Allostatic Changes Research Articles

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice.

Alcohol use disorder (AUD) is a complex psychiatric disease characterized by periods of heavy drinking and periods of withdrawal. Chronic exposure to ethanol causes profound neuroadaptations in the extended amygdala, which cause allostatic changes promoting excessive drinking. The bed nucleus of the stria terminalis (BNST), a brain region involved in both excessive drinking and anxiety-like behavior, shows particularly high levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a key mediator of the stress response. Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed; whether the PACAP system of the BNST is also recruited in other models of alcohol addiction and whether it is of local or nonlocal origin is currently unknown. Here, we show that PACAP immunoreactivity is increased selectively in the BNST of C57BL/6J mice exposed to a chronic, intermittent access to ethanol. While pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor-expressing cells were unchanged by chronic alcohol, the levels of a peptide closely related to PACAP, the calcitonin gene-related neuropeptide, were found to also be increased in the BNST. Finally, using a retrograde chemogenetic approach in PACAP-ires-Cre mice, we found that the inhibition of PACAP neuronal afferents to the BNST reduced heavy ethanol drinking. Our data suggest that the PACAP system of the BNST is recruited by chronic, voluntary alcohol drinking in mice and that nonlocally originating PACAP projections to the BNST regulate heavy alcohol intake, indicating that this system may represent a promising target for novel AUD therapies.

Home cage voluntary alcohol consumption increases binge drinking without affecting abstinence-related depressive-like behaviors or operant responding in crossed high alcohol-preferring mice (cHAPs)

Chronic alcohol consumption can lead to tolerance and escalation of drinking in humans and animals, but mechanisms underlying these changes are not fully characterized. Preclinical models can delineate which mechanisms are involved. The chronic intermittent ethanol exposure (CIE) procedure uses forced exposure to vaporized alcohol that elicits withdrawal and increased responding for alcohol in operant tasks in C57BL/6J inbred mice. Chronic two-bottle choice (2BC) drinking in the same strain elicits abstinent-related depression-like behavior, suggestive of allostatic changes. Selected lines such as crossed High Alcohol Preferring (cHAP) mice voluntarily drink to blood alcohol concentrations comparable to those attained in CIE and could be used to assess how alcohol affects these same endpoints without the confounds of involuntary vapor inhalation. In three experiments, we assess how 2BC drinking in cHAP mice affects abstinence-related depressive- and anxiety-like behavior, operant responding for alcohol, and binge consumption using drinking-in-the-dark (DID). We hypothesized that cHAPs with home-cage drinking experience would exhibit more depressive behavior after abstinence, increased responding for alcohol in the operant box, and increased DID intake. Of these, a drinking history increased DID intake in female cHAPs only and increased sucrose preference and intake following abstinence, but had no effects on operant responding or NSFT latency and FST immobility following forced abstinence. These results are consistent with recent findings using slice electrophysiology showing tolerance to alcohol's actions on the dorsolateral striatum following 2BC drinking in female, but not male cHAP mice. Overall, these data suggest that cHAPs may require procedures allowing rapid intoxication, such as DID, to demonstrate changes in alcohol's rewarding effects.

Peripheral blood infl ammatory markers as signals of mental disorders in a sample of elderly people

The physiological epiphenomena and the concurrent and altered emotional and cognitive states exhibit themselves in the brain and peripherally as well. Depres- sion also carries allostatic changes related to inflammation and hormonal imba- lances, the same applies to anxiety and cognitive impairments. After examining alterations in scientific literature, we proceed with a cross-sectional study consi- dering a sample made of a group of elderly people from Northern Italy, in order to highlight potentially altered hematic levels of inflammatory markers in the serum in combination with depression, anxiety, and cognitive impairment me- asurements. As far as we know, inflammatory markers such as PLR and MLR have never been studied for this purpose in the elderly. Results exhibit differen- ces in the PLR between people with and without depression, differences in the NLR, PLR, and MLR between people with anxiety, and a predictive value in the WBC parameter, PLR, and TSH related to the cognitive state. The data suggest that, in given circumstances, inflammatory markers taken from plasma could help diagnose mental disorders and develop targeted treatments.

The effect of obesity-related allostatic changes on cardio-metabolic risk in euthyroid children.

The hormonal thyroid changes related to obesity, even when in the euthyroid state, may contribute to the unfavorable cardio-metabolic profile of obese patients. In this retrospective study, we aim to investigate the biochemical thyroid changes and the association between serum TSH, FT4, FT3 and cardio-metabolic risk factors in euthyroid obese youths. Four hundred ninety-one Caucasian euthyroid obese children and adolescents aged 9.93 ± 2.90years were recruited. Each patient underwent clinical and auxological examination and laboratory workup including an OGTT and the measurement of thyroid function and lipid profile. Homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride to high-density lipoprotein cholesterol ratio, total cholesterol to HDL ratio, atherogenic index of plasma, insulinogenic index, area under the glucose and insulin curves were calculated. We found that TSH was positively correlated with BMI-SDS values and significantly associated with hypercholesterolemia and hyperinsulinemia; FT4 resulted negatively correlated with BMI-SDS; FT3 was positively correlated with BMI-SDS and the area under the curve of insulin and negatively correlated with HDL. FT3 and FT4 resulted significantly associated with severe obesity. In addition, children with high-normal TSH values showed higher triglyceride to high-density lipoprotein cholesterol ratio values than those with normal TSH levels. Our data showed that thyroid hormones could influence obesity, lipid and glycemic parameters in euthyroid youths. These findings could carry implications regarding optimal TSH levels in obese children and confirm the importance of evaluating the thyroid function as possible adjunctive cardio-metabolic risk factor related to obesity.

Chaos: A Complex Noise on Blood Pressure Orchestration

The equilibrium by constancy or just shifts in other intrinsic and extrinsic variables are known as allostatic changes in systemic blood pressure regulation. This short-review intends to introduce the Chaos.

Pseudo and resistant hypertension: A chaotic perspective.

Systemic blood pressure (BP) may oscillate for homeostatic needs (equilibrium by constancy) or just as shifts in other intrinsic and extrinsic variables known as allostatic changes. This transitory pressure often rises alerts physicians to out‐of‐control hypertension or even hypertensive crisis. There is a very complex theory underlying these stochastic phenomena, which physicists and mathematicians translate into a single word: chaos. These changes happen according to a stochastic probabilistic pattern that presumes chaotic but somewhat predictable and nonlinear modeling of BP‐related dynamics as a mathematical approach. Based on the chaos theory, small changes at the initial BP (baseline overtime) values could disturb the homeostasis leading to extreme BP chaotic shifts. These almost insignificant oscillations may also affect other variables and systems, leading to the misdiagnosis of hypertension, “out‐of‐control” BP levels, and resistant hypertension (RHT). Thus, these unpredictable and transient increases in BP values may be improperly diagnosed as the white coat and masked or resistant hypertension. Indeed, the interference of the chaos in any phenotype of (true or false) hard to control BP is not considered in clinical settings. This review provides some basic concepts on chaos theory and BP regulation. Besides pseudoresistant hypertension (lack of adherence, circadian variations, and others (white‐coat, masked, early morning effects or hypertension), chaotic changes can be responsible for out‐of‐control hypertension.

Brain Network Allostasis after Chronic Alcohol Drinking Is Characterized by Functional Dedifferentiation and Narrowing.

Alcohol use disorder (AUD) causes complex alterations in the brain that are poorly understood. The heterogeneity of drinking patterns and the high incidence of comorbid factors compromise mechanistic investigations in AUD patients. Here we used male Marchigian Sardinian alcohol-preferring (msP) rats, a well established animal model of chronic alcohol drinking, and a combination of longitudinal resting-state fMRI and manganese-enhanced MRI to provide objective measurements of brain connectivity and activity, respectively. We found that 1 month of chronic alcohol drinking changed the correlation between resting-state networks. The change was not homogeneous, resulting in the reorganization of pairwise interactions and a shift in the equilibrium of functional connections. We identified two fundamentally different forms of network reorganization. First is functional dedifferentiation, which is defined as a regional increase in neuronal activity and overall correlation, with a concomitant decrease in preferential connectivity between specific networks. Through this mechanism, occipital cortical areas lost their specific interaction with sensory-insular cortex, striatal, and sensorimotor networks. Second is functional narrowing, which is defined as an increase in neuronal activity and preferential connectivity between specific brain networks. Functional narrowing strengthened the interaction between striatal and prefrontocortical networks, involving the anterior insular, cingulate, orbitofrontal, prelimbic, and infralimbic cortices. Importantly, these two types of alterations persisted after alcohol discontinuation, suggesting that dedifferentiation and functional narrowing rendered persistent network states. Our results support the idea that chronic alcohol drinking, albeit at moderate intoxicating levels, induces an allostatic change in the brain functional connectivity that propagates into early abstinence.SIGNIFICANCE STATEMENT Excessive consumption of alcohol is positioned among the top five risk factors for disease and disability. Despite this priority, the transformations that the nervous system undergoes from an alcohol-naive state to a pathologic alcohol drinking are not well understood. In our study, we use an animal model with proven translational validity to study this transformation longitudinally. The results show that shortly after chronic alcohol consumption there is an increase in redundant activity shared by brain structures, and the specific communication shrinks to a set of pathways. This functional dedifferentiation and narrowing are not reversed immediately after alcohol withdrawal but persist during early abstinence. We causally link chronic alcohol drinking with an early and abstinence-persistent retuning of the functional equilibrium of the brain.

Algorithms underlying flexible phototaxis in larval zebrafish.

To thrive, organisms must maintain physiological and environmental variables in suitable ranges. Given that these variables undergo constant fluctuations over varying time scales, how do biological control systems maintain control over these values? We explored this question in the context of phototactic behavior in larval zebrafish. We demonstrate that larval zebrafish use phototaxis to maintain environmental luminance at a set point, that the value of this set point fluctuates on a time scale of seconds when environmental luminance changes, and that it is determined by calculating the mean input across both sides of the visual field. These results expand on previous studies of flexible phototaxis in larval zebrafish; they suggest that larval zebrafish exert homeostatic control over the luminance of their surroundings, and that feedback from the surroundings drives allostatic changes to the luminance set point. As such, we describe a novel behavioral algorithm with which larval zebrafish exert control over a sensory variable.

G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease.

BackgroundIn addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target.MethodsWe used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies.ResultsKnockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an “overload” hypothesis for the etiology of the psychiatric symptoms of Parkinson disease.LimitationsBehavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types.ConclusionGPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.

Insights into the Neurobiology of Craving in Opioid Use Disorder.

Opioids remain the most potent form of pain relief currently available, yet have a high abuse liability. Here we discuss underlying neurobiological changes in Opioid Use Disorder (OUD) that likely contribute to drug craving, which in turn drives continued drug use and relapse. Craving has emerged as a strong indicator in drug-seeking and relapse. Studies have demonstrated a number of allostatic changes in circuitry that facilitate learning of drug-stimuli relationships, thereby augmenting cue-triggered drug use and relapse. This review will focus on key neurobiological changes in underlying circuitry observed during the initial and continued exposure to opioids that result in an increase in neural-reactivity to drug-related intrinsic and extrinsic drug cues, and to enhanced learning of drug-context correlations. This sensitized learning state may be an indication of the underlying framework that drives craving and ultimately, motivates increased salience of drug cues and drives drug-seeking.

Нейрофизиологические механизмы аддиктивного поведения и употребления психоактивных веществ в подростковом возрасте: возможности профилактики и терапии

Поведенческие аддикции подростков, включающие употребление психоактивных веществ, являются одними из основных проблем здравоохранения большинства стран мира, в том числе России. Подростковый возраст - это период динамичных физиологических, психологических, и поведенческих изменений. Данный период также связан с повышенным риском употребления психоактивных веществ, и формированием различных аддиктивных расстройств. В подростковом возрасте происходящие изменения в нейронных системах вознаграждения, мотивации, когнитивного контроля и сопротивления стрессовым воздействиям способствуют формированию повышенного риска употреблении различных психоактивных веществ, и нехимических вариантов аддиктивной патологии. Современные патофизиологические модели возникновения аддиктивной патологии в подростковом возрасте включают данные о аллостатических изменениях функций и структуры дофаминергической системы среднего мозга, нейропластичности, связанной со стрессом, и нарушениии баланса между когнитивным контролем и процессами в системе вознаграждения. Результаты генетических и эпигенетических исследований, изучение промежуточных фенотипов / эндофенотипов могут помочь в изучении детей и подростков, входящих в группу риска возникновения аддиктивных расстройств.The use of psychoactive substances as a part of behavioral addictions of adolescents is a medical issue in most of countries all over the world, including Russia. Adolescence is a period of dynamic physiological, psychological, and behavioral changes. This period is also associated with increased risk of substance abuse and formation of various addictive disorders. In adolescence, changes in neural systems of reward, motivation, cognitive control, and resistance to stress contribute to increased risk of using various psychoactive substances and of non-chemical variants of addictive pathology. Current pathophysiological models of addictive pathology in adolescence include data on allostatic changes in functions and structure of the mid-brain dopaminergic system, neuroplasticity related with stress, and imbalance between cognitive control and processes in the reward system. Results of genetic and epigenetic studies and investigation of intermediate phenotypes / endophenotypes can help to study children and adolescents at risk of addictive disorders.

Allostatic Changes in the cAMP System Drive Opioid-Induced Adaptation in Striatal Dopamine Signaling

SUMMARYOpioids are powerful addictive agents that alter dopaminergic influence on reward signaling in medium spiny neurons (MSNs) of the nucleus accumbens. Repeated opioid exposure triggers adaptive changes, shifting reward valuation to the allostatic state underlying tolerance. However, the cellular substrates and molecular logic underlying such allostatic changes are not well understood. Here, we report that the plasticity of dopamine-induced cyclic AMP (cAMP) signaling in MSNs serves as a cellular substrate for drug-induced allostatic adjustments. By recording cAMP responses to optically evoked dopamine in brain slices from mice subjected to various opioid exposure paradigms, we define profound neuronal-type-specific adaptations. We find that opioid exposure pivots the initial hyper-responsiveness of D1-MSNs toward D2-MSN dominance as dependence escalates. Presynaptic dopamine transporters and postsynaptic phosphodiesterases critically enable cell-specific adjustments of cAMP that control the balance between opponent D1-MSN and D2-MSN channels. We propose a quantitative model of opioid-induced allostatic adjustments in cAMP signal strength that balances circuit activity.

Opioid-Induced Tolerance and Hyperalgesia.

Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.

Association of Cortical Glutamate and Working Memory Activation in Patients With Schizophrenia: A Multimodal Proton Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study

BackgroundCognitive deficits such as working memory (WM) impairment are core features of schizophrenia. One candidate marker for the integrity of synaptic neurotransmission necessary for cognitive processes is glutamate. It is frequently postulated that antipsychotic medication possibly alters functional mechanisms in the living brain. We tested in vivo for group differences in activation of the dorsolateral prefrontal cortex (DLPFC) during WM performance and the association with glutamate concentration in DLPFC depending on medication status. MethodsA total of 90 subjects (35 control subjects, 36 medicated patients, and 19 unmedicated patients) contributed magnetic resonance spectroscopy data. We estimated glutamate in left DLPFC. Subjects performed an n-back WM task (2-back vs. 0-back) during functional magnetic resonance imaging, and local activation in left DLPFC was measured. For analysis of association with medication status, we calculated linear regression models including an interaction effect with group. ResultsMedicated and unmedicated patients with schizophrenia showed impaired performance. We found significantly reduced WM activation in left DLPFC in medicated patients and a trendwise reduction in unmedicated patients as compared with control subjects. We found no group difference in local glutamate concentration. However, we found differential effects of medication status on the association between local glutamate concentration and WM activation in left DLPFC, with a positive association in unmedicated patients but not in medicated patients. ConclusionsWe provide evidence that WM-dependent activation is associated with glutamate concentration in unmedicated patients with schizophrenia. Our finding points to putative allostatic changes that affect the functioning of the brain and might be altered through medication.

(349) Pain-Induced Negative Affect is Mediated Via Recruitment of the Nucleus Accumben Kappa Opioid System

Prolonged negative affect significantly impacts the quality of life for patients suffering from pain. These maladaptive emotional states can lead to severe depression, suicide, involuntary opioid overdose, and related neuropsychiatric comorbidities. The nucleus accumbens (NAc) shell, which integrates both the aversive and rewarding valence of stimuli, exhibits allostatic changes in the presence of pain. In discrete regions of this structure, activation of the kappa opioid receptor (KOR), either by dynorphin, its endogenous agonist, or pharmacological ligands, acutely decreases the reinforcing properties of rewards and induces dysphoria and aversive behaviors. Using a wide range of complementary techniques including pharmacology, optogenetics, chemogenetics, physiology, biochemistry and in vivo positron emission tomography (PET) imaging, our current findings demonstrate that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is both necessary and sufficient to drive pain-induced negative affective states. Furthermore, we reveal that inflammatory pain impacts patterns of consumption of fentanyl using an intra-venous self-administration paradigm. Those particular patterns, where rats in pain display bursts of consumption interrupted by periods of “rest”, could lead to the occurrence of respiratory depression and subsequent involuntary lethal overdose. Taken together, our results provide evidence that adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention in pain that could circumvent affective disorders and may prevent life-threatening episodes.

Tooth Loss and Allostatic Load Changes Later in Life: A 12-Year Follow-Up Analysis of the English Longitudinal Study of Ageing (ELSA)

Tooth Loss and Allostatic Load Changes Later in Life: A 12-Year Follow-Up Analysis of the English Longitudinal Study of Ageing (ELSA)

Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans.

Stress plays a key role in addiction etiology and relapse. Rodent models posit that following repeated periods of alcohol and other drug intoxication, compensatory allostatic changes occur in the central nervous system (CNS) circuits involved in behavioral and emotional response to stressors. We examine a predicted manifestation of this neuroadaptation in recently abstinent alcohol-dependent humans. Participants completed a translational laboratory task that uses startle potentiation to unpredictable (vs. predictable) stressors implicated in the putative CNS mechanisms that mediate this neuroadaptation. Alcohol-dependent participants displayed significantly greater startle potentiation to unpredictable than predictable stressors relative to nonalcoholic controls. The size of this effect covaried with alcohol-related problems and degree of withdrawal syndrome. This supports the rodent model thesis of a sensitized stress response in abstinent alcoholics. However, this effect could also represent premorbid risk or mark more severe and/or comorbid psychopathology. Regardless, pharmacotherapy and psychological interventions may target unpredictable stressor response to reduce stress-induced relapse. (PsycINFO Database Record

Region-specific increases in FosB/ΔFosB immunoreactivity in the rat brain in response to chronic sleep restriction

Using a rat model of chronic sleep restriction (CSR) featuring periodic sleep deprivation with slowly rotating wheels (3h on/1h off), we previously observed that 99h of this protocol induced both homeostatic and allostatic (adaptive) changes in physiological and behavioural measures. Notably, the initial changes in sleep intensity and attention performance gradually adapted during CSR despite accumulating sleep loss. To identify brain regions involved in these responses, we used FosB/ΔFosB immunohistochemistry as a marker of chronic neuronal activation. Adult male rats were housed in motorized activity wheels and underwent the 3/1 CSR protocol for 99h, or 99h followed by 6 or 12days of recovery. Control rats were housed in home cages, locked activity wheels, or unlocked activity wheels that the animals could turn freely. Immunohistochemistry was conducted using an antibody that recognized both FosB and ΔFosB, and 24 brain regions involved in sleep/wake, autonomic, and limbic functions were examined. The number of darkly-stained FosB/ΔFosB-immunoreactive cells was increased immediately following 99h of CSR in 8/24 brain regions, including the medial preoptic and perifornical lateral hypothalamic areas, dorsomedial and paraventricular hypothalamic nuclei, and paraventricular thalamic nucleus. FosB/ΔFosB labeling was at control levels in all 8 brain areas following 6 or 12 recovery days, suggesting that most of the immunoreactivity immediately after CSR reflected FosB, the more transient marker of chronic neuronal activation. This region-specific induction of FosB/ΔFosB following CSR may be involved in the mechanisms underlying the allostatic changes in behavioural and physiological responses to CSR.

Neurobiology of opioid dependence in creating addiction vulnerability.

Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality — the “drug-dependent” state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is contributive to the current opioid epidemic in the USA.

The dark side of emotion: The addiction perspective

Emotions are “feeling” states and classic physiological emotive responses that are interpreted based on the history of the organism and the context. Motivation is a persistent state that leads to organized activity. Both are intervening variables and intimately related and have neural representations in the brain. The present thesis is that drugs of abuse elicit powerful emotions that can be interwoven conceptually into this framework. Such emotions range from pronounced euphoria to a devastating negative emotional state that in the extreme can create a break with homeostasis and thus an allostatic hedonic state that has been considered key to the etiology and maintenance of the pathophysiology of addiction. Drug addiction can be defined as a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. The negative emotional state that drives negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain incentive salience and stress systems. Specific neurochemical elements in these structures include not only decreases in incentive salience system function in the ventral striatum (within-system opponent processes) but also recruitment of the brain stress systems mediated by corticotropin-releasing factor (CRF), dynorphin-κ opioid systems, and norepinephrine, vasopressin, hypocretin, and substance P in the extended amygdala (between-system opponent processes). Neuropeptide Y, a powerful anti-stress neurotransmitter, has a profile of action on compulsive-like responding for drugs similar to a CRF1 receptor antagonist. Other stress buffers include nociceptin and endocannabinoids, which may also work through interactions with the extended amygdala. The thesis argued here is that the brain has specific neurochemical neurocircuitry coded by the hedonic extremes of pleasant and unpleasant emotions that have been identified through the study of opponent processes in the domain of addiction. These neurochemical systems need to be considered in the context of the framework that emotions involve the specific brain regions now identified to differentially interpreting emotive physiological expression.