Addiction Biology

It is becoming increasingly apparent that there is a degree of neurochemical overlap between the reward systems and those regulating energy balance. We therefore investigated whether ghrelin, a stomach‐derived and centrally derived orexigenic peptide, might act on the reward systems. Central ghrelin administration (1 µg/µL, to the third ventricle) induced an acute increase in locomotor activity as well as dopamine‐overflow in the nucleus accumbens, suggesting that ghrelin can activate the mesoaccumbal dopamine system originating in the ventral tegmental area, a system associated with reward and motivated behaviour. The cholinergic afferents to the ventral tegmental area have been implicated in natural reward and in regulating mesoaccumbal dopamine neurons. The possibility that nicotinic receptors are involved in mediating the stimulatory and dopamine‐enhancing effects of ghrelin is supported by the findings that peripheral injection of the unselective nicotinic antagonist mecamylamine (2.0 mg/kg) blocked these ghrelin‐induced effects. Tentatively, ghrelin may, via activation of the acetylcholine–dopamine reward link, increase the incentive values of signals associated with motivated behaviours of importance for survival such as feeding behaviour. It will be important to discover whether this has therapeutic implications for compulsive addictive behaviours, such as eating behaviour disorders and drug dependence.

During puberty, neuronal maturation of the brain, which began during perinatal development, is completed such that the behavioral potential of the adult organism can be fully achieved. These maturational events and processes of reorganization are needed for the occurrence of adult behavioral performance but simultaneously render the organism highly susceptible to perturbations, such as exposure to psychoactive drugs, during this critical developmental time span. Considering the variety of maturational processes occurring in the endocannabinoid system during this critical period, it is not surprising that the still‐developing brain might by highly susceptible to cannabis exposure. Emerging evidence from human studies and animal research demonstrates that an early onset of cannabis consumption might have lasting consequences on cognition, might increase the risk for neuropsychiatric disorders, promote further illegal drug intake and increase the likelihood of cannabis dependence. These findings suggest that young people represent a highly vulnerable cannabis consumer group and that they run a higher risk than adult consumers of suffering from adverse consequences from cannabinoid exposure. The aim of the present review is to provide an overview over the possible deleterious residual cannabinoid effects during critical periods of postnatal maturation and to offer a more precise delineation of the vulnerable time window for cannabinoid exposure.

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.

Adult human studies suggest frontal dysfunction associated with chronic marijuana (MJ) use, but due to continued neuromaturation, adult studies may not generalize to adolescents. This study characterized prefrontal cortex (PFC) morphometry in chronic MJ‐using adolescents following 1 month of monitored abstinence. Data were collected from MJ users (n = 16) and controls (n = 16) aged 16–18. Extensive exclusionary criteria included co‐morbid psychiatric and neurologic disorders. Substance use and anatomical measures were collected after 28 days of monitored abstinence. PFC volumes were ascertained from manual tracing by reliable raters on high‐resolution magnetic resonance images. After controlling for lifetime alcohol use, gender and intracranial volume, MJ users did not differ from controls in PFC volume. However, marginal group‐by‐gender interactions were observed (P < 0.09): female MJ users demonstrated comparatively larger PFC volumes while male MJ users had smaller volumes compared with same‐gender controls. Further, group status and total PFC volume interacted in predicting executive functioning (P < 0.05). Among MJ users, smaller PFC total volume was associated with better executive functioning while the opposite pattern was seen among the controls. These preliminary results indicate that gender may moderate the relationship between MJ use and PFC morphometry. Given the relationship between larger PFC total volumes and poorer executive functioning among MJ users, female MJ users may be at increased risk for neurocognitive consequences. Future research will measure PFC gray and white matter separately and follow boys and girls over adolescence to examine the influence of MJ use on neurodevelopment.

Ethanol non‐drinker (UChA) and drinker (UChB) rat lines derived from an original Wistar colony have been selectively bred at the University of Chile for over 70 generations. Two main differences between these lines are clear. (1) Drinker rats display a markedly faster acute tolerance than non‐drinker rats. In F₂ UChA × UChB rats (in which all genes are ‘shuffled’), a high acute tolerance of the offspring predicts higher drinking than a low acute tolerance. It is further shown that high‐drinker animals ‘learn’ to drink, starting from consumption levels that are one half of the maximum consumptions reached after 1 month of unrestricted access to 10% ethanol and water. It is likely that acquired tolerance is at the basis of the increases in ethanol consumption over time. (2) Non‐drinker rats carry a previously unreported allele of aldehyde dehydrogenase‐2 (Aldh2) that encodes an enzyme with a low affinity for Nicotinamide‐adenine‐dinuclectide (NAD⁺) (Aldh2²), while drinker rats present two Aldh2 alleles (Aldh2¹ and Aldh2³) with four‐ to fivefold higher affinities for NAD⁺. Further, the ALDH2 encoded by Aldh2¹ also shows a 33% higher Vmax than those encoded by Aldh2² and Aldh2³. Maximal voluntary ethanol intakes are the following: UChA Aldh2²/Aldh2² = 0.3–0.6 g/kg/day; UChB Aldh2³/Aldh2³ = 4.5–5.0 g/kg/day; UChB Aldh2¹/Aldh2¹ = 7.0–7.5 g/kg/day. In F₂ offspring of UChA × UChB, the Aldh2²/Aldh2² genotype predicts a 40–60% of the alcohol consumption. Studies also show that the low alcohol consumption phenotype of Aldh2²/Aldh2² animals depends on the existence of a maternally derived low‐activity mitochondrial reduced form of nicotinamide‐adenine‐dinucleotide (NADH)‐ubiquinone complex I. The latter does not influence ethanol consumption of animals exhibiting an ALDH2 with a higher affinity for NAD⁺. An illuminating finding is the existence of an ‘acetaldehyde burst’ in animals with a low capacity to oxidize acetaldehyde, being fivefold higher in UChA than in UChB animals. We propose that such a burst results from a great generation of acetaldehyde by alcohol dehydrogenase in pre‐steady‐state conditions that is not met by the high rate of acetaldehyde oxidation in mitochondria. The acetaldehyde burst is seen despite the lack of differences between UChA and UChB rats in acetaldehyde levels or rates of alcohol metabolism in steady state. Inferences are drawn as to how these studies might explain the protection against alcoholism seen in humans that carry the high‐activity alcohol dehydrogenase but metabolize ethanol at about normal rates.

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.

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.

A remarkable amount of literature has been generated demonstrating the functional similarities between the endogenous opioid and cannabinoid systems. Anatomical, biochemical and molecular data support the existence of reciprocal interactions between these two systems related to several pharmacological responses including reward, cognitive effects, and the development of tolerance and dependence. However, the assessment of the bidirectionality of these effects has been difficult due to their variety and complexity. Reciprocal interactions have been well established for the development of physical dependence. Cross‐tolerance and cross‐sensitization, although not always bidirectional, are also supported by a number of evidence, while less data have been gathered regarding the relationship of these systems in cognition and emotion. Nevertheless, the most recent advances in cannabinoid–opioid cross‐modulation have been made in the area of drug craving and relapse processes. The present review is focused on the latest developments in the cannabinoid–opioid cross‐modulation of their behavioural effects and the possible neurobiological substrates involved.

The role of kappa‐opioid receptors (KOR) in the regulation of alcohol‐related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self‐administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self‐administration, reinstatement of alcohol seeking induced by alcohol‐associated cues or stress, and acute alcohol withdrawal‐induced anxiety (‘hangover anxiety’). JDTic dose‐dependently reversed hangover anxiety when given 48 hours prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self‐administration and cue‐induced reinstatement of alcohol seeking when administered 2 hours prior to testing, but not at longer pre‐treatment times. For comparison, we determined that the prototypical KOR antagonist nor‐binaltorphimine can suppress self‐administration of alcohol at 2 hours pre‐treatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress‐induced reinstatement of alcohol seeking, self‐administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2 hours pre‐treatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine‐induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol‐related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism.