Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction.

https://www.ausl.fe.it/azienda/dipartimenti/daismdp/staff/osservatorio-epidemiologico/documenti-scaricabili/convegni/corso-di-formazione-aggiornamento-di-farmacoterapia-in-uso-al-sert/3-himan-mecc-dipendenza/at_download/file

NEURAL MECHANISMS OF ADDICTION: The Role of Reward-Related Learning and Memory

Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions

The Mesolimbic Dopamine Reward Circuit in Depression

To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.

Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action

Drugs of abuse have very different acute mechanisms of action but converge on the brain's reward pathways by producing a series of common functional effects after both acute and chronic administration. Some similar actions occur for natural rewards as well. Researchers are making progress in understanding the molecular and cellular basis of these common effects. 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.

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Is there a common molecular pathway for addiction

The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. 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.

https://www.pnas.org/content/pnas/99/17/11435.full.pdf

CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

many MAPK regulators (N-Shc, RasGRF, RasGRP, SynOne of the most intriguing questions in neurobiology GAP, Ca1/DAG GTP exhange factors [GEFs], NF1, is how neurons and synapses encode the long-term N-Ras, and B-Raf) is largely restricted to the CNS. An changes in synaptic efficacy that underlie memory coninitial clue to the role of the ERK/MAPK cascade in the solidation. A recent set of studies suggests that the CNS came from the observation that expression of ERK/mitogen-activated protein kinase (MAPK) plays a MAPK signaling components is especially high in assofundamental role in vertebrate and invertebrate memory ciational areas implicated in learning and memory, such consolidation. These findings suggest that the ERK/ as the hippocampus, neocortex, and cerebellum. BeMAPK cascade should join the cAMP response element cause long-term neuronal plasticity and memory consolbinding protein/cAMP response element (CREB/CRE) idation require de novo gene expression, the prominent and cAMP/protein kinase A (PKA) pathways as evolurole of MAPK in inducible gene expression supports the tionarily conserved regulators of memory formation. Beidea that MAPK may regulate synaptic plasticity and cause the MAPK cascade was previously identified as long-term memory (LTM) formation. The ability of the a critical regulator of cell growth, its regulatory role in

Daniel R. Storm

Papers

CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

Making New Connections: Minireview Role of ERK/MAP Kinase Signaling in Neuronal Plasticity