Elevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse?

In laboratory animals, repeated administration of drugs of abuse, such as cocaine, morphine or alcohol, causes sensitization (reverse tolerance) to their stimulant and rewarding effects. Neuroadaptations underlying sensitization could be related to those that contribute to addictive behaviors. An increased understanding of the molecular mechanisms of sensitization could lead to improved treatments for addiction.

Characterization of the mouse adenylyl cyclase type VIII gene promoter: regulation by cAMP and CREB.

Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. In the present study, we directly examined the role for the transcription factor CREB (cAMP response element binding protein) in regulating ACVIII expression by cloning a 5.2 kilobase region upstream of the translation start site of the mouse ACVIII gene.

From neurobiology to treatment: progress against addiction.

Most advances in addiction treatment to date have addressed the physical dependence and withdrawal that accompany addiction to some drugs of abuse. In contrast, it has proven more difficult to develop medications that effectively treat drug craving and relapse, the core features of addictive disorders. Current efforts focus on developing medications that prevent a drug from getting to its protein target, that mimic drug action and thereby partially alleviate drug craving, or that affect the addiction process per se.

Preclinical models: status of basic research in depression.

Approximately one half-century ago several classes of medications, discovered by serendipity, were introduced for the treatment of depression and bipolar disorder. These highly effective medications revolutionized our approach to mood disorders and helped launch the modern era of psychiatry. Yet our progress since those serendipitous discoveries has been disappointing.

Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures.

G protein-coupled receptor (GPCR) signaling cascades may be key substrates for the antidepressant effects of chronic electroconvulsive seizures (ECS). To better understand changes in these signaling pathways, alterations in levels of mRNA's encoding regulators of G protein signaling (RGS) protein subtypes-2, -4, -7, -8 and -10 were evaluated in rat brain using northern blotting and in situ hybridization. In prefrontal cortex, RGS2 mRNA levels were increased several-fold 2 h following an acute ECS.

Delta FosB regulates wheel running.

DeltaFosB is a transcription factor that accumulates in a region-specific manner in the brain after chronic perturbations. For example, repeated administration of drugs of abuse increases levels of DeltaFosB in the striatum. In the present study, we analyzed the effect of spontaneous wheel running, as a model for a natural rewarding behavior, on levels of DeltaFosB in striatal regions.

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

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.

Stimulation of protein kinase a activity in the rat amygdala enhances reward-related learning.

Background: Drug addiction in humans is associated with abnormal metabolic activity within the amygdala and heightened control of behavior by drugs and drug-related (conditioned) stimuli. Drug-induced neuroadaptations, including activation of cAMP (cyclic adenosine monophosphate)-dependent protein kinase A (PKA), within the amygdala may contribute to the synaptic plasticity and reward-related learning that underlies pathologic behavior in addicted individuals.

Methods: In this study, we tested the hypothesis that stimulation of PKA activity within the rat amygdala would facilitate the acquisition of Pavlovian approach behavior, a measure of reward-related learning.

Inducible, reversible hair loss in transgenic mice.

Telogen effluvium is a common type of hair loss. Although the morphological changes associated with telogen effluvium have been well characterized, the underlying molecular mechanisms remain unknown, and no animal models have been developed. We report here that inducible transgenic mice expressing high levels of the transcription factor, tTA (tetracycline transactivator), plus a reporter luciferase gene, show a reversible hair loss phenotype.

Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons.

Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates.

Inducible and brain region-specific CREB transgenic mice.

To investigate the role of cAMP response element-binding protein (CREB) in the adaptive responses to psychotropic drugs, we have developed inducible, brain region-specific CREB transgenic mice using the tetracycline-regulated gene expression system. The tetracycline transactivator (tTA) was placed under the control of 1.8-kilobase neuron-specific enolase (NSE) promoter for this purpose.

Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein.

The cAMP cascade, including the cAMP response element-binding protein (CREB), is known to play an important role in neuronal survival and plasticity. Here the influence of this cascade on neurogenesis in adult hippocampus was determined. Activation of the cAMP cascade by administration of rolipram, an inhibitor of cAMP breakdown, increased the proliferation of newborn cells in adult mouse hippocampus.

Regional and cellular mapping of cAMP response element-mediated transcription during naltrexone-precipitated morphine withdrawal.

Chronic opiate exposure is associated with upregulation of the cAMP signaling pathway and the transcription factor cAMP response element-binding protein in the locus ceruleus (LC) and certain other brain areas. To determine whether these adaptations ultimately affect transcription mediated by the cAMP response element (CRE), we induced morphine dependence in CRE-LacZ transgenic mice and performed a regional and cellular mapping of beta-galactosidase (beta-gal) expression during naltrexone-precipitated withdrawal. Consistent with our model of opiate dependence, beta-gal expression increased in the LC, but decreased in the lateral ventral tegmental area (VTA) and dorsal raphe nucleus (DRN).

Neurobiology of depression.

Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB.

cAMP/Ca2+ response element-binding protein function is essential for ocular dominance plasticity.

The monocular deprivation model of amblyopia is characterized by a reduction in cortical responses to stimulation of the deprived eye. Although the effects of monocular deprivation on the primary visual cortex have been well characterized physiologically and anatomically, the molecular mechanisms underlying ocular dominance plasticity remain unknown. Previous studies have indicated that the transcription factor adenosine cAMP/Ca(2+) response element-binding protein (CREB) is activated during monocular deprivation.