Addiction Biology

Attenuated activity in performance‐monitoring brain regions following erroneous actions may contribute to the repetition of maladaptive behaviors such as continued drug use. Externalizing is a broad personality construct characterized by deficient impulse control, vulnerability to addiction and reduced neurobiological indices of error processing. The insula and dorsal anterior cingulate cortex (dACC) are regions critically linked with error processing as well as the perpetuation of cigarette smoking. As such, we examined the interrelations between externalizing tendencies, erroneous task performance, and error‐related insula and dACC activity in overnight‐deprived smokers (n = 24) and non‐smokers (n = 20). Participants completed a self‐report measure assessing externalizing tendencies (Externalizing Spectrum Inventory) and a speeded Flanker task during functional magnetic resonance imaging scanning. We observed that higher externalizing tendencies correlated with the occurrence of more performance errors among smokers but not non‐smokers. Suggesting a neurobiological contribution to such suboptimal performance among smokers, higher externalizing also predicted less recruitment of the right insula and dACC following error commission. Critically, this error‐related activity fully mediated the relationship between externalizing traits and error rates. That is, higher externalizing scores predicted less error‐related right insula and dACC activity and, in turn, less error‐related activity predicted more errors. Relating such regional activity with a clinically relevant construct, less error‐related right insula and dACC responses correlated with higher tobacco craving during abstinence. Given that inadequate error‐related neuronal responses may contribute to continued drug use despite negative consequences, these results suggest that externalizing tendencies and/or compromised error processing among subsets of smokers may be relevant factors for smoking cessation success.

Nicotine withdrawal is associated with subtle working memory deficits that predict subsequent relapse. We examined the neural substrates underlying these processes in treatment‐seeking smokers, and explored the moderating influence of age on abstinence‐induced alterations in brain activity and performance. Sixty‐three smokers participated in two blood oxygen level‐dependent (BOLD) functional magnetic resonance imaging scans while performing a visual N‐back task on two separate occasions: smoking as usual and after 24 hours of biochemically confirmed abstinence (order counterbalanced). Abstinence (versus smoking) led to reduced accuracy, slower median correct response time and reduced BOLD signal change in the three a priori regions of interest: medial frontal/cingulate gyrus and right and left dorsolateral prefrontal cortex. Significant age × session effects were found for BOLD signal change in all three regions, as well as for withdrawal and craving; for all measures, abstinence effects were attenuated in smokers aged ≥50 years compared with those <50 years old. These results suggest that abstinence effects on neurocognitive function may be more pronounced for younger smokers, and may indicate a new avenue for research exploring mechanisms underlying age differences in smoking cessation success.

Smoking rates have declined in recent years less rapidly in women than in men. More adolescent girls than boys are currently smoking. Quitting smoking is reported in many studies to be more difficult in women than in men. These observations suggest that there may be gender differences in the nature of nicotine addiction. Gender differences in various pharmacological processes involved in nicotine addiction are reviewed. Women take in less nicotine from smoking per cigarette than men but, because of slower metabolism, nicotine levels in the body for a given number of cigarettes per day are similar in male and female smokers. Women tend to be less sensitive to the discriminative effects of nicotine and tend to regulate nicotine intake less precisely than men. On the other hand, women appear to be more sensitive to the effects of nicotine in reducing negative affect and reducing body weight. There is a strong association between depression and smoking, and this association appears to be stronger in women than in men. Women tend to respond more to environmental cues associated with smoking than do men. Thus, several lines of evidence suggest that nicotine addiction is different in women than in men. Understanding the basis for gender differences may be of utility in individualizing and optimizing smoking cessation therapy.

The mechanism of ethanol‐induced ascorbic acid (AA) release in striatum is not well understood. In the present work, the possible involvement of NMDA receptors in the corticostriatal pathway was studied by microdialysis coupled to high performance liquid chromatography with electrochemical detection. Ethanol (3.0 g/kg i.p.) stimulated significant striatal AA release to more than 200% above the baseline. This effect of ethanol could be partially antagonized by amantadine, a non‐selective NMDA receptor antagonist and dopamine releaser, at a dose of 200 mg/kg i.p. and significantly antagonized by MK‐801, a non‐competitive NMDA receptor antagonist, at the doses of 0.5 and 1.0 mg/kg i.p. Furthermore, deafferentation of the glutamatergic projection from cortex to striatum by undercutting the prefrontal cortex completely eliminated ethanol‐induced AA release in rat striatum. The basal level of AA in striatum could only be reduced by high doses of MK‐801, but not by low doses of MK‐801, amantadine or decortication. The results further confirm that NMDA receptors are involved in ethanol‐induced AA release and provide the first evidence for the necessity of the activation of corticostriatal glutamatergic pathway in ethanol‐induced AA release in rat striatum.

Acetaldehyde is suspected of being involved in the central mechanism of central nervous system depression and addiction to ethanol, but in contrast to ethanol, it can not penetrate easily from blood into the brain because of metabolic barriers. Therefore, the possibility of ethanol metabolism and acetaldehyde formation inside the brain has been one of the crucial questions in biomedical research of alcoholism. This article reviews the recent progress in this area and summarizes the evidence on the first stage of ethanol oxidation in the brain and the specific enzyme systems involved. The brain alcohol dehydrogenase and microsomal ethanol oxidizing systems, including cytochrome P450 II E1 and catalase are considered. Their physicochemical properties, the isoform composition, substrate specificity, the regional and subcellular distribution in CNS structures, their contribution to brain ethanol metabolism, induction under ethanol administration and the role in the neurochemical mechanisms of psychopharmacological and neurotoxic effects of ethanol are discussed. In addition, the nonoxidative pathway of ethanol metabolism with the formation of fatty acid ethyl esters and phosphatidylethanol in the brain is described.

A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N‐ethylhexedrone, 4‐chloroethcathinone (4‐CEC), and 4′‐methyl‐α‐pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant‐like effects to assess their abuse liability. Locomotor activity was assessed in an open‐field assay using Swiss–Webster mice to screen for locomotor stimulant effects and to identify behaviorally‐active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague–Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N‐ethylhexedrone, 4‐CEC, and MPHP dose‐dependently increased locomotor activity. Dipentylone, N‐ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4‐CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4‐CEC that produced peak effects lasted 2 to 3 h, the peak dose of N‐ethylhexedrone lasted 4 h, and the peak dose of MPHP lasted 6 h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4‐CEC occurred at doses that substantially decreased response rate. Only 4‐CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N‐ethylhexedrone, 4‐CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.

The objective of this study was to examine the relationship between subjective symptoms of inadequacy of methadone dose (not feeling “held”) and tobacco smoking in patients in methadone maintenance treatment (MMT). This was a cross‐sectional study of smoking behaviour, investigating subjective, physiological and psychological symptoms. The study took place in a community‐based methadone maintenance clinic of a psychiatric teaching hospital in South London. Fifty adult opiate addicts (37 males and 13 females) were on a stable daily methadone dose; the number of cigarettes smoked during the day and previous day of investigation, salivary cotinine measurements and carbon monoxide (CO) from expired air were measured. The Methadone Symptom Checklist (MSC) was used to score withdrawal symptoms encountered in patients not feeling “held” during MMT The Hamilton Anxiety Score was also used. The prevalence of tobacco‐smoking was high (98%), with two‐thirds (68%) smoking self‐fabricated cigarettes (“roll‐ups”). Scores from rating scales measuring symptoms of not being “held” correlated with number of cigarettes smoked the previous day (p < 0.05). A similar correlation was found with the Hamilton Anxiety Score. However, there was no correlation between rating scale scores and either salivary cotinine concentration or CO from expired air. Methadone patients who smoke more are significantly more likely to report problems of not feeling “held” by their methadone dose and they also show a higher level of anxiety. However, this increased cigarette consumption is not reflected in increased salivary continine levels or levels of CO in expired air, and it may be that the raised level of anxiety leads to a smoking‐pattern consisting of frequent lighting‐up of cigarettes or “roll‐ups” which are consumed incompletely and/or not smoked by inhalation.

With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 80% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol‐associated stimuli (cues) contribute to the relapse risk after detoxification. This article focuses on neuronal correlates of cue responses in detoxified alcoholics. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) can be associated with alcohol craving and functional brain activation in neuronal systems that process attentional relevant stimuli, reward expectancy and experience. Increased functional brain activation elicited by such alcohol‐associated cues predicted an increased relapse risk, whereas high brain activity elicited by affectively positive stimuli may represent a protective factor and was correlated with a decreased prospective relapse risk. These findings are discussed with respect to psychotherapeutic and pharmacological treatment options.