Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Corticotropin Releasing Factor-Induced CREB Activation in Striatal Neurons Occurs via a Novel Gβγ Signaling Pathway

The peptide corticotropin-releasing factor (CRF) was initially identified as a critical component of the stress response. CRF exerts its cellular effects by binding to one of two cognate G-protein coupled receptors (GPCRs), CRF receptor 1 (CRFR1) or 2 (CRFR2). While these GPCRs were originally characterized as being coupled to Gαs, leading to downstream activation of adenylyl cyclase (AC) and subsequent increases in cAMP, it has since become clear that CRFRs couple to and activate numerous other downstream signaling cascades. In addition, CRF signaling influences the activity of many diverse brain regions, affecting a variety of behaviors. One of these regions is the striatum, including the nucleus accumbens (NAc). CRF exerts profound effects on striatal-dependent behaviors such as drug addiction, pair-bonding, and natural reward. Recent data indicate that at least some of these behaviors regulated by CRF are mediated through CRF activation of the transcription factor CREB. Thus, we aimed to elucidate the signaling pathway by which CRF activates CREB in striatal neurons. Here we describe a novel neuronal signaling pathway whereby CRF leads to a rapid Gβγ- and MEK-dependent increase in CREB phosphorylation. These data are the first descriptions of CRF leading to activation of a Gβγ-dependent signaling pathway in neurons, as well as the first description of Gβγ activation leading to downstream CREB phosphorylation in any cellular system. Additionally, these data provide additional insight into the mechanisms by which CRF can regulate neuronal function

Alterations in gene expression at key points in the addiction cycle

Addiction is a disease in which individuals cannot control their need for drugs, despite negative health and social consequences. While previous research has delineated the brain circuitry mediating the addiction process, molecular mechanisms responsible for drug-mediated behaviors remain elusive. Therefore, in this thesis, I sought to examine alterations in gene expression during key transition points in the addiction cycle, reward and exinction. Using microarray analysis, cocaine-mediated effects on gene expression changes were investigated in the nucleus accumbens (NAc) following reward and the amygdala (AMYG) following extinction in the conditioned place preference paradigm. In addition, the role of the environment was examined at the reward time point; following extinction, the role of cyclic-AMP response element binding protein (CREB) was examined. While cocaine had a minimal effect on gene expression in both microarrays, the environment played a significant role in altering gene expression following reward and the CREB genotype impacted gene expression in the AMYG. This global gene analysis at two key transition points furthers our understanding of molecular alterations involved in mediating the addiction process. Stress is one of the primary causes of relapse back into drug seeking. Therefore, I also examined the role of acute and prolonged cocaine withdrawal on behavioral, endocrine and molecular outputs of stress responsivity to further understand the mechanisms behind stress-induced relapse. While no alterations in behavior were observed, corticosterone levels were augmented in cocaine-experienced mice following both acute and prolonged withdrawal, indicating a hyperactive hypothalamic-pituitary-adrenal axis that develops and persists well after drug is removed. Corticosterone releasing factor mRNA levels in the AMYG, as well as brain derived neurotrophic factor (BDNF) mRNA levels in the ventral tegmental area and NAc, were increased after stress exposure following prolonged withdrawal only in cocaine-treated mice, suggesting that alterations in the regulation of these genes occurs during the withdrawal period and may sensitize gene expression to a stressor. Taken together, these data indicate that alterations in endocrine pathways and gene expression can occur well into the withdrawal period

Alterations in gene expression at key points in the addiction cycle

Addiction is a disease in which individuals cannot control their need for drugs, despite negative health and social consequences. While previous research has delineated the brain circuitry mediating the addiction process, molecular mechanisms responsible for drug-mediated behaviors remain elusive. Therefore, in this thesis, I sought to examine alterations in gene expression during key transition points in the addiction cycle, reward and exinction. Using microarray analysis, cocaine-mediated effects on gene expression changes were investigated in the nucleus accumbens (NAc) following reward and the amygdala (AMYG) following extinction in the conditioned place preference paradigm. In addition, the role of the environment was examined at the reward time point; following extinction, the role of cyclic-AMP response element binding protein (CREB) was examined. While cocaine had a minimal effect on gene expression in both microarrays, the environment played a significant role in altering gene expression following reward and the CREB genotype impacted gene expression in the AMYG. This global gene analysis at two key transition points furthers our understanding of molecular alterations involved in mediating the addiction process. Stress is one of the primary causes of relapse back into drug seeking. Therefore, I also examined the role of acute and prolonged cocaine withdrawal on behavioral, endocrine and molecular outputs of stress responsivity to further understand the mechanisms behind stress-induced relapse. While no alterations in behavior were observed, corticosterone levels were augmented in cocaine-experienced mice following both acute and prolonged withdrawal, indicating a hyperactive hypothalamic-pituitary-adrenal axis that develops and persists well after drug is removed. Corticosterone releasing factor mRNA levels in the AMYG, as well as brain derived neurotrophic factor (BDNF) mRNA levels in the ventral tegmental area and NAc, were increased after stress exposure following prolonged withdrawal only in cocaine-treated mice, suggesting that alterations in the regulation of these genes occurs during the withdrawal period and may sensitize gene expression to a stressor. Taken together, these data indicate that alterations in endocrine pathways and gene expression can occur well into the withdrawal period

Physiological systems under pressure

The marked disruption of the homeostasis of a physiological system, be it a cell, tissue, organ, or whole organism, is more commonly known as stress. In many ways, aging can be considered the ultimate stress. However, physiological systems are constantly exposed to more acute stresses. Advances in our understanding of the molecular response of several physiological systems to both physiologic and pathologic stress is discussed in this Review Series. It is hoped that such understanding will facilitate the development of approaches to ameliorate some of the limitations these stresses place on individuals. However, as pointed out in many of the articles, much remains to be learned before such approaches can be envisioned

Cone calorimetry as a useful technique for the screening of cotton fibers

Cotton biotechnology offers the potential for breakthrough developments in fiber characteristics. In this process, the early selection of fibers with the best performance is of utmost importance. However, due to the limited availability of these specialty fibers, the use of available test methods is limited and thus new test methodologies are needed. The aim of this paper is to study Cone calorimetry for the characterization of cotton fibers. One of the main aspects of the procedure, namely sample weight, is optimized to improve the reproducibility

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

Morphine Withdrawal Stress Modulates Lipopolysaccharide-induced Interleukin 12 p40 (IL-12p40) Expression by Activating Extracellular Signal-regulated Kinase 1/2, Which Is Further Potentiated by Glucocorticoids

Withdrawal stress is a common occurrence in opioid users, yet very few studies have examined the effects of morphine withdrawal (MW) on immune functioning or the role of glucocorticoids in MW-induced immunomodulation. This study investigated for the first time the role of glucocorticoids in MW modulation of LPS-induced IL-12p40, a key cytokine playing a pivotal role in immunoprotection. Using WT and μ-opioid receptor knock-out mice, we show that MW in vivo significantly attenuated LPS-induced IL-12p40 mRNA and protein expression. The role of glucocorticoids in MW modulation of IL-12p40 was investigated using a murine macrophage cell line, CRL2019, in an in vitro MW model. Interestingly, MW alone in the absence of glucocorticoids resulted in a significant reduction in IL-12p40 promoter activity and mRNA and protein expression. EMSA revealed a concurrent decrease in consensus binding to transcription factors NFκB, Activator Protein-1, and CCAAT/enhancer-binding protein and Western blot analysis demonstrated a significant activation of LPS-induced ERK1/2 phosphorylation. Interestingly, although glucocorticoid treatment alone also modulated these transcription factors and ERK1/2 activation, the addition of glucocorticoids to MW samples resulted in a greater than additive reduction in the transcription factors and significant hyperactivation of LPS-induced ERK1/2 phosphorylation. ERK inhibitors reversed MW and MW plus corticosterone inhibition of LPS-induced IL-12p40. The potentiating effects of glucocorticoids were non-genomic because nuclear translocation of glucocorticoid receptor was not significantly different between MW and corticosterone treatment. This study demonstrates for the first time that MW and glucocorticoids independently modulate IL-12p40 production through a mechanism involving ERK1/2 hyperactivation and that glucocorticoids can significantly augment MW-induced inhibition of IL-12p40