Addiction neuroscience最新文献

A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking that is goal-directed but not habit-like. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry in rats trained to self-administer cocaine paired with an audiovisual cue to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habit-like cue-induced cocaine seeking and how it is impacted by cue extinction. After minimal fixed-ratio training, rats showed enhanced DMS and DLS calcium responses to cue-reinforced compared to unreinforced lever presses. After rats were trained on goal-promoting fixed ratio schedules or habit-promoting second-order schedules of reinforcement, different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses emerged. Rats trained on habit-promoting second-order schedules showed reduced DMS calcium responses and enhanced DLS dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habit-like behavior and the DLS are unaffected.

Addiction is characterized by continued drug use despite negative consequences. In an animal model, a subset of rats continues to self-administer cocaine despite footshock consequences, showing punishment resistance. We sought to test the hypothesis that punishment resistance arises from failure to exert goal-directed control over habitual cocaine seeking. While habits are not inherently permanent or maladaptive, continued use of habits under conditions that should encourage goal-directed control makes them maladaptive and inflexible. We trained male and female Sprague Dawley rats on a seeking-taking chained schedule of cocaine self-administration. We then exposed them to four days of punishment testing in which footshock was delivered randomly on one-third of trials. Before and after punishment testing (four days pre-punishment and ≥ four days post-punishment), we assessed whether cocaine seeking was goal-directed or habitual using outcome devaluation via cocaine satiety. We found that punishment resistance was associated with continued use of habits, whereas punishment sensitivity was associated with increased goal-directed control. Although punishment resistance for cocaine was not predicted by habitual responding pre-punishment, it was associated with habitual responding post-punishment. In parallel studies of food self-administration, we similarly observed that punishment resistance was associated with habitual responding post-punishment but not pre-punishment in males, although it was associated with habitual responding both pre- and post-punishment in females, indicating that punishment resistance was predicted by habitual responding in food-seeking females. These findings indicate that punishment resistance is related to habits that have become inflexible and persist under conditions that should encourage a transition to goal-directed behavior.

Adequate and timely assessment of learning abilities in individuals with alcohol-related cognitive disorders is highly relevant to optimize addiction care. Learning curves of episodic verbal memory tests have been used to assess learning ability in various neurocognitive disorders, but studies in alcohol-related cognitive disorders are lacking. Therefore, this study investigated California Verbal Learning Test (CVLT) learning curves in individuals with alcohol-use disorder (AUD) with and without cognitive impairments and examined associations between learning curves and changes in everyday functioning following a multicomponent care program. We fitted learning curves over the five immediate recall trials of the Dutch version of the CVLT of patients with Korsakoff's syndrome (KS; N = 117), alcohol-related cognitive impairment no KS (ARCI; N = 147), and uncomplicated AUD (N = 43) using a generalized non-linear mixed regression. This model was based on three different parameters: initial memory performance (attention), maximum number of correctly recalled words (maximum learning), and the increase of correctly recalled words over the trials (learning rate). Next, we related these learning curves with ratings of everyday activities using the Patient Competency Rating Scale (PCRS) before and after a care program following admission. Modelled learning curves differed across groups, with significant differences in Attention (KS<ARCI<AUD, p < 0.001), Maximum Learning (KS<ARCI<AUD, p<0.001), and Learning Rate (KS<ARCI=AUD, p < 0.001). However, modelled learning curves were not related to reliable improvement in PCRS scores (p>0.05). Although modelled learning curves may be used to differentiate diagnostic groups in alcohol-related cognitive disorders, future studies are needed to establish the criterion validity of learning curves in this population.

Computational models of addiction often rely on a model-free reinforcement learning (RL) formulation, owing to the close associations between model-free RL, habitual behavior and the dopaminergic system. However, such formulations typically do not capture key recurrent features of addiction phenomena such as craving and relapse. Moreover, they cannot account for goal-directed aspects of addiction that necessitate contrasting, model-based formulations. Here we synthesize a growing body of evidence and propose that a latent-cause framework can help unify our understanding of several recurrent phenomena in addiction, by viewing them as the inferred return of previous, persistent “latent causes”. We demonstrate that applying this framework to Pavlovian and instrumental settings can help account for defining features of craving and relapse such as outcome-specificity, generalization, and cyclical dynamics. Finally, we argue that this framework can bridge model-free and model-based formulations, and account for individual variability in phenomenology by accommodating the memories, beliefs, and goals of those living with addiction, motivating a centering of the individual, subjective experience of addiction and recovery.

Psychosocial and environmental factors, including loss of natural reward, contribute to the risk of drug abuse. Reward loss has been modeled in animals by removal from social or sexual contact, transfer from enriched to impoverished housing, or restriction of food. We previously showed that food restriction increases the unconditioned rewarding effects of abused drugs and the conditioned incentive effects of drug-paired environments. Mechanistic studies provided evidence of decreased basal dopamine (DA) transmission, adaptive upregulation of signaling downstream of D1 DA receptor stimulation, synaptic upscaling and incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in medium spiny neurons (MSNs) of nucleus accumbens (NAc). These findings align with the still evolving ‘reward deficiency’ hypothesis of drug abuse. The present study tested whether a compound natural reward that is known to increase DA utilization, environmental enrichment, would prevent the persistent expression of cocaine conditioned place preference (CPP) otherwise observed in food restricted rats, along with the mechanistic underpinnings. Because nearly all prior investigations of both food restriction and environmental enrichment effects on cocaine CPP were conducted in male rodents, both sexes were included in the present study. Results indicate that environmental enrichment curtailed the persistence of CPP expression, decreased signaling downstream of the D1R, and decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (EPSCs) in NAc MSNs of food restricted male, but not female, rats. The failure of environmental enrichment to significantly decrease food restriction-induced synaptic insertion of CP-AMPARs, and how this may accord with previous pharmacological findings that blockade of CP-AMPARs reverses behavioral effects of food restriction is discussed. In addition, it is speculated that estrous cycle-dependent fluctuations in DA release, receptor density and MSN excitability may obscure the effect of increased DA signaling during environmental enrichment, thereby interfering with development of the cellular and behavioral effects that enrichment produced in males.

Opioid use and opioid use disorder are characterized by sex and gender differences, and some of these differences may be mediated by differences in the hormonal milieu within and across individuals. This review focuses on the role of ovarian hormones, and particularly estradiol, on the endogenous mu opioid receptor system. There is an abundance of data indicating that estradiol influences the activity of endogenous mu opioid peptides, the activation of mu opioid receptors, and the internalization and desensitization of mu opioid receptors. These effects have functional consequences on behaviors mediated by endogenous mu opioid receptor activity and on sensitivity to mu opioid agonists and antagonists. Recent behavioral data suggest these consequences extend to mu opioid reward, and preclinical studies report that estradiol decreases self-administration of mu opioid receptor agonists across a range of experimental conditions. Data collected in human laboratory studies suggest that estradiol may have functionally similar effects in clinical populations, and thus estrogen receptors may be a potential target in the development of novel therapeutics. This review summarizes data from cellular assays to clinical trials to explore how estradiol influences mu opioid receptor activity, as well as potential ways in which estrogen receptors may be targeted to address the problems of opioid use.

Background

Patients treated for Substance Use Disorders exhibit highly fluctuating patterns of craving that could reveal novel prognostic markers of use. Accordingly, we 1) measured fluctuations within intensively repeated measures of craving and 2) linked fluctuations of craving to connectivity indices within resting-state (rs) brain regions to assess their relation to use among patients undergoing treatment for Alcohol, Tobacco and Cannabis Use Disorders

Method

Participants —64 individuals with SUD for tobacco, alcohol, or cannabis and 35 healthy controls— completed a week of Ecological Momentary Assessment (EMA) during which they reported craving intensity and substance use five times daily. Before EMA, a subsample of 50 patients, and 34 healthy controls also completed resting-state (rs)-MRI acquisitions. Craving temporal dynamics within each day were characterized using Standard Deviation (SD), Auto-Correlation Factor (ACF), and Mean Successive Square Difference (MSSD). Absolute Difference (AD) in craving between assessments was a prospective prediction measure.

Results

Within-day, higher MSSD predicted greater substance use while controlling for mean craving. Prospectively higher AD predicted later increased substance use independently of previous use or craving level. Moreover, MSSD was linked to strength in five functional neural connections, most involving frontotemporal systems. Cerebello-thalamic and thalamo-frontal connectivity were also linked to substance use and distinguished the SUD from the controls.

Conclusion

To the best of our knowledge, this is the first study to indicate that instability in craving may be a trigger for use in several SUD types, beyond the known effect of craving intensity.

Alcohol use disorder (AUD) produces cognitive deficits, indicating a shift in prefrontal cortex (PFC) function. PFC glutamate neurotransmission is mostly mediated by α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic receptors (AMPARs); however preclinical studies have mostly focused on other receptor subtypes. Here we examined the impact of early withdrawal from chronic ethanol on AMPAR function in the mouse medial PFC (mPFC). Dependent male C57BL/6J mice were generated using the chronic intermittent ethanol vapor-two bottle choice (CIE-2BC) paradigm. Non-dependent mice had access to water and ethanol bottles but did not receive ethanol vapor. Naïve mice had no ethanol exposure. We used patch-clamp electrophysiology to measure glutamate neurotransmission in layer 2/3 prelimbic mPFC pyramidal neurons. Since AMPAR function can be impacted by subunit composition or plasticity-related proteins, we probed their mPFC expression levels. Dependent mice had higher spontaneous excitatory postsynaptic current (sEPSC) amplitude and kinetics compared to the Naïve/Non-dependent mice. These effects were seen during intoxication and after 3–8 days withdrawal, and were action potential-independent, suggesting direct enhancement of AMPAR function. Surprisingly, 3 days withdrawal decreased expression of genes encoding AMPAR subunits (Gria1/2) and synaptic plasticity proteins (Dlg4 and Grip1) in Dependent mice. Further analysis within the Dependent group revealed a negative correlation between Gria1 mRNA levels and ethanol intake. Collectively, these data establish a role for mPFC AMPAR adaptations in the glutamatergic dysfunction associated with ethanol dependence. Future studies on the underlying AMPAR plasticity mechanisms that promote alcohol reinforcement, seeking, drinking and relapse behavior may help identify new targets for AUD treatment.