Effects of alcohol preload on attentional bias towards cocaine-related cues

Background  

Drug and alcohol users have an ‘attentional bias’ for substance-related cues, which is likely to reflect the incentive-motivational properties of those cues. Furthermore, administration of an alcohol preload increases attentional bias for alcohol and tobacco-related cues in heavy drinkers and tobacco smokers, respectively. The present study investigated attentional bias for cocaine cues in cocaine users and non-users following administration of either alcohol or placebo.     

Eye Movement Evidence of Attentional Bias for Substance-Related Cues in Heroin Dependents on Methadone Maintenance Therapy

Background: Attentional biases toward substance-related stimuli might play a contributing role in addictive behaviors. Objectives: This study investigated the selective attention to substance-related stimuli in heroin dependents receiving methadone maintenance therapy. Methods: Thirty outpatients receiving methadone maintenance treatment for heroin dependence and 38 healthy controls completed a visual probe task with concurrent eye movement monitoring. Results: The results showed that the heroin group reacted faster to probes associated with substance-related pictures than neutral pictures, and they directed more initial fixations and maintained longer initial fixation durations toward substance-related pictures than neutral pictures. However, attentional bias was not correlated with addiction severity in the heroin group. Conclusion: These findings suggest that attentional bias towards substance-related cues occurs in heroin dependents, although this bias might not be associated with the severity of drug-using behavior.     

The effects of the dopamine D₃ receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D? receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D? receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m2) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D? receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.     

Neural Substrates of Attentional Bias for Smoking-Related Cues: An fMRI Study

Attentional bias for drug-related stimuli, as measured by emotional Stroop (ES) tasks, is predictive of treatment outcomes for tobacco smoking and other abused drugs. Characterizing relationships between smoking-related attentional bias and brain reactivity to smoking images may help in identifying neural substrates critical to relapse vulnerability. To this end, we investigated putative relationships between interference effects in an offline smoking ES task and functional MRI (fMRI) measures of brain reactivity to smoking vs neutral images in women smokers. Positive correlations were found between attentional bias and reactivity to smoking images in brain areas involved in emotion, memory, interoception, and visual processing, including the amygdala, hippocampus, parahippocampal gyrus, insula, and occipital cortex. These findings suggest that smokers with elevated attentional biases to smoking-related stimuli may more readily shift attention away from other external stimuli and toward smoking stimuli-induced internal states and emotional memories. Such attentional shifts may contribute to increased interference by smoking cues, possibly increasing relapse vulnerability. Treatments capable of inhibiting shifts to drug cue-induced memories and internal states may lead to personalized tobacco dependence treatment for smokers with high attentional bias to smoking-related stimuli.     

A role for dopamine in the processing of drug cues in heroin dependent patients

Drug and alcohol dependence are associated with enhanced attention for drug-related stimuli. This cognitive processing bias has been suggested to be related to craving and to represent one of the core mechanisms of addition. The present study tests the hypothesis that enhanced attention for heroin cues is mediated by the dopaminergic system using haloperidol as dopamine antagonist. In a double blind, randomized crossover design, 17 detoxified heroin dependent patients received a single oral dose of haloperidol 2 mg and placebo. Patients performed an Emotional Stroop Task to assess the cognitive processing of drug cues under both conditions. In addition, self-reported craving was assessed. In the haloperidol condition, patients performed better on the Emotional Stroop Task than in the placebo condition. However, no effect of haloperidol on subjective craving was found. These findings provide preliminary indications that attentional bias in heroin dependent humans is mediated by dopaminergic mechanisms.     

Activation of midbrain presumed dopaminergic neurones by muscarinic cholinergic receptors: an in vivo electrophysiological study in the rat

1. Extracellular single-unit recording and iontophoresis were used to examine the effects of different cholinoceptor agonists and antagonists on the firing rate and firing pattern of A9 and A10 presumed dopaminergic neurones in the anaesthetized rat.
2. Administration of low currents (1–5 nA) of the selective muscarinic agonists oxotremorine M (Oxo M) and muscarine and of the non-selective muscarinic/nicotinic agonist carbamylcholine (CCh) produced a dose-dependent increase in firing rate in most of the A9 and A10 presumed dopaminergic neurones tested. Oxo M-induced activation could be completely blocked by iontophoretic application of the muscarinic antagonist butyl-scopolamine or systemic administration of the muscarinic antagonist scopolamine (300 μg kg⁻¹, i.v.).
3. Iontophoretic application of the selective nicotinic agonist methylcarbamylcholine (MCCh), but not nicotine, induced a consistent increase in firing rate. Surprisingly, the excitatory effect of MCCh was significantly reduced by the selective muscarinic antagonist scopolamine (300 μg kg⁻¹, i.v.), but not by the selective nicotinic antagonist mecamylamine (2.2 mg kg⁻¹, i.v.). Mecamylamine (3 mg kg⁻¹, i.v.) was also ineffective in reducing the CCh-induced activation of presumed dopamine neurones, suggesting that both CCh and MCCh increased the activity of dopamine neurones via an interaction with muscarinic receptors.
4. Iontophoretic application of the endogenous agonist acetylcholine (ACh) had no or little effect on the firing activity of A10 presumed dopaminergic neurones. However, concomitant application of neostigmine, a potent cholinesterase inhibitor, with acetylcholine induced a substantial activation of these neurones. This activation consisted of two components; one, which was prevalent, was scopolamine (300 μg kg⁻¹, i.v.)-sensitive, and the other was mecamylamine (2 mg kg⁻¹, i.v.)-sensitive.
5. In addition to their effect on firing activity, Oxo M, muscarine and concomitant neostigmine/ACh caused a significant increase in burst firing of A10 neurones, but not of A9 neurones.
6. These data suggest that dopamine cells, both in the A9 and A10 regions, possess functional muscarinic receptors, the activation of which can increase their firing rate and, for A10 neurones, their amount of burst activity. These cholinoceptors would be able to influence the activity of the midbrain dopamine system greatly and may play a role in, and/or be a therapeutic target for, brain disorders in which dopamine is involved (e.g., Parkinson''s disease, drug addiction and schizophrenia).

     

Attentional bias modification in smokers trying to quit: A longitudinal study about the effects of number of sessions

Attentional bias modification (ABM) to avoid smoking-related cues is a potentially new intervention in addition to existing therapy to stop smoking. We examined immediate and long-term changes in attentional bias and treatment outcomes from multiple ABM sessions in 67 smokers trying to quit. After assessing attentional bias baseline, participants were randomly allocated to one of three training groups: three sessions of ABM (avoid 3); two sessions of placebo-ABM and one session of ABM (avoid 1); and three sessions of placebo-ABM (avoid 0). At baseline, all groups had similar positive attentional bias, which became negative at 24 h post-training. After 1 month, avoid 1 and avoid 3 still exhibited negative attentional biases. Only avoid 3 maintained this effect at 6-month, but not at 12-month assessments. ABM produced a long-lasting automatic and maintained avoidance to smoking-related cues which depended on number of sessions; however its effects on treatment outcomes are uncertain.     

Selective attention to smoking cues in former smokers

Repeated drug use modifies the emotional and cognitive processing of drug-associated cues. These changes are supposed to persist even after prolonged abstinence. Several studies demonstrated that smoking cues selectively attract the attention of smokers, but empirical evidence for such an attentional bias among successful quitters is inconclusive. Here, we investigated whether attentional biases persist after smoking cessation. Thirty-eight former smokers, 34 current smokers, and 29 non-smokers participated in a single experimental session. We used three measures of attentional bias for smoking stimuli: A visual probe task with short (500 ms) and long (2000 ms) picture stimulus durations, and a modified Stroop task with smoking-related and neutral words. Former smokers and current smokers, as compared to non-smokers, showed an attentional bias in visual orienting to smoking pictures in the 500 ms condition of the visual probe task. The Stroop interference index of smoking words was negatively related to nicotine dependence in current smokers. Former smokers and mildly dependent smokers, as compared to non-smokers, showed increased interference by smoking words in the Stroop task. Neither current nor former smokers showed an attentional bias in maintained attention (2000 ms visual probe task). In conclusion, even after prolonged abstinence smoking cues retain incentive salience in former smokers, who differed from non-smokers on two attentional bias indices. Attentional biases in former smokers operate mainly in early involuntary rather than in controlled processing, and may represent a vulnerability factor for relapse. Therefore, smoking cessation programs should strengthen self-control abilities to prevent relapses.     

Modeling Causal Relationship Between Brain Regions Within the Drug-Cue Processing Network in Chronic Cocaine Smokers

The cues associated with drugs of abuse have an essential role in perpetuating problematic use, yet effective connectivity or the causal interaction between brain regions mediating the processing of drug cues has not been defined. The aim of this fMRI study was to model the causal interaction between brain regions within the drug-cue processing network in chronic cocaine smokers and matched control participants during a cocaine-cue exposure task. Specifically, cocaine-smoking (15M; 5F) and healthy control (13M; 4F) participants viewed cocaine and neutral cues while in the scanner (a Siemens 3 T magnet). We examined whole brain activation, including activation related to drug-cue processing. Time series data extracted from ROIs determined through our General Linear Model (GLM) analysis and prior publications were used as input to IMaGES, a computationally powerful Bayesian search algorithm. During cocaine-cue exposure, cocaine users showed a particular feed-forward effective connectivity pattern between the ROIs of the drug-cue processing network (amygdala→hippocampus→dorsal striatum→insula→medial frontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex) that was not present when the controls viewed the cocaine cues. Cocaine craving ratings positively correlated with the strength of the causal influence of the insula on the dorsolateral prefrontal cortex in cocaine users. This study is the first demonstration of a causal interaction between ROIs within the drug-cue processing network in cocaine users. This study provides insight into the mechanism underlying continued substance use and has implications for monitoring treatment response.     

Effect of tryptophan depletion on the attentional salience of smoking cues

Rationale There is increasing evidence linking cigarette craving and smoking behavior to serotonergic neurotransmission. Objectives The purpose of the current study was to examine the effects of a serotonergic challenge on the attentional salience of various cues associated with cigarettes. We hypothesized that cigarette-related word cues would be more distracting after acute tryptophan depletion than after a placebo challenge. We also hypothesized that smokers vulnerable to recurrent depression would show greater attentional bias towards these cues than smokers without a history of depression. Methods Thirty-four smokers diagnosed as having (n = 15) or lacking (n = 19) a history of DSM-IV major depressive disorder (MDD) underwent acute tryptophan depletion (ATD) and placebo challenges in double-blind and counterbalanced order 1 week apart. Five hours after consumption of each mixture, subjects completed a modified Stroop task to measure attentional bias to smoking-related, positive affect, and negative affect word cues. Stroop interference was calculated as a difference score between latencies for the motivationally salient and the neutral (furniture) word lists. Results Controlling for change in dysphoric mood from baseline to 5 h, repeated measures MANOVAs showed that ATD, as compared to placebo challenge, produced greater interference for smoking word cues [F(1,29)=4.15, p = 0.05], but not for negative [F(1,29)=2.78, p = 0.11] or positive [F(1,29)=1.60, p = 0.22] affect word cues. Conclusions Acutely compromising central serotonergic neurotransmission via ATD heightens the attentional salience of cigarette-related cues, perhaps by triggering reward and motivational deficits underlying nicotine dependence.     

The role of dopamine in inhibitory control in smokers and non-smokers: A pharmacological fMRI study

Contemporary theoretical models of substance dependence posit that deficits in inhibitory control play an important role in substance dependence. The neural network underlying inhibitory control and its association with substance dependence have been widely investigated. However, the pharmacology of inhibitory control is still insufficiently clear. The aims of the current study were twofold. First, we investigated the role of dopamine in inhibitory control and associated brain activation. Second, the proposed link between dopamine and impaired inhibitory control in nicotine dependence was investigated by comparing smokers and non-smoking controls. Haloperidol (2 mg), a dopamine D2/D3 receptor antagonist, and placebo were administered to 25 smokers and 25 non-smoking controls in a double-blind randomized cross-over design while performing a Go/NoGo task during fMRI scanning. Haloperidol reduced NoGo accuracy and associated brain activation in the ACC, right SFG and left IFG, showing that optimal dopamine levels are crucial to effectively implement inhibitory control. In addition, smokers showed behavioral deficits on the Go/NoGo task as well as hypoactivity in the left IFG, right MFG and ACC after placebo, supporting the hypothesis of a hypoactive prefrontal system in smokers. Haloperidol had a stronger impact on prefrontal brain activation in non-smoking controls compared to smokers, which is in line with the inverted ‘U’ curve theory of dopamine and cognitive control. The current findings suggest that altered baseline dopamine levels in addicted individuals may contribute to the often observed reduction in inhibitory control in these populations.     

The effects of nalmefene on emotion processing in alcohol use disorder – A randomized,controlled fMRI study

Nalmefene is a µ- and δ-opioid receptor antagonist and a partial κ-opioid receptor agonist. The drug is suggested to reduce the craving for, and the consumption of alcohol effectively, also alleviating anxiety and anhedonia. The present fMRI study is the first to investigate the processing of emotions as a possible mechanism of action of nalmefene in humans. Fifteen non-treatment-seeking participants suffering from alcohol use disorder (AUD) (24–66 years; 5 females) finished this randomized, placebo controlled, double blind study. Following a cross over design, participants received either a single dose nalmefene or a placebo, with an interval of one week between sessions. Using fMRI, we investigated neural reactivity during the presentation of emotional faces picture sets. Additionally, we performed a visual dot-probe task to detect nalmefene's effects on attentional bias. We detected an increase in the response to emotional faces in the supramarginal gyrus, the angular gyrus as well as the putamen in the nalmefene vs. placebo condition. However, contradictory to our initial hypotheses, amygdala activation was not altered significantly in the placebo condition – a limitation, which might be associated with a lack of activation in the placebo condition maybe due to the small sample size. Attentional bias analyses revealed an interaction effect by trend, which was driven by a significant effect in a sub-analysis showing increased attentional shift towards happy compared to fearful facial expressions under nalmefene. Nalmefene increased brain activation in areas responsible for empathy, social cognition and behavior, which might help alleviating the reinforcing properties of alcohol.     

Experimental manipulation of attentional bias increases the motivation to drink alcohol

RATIONALE: Attentional bias for alcohol-related cues is associated with the motivation to drink alcohol, possibly because attentional bias increases craving. OBJECTIVES: We examined whether an experimentally induced attentional bias would influence subjective and behavioural indices of the motivation to drink. METHODS: Heavy social drinkers (N=40) completed an attentional training procedure, in which half of the participants were trained to direct their attention towards alcohol-related cues ('attend alcohol'), and half of the participants were trained to direct their attention away from alcohol-related cues ('avoid alcohol'). After attentional training, participants rated their urge to drink alcohol, and the amount of beer consumed during a taste test was measured. RESULTS: The attentional training procedure produced significant changes in attentional bias in the predicted direction in both experimental groups. Attentional training produced an increase in the urge to drink alcohol in the attend alcohol group, and the attend alcohol group consumed more beer than the avoid alcohol group during the taste test. CONCLUSIONS: These results suggest that a potentiated attentional bias for alcohol-related cues can increase the motivation to drink alcohol. Theoretical and clinical implications are discussed.     

Selective Blockade of Dopamine D3 Receptors Enhances while D2 Receptor Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex

Dopamine D₃ receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D₃ vs D₂ receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D₃ receptor antagonist, {"type":"entrez-protein","attrs":{"text":"S33084","term_id":"420474","term_text":"pir||S33084"}}S33084 (0.04–0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D₃ receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D₂ receptor antagonist, L741,626 (0.16–5.0 mg/kg), or with the dopamine D₃ agonist, PD128,907 (0.63–40 μg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of {"type":"entrez-protein","attrs":{"text":"S33084","term_id":"420474","term_text":"pir||S33084"}}S33084 (2.5 μg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63–2.5 μg/side) improvement in NOR, while intra-striatal injection (2.5 μg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63–2.5 μg/side) impairment of NOR. These observations suggest that blockade of dopamine D₃ receptors enhances both SND and NOR, whereas D₃ receptor activation or antagonism of dopamine D₂ receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D₃ receptor antagonism.     

Acute depletion of dopamine precursors in the human brain: effects on functional connectivity and alcohol attentional bias

Individuals who abuse alcohol often show exaggerated attentional bias (AB) towards alcohol-related cues, which is thought to reflect reward conditioning processes. Rodent studies indicate that dopaminergic pathways play a key role in conditioned responses to reward- and alcohol-associated cues. However, investigation of the dopaminergic circuitry mediating this process in humans remains limited. We hypothesized that depletion of central dopamine levels in adult alcohol drinkers would attenuate AB and that these effects would be mediated by altered function in frontolimbic circuitry. Thirty-four male participants (22–38 years, including both social and heavy drinkers) underwent a two-session, placebo-controlled, double-blind dopamine precursor depletion procedure. At each visit, participants consumed either a balanced amino acid (control) beverage or an amino acid beverage lacking dopamine precursors (order counterbalanced), underwent resting-state fMRI, and completed behavioral testing on three AB tasks: an alcohol dot-probe task, an alcohol attentional blink task, and a task measuring AB to a reward-conditioned cue. Dopamine depletion significantly diminished AB in each behavioral task, with larger effects among subjects reporting higher levels of binge drinking. The depletion procedure significantly decreased resting-state functional connectivity among ventral tegmental area, striatum, amygdala, and prefrontal regions. Beverage-related AB decreases were mediated by decreases in functional connectivity between the fronto-insular cortex and striatum and, for alcohol AB only, between anterior cingulate cortex and amygdala. The results support a substantial role for dopamine in AB, and suggest specific dopamine-modulated functional connections between frontal, limbic, striatal, and brainstem regions mediate general reward AB versus alcohol AB.Subject terms: Cognitive control, Brain, Human behaviour, Reward     

Insula–Dorsal Anterior Cingulate Cortex Coupling is Associated with Enhanced Brain Reactivity to Smoking Cues

The insula plays a critical role in maintaining nicotine dependence and reactivity to smoking cues. More broadly, the insula and the dorsal anterior cingulate cortex (dACC) are key nodes of the salience network (SN), which integrates internal and extrapersonal information to guide behavior. Thus, insula–dACC interactions may be integral in processing salient information such as smoking cues that facilitate continued nicotine use. We evaluated functional magnetic resonance imaging (fMRI) data from nicotine-dependent participants during rest, and again when they viewed smoking-related images. Greater insula–dACC coupling at rest was significantly correlated with enhanced smoking cue-reactivity in brain areas associated with attention and motor preparation, including the visual cortex, right ventral lateral prefrontal cortex, and the dorsal striatum. In an independent cohort, we found that insula–dACC connectivity was stable over 1-h delay and was not influenced by changes in subjective craving or expired carbon monoxide, suggesting that connectivity strength between these regions may be a trait associated with heightened cue-reactivity. Finally, we also showed that insula reactivity to smoking cues correlates with a rise in cue-reactivity throughout the entire SN, indicating that the insula''s role in smoking cue-reactivity is not functionally independent, and may actually represent the engagement of the entire SN. Collectively, these data provide a more network-level understanding of the insula''s role in nicotine dependence and shows a relationship between inherent brain organization and smoking cue-reactivity.     

Alpha-2 Adrenoreceptor Antagonist Yohimbine Potentiates Consolidation of Conditioned Fear

BackgroundHyperconsolidation of aversive associations and poor extinction learning have been hypothesized to be crucial in the acquisition of pathological fear. Previous animal and human research points to the potential role of the catecholaminergic system, particularly noradrenaline and dopamine, in acquiring emotional memories. Here, we investigated in a between-participants design with 3 groups whether the noradrenergic alpha-2 adrenoreceptor antagonist yohimbine and the dopaminergic D2-receptor antagonist sulpiride modulate long-term fear conditioning and extinction in humans.MethodsFifty-five healthy male students were recruited. The final sample consisted of n = 51 participants who were explicitly aware of the contingencies between conditioned stimuli (CS) and unconditioned stimuli after fear acquisition. The participants were then randomly assigned to 1 of the 3 groups and received either yohimbine (10 mg, n = 17), sulpiride (200 mg, n = 16), or placebo (n = 18) between fear acquisition and extinction. Recall of conditioned (non-extinguished CS+ vs CS−) and extinguished fear (extinguished CS+ vs CS−) was assessed 1 day later, and a 64-channel electroencephalogram was recorded.ResultsThe yohimbine group showed increased salivary alpha-amylase activity, confirming a successful manipulation of central noradrenergic release. Elevated fear-conditioned bradycardia and larger differential amplitudes of the N170 and late positive potential components in the event-related brain potential indicated that yohimbine treatment (compared with a placebo and sulpiride) enhanced fear recall during day 2.ConclusionsThese results suggest that yohimbine potentiates cardiac and central electrophysiological signatures of fear memory consolidation. They thereby elucidate the key role of noradrenaline in strengthening the consolidation of conditioned fear associations, which may be a key mechanism in the etiology of fear-related disorders.     

Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized,placebo-controlled trial

Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.Subject terms: Translational research, Predictive markers     

Effects of haloperidol on reactions to smoking cues in humans

Both preclinical and clinical evidence suggest that brain dopamine (DA) systems are involved in conditioned responses to drug cues. In smokers, such responses to smoking cues include the subjective urge to smoke and increases in heart rate and reaction time. This study investigated the role of DA in cues associated with smoking and nicotine in cigarette smokers, by acutely pretreating subjects with a DA receptor antagonist. Twenty temporarily abstinent smokers participated in three sessions in which they received haloperidol (HAL; 2 and 4 mg) or placebo before presentations of visual and tactile stimuli related to smoking. HAL (2 mg) attenuated heart rate increases induced by smoking cues, but did not change subjective ratings of smoking urge. HAL (4 mg) also failed to reduce urge to smoke ratings, and did not significantly reduce other cue reactions. These results provide preliminary evidence that acute administration of a low-dose DA antagonist can attenuate some conditioned responses to smoking cues, but not cue-induced urge to smoke.     

Effects of acute tyrosine/phenylalanine depletion on the selective processing of smoking-related cues and the relative value of cigarettes in smokers

Rationale Acute tyrosine/phenylalanine depletion (ATPD) is a validated neurobiological challenge that results in reduced dopaminergic neurotransmission, allowing examination of the effects of a hypodopaminergic state on craving-related processes. Objectives We studied 16 nonabstaining smokers (>10 cigarettes/day; 9 males; age 20–33 years) to whom was administered a tyrosine/phenylalanine-free mixture (TYR/PHE-free) and a balanced amino acid mixture (BAL) in a double-blind, counterbalanced, crossover design. Methods Subjective cigarette craving, attentional bias to smoking-related word cues, relative value of cigarettes, negative mood, and expired carbon monoxide (CO) levels were measured at various timepoints through 300 min. Participants smoked at hourly intervals to prevent acute nicotine withdrawal during testing. Results The TYR/PHE-free mixture, as compared to the BAL mixture, was associated with a greater increase in CO levels from baseline (p = 0.01). Adjusting for the potential confounding influence of between-condition differences in CO levels across time, TYR/PHE-free mixture was associated with increased demand for cigarettes (p = 0.01) and decreased attentional bias toward smoking-related words (p = 0.003). There were no significant differences between conditions in either subjective craving or depressed or anxious mood (p values > 0.05). Conclusion Among nonabstaining daily smokers, acute dopaminergic depletion via ATPD may influence smoking behavior and indices of smoking-related motivation, such as attentional bias to smoking cues and relative cigarette value, which are not readily captured by subjective craving.