Making a bad thing worse: adverse effects of stress on drug addiction.

Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle. We also discuss both animal and human studies that suggest treating the stress-related aspects of drug addiction is likely to be an important contributing factor to a long-lasting recovery from this disorder.

CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine.

The neuronal circuitry underlying stress- and drug-induced reinstatement of cocaine-seeking has been relatively well characterized; however, less is known regarding the long-term molecular changes following cocaine administration that may promote future reinstatement. The transcription factor cAMP response element-binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned reward, suggesting that different molecular mechanisms may underlie these two types of reinstatement. To explore the relationship between this transcription factor and reinstatement, we utilized the place-conditioning paradigm to examine alterations in gene expression in the amygdala, a neural substrate critically involved in stress-induced reinstatement, following the development of cocaine reward and subsequent extinction. Our findings demonstrate that the amygdala transcriptome was altered by CREB deficiency more than by previous cocaine experience, with an over-representation of genes involved in the immune response. However, a subset of genes involved in stress and immune response demonstrated a drug×genotype interaction, indicating that cocaine produces different long-term alterations in gene expression depending on the presence or absence of CREB. This profile of gene expression in the context of addiction enhances our understanding of the long-term molecular changes that occur throughout the addiction cycle and identifies novel genes and pathways that might lead to the creation of better therapeutic agents.

Mu-opioid receptor and CREB activation are required for nicotine reward.

Environmental cues associated with nicotine delivery are an important part of the stimulus that sustains smoking behavior and is often coupled with craving and relapse; however, the neuronal circuitry and molecular substrates underlying this process are still poorly understood. Exposure to an environment previously associated with rewarding properties of nicotine results in an increase of CREB phosphorylation similar to that seen following nicotine administration, and this response is absent in MOR(-/-) mice. Moreover, a single administration of an opioid receptor antagonist, naloxone, blocks both the conditioned molecular response (CREB phosphorylation) and the conditioned behavioral response (nicotine reward) in a place preference paradigm. Lastly, repeated nicotine administration results in increased expression of MORs. However, this effect, along with rewarding properties of nicotine, is blocked in mice with a targeted disruption in the CREB gene. Together, pharmacologic and genetic manipulations indicate that phosphorylation of CREB and upregulation of functional MORs are required for nicotine-conditioned reward.

Endocrine and gene expression changes following forced swim stress exposure during cocaine abstinence in mice.

RATIONALE: Stress can reinstate previous cocaine-seeking long after drug is no longer present. However, little is known regarding the effect of chronic drug exposure and subsequent drug abstinence on responsivity to stress. OBJECTIVE: To determine the effect of acute (24-h) and prolonged (14-day) drug-free periods in cocaine-experienced mice on behavioral, endocrine, and molecular outputs following stress exposure. MATERIALS AND METHODS: Mice were administered a cocaine binge (15 mg/kg, every hour for 3h) for 2 weeks. Following a 24-h or 14-day drug-free period, stress responsivity, along with levels of anxiety, were measured using the forced swim test and elevated zero maze, respectively. In addition, alterations in the levels of plasma corticosterone, corticotrophin-releasing factor (CRF) mRNA, brain-derived neurotrophic factor (BDNF) mRNA, and histone acetylation at their respective promoters were examined following stress exposure. RESULTS: At both acute and prolonged abstinence time points, behavioral measures were essentially unaltered; however, cocaine-experienced mice exhibited an augmented corticosterone response to the forced swim stress compared to saline-treated mice. Stress exposure increased BDNF mRNA levels in the ventral tegmental area (VTA) and nucleus accumbens (NAc) only in cocaine-experienced mice following a prolonged, but not acute, drug-free period. Increased BDNF mRNA in the NAc was associated with an increase in acetylated histone 3 (AcH3) at the BDNF I promoter. CRF mRNA levels were increased in the amygdala (AMYG); however, this was not associated with alterations in histone acetylation at the promoter. CONCLUSION: These results demonstrate that drug history and prolonged abstinence can alter the endocrine and molecular responses to stress, which may facilitate the reinstatement of drug-seeking behaviors.

Vps51p mediates the association of the GARP (Vps52/53/54) complex with the late Golgi t-SNARE Tlg1p.

Multisubunit tethering complexes may contribute to the specificity of membrane fusion events by linking transport vesicles to their target membrane in an initial recognition event that promotes SNARE assembly. However, the interactions that link tethering factors to the other components of the vesicle fusion machinery are still largely unknown. We have previously identified three subunits of a Golgi-localized complex (the Vps52/53/54 complex) that is required for retrograde transport to the late Golgi. This complex interacts with a Rab and a SNARE protein found at the late Golgi and is related to two other multisubunit tethering complexes: the COG complex and the exocyst. Here we show that the Vps52/53/54 complex has an additional subunit, Vps51p. All four members of this tetrameric GARP (Golgi-associated retrograde protein) complex are required for two distinct retrograde transport pathways, from both early and late endosomes, back to the TGN. vps51 mutants exhibit a distinct phenotype suggestive of a regulatory role. Indeed, we find that Vps51p mediates the interaction between Vps52/53/54 and the t-SNARE Tlg1p. The binding of this small, coiled-coil protein to the conserved N-terminal domain of the t-SNARE therefore provides a crucial link between components of the tethering and the fusion machinery.

Adverse effects of anticancer agents that target the VEGF pathway.

Antiangiogenesis agents that target the VEGF/VEGF receptor pathway have become an important part of standard therapy in multiple cancer indications. With expanded clinical experience with this class of agents has come the increasing recognition of the diverse adverse effects related to disturbance of VEGF-dependent physiological functions and homeostasis in the cardiovascular and renal systems, as well as wound healing and tissue repair. Although most adverse effects of VEGF inhibitors are modest and manageable, some are associated with serious and life-threatening consequences, particularly in high-risk patients and in certain clinical settings. This Review examines the toxicity profiles of anti-VEGF antibodies and small-molecule inhibitors. The potential mechanisms of the adverse effects, risk factors, and the implications for selection of patients and management are discussed.

Stress-induced potentiation of cocaine reward: a role for CRF R1 and CREB.

Both clinical and preclinical research have shown that stress can potentiate drug use; however, the underlying mechanisms of this interaction are unknown. Previously, we have shown that a single exposure to forced swim (FS) reinstates extinguished conditioned place preference (CPP) to cocaine and that cAMP response element binding protein (CREB) is necessary for this response. CREB can be activated by corticotropin releasing factor (CRF) receptor type 1 (CRF(R1)) binding, which mediates neuroendocrine and behavioral responses to stress as well as to drugs of abuse. The present experiments investigate whether changes in cocaine reward elicited by previous exposure to stress are mediated by CREB and/or CRF(R1). Chronic exposure to FS in advance of conditioning enhances cocaine CPP in wild-type mice, but this is blocked in CREB-deficient mice. In addition, pretreatment with the CRF(R1) antagonist, antalarmin, before FS exposure blocks this stress-induced enhancement of cocaine CPP. Furthermore, FS-induced increase in phosphorylated CREB (pCREB), specifically in the lateral septum (LS) and nucleus accumbens (NAc) is also blocked by antalarmin. Taken together, these studies suggest that both CREB and CRF(R1) activation are necessary for stress-induced potentiation of drug reward.