Eric Nestler

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..We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported...

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..These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli...

..Together, these findings establish a previously unknown molecular pathway underlying both resilience and antidepressant action...

..We define areas where future investigation can provide a more detailed picture of drug-induced synaptic reorganization, including ultrastructural, electrophysiological and behavioral studies...

..These changes shape the functioning of the neural circuits that regulate reward, fear, emotion reactivity and social behaviour, which together are thought to mediate successful coping with stress...

..These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward...

..This review discusses recent advances in our understanding of how BDNF and its signaling pathways regulate structural and behavioral plasticity in the context of drug addiction...

..Together, these studies establish a direct role for NFkappaB pathways in the NAc to regulate structural and behavioral plasticity to cocaine...

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..The molecular mechanisms of stress-induced depressive behaviors have been characterized extensively in male rodents; however, much less is known about female subjects, despite the fact that human depression is far more prevalent in women...

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..These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors...

..They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress...

..Although some of these targets for depression already appear promising, new waves of more selective compounds for any molecular system should promote a better understanding of this complex disease and perhaps improved treatments...

..Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity...

..A major goal for future research is to determine whether such common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders...

..Together, these experiments demonstrated that DeltaFosB in the NAc, partly through the repression of dynorphin expression, mediates several major features of opiate addiction...

..These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences...

..Here we review progress in identifying candidate mechanisms of addiction...

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..Further pursuit of this and similar leads are first steps toward a complete understanding of the transition from cocaine abuse to addiction -- and, ultimately, more effective treatments for those who are addicted...

..This study reveals a novel epigenetic pathway through which DeltaFosB mediates distinct transcriptional programs that may ultimately alter behavioral plasticity to chronic amphetamine exposure...

..This novel mechanistic insight might open new avenues for improved treatments of drug addiction...

..Additionally, our findings show that chronic exposure to stimuli that induce DeltaFosB in the NAc can increase consumption of other natural rewards...

..These results indicate that IS-induced accumulation of DeltaFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses...

..These findings establish that chronic stress induces DeltaFosB in several discrete regions of the brain. Such induction could contribute to the long-term effects of stress on the brain...

..These findings help define the molecular functions of CREB and DeltaFosB and identify clusters of genes that contribute to cocaine addiction...

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..CRE-mediated transcription may itself contribute to re-establishing homeostasis in the organism through target gene regulation in these regions...

..They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments...

..This interpretation is intriguing in that it suggests a role for BDNF in the VTA-NAc that is opposite of the proposed role for BDNF in the hippocampus...

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..Knowledge of these mechanisms could lead to more effective treatments for addictive disorders...

..Here the evidence for the role of neurotrophins and other neurotrophic factors-and the signaling pathways they activate-in mediating long-term molecular, cellular, and behavioral adaptations associated with drug addiction is reviewed...

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..Moreover, these data also support a role for drug-induced elevations in PLCgamma1 expression in the VTA in mediating long-term adaptations to drugs of abuse and aversive stimuli...

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..Finally, there was a significant reduction in cocaine-induced locomotor activity in the CREB bitransgenic mice. These results are consistent with a role for CREB in mediating adaptive changes that occur in response to drugs of abuse...

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..This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed...

..The latter approach is the most speculative, but also the most promising in terms of translating basic knowledge of addiction into clinical progress...

..However, there is ongoing debate over whether elevated levels of GluR1 in the VTA are a primary cause, or secondary effect, of the neurobiological underpinnings of sensitization...

..A better understanding of the molecular and cellular adaptations that occur in these neural circuits may lead to novel interventions to improve memory and combat addiction in humans...

..Together, these studies support a role for the orexin system in molecular adaptations to morphine, and demonstrate dramatic differences in molecular responses among different populations of LH neurons...

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..Regulation of LH intracellular signaling pathways in response to drugs of abuse supports a role for the LH neuropeptides in addiction...

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..Earlier work revealed the selective induction of two calmodulin-dependent AC isoforms, AC1 and AC8, after chronic morphine, but their role in opiate dependence has remained unknown...

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..This work identifies a novel hypothalamic-AcSh circuit that influences appetitive behavior and mediates the antidepressant activity of MCH1R antagonists...

..Modulation of cocaine reward is a novel action of the melanocortin-MC4-R system and could be targeted for the development of new medications for cocaine addiction...

..The results also provide insight into the molecular mechanisms by which social interactions affect brain plasticity and behavior...

..These results provide the first evidence of deltaFosB induction in a discrete population of GABA cells in the VTA, which may regulate the functioning of the brain's reward mechanisms...

..These results suggest a novel role for CREB in mediating drug-induced plasticity in the VTA and establish two functionally distinct subregions of the VTA in which CREB differentially regulates drug reward...

..These findings demonstrate the involvement of a circadian-associated gene, Clock, in regulating dopamine function and cocaine reward...

..These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens...

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..Identification of deltaFosB in the OFC as a mediator of tolerance to the effects of cocaine on cognition provides fundamentally new insight into the transcriptional modifications associated with addiction...

..This review summarizes some of the major transcriptional mechanisms that are thought to underlie neuronal and behavioral plasticity...

..These findings highlight distinct roles of the Thr-34 and Thr-75 phosphorylation sites of DARPP-32 in mediating short- and long-term behavioral and biochemical actions of cocaine...

..These data indicate that alternative splicing specifically removes two destabilizing elements from FosB in order to generate a longer-lived transcription factor, DeltaFosB, in response to chronic perturbations to the brain...

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..In contrast, Ser27 does not seem to play a role in the transactivation potential of full-length FosB. These findings constitute the first evidence of a role for phosphorylation in DeltaFosB's transcriptional activity...

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..Moreover, in a more general sense, the proposed studies will utilize models of addiction to better understand the potent influence of BDNF on mesolimbic dopamine function in the fully differentiated, adult brain. ..

..This work will contribute to our growing knowledge of drug-induced neuroadaptations in the brain at the molecular level. ..

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..Moreover, in a more general sense, the proposed studies will utilize models of addiction to better understand the potent influence of BDNF on mesolimbic dopamine function in the fully differentiated, adult brain. ..

..More fundamentally, however, the proposed studies will improve our general understanding of the precise molecular mechanisms that control the expression of glutamate receptors, key mediators of synaptic transmission, in the brain. ..

..Moreover, in a general sense, the studies will utilize models of addiction to better understand the continued influence of neurotrophic factors in controlling mesolimbic dopamine function in the fully differentiated, adult brain. ..

..This work will contribute to our growing knowledge of drug-induced neuroadaptations in the brain at the molecular level. ..

..Together, the proposed research will improve our understanding of the ways in which the brain adapts to chronic stress and antidepressant treatments. ..

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