Table of Contents. Tanja N. Alim, M. Lawson, M. Iacoviello, Ph. Bailey; Allison M. Greene, M. Adriana Feder, M. Baileyand Allison M. Alexander Neumeister, M. Acute and chronic stress—related mechanisms play an important role in the development of addiction and its chronic, relapsing nature. Multisystem adaptations in brain, body, behavioral, and social function may contribute to a dysregulated physiological state that is maintained beyond the homeostatic range.
In addition, chronic abuse of substances leads to an altered set point across multiple systems. The study of resilience can be approached by examining interindividual stress responsibility at multiple phenotypic levels, ranging from psychological differences in the way people cope with stress to differences in neurochemical or neural circuitry function.
The ultimate goal of such research is the development of strategies and interventions to enhance resilience and coping in the face of stress and prevent the onset of addiction problems or relapse. Evidence from different disciplines suggests that acute and chronic stress—related mechanisms play an important role in both the development and the chronic, relapsing nature of addiction Baumeister ; Baumeister et al.
Stress is defined as the physiological and esser cifrato da alcool in Yuzhno-Sakhalinsk process resulting from a challenge to homeostasis by any real or perceived demand on the body Lazarus and Fokman ; McEwen ; Selye Stress often induces multisystem adaptations that occur in the brain and body and affect behavioral and social function.
The resulting dynamic condition is a dysregulated physiological state maintained beyond the homeostatic range.
This definition and conceptualization of stress was further developed to explain the chronic abuse of substances and comfort foods and has been studied in the context of behavioral addiction i. Persistent challenges to an organism through chronic substance use may ultimately lead to an altered set point across multiple systems. This hypothesis is consistent with evidence that suggests adaptations in brain reward and stress circuits, and local physiology e.
Cravings or urges, decreases in self-control, and a compulsive engagement in unhealthy behaviors each characterize patients with addiction Dallman et al. Responsivity ranges from psychological differences in the way individuals cope with stress to differences in neurochemical or neural circuitry function Cicchetti and Blender Variability within the genetic makeup and quality of early-life experience, as well as interactions between the two, are known to contribute to differences in stress resilience Enoch ; Heim and Nemeroff Genetic esser cifrato da alcool in Yuzhno-Sakhalinsk can stem from gene—environment interactions, changes in gene expression influenced by the environment i.
This gene-by-environment interaction predicted the initiation of drinking in adolescence as well as progression to esser cifrato da alcool in Yuzhno-Sakhalinsk drinking by young adulthood Schmid et al. The following sections highlight resilient responses to stress in studies in which stress was identified as an important factor contributing to the neurobiology of alcohol dependence. Early studies of children exposed to esser cifrato da alcool in Yuzhno-Sakhalinsk Masten ; Masten and Coatsworth ; Rutter as well as more recent studies in resilient adults Ahmad et al.
For example, the ability to simultaneously experience both positive and negative emotions when confronted with a high-stress situation increases flexibility of thinking and problem solving and can buffer individuals from developing stress-induced adverse consequences Fredrickson ; Ong et al. Likewise, optimism has been associated with resilience to stress-related disorders, including alcohol use disorders Ahmad et al.
Unlike personality characteristics associated with increased risk for substance use disorders e. In this study, positive emotionality was found to buffer the effects of parent— child conflict and of parental and peer substance use on adolescent substance use. The ability to focus attention on performing and completing tasks was identified as a protective factor against substance use Wills et al.
The ability to focus attention might relate to the capacity to cope by planning and problem solving in times of stress, both types of coping styles characteristic of resilient individuals Southwick et al. Veenstra and colleagues examined esser cifrato da alcool in Yuzhno-Sakhalinsk impact of coping style on alcohol use in response to stressful life events in a sample of 1, men and 1, women drawn randomly from the Dutch Lifestyle and Health Study Veenstra et al Individuals who scored high on emotion coping, a coping style focused on feelings and emotional content to cope with stress, used more alcohol when experiencing a negative life event, compared with those who scored low on emotion coping.
Alcohol use in times of stress did not vary by cognitive or by action coping, but the study esser cifrato da alcool in Yuzhno-Sakhalinsk that cognitive coping and having more social contacts was linked to lower alcohol use in general. Another study of more than 1, adult drinkers in the general population from a New York county found stress-induced drinking in a subset of men but not women who scored high on avoidance coping and on positive expectancy from esser cifrato da alcool in Yuzhno-Sakhalinsk Cooper et al.
Men with low-avoidance coping and low expectancy from alcohol, on the other hand, actually showed a negative relationship between stressful life events and alcohol use. Of note, low avoidance coping has been linked to stress resilience in general, in several other studies Alim et al. This process is mediated by a stress circuit see figure 1which is consistently implicated in stress-related disorders such as mood and anxiety disorders and addictive disorders.
Interindividual variability in stress resilience results from differences in the coordinated stress response. This response comprises the function and interactions of numerous hormones, neurotransmitters, and neuropeptides, some of which are discussed below.
Figure 1 Norepinephrine NE and dopamine DA are the principle chemical messengers employed in central and peripheral sympathetic synapses, and the human NE transporter rapidly clears NE and DA from the synaptic cleft via efficient transport systemattenuating signaling, recycling 90 percent of these synaptic monoamines.
NE neurons innervate nearly all parts of the neuroaxis, with the locus coeruleus LC being responsible for most of the NE in the brain. NE exerts neuromodulatory effects on the cellular activity of post-synaptic target neurons in esser cifrato da alcool in Yuzhno-Sakhalinsk brain circuits, thereby moderating synaptic transmission in target circuits including the thalamus, prefrontalcortex Esser cifrato da alcool in Yuzhno-Sakhalinskventral striatum via PFCand amygdala, which have been implicated in substance use disorders.
The widespread and divergent anatomical organization positions the NE system to be involved in widely varying functions including responses to stress, which alters both the electrophysiological activity of NE neurons in the LC and the release of NE in the terminal regions of these cells, as well as crucial cognitive functions, including attention and arousal.
NE mediates many of the adaptive and maladaptive consequences of stress esser cifrato da alcool in Yuzhno-Sakhalinsk, implicating this system in a variety of abnormal behaviors including alcohol dependence.
The HPA axis is a system regulated by a esser cifrato da alcool in Yuzhno-Sakhalinsk negative-feedback system. CRF, released by the hypothalamus in response to stress, triggers the release of adrenocorticotrophic hormone ACTH from the anterior pituitary gland. This process leads to the synthesis and release of cortisol by the adrenal cortex. Cortisol secretion acutely facilitates cognitive, metabolic, immunologic, and behavioral adaptations to stress. Resilience is maintained when the stress response is both activated and terminated efficiently.
The adaptive responses of the HPA axis are thought to involve an optimal balance of the cortisol-binding receptors GR and mineralocorticoid receptor de Kloet et al. Studies showing lower plasma levels of ACTH but not cortisol in men with a family history of alcoholism Dai et al. Long-term alcohol abuse is associated with esser cifrato da alcool in Yuzhno-Sakhalinsk extrahypothalamic CRF signaling and dampened HPA axis responsivity Richardson et al.
Increases in extrahypothalamic CRF contribute to negative emotional states during abstinence, increasing risk for relapse Koob and Le Moal In a recent study, researchers asked alcoholics who had been abstinent for 1 month to imagine a relaxing situation of their choice while listening to a previously recorded audiotape of this situation. A greater cortisol-to-corticotropin ratio i.
During the acute stress response, the hormone norepinephrine NE is released through direct projections from the brain site where NE is synthesized i. In combination with CRF, NE also might contribute to the consolidation of emotional memories associated with drug use in the amygdala Koob et al.
Stress resilience may be enhanced through the regulation of NE system responsiveness, which is mediated through effects on the NE transporter on catecholamine receptors i. This mechanism deserves further study in humans with positron emission esser cifrato da alcool in Yuzhno-Sakhalinsk PETwhich uses positron-emitting radiotracers to show where and how compounds act in the brain Ding et al.
The serotonin 5-HT system, which consists primarily of neurons from the dorsal raphe nuclei that project widely throughout the brain including the amygdala, ventral striatum, and PFCis involved in the regulation of stress and anxiety. Serotonin has an important role in promoting neuroplasticity in the central nervous system, both during development and in adulthood. Serotonin also regulates the neurochemical effects of drugs of abuse, including alcohol, and is involved in modulating impulsivity, known to increase risk for alcohol and esser cifrato da alcool in Yuzhno-Sakhalinsk abuse Kirby et al.
The 5-HT system is itself modulated by drugs of abuse. For example, alcohol administration elevates 5-HT levels in the nucleus accumbens, ventral tegmental area VTAamygdala, and hippocampus, an effect that is more pronounced in alcohol-preferring rats.
Reduced activity of the 5-HT system might contribute to depression during withdrawal and increase vulnerability to relapse Kirby et al. In studies of macaques, differential function of the 5-HT system in interaction with early life stress was found to affect alcohol consumption: peer-reared female macaques with a specific variant i. The 5-HT system is extremely complex, including at least 14 receptor subtypes.
Restrained function of another 5-HT receptor, 5HT1B, might be central to resilient stress responses by enhancing synaptic availability of 5-HT in the amygdala and other cortical regions as well as promoting dopamine release in the ventral striatum Clark and Neumaier ; Krystal and Neumeister ; Sari see figure 2. The role of this receptor subtype in addiction disorders recently was studied in humans. The report demonstrated that alcohol dependence in humans, like in rodent models, is associated with increased levels of ventral striatal 5-HT1 B receptors Hu et al.
Additional research is necessary to understand the complex function of the 5-HT system. However, these findings suggest possible novel targets for the treatment of stress-related disorders and, most important, addiction disorders.
Dopaminergic neurons in the ventral tegmental area VTA of the midbrain project to the nucleus accumbens and other limbic areas to form the esser cifrato da alcool in Yuzhno-Sakhalinsk dopamine system, the most studied reward circuit. Dopamine neurons are activated in response to reward or the expectation of reward, and generally are inhibited by aversive stimuli.
Dopamine signaling is central to the onset of addiction, as well as to the transition to dependence in interaction with other neurotransmitter esser cifrato da alcool in Yuzhno-Sakhalinsk Ross and Peselow Drugs of addiction trigger large but brief increases in extracellular dopamine in the nucleus accumbens. Over time, chronic esser cifrato da alcool in Yuzhno-Sakhalinsk use downregulates dopamine receptors and dopamine release, leading to decreased sensitivity to natural rewards, such as food and sex, and leading also to further drug use Volkow et al Although findings from animal studies suggest that early-life stress can lead to long-lasting changes in gene expression in the mesolimbic dopamine pathway, ultimately increasing vulnerability to addictive disorders, not all individuals with a history of childhood abuse develop addictive or other disorders, thereby stressing the role of protective factors such as genetic variants conferring resilience Enoch Findings from several studies suggest that higher dopamine D2 receptor availability in the striatum might promote resilience to alcohol use disorders.
In a study of unaffected members of alcoholic families, higher striatal dopamine D2 receptor availability was associated with higher positive emotionality, discussed above as a protective factor against alcohol use disorders Volkow et al Other studies found that higher striatal dopamine D2 receptor availability was associated with resistance to the reinforcing effects of stimulants in healthy volunteers Volkow et al.
NPY, a 36—amino acid peptide, is widely distributed in the brain. NPY has anxiety-reducing properties in rodents and is thought to enhance resilience to stress in humans Feder et al. Evidence from animal and human studies suggests that NPY has a key role in regulating alcohol intake, esser cifrato da alcool in Yuzhno-Sakhalinsk, and withdrawal.
Mice genetically modified to overexpress NPY consume less alcohol Thiele et al. Infusion of NPY into the central nucleus of the amygdala has been shown to normalize both anxiety behaviors and alcohol intake, suggesting that NPY might work by modulating anxiety esser cifrato da alcool in Yuzhno-Sakhalinsk Zhang et al.
In rhesus macaques exposed to early life stress, and in human studies, certain NPY gene polymorphisms are associated with differential susceptibility to alcohol or cocaine dependence Koehnke et al. An emerging body of evidence suggests an important role for the endogenous cannabinoid eCB system and specifically the CB 1 receptor esser cifrato da alcool in Yuzhno-Sakhalinsk alcohol-related behaviors for review, see Basavarajappa To date, however, only peripheral measures of eCB function have been collected in living humans with alcohol dependence AD Mangieri et al.
At a neurobiological level, studies show impairments in decision making in alcohol-dependent patients Dom et al. Three sets of factors are thought to be responsible for high alcohol relapse rates.
First, individual differences in the positive, reinforcing properties of alcohol are known to increase risk esser cifrato da alcool in Yuzhno-Sakhalinsk alcoholism and possibly alcohol relapse Schuckit and Smith Finally, stress has been found to increase the risk of alcohol relapse Brown et al.
All three factors can be linked to the eCB system and its attending CB 1 receptor and increasing evidence derived from animal studies suggests a role esser cifrato da alcool in Yuzhno-Sakhalinsk the eCB system in alcohol-related behaviors Vinod and Hungund