Human Addicts Research Articles

Sensitivity of Hypocretin System to Chronic Alcohol Exposure: A Human and Animal Study

Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse.

Genotype-by-diagnosis interaction influences self-control in human cocaine addiction

Not everyone who uses drugs loses control over their intake, which is a hallmark of addiction. Although familial risk studies suggest significant addiction heritability, the genetic basis of vulnerability to drug addiction remains largely unknown. In the present study, we investigate the relationship between self-control, cocaine use, and the rs36024 single nucleotide polymorphism of the noradrenaline transporter gene (SLC6A2). We hypothesize that C-allele-carrying adults show impaired self-control, as measured by the stop-signal task and demonstrated previously in adolescents, and further exacerbated by chronic cocaine use. Patients with cocaine use disorder (CUD, n = 79) and healthy unrelated participants with no history of drug abuse (n = 54) completed the stop-signal task. All participants were genotyped for rs36024 allelic variants (CC/TT homozygotes, CT heterozygotes). We measured mean stop-signal reaction time, reflecting the ability to inhibit ongoing motor responses, reaction times to go stimuli, and the proportion of successful stops. CUD patients showed prolonged stop-signal reaction time, however, there was no main effect of rs36024 genotype. Importantly, there was a significant genotype-by-diagnosis interaction such that CUD patients with CC genotype had longer stop-signal reaction time and fewer successful stops compared with CC healthy controls and TT CUD patients. CT CUD patients showed an intermediate performance. Self-control deficits were associated with cocaine use disorder diagnosis, which interacts with the noradrenaline transporter rs36024 polymorphism. Our findings suggest that rs36024 may represent a potential genetic vulnerability marker, which facilitates the transition from first cocaine use to addiction by weakening the inhibitory control over behavior.

Theory-driven computational models of drug addiction in humans: Fruitful or futile?

Maladaptive behavior in drug addiction is widely regarded as a result of neurocognitive dysfunctions. Recently, there has been a growing trend to adopt computational methods to study these dysfunctions in drug-addicted patients, not least because it provides a quantitative framework to infer the psychological mechanisms that may have gone awry in addiction. We therefore sought to evaluate the extent to which these theory-driven computational models have fulfilled this purpose in addiction research. We discuss several learning and decision-making theories proposed to explain symptoms that characterize impaired control and the intense urge to use drugs in addiction, and outline the computational algorithms frequently used to model these processes. Specifically, impaired behavioral control over drugs have been explained by aberrant reinforcement learning algorithms and an imbalance between model-based and model-free control, whereas the strong desire for drugs might be explained by a neurocomputational model of incentive sensitization and behavioral economic theory. We argue that while theory-driven computational models may appear to be useful tools that generate novel mechanistic insights into drug addiction, their use should be informed by psychological theory, experimental data, and clinical observations.

Altered Expression of Genes Associated with Major Neurotransmitter Systems in the Reward-Related Brain Regions of Mice with Positive Fighting Experience.

The main neurotransmitters in the brain-dopamine, γ-aminobutyric acid (GABA), glutamate, and opioids-are recognized to be the most important for the regulation of aggression and addiction. The aim of this work was to study differentially expressed genes (DEGs) in the main reward-related brain regions, including the ventral tegmental area (VTA), dorsal striatum (STR), ventral striatum (nucleus accumbens, NAcc), prefrontal cortex (PFC), and midbrain raphe nuclei (MRNs), in male mice with 20-day positive fighting experience in daily agonistic interactions. Expression of opioidergic, catecholaminergic, glutamatergic, and GABAergic genes was analyzed to confirm or refute the influence of repeated positive fighting experience on the development of "addiction-like" signs shown in our previous studies. High-throughput RNA sequencing was performed to identify differentially expressed genes in the brain regions of chronically aggressive mice. In the aggressive mice, upregulation of opioidergic genes was shown (Oprk1 in VTA, Pdyn in NAcc, Penk in PFC, and Oprd1 in MRNs and PFC), as was downregulation of genes Opcml and Oprk1 in STR and Pomc in VTA and NAcc. Upregulation of catecholaminergic genes in VTA (Ddc and Slc6a2) and in NAcc (Th and Drd2) and downregulation of some differentially expressed genes in MRNs (Th, Ddc, Dbh, Drd2, Slc18a2, and Sncg) and in VTA (Adra2c, Sncg, and Sncb) were also documented. The expression of GABAergic and glutamatergic genes that participate in drug addiction changed in all brain regions. According to literature data, the proteins encoded by genes Drd2, Oprk1, Oprd1, Pdyn, Penk, and Pomc are directly involved in drug addiction in humans. Thus, our results confirm our earlier claim about the formation of addiction-like signs following repeated positive fighting experience in mice, as shown previously in our biobehavioral studies.

The Role of Genetics in Human Addiction

The Role of Genetics in Human Addiction

Comprehensive visual electrophysiological measurements discover crucial changes caused by alcohol addiction in humans: Clinical values in early prevention of alcoholic vision decline.

Alcohol addiction often compromises vision by impairing the visual pathway, particularly the retina and optic nerve. Vision decline in alcoholics consists of a sequential transition from reversible functional deterioration of the visual pathway to irreversible clinical vision degeneration or vision loss. Thus, the control of alcoholic vision decline should focus on prevention before permanent damage occurs. Visual electrophysiology is a promising method for early detection of retinal dysfunction and optic neuropathy, including full-field electroretinography (ffERG) and pattern-reversal visual evoked potential (PR-VEP). So far, however, research studying the electrophysiological characteristics in the preclinical stage of vision decline caused by alcohol addiction is still lacking. Here we conducted a retrospective study with 11 alcoholics and 14 matched control individuals to address this need. We had performed comprehensive visual electrophysiological tests, including ffERG and PR-VEP. We next analyzed all electrophysiological parameters using multivariate statistical analyses and discovered some highly sensitive alterations to alcohol addiction. We found severely reduced amplitudes in scotopic ffERG oscillatory potentials (OPs) in alcohol addicts. These changes indicate the alcohol-induced disturbances of amacrine cells and retinal circulation. In subjects with alcohol addiction, the amplitudes of b-waves diminish significantly in scotopic but not photopic ffERG, implying the impaired function of the retinal rod system and the dysfunction of the inner retina. PR-VEPs elicited by checkerboard stimuli with large 1 degree (°) checks mainly reflect the state of the optic nerve and ganglion cells, and PR-VEPs provoked by small 0.25° checks mainly reflect the function of the macular. We performed both measurements and observed a robust amplitude reduction in all three peaks (N75–P100, P100–N135) and a significant peak time extension in P100. Our research provides an affordable and non-invasive tool to accurately evaluate visual pathway conditions in alcohol addicts and help clinicians take targeted treatment.

The impulsive horse: Comparing genetic, physiological and behavioral indicators to those of human addiction.

Stress and genotype elicit changes in impulse control in a range of species that are attributable to adaptations in both the central and peripheral nervous system. We examined aspects of this mechanism in the horse by assessing the effect of a dopamine receptor genotype (DRD4) and central dopaminergic tone (measured via spontaneous blink rate [SBR] and behavioral initiation rate [BIR]), on measures of impulsivity, compulsivity (3-choice serial reaction time task) and sympathetic/ parasympathetic system balance (heart rate variability [HRV]). Genotype did not have a significant effect on any of the parameters measured. SBR but not BIR correlated significantly with levels of impulsivity. There was no clear association of HRV parameters with either measures of central dopaminergic activity or impulsivity/compulsivity. Overall, some elements of the data suggest that the horse may be a useful animal model for assessing the genetic and environmental factors that lead to the physiological and behavioral phenotype of human addiction, particularly when considering the relationship between central dopaminergic tone and impulsivity.

Genotypic Differences in the Effects of Menthol on Nicotine Intake and Preference in Mice

Menthol has been shown to exacerbate elements of nicotine addiction in humans and rodents; however, the mechanisms mediating its effects are not fully understood. This study examined the impact of genetic factors in menthol’s effects on oral nicotine consumption by comparing two inbred mouse strains with differing sensitivities to nicotine. C57BL/6J (B6J) mice are nicotine-preferring, while DBA/2J (D2J) mice are not. While the effects of menthol on oral nicotine consumption have been highlighted in B6J mice, it is unknown if they extend to the D2J strain as well. Consequently, adolescent (PND 21) and adult (PND 63), male and female D2J mice were subjected to the nicotine two-bottle choice (2BC) paradigm with orally and systemically administered menthol. Then, we evaluated its impact on nicotine pharmacological responses in conditioned reward and nociception after systemic administration and, lastly, investigated the potential involvement of the TAAR1 gene and α7 nAChRs in menthol’s effects. Menthol failed to enhance oral nicotine consumption in adult and adolescent female and male D2J mice. Moreover, this lack in effect was not due to nicotine concentration, oral aversion to menthol, or basal preference for nicotine. Menthol also failed to augment nicotine reward or enhance nicotine-induced antinociception in D2J mice, demonstrating that genetic background plays a significant role in sensitivity to menthol’s effects on nicotine. Furthermore, TAAR1 or α7 nAChRs did not seem to mediate menthol’s differential effects in D2J mice. These findings support the existence of genotype-specific mechanisms that may contribute to the variable effects of menthol in different populations.

MiRNA signatures associated with vulnerability to food addiction in mice and humans.

Food addiction is characterized by a loss of behavioral control over food intake and is associated with obesity and other eating disorders. The mechanisms underlying this behavioral disorder are largely unknown. We aimed to investigate the changes in miRNA expression promoted by food addiction in animals and humans and their involvement in the mechanisms underlying the behavioral hallmarks of this disorder. We found sharp similitudes between miRNA signatures in the medial prefrontal cortex (mPFC) of our animal cohort and circulating miRNA levels in our human cohort, which allowed us to identify several miRNAs of potential interest in the development of this disorder. Tough decoy (TuD) inhibition of miRNA-29c-3p in the mouse mPFC promoted persistence of the response and enhanced vulnerability to developing food addiction, whereas miRNA-665-3p inhibition promoted compulsion-like behavior and also enhanced food addiction vulnerability. In contrast, we found that miRNA-137-3p inhibition in the mPFC did not lead to the development of food addiction. Therefore, miRNA-29c-3p and miRNA-665-3p could be acting as protective factors with regard to food addiction. We believe the elucidation of these epigenetic mechanisms will lead to advances toward identifying innovative biomarkers and possible future interventions for food addiction and related disorders based on the strategies now available to modify miRNA activity and expression.

Neuroimaging Recovery in Human Drug Addiction: An Eye Towards Intervention Development

Drug addiction is on the rise during these COVID-19 times that intensify the factors contributing to relapse and overdose across drugs of abuse and continents. Using a multimodal approach (neuropsychology, fMRI, ERP), human neuroimaging studies in my lab have elucidated core mechanisms underlying drug addiction, with a focus on the role of the dopaminergic mesocorticolimbic circuit, especially the prefrontal cortex, in higher-order cognitive and emotional dysfunction in this population. Our theoretical model is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex (and other cortical regions underlying higher order executive function), contribute to the core clinical symptoms in addiction. Specifically, our program of research is guided by the working hypothesis that drug addicted individuals disproportionately attribute salience and value to their drug of choice at the expense of other reinforcing stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. Our complex and multifaceted dataset has allowed us to study the impact of abstinence on recovery in these brain-behavior compromises in treatment-seeking addicted individuals, where non-linear relationships exemplify incubation of craving while other trajectories of change, including in white matter tracks and for small subcortical regions (such as the habenula), are also explored. Novel paradigm shifts in the lab include the use of naturalistic and dynamic stimuli for enhanced generalizability and validity, in addition to development of effective neurorehabilitation strategies (including cognitive reappraisal, mindfulness, and transcranial direct current stimulation) in drug addiction.

Disruption of amphetamine sensitization by alteration of dendritic thin spines in the nucleus accumbens core.

Repeated injections of psychomotor stimulants like amphetamine (AMPH) to rodents can induce behavioral sensitization, which represents a long-lasting craving that is usually observed in human addicts. Behavioral sensitization is characteristically maintained for a long duration, accompanied by structural plasticity in some brain areas involved in reward circuitry. For example, it increased dendritic spine densities in the nucleus accumbens (NAcc), which is considered to reflect neurophysiological changes at this site, leading to addictive behaviors. The ezrin, radixin, and moesin (ERM) proteins regulate spine maturity by modifying their phosphorylation at the C-terminal region. We previously showed that ERM phosphorylation is reduced by AMPH in the NAcc core, suggesting that ERM-mediated spine changes at this site might be associated with AMPH sensitization. To test this hypothesis, we administered AMPH to rats according to a sensitization development schedule, with lentivirus encoding a phosphomimetic pseudo-active mutant of radixin (Rdx T564D) in the NAcc core, and examined dendritic spines at this site. We found that compared to acute AMPH, AMPH sensitization increased thin spine density with a similar ratio of filopodia-like to mature thin spines. However, with Rdx T564D, the density of thin spines increased, with augmented filopodia-like thin spines, resulting in no AMPH sensitization. These results indicate that Rdx T564D forces thin spines to immaturity and thereby inhibits AMPH sensitization, for which an increase in mature thin spines is normally necessary. These findings provide significant clues to our understanding of the role of dendritic spines in mediating the development of psychomotor stimulant addiction.

FOSTERING NIGERIA SECURITY: THEATRE FOR DEVELOPMENT (TFD) AS TOOL

Nigeria as a sovereign state is currently passing through security challenges such that no one is sure which part of the nation is safe. Issues of unwarranted killings, insurgency, raping, domestic violence, kidnapping, armed banditry, broad day light robbery, cultism, human trafficking drug addiction, thuggery and so on which make our environment unsafe are common sights in Nigeria today. These crimes are at an alarming rate to the extent that they pose sleepless nights to most communities, government and other relevant authorities in Nigeria. While the government is making concerted efforts in tackling the menace of militant and terrorist groups like the dreaded Boko Haram jihadist, Indigenous people of Biafra (IPOB), movement for the emancipation of the Niger Delta (MEND) among others, the incessant herders versus farmers clashes, coupled with inter ethnic conflicts, are threatening the fragile peace of the nation. It is against this backdrop that this paper explores Theatre for Development (TfD) as an avenue for fostering security in the Nigeria state. Theatre for development (TfD) is a genre of theatrical exegesis that stresses development communication for the purpose of enlightenment through participation and critical consciousness for transformation. Theatre for Development (TfD) employs advocacy, dialogue and folk media in preparation, action plan as well as mobilization for transformational education. These are done using research, analysis and dramatization. This paper shall interrogate the causes of security challenges such as unemployment, poverty, crime, drug abuse, to mention just a few. It will also examine the effects and how they can be addressed with the aid of Theatre for Development (TfD). The paper recommends among others that communication and dialogue remain the best forms of instrument for conflict resolution in a nation bedeviled with security challenges.

Effects of Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 on the Reinstatement of Cocaine-Mediated Conditioned Place Preference in Mice.

A high percentage of relapse to compulsive cocaine-taking and cocaine-seeking behaviors following abstinence constitutes a major obstacle to the clinical treatment of cocaine addiction. Thus, there is a substantial need to develop effective pharmacotherapies for the prevention of cocaine relapse. The reinstatement paradigm is known as the most commonly used animal model to study relapse in abstinent human addicts. The primary aim of this study is to investigate the potential effects of systemic administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) on the cocaine- and stress-triggered reinstatement of cocaine-induced conditioned place preference (CPP) in male C57BL/6J mice. The biased CPP paradigm was induced by alternating administration of saline and cocaine (20 mg/kg), followed by extinction training and then reinstatement by either a cocaine prime (10 mg/kg) or exposure to swimming on the reinstatement test day. To examine the effects of Ex4 on the reinstatement, Ex4 was systemically administered 1 h after the daily extinction session. Additionally, we also explored the associated molecular basis of the behavioral effects of Ex4. The expression of nuclear factor κβ (NF-κβ) in the nucleus accumbens (NAc) was detected using Western blotting. As a result, all animals that were treated with cocaine during the conditioning period successfully acquired CPP, and their CPP response was extinguished after 8 extinction sessions. Furthermore, the animals that were exposed to cocaine or swimming on the reinstatement day showed a significant reinstatement of CPP. Interestingly, systemic pretreatment with Ex4 was sufficient to attenuate cocaine- and stress-primed reinstatement of cocaine-induced CPP. Additionally, the expression of NF-κβ, which was upregulated by cocaine, was normalized by Ex4 in the cocaine-experienced mice. Altogether, our study reveals the novel effect of Ex4 on the reinstatement of cocaine-induced CPP and suggests that GLP-1R agonists appear to be highly promising drugs in the treatment of cocaine use disorder.

Simultaneous HPLC estimation of Amphetamine and Caffeine abuse drugs in Iraqi human addicts

The main aim of this research is to establish and validate a high performance liquid chromatography (HPLC) process for the separation and estimation of Amphetamine (AM) and Caffeine (CAF) in its illegal formula and in sera of addicts. This method is established on the HPLC separation of the two drugs on the ZORBAX ODS column (250×4.6×5µm particle size). The mobile phase contained 1% ortho-phosphoric acid 85% and 1%of diethyl amine 99%, acetonitrile and methanol ratio was 85:10:5 v/v/v. The flow rate is 1.2 mL.min-1, buffer value pH of 2.5 via isocratic elution also UV detection at 210 nm. The retention times for the two drugs AM and CAF were obtained at 4.425 and 6.456 min, respectively. The calibration curves founded that the linear regression analysis data gave a good linear relationship for the concentration range 1 to 100 µg.mL-1 for AM and CAF. The values achieved for correlation coefficient, slope and intercept were 9999, 8104.2 and 5012 for AM and 0.9999, 9698.5 and 6342.9 for CAF, whereas the LOD and LOQ was 0.51, 1.64 µg.mL-1 for AM and 0.60, 1.32 µg.mL-1 for CAF

Hypocretin/Orexin Interactions with Norepinephrine Contribute to the Opiate Withdrawal Syndrome.

We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a significant increase in the number of detected hypocretin/orexin (Hcrt)-producing neurons. However, it remains unknown how this increase affects target areas of the hypocretin system involved in opioid withdrawal, including norepinephrine containing structures locus coeruleus (LC) and A1/A2 medullary regions. Using a combination of immunohistochemical, biochemical, imaging, and behavioral techniques, we now show that the increase in detected hypocretin cell number translates into a significant increase in hypocretin innervation and tyrosine hydroxylase (TH) levels in the LC without affecting norepinephrine-containing neuronal cell number. We show that the increase in TH is completely dependent on Hcrt innervation. The A1/A2 regions were unaffected by morphine treatment. Manipulation of the Hcrt system may affect opioid addiction and withdrawal.SIGNIFICANCE STATEMENT Previously, we have shown that the hypothalamic hypocretin system undergoes profound anatomic changes in human heroin addicts and in mice exposed to morphine, suggesting a role of this system in the development of addictive behaviors. The locus coeruleus plays a key role in opioid addiction. Here we report that the hypothalamic hypocretin innervation of the locus coeruleus increases dramatically with morphine administration to mice. This increase is correlated with a massive increase in tyrosine hydroxylase expression in locus coeruleus. Elimination of hypocretin neurons prevents the tyrosine hydroxylase increase in locus coeruleus and dampens the somatic and affective components of opioid withdrawal.

Nucleus accumbens as a stereotactic target for the treatment of addictions in humans: a literature review.

Deep brain stimulation (DBS) has achieved substantial success as a treatment for movement disorders such as Parkinson's Disease (PD), essential tremor (ET), and dystonia. More recently, a limited number of basic and clinical studies have indicated that DBS of the nucleus accumbens (NAc) and other neighbouring structures of the reward circuit may be an effective intervention for patients with treatment-refractory addiction. We performed a structured literature review of human studies of DBS for addiction outlining the clinical efficacy and adverse events. We found 14 human studies targeting mostly the NAc with neighbouring structures such as anterior limb of the internal capsule (ALIC). Five studies including 12 patients reported the outcomes for alcohol dependence. Nine studies including 18 patients reported the outcomes for addictions to various psychoactive substances. The most common indication was addiction to heroin, found in 13 patients, followed by methamphetamine, 3 patients, cocaine, one patient, and polysubstance drug abuse in one patient. The limited clinical data available indicates that DBS may be a promising therapeutic modality for the treatment of intractable addiction. In general, the safety profile of DBS in patients with addiction is good. Based on the data published in the literature, the NAc is the most often targeted, and is probably the most effective, structure of the reward circuit in the treatment of addiction in humans. Given the ever-expanding understanding of the psychosurgery of addiction, DBS could in the future be a treatment option for patients suffering from intractable addictive disorders.

Strain and sex dependent effects of isolation housing relative to environmental enrichment on operant sensation seeking in mice

Sensation seeking is a multidimensional phenotype that predicts the development of drug addiction in humans and addiction-like drug seeking in rodents. Several lines of evidence suggest that chronic stress increases sensation seeking and addiction-like drug seeking through common genetic mechanisms. Discovery and characterization of these mechanisms would reveal how chronic stress interacts with the genome to influence sensation seeking and how drugs of abuse hijack these fundamental reward mechanisms to drive addiction. To this end, we tested the hypothesis that chronic isolation housing stress (relative to environmental enrichment) influences operant sensation seeking as a function of strain, sex, or their interaction. To determine if the BXD recombinant inbred panel could be used to identify genetic and epigenetic mechanisms underlying any identified gene-by-environment interactions, we used mice from the two BXD founder strains. Following 10 weeks of differential housing, we assessed operant sensation seeking using several reinforcement schedules. The primary finding from this study was that DBA/2J but not C57BL/6J mice were significantly vulnerable to an isolation-induced increase (relative to environmental enrichment) in sensation seeking during extinction when the sensory reward was no longer available; this effect was significantly more robust in females. These data reveal a previously unknown isolation-induced effect on extinction of operant sensation seeking that is sex-dependent, addiction-relevant, and that can be dissected using the BXD recombinant inbred panel.

The neurobiology of drug addiction: cross-species insights into the dysfunction and recovery of the prefrontal cortex.

A growing preclinical and clinical body of work on the effects of chronic drug use and drug addiction has extended the scope of inquiry from the putative reward-related subcortical mechanisms to higher-order executive functions as regulated by the prefrontal cortex. Here we review the neuroimaging evidence in humans and non-human primates to demonstrate the involvement of the prefrontal cortex in emotional, cognitive, and behavioral alterations in drug addiction, with particular attention to the impaired response inhibition and salience attribution (iRISA) framework. In support of iRISA, functional and structural neuroimaging studies document a role for the prefrontal cortex in assigning excessive salience to drug over non-drug-related processes with concomitant lapses in self-control, and deficits in reward-related decision-making and insight into illness. Importantly, converging insights from human and non-human primate studies suggest a causal relationship between drug addiction and prefrontal insult, indicating that chronic drug use causes the prefrontal cortex damage that underlies iRISA while changes with abstinence and recovery with treatment suggest plasticity of these same brain regions and functions. We further dissect the overlapping and distinct characteristics of drug classes, potential biomarkers that inform vulnerability and resilience, and advancements in cutting-edge psychological and neuromodulatory treatment strategies, providing a comprehensive landscape of the human and non-human primate drug addiction literature as it relates to the prefrontal cortex.

The dynamics of the smoking wage penalty

Cigarette smokers earn significantly less than nonsmokers, but the magnitude of the smoking wage gap and the pathways by which it originates are unclear. Proposed mechanisms often focus on spot differences in employee productivity or employer preferences, neglecting the dynamic nature of human capital development and addiction. In this paper, we formulate a dynamic model of young workers as they transition from schooling to the labor market, a period in which the lifetime trajectory of wages is being developed. We estimate the model with data from the National Longitudinal Survey of Youth, 1997 Cohort, and we simulate the model under counterfactual scenarios that isolate the contemporaneous effects of smoking from dynamic differences in human capital accumulation and occupational selection. Results from our preferred model, which accounts for unobserved heterogeneity in the joint determination of smoking, human capital, labor supply, and wages, suggest that continued heavy smoking in young adulthood results in a wage penalty at age 30 of 15.9% and 15.2% for women and men, respectively. These differences are much smaller than the raw difference in means in wages at age 30. We show that the contemporaneous effect of heavy smoking net of any life-cycle effects explains 62.9% of the female smoking wage gap but only 20.4% of the male smoking wage gap.

GABAB receptors blockage modulates somatic and aversive manifestations induced by nicotine withdrawal

There is substantial evidence that GABAB agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue vulnerabilities in humans. In this context, we explored different aspects associated with the possible mechanisms whereby the GABAB receptors might influence nicotine withdrawal. Male mice received nicotine (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. Nicotine-treated mice received the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC, 2 or 3.5 mg/kg, s.c.), to precipitate the withdrawal state. A second group of dependent mice received 2-hydroxysaclofen (GABAB receptor antagonist, 1 mg/kg, s.c.) before MEC-precipitated abstinence. Somatic signs of nicotine withdrawal were measured for 30 min. Anxiogenic-like response associated to nicotine withdrawal was assessed by the elevated plus maze test. The dysphoric/aversive effect induced by nicotine withdrawal was evaluated using conditioned place aversion paradigm. Dopamine, serotonin and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. Finally, α4β2 nicotinic acetylcholine receptor density was determined in several brain regions using autoradiography assays. The results showed that MEC-precipitated nicotine withdrawal induced somatic manifestations, anxiogenic-like response and dysphoric/aversive effect, and 2-hydroxysaclofen potentiated these behavioral responses. Additionally, 2-hydroxysaclofen was able to change striatal dopamine levels and α4β2 nicotinic acetylcholine receptor density, both altered by MEC-precipitated nicotine withdrawal. These findings provide important contributions to elucidate neurobiological mechanisms implicated in nicotine withdrawal. We suggest that GABAB receptor activity is necessary to control alterations induced by nicotine withdrawal, which supports the idea of targeting GABAB receptors to treat tobacco addiction in humans.