Heroin addiction engages negative emotional learning brain circuits in rats

Carmack, Stephanie A; Keeley, Robin J.; Vendruscolo, Janaina C. M.; Lowery-Gionta, Emily G.; Lu, Hanbing; Koob, George F.; Stein, Elliot A.; Vendruscolo, Leandro F.

doi:10.1172/jci125534

Cited by 43 publications

(49 citation statements)

References 35 publications

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“…Relatedly, other animal studies have demonstrated that withdrawal or conditioned withdrawal motivate drug vs. food choice, or reinstate drug self-administration, or activate negative emotional brain circuits. However, these motivational effects may not necessarily be goal-directed, there are several null effects to consider, and it is possible that the motivational impact of withdrawal may differ between drug classes [75][76][77][78][79][80][81][82].…”

Section: Methodsmentioning

confidence: 99%

Addiction is driven by excessive goal-directed drug choice under negative affect: translational critique of habit and compulsion theory

Hogarth

2020

Neuropsychopharmacol.

217

158

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Drug addiction may be a goal-directed choice driven by excessive drug value in negative affective states, a habit driven by strong stimulus−response associations, or a compulsion driven by insensitivity to costs imposed on drug seeking. Laboratory animal and human evidence for these three theories is evaluated. Excessive goal theory is supported by dependence severity being associated with greater drug choice/economic demand. Drug choice is demonstrably goal-directed (driven by the expected value of the drug) and can be augmented by stress/negative mood induction and withdrawal-effects amplified in those with psychiatric symptoms and drug use coping motives. Furthermore, psychiatric symptoms confer risk of dependence, and coping motives mediate this risk. Habit theory of addiction has weaker support. Habitual behaviour seen in drug-exposed animals often does not occur in complex decision scenarios, or where responding is rewarded, so habit is unlikely to explain most human addictive behaviour where these conditions apply. Furthermore, most human studies have not found greater propensity to habitual behaviour in drug users or as a function of dependence severity, and the minority that have can be explained by task disengagement producing impaired explicit contingency knowledge. Compulsion theory of addiction also has weak support. The persistence of punished drug seeking in animals is better explained by greater drug value (evinced by the association with economic demand) than by insensitivity to costs. Furthermore, human studies have provided weak evidence that propensity to discount cost imposed on drug seeking is associated with dependence severity. These data suggest that human addiction is primarily driven by excessive goal-directed drug choice under negative affect, and less by habit or compulsion. Addiction is pathological because negative states powerfully increase expected drug value acutely outweighing abstinence goals.

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Section: Methodsmentioning

confidence: 99%

Addiction is driven by excessive goal-directed drug choice under negative affect: translational critique of habit and compulsion theory

Hogarth

2020

Neuropsychopharmacol.

217

158

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“…Additionally, cues that are paired with withdrawal can have significant motivational power in driving craving and relapse. Cues that were associated with conditioned withdrawal activated the extended amygdala and hypothalamic circuits in a preclinical imaging study (104). Very little work has focused on the neurobiology of conditioned withdrawal and the ways in which it may be applied to the sustained treatment of opioid use disorder.…”

Section: Implications For the Etiology And Treatment Of Opioid Use DImentioning

confidence: 99%

Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement

Koob

2020

Biological Psychiatry

Self Cite

345

252

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“…Here we used the well-established light-dark test to repeatedly assess the state of anxiety [48] [55] (Figure 2G). Using linear regression analysis we found that, although the DHA diet did not alter the basal levels of anxiety (p = 0.4845, F [1,12] = − 0.5203), that the DHA-enriched diet reduced anxietylike behavior as assessed by decreased latency into the anxiogenic light compartment (p<0.05, F[1,12] = 7.027).…”

Section: The Dha-enriched Diet Reduced Anxiety-like Behavior During Ementioning

confidence: 98%

“…According to the iRISA model of addiction proposed by Rita Goldstein and colleagues, the increased salience of drug-paired cues and impaired response inhibition in the absence of drug contribute to increased drug seeking over time and a persistence of seeking in the absence of drug [9][10][11]. These physical and emotional changes result in a persistent negative emotional state culminating in an inability to transition to an opioid-free state and to remain opioid-free [12]. Coupled with an increased vulnerability to stress and both physical and psychological stressors that trigger drug use in drug addicted humans and animals [13], relapse after prior opioid use is a common occurrence that must be addressed.…”

Section: Introductionmentioning

confidence: 99%

Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome

Hakimian¹,

Dong²,

Barahona³

et al. 2019

Preprint

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Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 fatty acids such as docosahexaenoic acid (DHA), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that a diet enriched in polyunsaturated fat acids (PUFAs) ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and DHA supplementation. We demonstrate that withdrawal of opioids led to a significant depletion in specific microbiota genera whereas DHA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that DHA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

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Heroin addiction engages negative emotional learning brain circuits in rats

Cited by 43 publications

References 35 publications

Addiction is driven by excessive goal-directed drug choice under negative affect: translational critique of habit and compulsion theory

Addiction is driven by excessive goal-directed drug choice under negative affect: translational critique of habit and compulsion theory

Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement

Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome

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