Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity.

Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS+ and a DS-, respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS+ to reinstate cocaine seeking behavior. The DS+ was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS+ We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability.

Circuit and Synaptic Plasticity Mechanisms of Drug Relapse.

High rates of relapse to drug use during abstinence is a defining feature of human drug addiction. This clinical scenario has been studied at the preclinical level using different animal models in which relapse to drug seeking is assessed after cessation of operant drug self-administration in rodents and monkeys. In our Society for Neuroscience (SFN) session entitled "Circuit and Synaptic Plasticity Mechanisms of Drug Relapse," we will discuss new developments of our understanding of circuits and synaptic plasticity mechanisms of drug relapse from studies combining established and novel animal models with state-of-the-art cellular, electrophysiology, anatomical, chemogenetic, and optogenetic methods. We will also discuss the translational implications of these new developments. In the mini-review that introduces our SFN session, we summarize results from our laboratories on behavioral, cellular, and circuit mechanisms of drug relapse within the context of our session.

Effects of childhood maltreatment on the neural correlates of stress- and drug cue-induced cocaine craving.

Childhood adversity negatively influences all stages of the addiction process and is associated with persistent alterations in neuroendocrine, autonomic and brain responses to stress. We sought to characterize the impact of childhood abuse and neglect on the neural correlates of stress- and drug cue-induced drug craving associated with cocaine addiction. Cocaine-dependent men with (n = 20) and without (n = 18) moderate to severe childhood maltreatment histories underwent functional magnetic resonance imaging during script-guided mental imagery of personalized stress, drug use and neutral experiences. Compared to the neutral script, the stress and drug use scripts activated striatal, prefrontal, posterior cingulate, temporal and cerebellar regions consistent with prior studies of induced states of stress and drug craving. For the stress script, maltreated men exhibited reduced activation of the anterior precuneus and supplementary motor area (SMA); the interaction of maltreatment severity and stress-induced craving responses predicted lesser rostral anterior cingulate cortex activation. For the drug use script, maltreated men exhibited greater left dorsolateral prefrontal cortex activation. The interaction of maltreatment severity and craving responses was associated with greater activation of the visual cortex and SMA, whereas a maltreatment-by-anxiety interaction effect included lesser ventromedial prefrontal cortex activation. The outcomes indicate an association of childhood maltreatment with a heightened appetitive anticipatory response to drug cues and a diminished engagement of regulatory and controlled action selection processes in response to stress- or drug cue-induced drug craving and anxiety responses for cocaine-dependent men. These findings provide novel insights into possible brain mechanisms by which childhood maltreatment heightens risk for relapse in drug-dependent individuals.

Sex differences in neural responses to stress and drug cues predicts future drug use in individuals with substance use disorder.

BACKGROUND: Substance use disorders (SUDs) are chronically recurring illnesses, where stress and drug cues significantly increase drug craving and risk of drug use recurrence. This study examined sex differences in functional magnetic resonance imaging (fMRI) brain responses to stress and drug cue exposure and assessed their prospective association with future drug use post-treatment. METHODS: Inpatient, treatment engaged men (N = 46) and women (N = 26) with SUDs, including alcohol, cocaine and/or cannabis use disorders, participated in an fMRI scan that assessed subjective (anxiety, drug craving), heart rate and neural responses to brief individualized script-driven imagery of stress, drug, and neutral-relaxing trials. Prospective follow-up interviews post-treatment assessed future drug use recurrence over 90 days. RESULTS: During fMRI, stress and drug versus neutral cue exposure led to increased anxiety, heart rate and craving responses (p's < 0.004) in both men and women, but greater drug cue-induced anxiety (p < .017) and higher drug use days during follow-up (p < .006) in women relative to men. In whole brain analyses of stress and drug cues (p < .05 FWE corrected), and in whole brain correlation (p < .05, FWE corrected) with drug use days, significant sex differences revealed drug cue-related striatal hyperactivation (caudate, putamen) in men, but drug cue-related cortico-limbic (insula and dorsolateral prefrontal cortex) hypoactivation and stress-related hypoactivation in the ventromedial prefrontal cortex (VmPFC) in women; and these were significantly associated with higher future drug use days. CONCLUSIONS: Findings indicate sex-specific pathophysiology of SUD recurrence and support the need for differential treatment development for men and women with SUD to improve drug use outcomes.

Identifying Methamphetamine Abstainers With Convolutional Neural Networks and Short-Time Fourier Transform.

Few studies have investigated the functional patterns of methamphetamine abstainers. A better understanding of the underlying neurobiological mechanism in the brains of methamphetamine abstainers will help to explain their abnormal behaviors. Forty-two male methamphetamine abstainers, currently in a long-term abstinence status (for at least 14 months), and 32 male healthy controls were recruited. All subjects underwent functional MRI while responding to drug-associated cues. This study proposes to combine a convolutional neural network with a short-time Fourier transform to identify different brain patterns between methamphetamine abstainers and controls. The short-time Fourier transformation provides time-localized frequency information, while the convolutional neural network extracts the structural features of the time-frequency spectrograms. The results showed that the classifier achieved a satisfactory performance (98.9% accuracy) and could extract robust brain voxel information. The highly discriminative power voxels were mainly concentrated in the left inferior orbital frontal gyrus, the bilateral postcentral gyri, and the bilateral paracentral lobules. This study provides a novel insight into the different functional patterns between methamphetamine abstainers and healthy controls. It also elucidates the pathological mechanism of methamphetamine abstainers from the view of time-frequency spectrograms.

Eye tracking of smoking-related stimuli in tobacco use disorder: A proof-of-concept study combining attention bias modification with alpha-transcranial alternating current stimulation.

BACKGROUND: Tobacco use disorder (TUD) is characterized by the presence of an attentional bias (AB) towards smoking-related stimuli. We investigated whether combining an AB modification paradigm (ABM) with transcranial alternating current stimulation (tACS) applied over the dorsolateral prefrontal cortex (DLPFC) reduces the AB towards smoking-related stimuli, as well as craving level and impulsive choices. METHODS: In a sham-controlled, crossover preliminary study, 19 subjects with TUD received two stimulation arms: 1) active tACS (10 Hz, 2 mA, 30 min) combined with ABM and 2) sham tACS combined with ABM, in a randomized order, separated by one week. AB towards smoking cues during passive observation of smoking and neutral cues was assessed with an eye-tracking device and reactions times at a visual-probe task. Craving level was measured with the Questionnaire of Smoking Urges. Impulsive choices were assessed with the delay discounting task. RESULTS: Active tACS combined with ABM reduced the amount of time spent looking at smoking-related pictures (p = 0.03), prevented the increase of self-reported desire to smoke (p = 0.026), and reduced the proportion of impulsive choices (p = 0.049), compared to sham tACS combined with ABM. No significant effects were reported on other craving dimensions and on AB based on reaction times. CONCLUSIONS: These preliminary findings suggest that combining tACS with ABM may help smokers who wish to quit by reducing the desire to smoke, attention to smoking-cues, and impulsive decision-making.

In a Rat Model of Opioid Maintenance, the G Protein-Biased Mu Opioid Receptor Agonist TRV130 Decreases Relapse to Oxycodone Seeking and Taking and Prevents Oxycodone-Induced Brain Hypoxia.

BACKGROUND: Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. We modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G protein-biased mu opioid receptor agonist TRV130. We then tested prevention of oxycodone seeking and taking during abstinence using a modified context-induced reinstatement procedure, a rat relapse model. METHODS: We trained rats to self-administer oxycodone (6 hours/day, 14 days) in context A; infusions were paired with discrete tone-light cues. We then implanted osmotic pumps containing buprenorphine or TRV130 (0, 3, 6, or 9 mg/kg/day) and performed 3 consecutive tests: lever pressing reinforced by oxycodone-associated discrete cues in nondrug context B (extinction responding), context-induced reinstatement of oxycodone seeking in context A, and reacquisition of oxycodone self-administration in context A. We also tested whether TRV130 maintenance would protect against acute oxycodone-induced decreases in nucleus accumbens oxygen levels. RESULTS: In male rats, buprenorphine and TRV130 decreased extinction responding and reacquisition of oxycodone self-administration but had a weaker (nonsignificant) effect on context-induced reinstatement. In female rats, buprenorphine decreased responding in all 3 tests, while TRV130 decreased only extinction responding. In both sexes, TRV130 prevented acute brain hypoxia induced by moderate doses of oxycodone. CONCLUSIONS: TRV130 decreased oxycodone seeking and taking during abstinence in a partly sex-specific manner and prevented acute oxycodone-induced brain hypoxia. We propose that G protein-biased mu opioid receptor agonists, currently in development as analgesics, should be considered as relapse prevention maintenance treatment for opioid addiction.

Left frontoparietal network activity is modulated by drug stimuli in cocaine addiction.

Cocaine addicts present reduced activity in the left frontoparietal network, a brain network associated with cognitive control, during the processing of non-drug reward related stimuli (Costumero et al., Addiction Biology 22:479-489, 2015). However, the involvement of this network in drug-related stimuli processing remains unclear. Here, fifteen cocaine-dependent men and fifteen healthy matched controls viewed cocaine-related, erotic, aversive, and neutral pictures during an fMRI session. Group independent component analysis was then performed to investigate how functional networks were modulated by the different emotional images. The results showed that the cocaine-dependent group showed stronger left frontoparietal network activity during the processing of cocaine-related pictures than the control group. Furthermore, the activity of this network during cocaine image processing was positively associated with the years of cocaine use in addicted subjects. In conclusion, our results indicate that the left frontoparietal network is affected in cocaine-dependent men, and may be related to the cognitive control deficits shown in addiction.

Effects of yohimbine and drug cues on impulsivity and attention in cocaine-dependent men and women and sex-matched controls.

BACKGROUND: Deficits in executive function have been associated with risk for relapse. Data from previous studies suggest that relapse may be triggered by stress and drug-paired cues and that there are significant sex differences in the magnitude of these responses. The aim of this study was to examine the impact of the pharmacological stressor and alpha-2 adrenergic receptor antagonist yohimbine and cocaine cues on executive function in cocaine-dependent men and women. METHODS: In a double-blind placebo controlled cross-over study, cocaine-dependent men (n=12), cocaine-dependent women (n=27), control men (n=31) and control women (n=25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Participants performed the Connors' Continuous Performance Test II prior to medication/placebo administration and immediately after each cue exposure session RESULTS: Healthy controls had a significant increase in commission errors under the yohimbine condition [RR (95% CI)=1.1 (1.0-1.3), χ(2)1=2.0, p=0.050]. Cocaine-dependent individuals exhibited a significant decrease in omission errors under the yohimbine condition [RR (95% CI)=0.6 (0.4-0.8), χ(2)1=8.6, p=0.003]. Cocaine-dependent women had more omission errors as compared to cocaine-dependent men regardless of treatment [RR (95% CI)=7.2 (3.6-14.7), χ(2)1=30.1, p<0.001]. Cocaine-dependent women exhibited a slower hit reaction time as compared to cocaine-dependent men [Female 354 ± 13 vs. Male 415 ± 14; t89=2.6, p=0.012]. CONCLUSIONS: These data add to a growing literature demonstrating significant sex differences in behaviors associated with relapse in cocaine-dependent individuals.

What is abnormal about addiction-related attentional biases?

BACKGROUND: The phenotype of addiction includes prominent attentional biases for drug cues, which play a role in motivating drug-seeking behavior and contribute to relapse. In a separate line of research, arbitrary stimuli have been shown to automatically capture attention when previously associated with reward in non-clinical samples. METHODS AND RESULTS: Here, I argue that these two attentional biases reflect the same cognitive process. I outline five characteristics that exemplify attentional biases for drug cues: resistant to conflicting goals, robust to extinction, linked to dorsal striatal dopamine and to biases in approach behavior, and can distinguish between individuals with and without a history of drug dependence. I then go on to describe how attentional biases for arbitrary reward-associated stimuli share all of these features, and conclude by arguing that the attentional components of addiction reflect a normal cognitive process that promotes reward-seeking behavior.

Sex differences in cocaine/heroin users: drug-use triggers and craving in daily life.

BACKGROUND: Studies of sex differences have shown that men and women with drug-use disorders differ in course and outcome and in cue-induced activation of putative brain "control network" areas. We evaluated sex differences in daily functioning and subjective events related to drug use with ecological momentary assessment (EMA). METHODS: EMA data were collected from cocaine- and heroin-using outpatients (72 men; 42 women) in methadone maintenance in 2-5 randomly prompted (RP) entries per day and in participant-initiated entries for heroin or cocaine use or craving, for up to 25 weeks. Urine drug screens were conducted three times weekly. Data were analyzed via repeated-measures logistic regression, using sex as a predictor of responses. RESULTS: In RP reports, women and men reported significantly different patterns of drug-cue exposure, with women significantly more likely to report having seen cocaine or been tempted to use in the past hour. Women also had higher craving after past-hour exposure to drug cues. In reports of drug use, women, compared to men, were more likely to report that they had used more cocaine than they had meant to, tended to feel guilty more often after drug use, and to have used despite trying not to use. CONCLUSIONS: These findings provide real-time behavioral evidence that women respond differently than men to exposure to drug cues and to drug use, consistent with laboratory and brain-imaging findings. This information may be useful for development of sex-specific treatment strategies.

Outcome specificity in deepened extinction may limit treatment feasibility: co-presentation of a food cue interferes with extinction of cue-elicited cocaine seeking.

BACKGROUND: We previously showed that presenting two cocaine cues simultaneously during extinction deepens the extinction of cue-elicited cocaine seeking (Kearns et al., 2012). The present study investigated whether compounding a non-drug appetitive cue with a cocaine cue would similarly deepen extinction. METHODS: In Experiment 1, tone and click were each first established as discriminative stimuli for cocaine-reinforced responding and light was a cue for food-reinforced responding. In an initial extinction phase, all stimuli were presented individually. Then, during an additional compound extinction session, rats received 8 presentations of one of the cocaine cues (counterbalanced over subjects) simultaneously with light and 8 presentations of the other cue alone. A spontaneous recovery test was used to evaluate the effectiveness of the extinction treatments. Experiment 2 was performed under conditions designed to match those of Experiment 1, except food was the reinforcer in tone and click instead of cocaine. RESULTS: In Experiment 1, the cocaine cue compounded with the food cue during extinction controlled greater spontaneous recovery of cocaine seeking than the cocaine cue always presented alone. In contrast, Experiment 2 demonstrated deepened extinction of responding to a food cue when both compounded cues were food cues. CONCLUSIONS: Results suggest that deepened extinction depends on the compound presentation of cues associated with the same reinforcer. Compound presentation of cues associated with different reinforcers could lead to an enhancement of responding. Care is urged in attempts to deepen the extinction of cue-elicited drug seeking by compounding drug cues with non-drug cues.

Concurrent-chains schedules as a method to study choice between alcohol-associated conditioned reinforcers.

An extensive body of research using concurrent-chains schedules of reinforcement has shown that choice for one of two differentially valued food-associated stimuli is dependent upon the overall temporal context in which those stimuli are embedded. The present experiments examined whether the concurrent chains procedure was useful for the study of behavior maintained by alcohol and alcohol-associated stimuli. In Experiment 1, rats responded on concurrent-chains schedules with equal variable-interval (VI) 10-s schedules in the initial links. Across conditions, fixed-interval schedules in the terminal links were varied to yield 1∶1, 9∶1, and 1∶9 ratios of alcohol delivery. Initial-link response rates reflected changes in terminal-link schedules, with greater relative responding in the rich terminal link. In Experiment 2, terminal-link schedules remained constant with a 9∶1 ratio of alcohol delivery rates while the length of two equal duration initial-link schedules was varied. Preference for the rich terminal link was less extreme when initial links were longer (i.e., the initial-link effect), as has been previously reported with food reinforcers. This result suggests that the conditioned reinforcing value of an alcohol-associated stimulus depends on the temporal context in which it is embedded. The concurrent-chains procedure and quantitative models of concurrent chains performance may provide a useful framework within which to study how contextual variables modulate preference for drug-associated conditioned reinforcers.