Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell

Chronic intermittent ethanol vapor exposure (CIE) in rodents produces reliable and high blood ethanol concentration and behavioral symptoms associated with moderate to severe alcohol use disorder (AUD)—for example, escalation of operant ethanol self-administration, a feature suggestive of transition from recreational to addictive use, is a widely replicated behavior in rats that experience CIE. Herein, we present evidence from a subset of rats that do not demonstrate escalation of ethanol self-administration following seven weeks of CIE. These low responders (LR) maintain low ethanol self-administration during CIE, demonstrate lower relapse to drinking during abstinence and reduced reinstatement of ethanol seeking triggered by ethanol cues when compared with high responders (HR). We examined the blood ethanol levels in LR and HR rats during CIE and show higher levels in LR compared with HR. We also examined peak corticosterone levels during CIE and show that LR rats have higher levels compared with HR rats. Lastly, we evaluated the levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the nucleus accumbens shell and reveal that the activity of CaMKII, which is autophosphorylated at site Tyr-286, is significantly reduced in HR rats compared with LR rats. These findings demonstrate that dysregulation of the hypothalamic–pituitary–adrenal axis activity and plasticity-related proteins regulating molecular memory in the nucleus accumbens shell are associated with higher ethanol-drinking and -seeking in HR rats. Future mechanistic studies should evaluate CaMKII autophosphorylation-dependent remodeling of glutamatergic synapses in the ventral striatum as a plausible mechanism for the CIE-induced enhanced ethanol drinking and seeking behaviors.

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Role of neuropeptide neuromedin U in the nucleus accumbens shell in cocaine self-administration in male rats

Neuropsychopharmacology ◽

10.1038/s41386-021-01234-9 ◽

2021 ◽

Author(s):

James M. Kasper ◽

Ashley E. Smith ◽

Sierra N. Miller ◽

Ara ◽

William K. Russell ◽

...

Keyword(s):

Nucleus Accumbens ◽

Male Rats ◽

Nucleus Accumbens Shell ◽

Self Administration

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BDNF-TrkB controls cocaine-induced dendritic spines in rodent nucleus accumbens dissociated from increases in addictive behaviors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1702441114 ◽

2017 ◽

Vol 114 (35) ◽

pp. 9469-9474 ◽

Cited By ~ 12

Author(s):

Ethan M. Anderson ◽

Anne Marie Wissman ◽

Joyce Chemplanikal ◽

Nicole Buzin ◽

Daniel Guzman ◽

...

Keyword(s):

Nucleus Accumbens ◽

Dendritic Spine ◽

Morphological Changes ◽

Dominant Negative ◽

Addictive Behaviors ◽

Spine Density ◽

Nucleus Accumbens Shell ◽

Self Administration ◽

Dendritic Spine Density ◽

Chronic Cocaine

Chronic cocaine use is associated with prominent morphological changes in nucleus accumbens shell (NACsh) neurons, including increases in dendritic spine density along with enhanced motivation for cocaine, but a functional relationship between these morphological and behavioral phenomena has not been shown. Here we show that brain-derived neurotrophic factor (BDNF) signaling through tyrosine kinase B (TrkB) receptors in NACsh neurons is necessary for cocaine-induced dendritic spine formation by using either localized TrkB knockout or viral-mediated expression of a dominant negative, kinase-dead TrkB mutant. Interestingly, augmenting wild-type TrkB expression after chronic cocaine self-administration reverses the sustained increase in dendritic spine density, an effect mediated by TrkB signaling pathways that converge on extracellular regulated kinase. Loss of TrkB function after cocaine self-administration, however, leaves spine density intact but markedly enhances the motivation for cocaine, an effect mediated by specific loss of TrkB signaling through phospholipase Cgamma1 (PLCγ1). Conversely, overexpression of PLCγ1 both reduces the motivation for cocaine and reverses dendritic spine density, suggesting a potential target for the treatment of addiction in chronic users. Together, these findings indicate that BDNF-TrkB signaling both mediates and reverses cocaine-induced increases in dendritic spine density in NACsh neurons, and these morphological changes are entirely dissociable from changes in addictive behavior.

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Overexpression of the Histone Dimethyltransferase G9a in Nucleus Accumbens Shell Increases Cocaine Self-Administration, Stress-Induced Reinstatement, and Anxiety

Journal of Neuroscience ◽

10.1523/jneurosci.1657-17.2017 ◽

2017 ◽

Vol 38 (4) ◽

pp. 803-813 ◽

Cited By ~ 25

Author(s):

Ethan M. Anderson ◽

Erin B. Larson ◽

Daniel Guzman ◽

Anne Marie Wissman ◽

Rachael L. Neve ◽

...

Keyword(s):

Nucleus Accumbens ◽

Nucleus Accumbens Shell ◽

Self Administration

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Blockade of N-methyl-d-aspartate receptors in the nucleus accumbens shell increased nicotine self-administration but had no effect on nicotine-induced conditioned taste aversion

Drug and Alcohol Dependence ◽

10.1016/j.drugalcdep.2014.02.136 ◽

2014 ◽

Vol 140 ◽

pp. e42

Author(s):

Manoranjan S. DSouza ◽

Athina Markou

Keyword(s):

Nucleus Accumbens ◽

Taste Aversion ◽

Conditioned Taste Aversion ◽

Nucleus Accumbens Shell ◽

Self Administration

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Transient viral-mediated overexpression of α-calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell leads to long-lasting functional upregulation of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors: dopamine type-1 receptor and protein kinase A dependence

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2010.07155.x ◽

2010 ◽

Vol 31 (7) ◽

pp. 1243-1251 ◽

Cited By ~ 8

Author(s):

B. F. Singer ◽

J. A. Loweth ◽

R. L. Neve ◽

P. Vezina

Keyword(s):

Nucleus Accumbens ◽

Protein Kinase ◽

Protein Kinase A ◽

Nucleus Accumbens Shell ◽

Dependent Protein Kinase ◽

Calcium Calmodulin Dependent ◽

Protein Kinase Ii ◽

Dependent Protein ◽

Kinase A

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Cocaine Triggers Glial-Mediated Synaptogenesis

10.1101/2020.01.20.896233 ◽

2020 ◽

Cited By ~ 2

Author(s):

Junshi Wang ◽

King-Lun Li ◽

Avani Shukla ◽

Ania Beroun ◽

Masago Ishikawa ◽

...

Keyword(s):

Nucleus Accumbens ◽

Ampa Receptor ◽

Self Administration ◽

Glutamatergic Synapses ◽

Cocaine Administration ◽

Silent Synapses ◽

Memory Traces ◽

Cocaine Seeking ◽

Silent Synapse ◽

Neuronal Receptor

AbstractSynaptogenesis is essential in forming new neurocircuits during development, and this is mediated in part by astrocyte-released thrombospondins (TSPs) and activation of their neuronal receptor, α2δ-1. Here, we show that this developmental synaptogenic mechanism is utilized during cocaine experience to induce spinogenesis and the generation of AMPA receptor-silent glutamatergic synapses in the adult nucleus accumbens (NAc). Specifically, cocaine administration activates NAc astrocytes, and preventing this activation blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of α2δ-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-α2δ-1-mediated spinogenesis and silent synapse generation in the NAc occludes cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction. These results establish that silent synapses are generated by an astrocyte-mediated synaptogenic mechanism in response to cocaine experience and embed critical cue-associated memory traces that promote cocaine relapse.

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