by pathway-specific co-release of opioids through ?-opioid receptors. J Physiol 595:5637-5652
Förstera, B; Muñoz, B; Lobo, M K et al. (2017) Presence of ethanol-sensitive glycine receptors in medium spiny neurons in the mouse nucleus accumbens. J Physiol 595:5285-5300
Sgobio, Carmelo; Wu, Junbing; Zheng, Wang et al. (2017) Aldehyde dehydrogenase 1-positive nigrostriatal dopaminergic fibers exhibit distinct projection pattern and dopamine release dynamics at mouse dorsal striatum. Sci Rep 7:5283
Cho, Sue J; Lovinger, David M; N'Gouemo, Prosper (2017) Prenatal alcohol exposure enhances the susceptibility to NMDA-induced generalized tonic-clonic seizures in developing rats. CNS Neurosci Ther 23:808-817
Johnson, Kari A; Mateo, Yolanda; Lovinger, David M (2017) Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum. Neuropharmacology 117:114-123

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