Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens

Repeated exposure to psychostimulant drugs such as cocaine or amphetamine can promote drug-seeking and -taking behavior. In rodent addiction models, persistent changes in excitatory glutamatergic neurotransmission in the nucleus accumbens (NAc) appear to drive this drug-induced behavioral plasticity. To study whether changes in glutamatergic signaling are shared between or exclusive to specific psychostimulant drugs, we examined synaptic transmission from mice following repeated amphetamine or cocaine administration. Synaptic transmission mediated by AMPA-type glutamate receptors was potentiated in the NAc shell 10-14 days following repeated amphetamine or cocaine treatment. This synaptic enhancement was depotentiated by re-exposure to amphetamine or cocaine. By contrast, in the NAc core only repeated cocaine exposure enhanced synaptic transmission, which was subsequently depotentiated by an additional cocaine but not amphetamine injection during drug abstinence. To better understand the drug-induced depotentiation, we replicated these in vivo findings using an ex vivo model termed 'challenge in the bath,' and showed that drug-induced decreases in synaptic strength occur rapidly (within 30 min) and require activation of metabotropic glutamate receptor 5 (mGluR5) and protein synthesis in the NAc shell, but not NAc core. Overall, these data demonstrate the specificity of neuronal circuit changes induced by amphetamine, introduce a novel method for studying drug challenge-induced plasticity, and define NAc shell medium spiny neurons as a primary site of persistent AMPA-type glutamate receptor plasticity by two widely used psychostimulant drugs.

Section: In Vivo Amphetamine Induces Bidirectional Plasticity In Synamentioning

confidence: 57%

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

Jedynak

Hearing

Ingebretson

et al. 2015

“…Studies of cocaine's effects in the NAc have shown dopamine receptor 1 (D 1 R)-expressing cells to be the primary longterm locus of spine change (Lee et al, 2006;Lobo et al, 2010), and as mentioned above, IkK is a potent regulator of spine density in this region. IkK activity in response to stress or stimulant administration may similarly be regulated in a cell-type-specific manner.…”

Section: Discussionmentioning

confidence: 99%

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

Christoffel

Golden

Heshmati

et al. 2012

Inhibitor of kB kinase (IkK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IkK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IkK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IkK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IkK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IkK (IkKca), or a dominant negative form of IkK into the NAc. Of all three experimental groups, only mice expressing IkKca show a behavioral phenotype. Expression of IkKca results in a decrease in the time spent in the nonperiphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IkK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IkKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IkK in NAc is a critical regulator of both depressive-and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.

“…Likewise, its induction in NAc by antidepressants is required for the therapeutic-like effects of these drugs (Vialou et al, 2010). Although DFosB is known to affect both the morphology (Lee et al, 2006;Maze et al, 2010;Robison et al, 2013) and synaptic physiology (Grueter et al, 2013) of NAc medium spiny neurons, identification of its specific mechanisms of action and gene targets remains a goal for the field.…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

Robison

Vialou

Sun

et al. 2013

Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor DFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that DFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that DFosB binds the CaMKIIa gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of DFosB to the CaMKIIa promoter and reduces CaMKII expression in NAc, despite the fact that DFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIa promoter, which blocks the DFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKIIa promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIa expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.