CaMKII Activity in the Ventral Tegmental Area Gates Cocaine-Induced Synaptic Plasticity in the Nucleus Accumbens.
ABSTRACT Addictive drugs such as cocaine induce synaptic plasticity in discrete regions of the reward circuit. The goal of the present study is to investigate whether cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA) and nucleus accumbens (NAc) is causally linked. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of long-term synaptic plasticity, learning and drug addiction. We examined whether blocking CaMKII activity in the VTA affected cocaine conditioned place preference (CPP) and cocaine-evoked synaptic plasticity in its target brain region, the NAc. TatCN21 is a CaMKII inhibitory peptide that blocks both stimulated and autonomous CaMKII activity with high selectivity. We report that intra-VTA microinjections of tatCN21 prior to cocaine conditioning blocked the acquisition of cocaine CPP, whereas intra-VTA microinjections of tatCN21 prior to saline conditioning did not significantly affect cocaine CPP, suggesting that the CaMKII inhibitor blocks cocaine CPP through selective disruption of cocaine-cue associated learning. Intra-VTA tatCN21 prior to cocaine conditioning blocked cocaine-evoked depression of excitatory synaptic transmission in the shell of the NAc slices ex vivo. In contrast, intra-VTA microinjection of tatCN21 just prior to the CPP test did not affect the expression of cocaine CPP and cocaine-induced synaptic plasticity in the NAc shell. These results suggest that CaMKII activity in the VTA governs cocaine-evoked synaptic plasticity in the NAc during the time window of cocaine conditioning.Neuropsychopharmacology accepted article preview online, 24 October 2013; doi:10.1038/npp.2013.299.
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ABSTRACT: Adolescence is a developmental period that has been associated with heightened sensitivity to psychostimulant-induced reward, thus placing adolescents at increased risk to develop drug addiction. Although alterations in dopamine-induced synaptic plasticity are perhaps the most critical factor in mediating addiction processes, developmental differences in the cell signaling mechanisms that contribute to synaptic plasticity, and their contribution to adolescent reward sensitivity, has been grossly understudied. The most abundant dopamine receptors, the D1 and D2 receptors, as well as the dopamine D1-D2 receptor heteromer, exhibit age-dependent and brain region-specific changes in their expression and function and are responsible for regulating cell signaling pathways known to significantly contribute to the neurobiological mechanisms underlying addiction. The D1-D2 receptor heteromer, for instance, has been associated with calcium calmodulin kinase IIα, brain-derived neurotrophic factor and glycogen synthase kinase 3 (GSK-3) signaling, three proteins highly implicated in the regulation of glutamate transmission and synaptic plasticity and which regulate addiction to amphetamine, opioids and cocaine. Therefore, in this review the importance of these signaling proteins as potential mediators of addiction susceptibility in adolescence will be highlighted, and the therapeutic potential of the D1-D2 receptor heteromer in addiction will be discussed. It is the overall goal of this review to draw attention to the research gap in dopamine-induced cell signaling in the adolescent brain - knowledge that would provide much-needed insights into adolescent addiction vulnerability. © 2014 S. Karger AG, Basel.Developmental Neuroscience 05/2014; 36(3-4). DOI:10.1159/000360158 · 2.45 Impact Factor
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ABSTRACT: Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca(2+)/calmodulin-dependent protein kinase-II (αCaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. The autophosphorylation of αCaMKII was shown to accelerate learning. Thus, we investigated the role of αCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg(-1), intraperitoneal). In vivo microdialysis revealed that αCaMKII(T286A) mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg(-1), intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in αCaMKII(T286A) mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n=688) and Switzerland (n=141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that αCaMKII controls the speed for the establishment of cocaine's reinforcing effects.Translational Psychiatry 10/2014; 4:e457. DOI:10.1038/tp.2014.97 · 4.36 Impact Factor
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase Cγ pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB1 receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. Copyright © 2015 the authors 0270-6474/15/354469-13$15.00/0.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2015; 35(10):4469-81. DOI:10.1523/JNEUROSCI.2924-14.2015 · 6.75 Impact Factor