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Mechanisms of Neuroplasticity and Ethanol's Effects on Plasticity in the Striatum and Bed Nucleus of the Stria Terminalis.

Lovinger DM, Kash TL - Alcohol Res (2015)

Bottom Line: Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction.Two brain regions subject to alcohol's effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol's actions and control of intake.The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic).Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder.

View Article: PubMed Central - PubMed

Affiliation: Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.

ABSTRACT
Long-lasting changes in synaptic function (i.e., synaptic plasticity) have long been thought to contribute to information storage in the nervous system. Although synaptic plasticity mainly has adaptive functions that allow the organism to function in complex environments, it is now clear that certain events or exposure to various substances can produce plasticity that has negative consequences for organisms. Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction.Two brain regions subject to alcohol's effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol's actions and control of intake. The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic). Plastic changes in synaptic transmission in these two brain regions following prolonged ethanol exposure are thought to contribute to excessive alcohol drinking and relapse to drinking. Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder.

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Related in: MedlinePlus

Schematic illustration of neuronal circuits in the dorsomedial striatum (DMS) and of the effects of acute and chronic ethanol exposure on plasticity in this region. (A) Simplified diagram of the circuits in the DMS, showing glutamatergic cortical inputs to the major projection neurons in the striatum (i.e., medium spiny neurons [MSNs]). Also indicated is GABAergic microcircuitry involving MSN–MSN synapses that tend to innervate dendrites and synapses made by fast-spiking interneurons (FSIs) on MSN cell bodies. These MSNs project out of the striatum to the globus pallidus external segement (GPe) and the substantia nigra pars reticulata (SNr). Boxed areas indicate the predominate sites of synapses on the MSNs. (B) Effects of acute ethanol exposure on plasticity at synapses onto DMS MSNs. The net effects are prevention of normal plasticity (i.e., inhibition of long-term potentiation [LTP]) at excitatory cortical glutamatergic inputs, while a new form of NMDA receptor (NMDAR)-dependent long-term facilitation (LTF) occurs. Increased synaptic inhibition also occurs. Thus, the net signal output from the DMS may be dampened, while responses to associative cortical input may become aberrant. (C) Effects of chronic ethanol exposure on plasticity at synapses in the DMS. Net effects include prolonged LTF and LTP-like increase in AMPA receptor function at glutamatergic synapses, accompanied by net decreases in inhibition. These changes may alter goal-directed ethanol-related behaviors, particularly those controlled by the prefrontal cortex and related associative cortices.
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f1-arcr-37-1-109: Schematic illustration of neuronal circuits in the dorsomedial striatum (DMS) and of the effects of acute and chronic ethanol exposure on plasticity in this region. (A) Simplified diagram of the circuits in the DMS, showing glutamatergic cortical inputs to the major projection neurons in the striatum (i.e., medium spiny neurons [MSNs]). Also indicated is GABAergic microcircuitry involving MSN–MSN synapses that tend to innervate dendrites and synapses made by fast-spiking interneurons (FSIs) on MSN cell bodies. These MSNs project out of the striatum to the globus pallidus external segement (GPe) and the substantia nigra pars reticulata (SNr). Boxed areas indicate the predominate sites of synapses on the MSNs. (B) Effects of acute ethanol exposure on plasticity at synapses onto DMS MSNs. The net effects are prevention of normal plasticity (i.e., inhibition of long-term potentiation [LTP]) at excitatory cortical glutamatergic inputs, while a new form of NMDA receptor (NMDAR)-dependent long-term facilitation (LTF) occurs. Increased synaptic inhibition also occurs. Thus, the net signal output from the DMS may be dampened, while responses to associative cortical input may become aberrant. (C) Effects of chronic ethanol exposure on plasticity at synapses in the DMS. Net effects include prolonged LTF and LTP-like increase in AMPA receptor function at glutamatergic synapses, accompanied by net decreases in inhibition. These changes may alter goal-directed ethanol-related behaviors, particularly those controlled by the prefrontal cortex and related associative cortices.

Mentions: Acute intoxication occurs over a range of brain ethanol concentrations from approximately 5 to 100 mM, with increasing severity as the concentration ascends. Thus far, only a few studies have examined the acute effects of ethanol on plasticity. One series of studies using brain slices of the DMS found that a lasting facilitation of glutamatergic transmission mediated by NMDARs occurred after the slices had been exposed for a few minutes to 25 to 100 mM ethanol (Wang et al. 2007, 2010, 2012). The investigators dubbed this process long-term facilitation (LTF) to distinguish it from LTP, because LTF involves a lasting increase in NMDAR function and may not share all of the mechanisms involved in LTP. LTF occur only after the inhibition of NMDAR-mediated transmission, normally observed during acute ethanol exposure, ends (see figure 1A and 1B). It is thought that ethanol stimulates Fyn tyrosine kinase, which then mediates phosphorylation of the NR2B NMDAR subunit, thereby inducing LTF (Gibb et al. 2011; Wang et al. 2010). Indeed, LTF only affects transmission mediated by receptors that contain NR2B.


Mechanisms of Neuroplasticity and Ethanol's Effects on Plasticity in the Striatum and Bed Nucleus of the Stria Terminalis.

Lovinger DM, Kash TL - Alcohol Res (2015)

Schematic illustration of neuronal circuits in the dorsomedial striatum (DMS) and of the effects of acute and chronic ethanol exposure on plasticity in this region. (A) Simplified diagram of the circuits in the DMS, showing glutamatergic cortical inputs to the major projection neurons in the striatum (i.e., medium spiny neurons [MSNs]). Also indicated is GABAergic microcircuitry involving MSN–MSN synapses that tend to innervate dendrites and synapses made by fast-spiking interneurons (FSIs) on MSN cell bodies. These MSNs project out of the striatum to the globus pallidus external segement (GPe) and the substantia nigra pars reticulata (SNr). Boxed areas indicate the predominate sites of synapses on the MSNs. (B) Effects of acute ethanol exposure on plasticity at synapses onto DMS MSNs. The net effects are prevention of normal plasticity (i.e., inhibition of long-term potentiation [LTP]) at excitatory cortical glutamatergic inputs, while a new form of NMDA receptor (NMDAR)-dependent long-term facilitation (LTF) occurs. Increased synaptic inhibition also occurs. Thus, the net signal output from the DMS may be dampened, while responses to associative cortical input may become aberrant. (C) Effects of chronic ethanol exposure on plasticity at synapses in the DMS. Net effects include prolonged LTF and LTP-like increase in AMPA receptor function at glutamatergic synapses, accompanied by net decreases in inhibition. These changes may alter goal-directed ethanol-related behaviors, particularly those controlled by the prefrontal cortex and related associative cortices.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476598&req=5

f1-arcr-37-1-109: Schematic illustration of neuronal circuits in the dorsomedial striatum (DMS) and of the effects of acute and chronic ethanol exposure on plasticity in this region. (A) Simplified diagram of the circuits in the DMS, showing glutamatergic cortical inputs to the major projection neurons in the striatum (i.e., medium spiny neurons [MSNs]). Also indicated is GABAergic microcircuitry involving MSN–MSN synapses that tend to innervate dendrites and synapses made by fast-spiking interneurons (FSIs) on MSN cell bodies. These MSNs project out of the striatum to the globus pallidus external segement (GPe) and the substantia nigra pars reticulata (SNr). Boxed areas indicate the predominate sites of synapses on the MSNs. (B) Effects of acute ethanol exposure on plasticity at synapses onto DMS MSNs. The net effects are prevention of normal plasticity (i.e., inhibition of long-term potentiation [LTP]) at excitatory cortical glutamatergic inputs, while a new form of NMDA receptor (NMDAR)-dependent long-term facilitation (LTF) occurs. Increased synaptic inhibition also occurs. Thus, the net signal output from the DMS may be dampened, while responses to associative cortical input may become aberrant. (C) Effects of chronic ethanol exposure on plasticity at synapses in the DMS. Net effects include prolonged LTF and LTP-like increase in AMPA receptor function at glutamatergic synapses, accompanied by net decreases in inhibition. These changes may alter goal-directed ethanol-related behaviors, particularly those controlled by the prefrontal cortex and related associative cortices.
Mentions: Acute intoxication occurs over a range of brain ethanol concentrations from approximately 5 to 100 mM, with increasing severity as the concentration ascends. Thus far, only a few studies have examined the acute effects of ethanol on plasticity. One series of studies using brain slices of the DMS found that a lasting facilitation of glutamatergic transmission mediated by NMDARs occurred after the slices had been exposed for a few minutes to 25 to 100 mM ethanol (Wang et al. 2007, 2010, 2012). The investigators dubbed this process long-term facilitation (LTF) to distinguish it from LTP, because LTF involves a lasting increase in NMDAR function and may not share all of the mechanisms involved in LTP. LTF occur only after the inhibition of NMDAR-mediated transmission, normally observed during acute ethanol exposure, ends (see figure 1A and 1B). It is thought that ethanol stimulates Fyn tyrosine kinase, which then mediates phosphorylation of the NR2B NMDAR subunit, thereby inducing LTF (Gibb et al. 2011; Wang et al. 2010). Indeed, LTF only affects transmission mediated by receptors that contain NR2B.

Bottom Line: Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction.Two brain regions subject to alcohol's effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol's actions and control of intake.The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic).Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder.

View Article: PubMed Central - PubMed

Affiliation: Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.

ABSTRACT
Long-lasting changes in synaptic function (i.e., synaptic plasticity) have long been thought to contribute to information storage in the nervous system. Although synaptic plasticity mainly has adaptive functions that allow the organism to function in complex environments, it is now clear that certain events or exposure to various substances can produce plasticity that has negative consequences for organisms. Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction.Two brain regions subject to alcohol's effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol's actions and control of intake. The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic). Plastic changes in synaptic transmission in these two brain regions following prolonged ethanol exposure are thought to contribute to excessive alcohol drinking and relapse to drinking. Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder.

Show MeSH
Related in: MedlinePlus