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In this Section
- Office of the Scientific Director
- Office of the Clinical Director
- NIAAA Laboratories
- Laboratory of Behavioral & Genomic Neuroscience
- Laboratory of Cardiovascular Physiology and Tissue Injury
- Laboratory for Integrative Neuroscience
- LIN - Office of the Chief
- LIN - Section on Neuronal Structure
- LIN - Section of Synaptic Pharmacology (SP)
- Laboratory of Liver Diseases
- Laboratory of Metabolic Control
- Laboratory of Molecular Signaling
- Laboratory of Molecular Physiology
- Laboratory of Membrane Biochemistry and Biophysics
- Laboratory of Neurogenetics
- Laboratory for Neuroimaging
- Laboratory of Physiologic Studies
- Chemical Biology Research Branch (joint lab with NIDA)
- Clinical NeuroImaging Core
- Section on Clinical Genomics and Experimental Therapeutics (CGET)
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)
- Section on Human Psychopharmacology (HP)
- Office of Laboratory Animal Science (OLAS)
- Research and Training
- Clinical Trials at NIAAA/NIH
LIN - Section of Synaptic Pharmacology (SP)
David M. Lovinger PhD, Chief
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5625 Fishers Lane, Room TS-13A:MSC 9411
Bethesda, MD 20892-9412
fax: +1 301.480.8035
1) Research in SSP focuses on examination of the mechanisms involved in synaptic plasticity related to habit formation and addiction, with particular emphasis on the striatum. 2) Studies in this section also examine the function and roles of cortico-basal ganglia circuits in habit formation and addiction, using a combination of behavioral and in vivo physiological techniques. Genetically engineered mice are employed to help determine the roles of particular molecules and neurons in behavior and the underlying physiology. 3) Research in the section also explores effects of alcohol and other drugs of abuse on synaptic transmission. Different in vitro preparations, including single cells and brain slices are used to accomplish this aim. 4) In addition, we are interested in determining the molecular mechanisms underlying these drug actions, through the combined use of molecular biological and physiological techniques
L-Type Calcium Channels as Molecular Triggers for Striatal Synaptic Plasticity (Adermark and Lovinger 2007)
Long-term depression (LTD) at striatal synapses is a long-lasting decrease in the strength of synaptic transmission that is mediated by postsynaptic endocannabinoid (eCB) release and presynaptic cannabinoid 1 receptor (CB 1 R) activation. This form of synaptic plasticity is thought to play roles in skill and habit learning, two forms of learning that involve the striatum. Several molecular mechanisms have been implicated in striatal LTD, but it is not clear which mechanisms are crucial for LTD induction. At striatal glutamatergic synapses we found that the activation of L-type calcium channels by 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole¬3-carboxylic acid methylester (FPL64 176), combined with modest postsynaptic depolarization and synaptic activation, is sufficient to induce robust LTD (FPL-LTD). The L-channel activator 1 ,4-dihydro-2,6-dimethyl-5-nitro-4- [2(trifluoromethyl)phenyl]pyridine-3 -carboxylic acid methyl ester (Bay K 8644) has a similar action. FPL-LTD occludes LTD induced by high-frequency stimulation (HFS-LTD) and requires elevated postsynaptic calcium and retrograde endocannabinoid signaling, properties similar to those of HFS-LTD. In contrast, FPL-LTD does not require the activation of metabotropic glutamate receptors (mGluRs), phospholipase C, or dopamine D2 receptors, molecules implicated in eCB production and HFS-LTD induction. FPL-LTD induction also requires afferent stimulation. These findings suggest a scenario in which L- type calcium channel activation is a crucial switch for LTD induction, and mGluRs and D2 receptors can be bypassed if this channel is activated.
We have now observed that LTD can be induced at striatal synapses that use both gamma-aminobutyric acid (GABA) and glutamate as neurotransmitters. Thus, we wanted to determine if L-channel activation was effective at GABAergic synapses, and the extent to which eCB mobilization at the two types of synapses might be regulated by afferent activation. We found that the basic mechanisms for FPL-mediated eCB signaling are the same at glutamatergic and GABAergic synapses. FPL-induced LTD (FPL-LTD) was blocked in slices treated with the CB1R antagonist AM251 (2 micromolar), but established depression was not reversed by AM25 1. FPL-LTD was temperature dependent, blocked by protein translation inhibitors and prevented by intracellular loading of the anandamide transporter inhibitor VDM1 1 (10 micromolar) at both glutamatergic and GABAergic synapses. FPL-LTD at glutamatergic synapses required paired-pulse afferent stimulation, while FPL-LTD at GABAergic synapses could be induced even in the absence of explicit afferent activation. Our findings suggest that activation of L-type calcium channels, most likely the CaV1 .3 channel, is crucial for LTD induction at both striatal GABAergic and glutamatergic synapses. GABAergic synapses appear to be more sensitive to LTD induction, perhaps due to the greater number of CB1 receptors present at these synapses.
Involvement of a Regulated Postsynaptic Release Step in Striatal Endocannabinoid Signaling (Adermark and Lovinger, 2008)
Endocannabinoids mediate short- and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it was not known whether this release process occurs automatically upon eCB synthesis or whether it was regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM1 1 and UCM707, but did not require activation of metabotropic glutamate receptors, L-type calcium channels, nitric oxide, voltage-activated Na(+) channels, or intracellular calcium. Application of the CB1R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB1R by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. We subsequently observed that combining CB1 activation via postsynaptic AEA loading with a short period of low frequency synaptic activation is sufficient to induce LTD at glutamatergic synapses. These data support the idea that LTD induction involves a stimulus- dependent regulated postsynaptic release step as well as elevated activity at afferent inputs to striatal neurons. Our findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.
Ethanol Effects on Striatal Synaptic Transmission and Plasticity (Wang et al. 2007, Yin et al. 2007)
Addiction to drugs and alcohol is characterized by compulsive alcohol or drug taking and seeking, and the dorsal striatum has been implicated in such maladaptive persistent habits. Ethanol effects on striatal synaptic transmission may underlie ethanol intoxication, ethanol effects on striatal-based learning, and ultimately may predispose drinkers to habitual learning related to alcohol drinking. We have thus initiated studies examining ethanol effects on synaptic transmission and plasticity in the striatum, with the initial emphasis on glutamatergic synapses.
In collaboration with the laboratory of Dr. Dorit Ron at the University of California at San Francisco, we undertook studies examining ethanol effects on synaptic transmission mediated by NMDA-type glutamate receptors in striatal brain slices. It has long been known that ethanol inhibits NMDA receptor function at concentrations that occur in the brain during acute intoxication. In addition, the NMDAR is implicated in striatal-based habit learning. We found that, in the dorsal striatum, ethanol exposure produced an increase in the phosphorylation of the NR2B subunit of the NMDAR, and a corresponding increase in the activity of Fyn kinase, which phosphorylates NR2B. We further observed an ethanol decreased NMDAR-mediated synaptic transmission in the dorsal striatum, but after ethanol was removed from the preparation a long¬term facilitation (LTF) of the activity of NR2B-containing NMDARs (NR2B-NMDARs) developed. This LTF was Fyn kinase dependent, because it was observed in Fyn wild-type but not in Fyn knock-out mice. Importantly, none of these biochemical and physiological changes was observed in the ventral striatum. Finally, dorsal but not ventral striatum infusion of a Fyn or NR2B-NMDAR inhibitor reduced rat operant self-administration of ethanol. Our results suggest that the Fyn-mediated phosphorylation and LTF of NR2B-NMDAR activity in the dorsal striatum after exposure to ethanol may underlie aberrant plasticity that contributes to mechanisms underlying alcohol drinking behavior.
As ethanol consumption can cause impairments in cognition, learning, and action selection, it is important to understand the effects of this drug on striatal synaptic plasticity thought to be involved in these brain functions. To this end, we examined the effects of ethanol on long-term synaptic plasticity in the dorsomedial striatum (DMS), a striatal subregion that plays a central role in the acquisition and selection of goal-directed actions. Ethanol was found to impair NMDAR-dependent long-term potentiation (LTP) dose-dependently in the DMS starting at concentrations in the low mM range, and to promote long-term depression (LTD) at the highest concentration (50 mM) used. These results suggest that ethanol, at concentrations usually associated with mild-to-moderate intoxication, could significantly change experience-dependent modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions.
Wang J, Carnicella S, Phamluong K, Jeanblanc J, Ronesi JL, Janak PH, Lovinger DM, Ron D. Long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum in response to ethanol: Implications for consumption of alcohol.
J Neurosci 27:3593-602, 2007.
Zhu P, Lovinger DM. Persistent Synaptic Activity Produces Long-Lasting Enhancement of Endocannabinoid Modulation and Alters Long-Term Synaptic Plasticity.
J Neurophysiol 97:4386-9, 2007.
Yin HH, Park B, Adermark L, Lovinger DM. Ethanol reverses the direction of long-term synaptic plasticity in the dorsomedial stiatum.
Eur J Neurosci 25:3226-32, 2007.
Adermark L, Lovinger DM. Combined activation of L-type Ca2+ channels and synaptic transmission is sufficient to induce striatal long-term depression.
J Neurosci 27:6781-7, 2007.
Adermark L, Lovinger DM. Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step.
Proc Natl Acad Sci USA 104:20564-9, 2007.
Yin HH, Adermark L, Lovinger DM. Neurotensin reduces glutamatergic transmission in the dorsolateral striatum via retrograde endocannabinoid signaling.
Neuropharmacology 54:79-86, 2008.
Adermark L, Lovinger DM. Electrophysiological properties and gap junction coupling of striatal astrocytes.
Neurochem Int 52:1365-72, 2008.
Hu X-Q, Lovinger DM. The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole.
Neuropharmacology 54:1153-65, 2008.
Sheinin A, Talani G, Davis MI, Lovinger DM. Endocannabinoid- and mGluR5-dependent short- term synaptic depression in an isolated neuron/bouton preparation from the hippocampal CA1 region.
J Neurophysiol 100:1041-52, 2008.