Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

Addictions are highly heritable disorders, with heritability estimates ranging from 39% to 72%. Multiple studies suggest a link between paternal drug abuse and addiction in their children. However, patterns of inheritance cannot be explained purely by Mendelian genetic mechanisms. Exposure to drugs of abuse results in epigenetic changes that may be passed on through the germline. This mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring. Recent studies have begun to investigate the effect of paternal drug exposure on behavioral and neurobiological phenotypes in offspring of drug‐exposed fathers in rodent models. This review aims to discuss behavioral and neural effects of paternal exposure to alcohol, cocaine, opioids, and nicotine. Although a special focus will be on addiction‐relevant behaviors, additional behavioral effects including cognition, anxiety, and depressive‐like behaviors will be discussed.     

Electroencephalography reveals a selective disruption of cognitive control processes in craving cigarette smokers

Addiction to nicotine is extremely challenging to overcome, and the intense craving for the next cigarette often leads to relapse in smokers who wish to quit. To dampen the urges of craving and inhibit unwanted behaviour, smokers must harness cognitive control, which is itself impaired in addiction. It is likely that craving may interact with cognitive control, and the present study sought to test the specificity of such interactions. To this end, data from 24 smokers were gathered using EEG and behavioural measures in a craving session (following a three‐hour nicotine abstention period) and a non‐craving session (having just smoked). In both sessions, participants performed a task probing various facets of cognitive control (response inhibition, task switching and conflict processing). Results showed that craving smokers were less flexible with the implementation of cognitive control, with demands of task switching and incongruency yielding greater deficits under conditions of craving. Importantly, inhibitory control was not affected by craving, suggesting that the interactions of craving and cognitive control are selective. Together, these results provide evidence that smokers already exhibit specific control‐related deficits after brief nicotine deprivation. This disruption of cognitive control while craving may help to explain why abstinence is so difficult to maintain.     

Acupuncture inhibits cue-induced heroin craving and brain activation

Previous research using functional MRI has shown that specific brain regions associated with drug dependence and cue-elicited heroin craving are activated by environmental cues. Craving is an important trigger of heroin relapse, and acupuncture may inhibit craving. In this study, we performed functional MRI in heroin addicts and control subjects. We compared differences in brain activation between the two groups during heroin cue exposure, heroin cue exposure plus acupuncture at the Zusanli point (ST36) without twirling of the needle, and heroin cue exposure plus acupuncture at the Zusanli point with twirling of the needle. Heroin cue exposure elicited significant activation in craving-related brain regions mainly in the frontal lobes and callosal gyri. Acupuncture without twirling did not significantly affect the range of brain activation induced by heroin cue exposure, but significantly changed the extent of the activation in the heroin addicts group. Acupuncture at the Zusanli point with twirling of the needle significantly decreased both the range and extent of activation induced by heroin cue exposure compared with heroin cue exposure plus acupuncture without twirling of the needle. These experimental findings indicate that presentation of heroin cues can induce activation in craving-related brain regions, which are involved in reward, learning and memory, cognition and emotion. Acupuncture at the Zusanli point can rapidly suppress the activation of specific brain regions related to craving, supporting its potential as an intervention for drug craving.     

A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with bipolar disorder: a preliminary report

Tolliver BK, DeSantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double‐blind, placebo‐controlled clinical trial of acamprosate in alcohol‐dependent individuals with bipolar disorder: a preliminary report. Bipolar Disord 2012: 14: 54–63. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Background: Alcohol use disorders commonly co‐occur with bipolar disorder and are associated with a more severe course of bipolar illness, yet treatment research in this important clinical population is scarce. The current study assessed the effects of acamprosate on alcohol use and mood symptoms in subjects with co‐occurring bipolar disorder and active alcohol dependence. Methods: Thirty‐three adults meeting criteria for bipolar I or bipolar II disorder and current alcohol dependence were randomized to receive add‐on acamprosate (1998 mg/day) or placebo while concurrently maintained on mood stabilizing medications. Participants were assessed weekly for frequency and quantity of alcohol consumption and general clinical severity for eight weeks. Depressive symptoms, manic symptoms, and alcohol craving were assessed biweekly. Biomarkers of alcohol use were assessed at study baseline and endpoint. Results: Of the 33 subjects randomized, 23 (69.7%) completed all active phase visits. Over the trial as a whole, no statistically significant treatment differences were detected in drinking outcomes. Post‐hoc analysis revealed lower Clinical Global Impression scores of substance use severity in acamprosate‐treated participants in weeks 7–8 of the trial. No significant differences in depressive symptoms, manic symptoms, or adverse events were observed between groups. Conclusions: Acamprosate was well‐tolerated, with no worsening of depressive or manic symptoms, and appeared to confer some clinical benefit in study completers in the last two weeks of the trial. Larger studies of longer duration are required to fully explore the utility of acamprosate in this population.     

Systemic administration of 1R,4S-4-amino-cyclopent-2-ene-carboxylic acid, a reversible inhibitor of GABA transaminase, blocks expression of conditioned place preference to cocaine and nicotine in rats

We examined the effect of 1R,4S-4-amino-cyclopent-2-ene-carboxylic acid (ACC), a reversible inhibitor of GABA transaminase, on the expression of conditioned place preference response to cocaine and nicotine in rats. Cocaine (20 mg/kg i.p.) and nicotine (0.4 mg/kg s.c.), but not vehicle or 300 mg/kg i.p. of ACC, produced a significant conditioned place preference response. Pretreatment of animals with 300 and 75 mg/kg i.p. of ACC significantly attenuated the expression of the cocaine- and nicotine-induced conditioned place preference responses, respectively. These results are the first to suggest that reversible inhibition of GABA transaminase may be useful in blocking cue-induced relapse to nicotine and cocaine.     

Antidepressant treatment facilitates dopamine release and drug seeking behavior in a genetic animal model of depression

Anhedonia and lack of motivation are core symptoms of depression. In contrast, hyper-motivation and euphoria characterize intoxicated states. In order to explore the relationship between these two behavioral states we examined cocaine self-administration tasks in an animal model of depression [Flinders Sensitive Line (FSL) rats]. We found that FSL rats exhibit sub-sensitivity in their cocaine-seeking behavior, which was normalized following a chronic treatment with the antidepressant desipramine. However, when the cocaine dosage was increased, FSL rats demonstrated a similar cocaine-seeking behavior to that of controls. In light of dopamine's central role in modulating cocaine reinforcement, we examined dopaminergic neurotransmission in the nucleus accumbens, a brain region implicated in the rewarding and hedonic effects of substances of misuse. FSL rats exhibited low but dose-dependent increases in extracellular levels of dopamine in the nucleus accumbens after acute intravenous cocaine injection. Furthermore, by using the dopamine transporter blocker GBR-12909 we were able to demonstrate that the low extracellular dopamine levels, observed in FSL rats, were a consequence of low dopamine release in the nucleus accumbens, as opposed to the possibility of increased uptake. Treatment of FSL rats with the antidepressant desipramine raised cocaine- and GBR-12909-induced dopamine release to the level of controls. This treatment also resulted in increased cocaine-seeking behavior.     

Schedule-induced self injection of drugs

1. The schedule-induced polydipsia paradigm has been used to induce oral Ingestion of large volumes of alcohol, barbiturate and other drug solutions. We have developed a method of schedule-induced self Injection which allows the study of acquisition and maintenance of drug intake behaviour in changing environments free from the interference of taste factors or imbalances due to excessive water intake.2. In this paper we review our findings on the acquisition and maintenance patterns of amphetamine, methadone, heroin, alcohol, nicotine, cocaine, Δ⁹THC and haloperidol.3. For all drugs except amphetamine, the combination of schedule and nutritional deprivation leads to the highest rates of drug Intake although the schedule does not appear to be a potent factor at free feeding weight. Drug intake is the result of the interaction of environmental factors and pharmacological properties of the drugs, rather than the effects of drug or environmental factors separately.4. From a number of preliminary studies, data on corticosterone response in drug self-injection behaviour and the function of the nucleus accumbens septum are presented.     

Emotional states and informational brain processing in drug addicts free of drugs: An ERPs study

Objective

To analyze brain event-related responses in heroin-dependent patients under different emotional conditions, in order to determine the influence of specific emotional loading on information processing in drug addicts.

Methods

Fifteen male heroin-dependent patients, matched to 11 male healthy individuals, were exposed to emotion-triggering slides designed to elicit neutral, pleasant or unpleasant emotions, while ERPs were obtained by means of an auditory oddball paradigm. Evoked potential analysis consisted of measuring the amplitude, latency, and topographic distribution (mapped from 19 scalp sites) of the early and late latency component waveforms.

Results

Both groups showed large-amplitude, long-latency, and positive-polarity responses to odd stimuli under all emotional conditions. A within-group comparison between the three emotional conditions showed that the control group had smaller P300 amplitudes under pleasant stimulation; drug addicts showed no differences between all three emotional conditions. Between-group analysis revealed smaller P300 amplitudes in drug addicts than in controls, both for unpleasant and neutral emotional conditions, but this was only significant for some electrode sites. Brain electrical activity mapping at P300 showed that high activation is less spread in the brain areas of drug addicts than in controls for unpleasant and neutral emotional conditions.

Conclusion

Drug addicts have deficits in extracting relevant information from sensory stimuli under different emotional conditions, particularly under unpleasant and neutral stimulation. Decreased P300 in controls under pleasant stimulation is interpreted as a result of an attentional bias mechanism that directs attentional resources to environmental stimuli of positive emotional valence, in contrast to drug addicts where there is no such effect.     

Neuroticism and the brain: A quantitative meta-analysis of neuroimaging studies investigating emotion processing

Neuroticism is a robust personality trait that constitutes a risk factor for mood disorders. Neuroimaging findings related to neuroticism have been inconsistent across studies and hardly integrated in order to construct a model of the underlying neural correlates of neuroticism. The aim of the current meta-analysis was to provide a quantitative summary of the literature, using a parametric coordinate-based meta-analysis (PCM) approach. Data were pooled for emotion processing tasks investigating the contrasts (negative > neutral) and (positive > neutral) to identify brain regions that are consistently associated with neuroticism across studies. Significant negative and positive correlations with neuroticism were found only for the contrast (negative > neutral) after multiple comparisons correction. Differences in brain activation were found to be associated with neuroticism during fear learning, anticipation of aversive stimuli and the processing and regulation of emotion. The relationship between neuroticism and these three psychological processes and their corresponding neural correlates is discussed. Furthermore, the meta-analytic findings are incorporated into a general model of emotion processing in neuroticism.     

Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability

Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [¹¹C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction.     

Effects of single-session versus multi-session non-invasive brain stimulation on craving and consumption in individuals with drug addiction,eating disorders or obesity: A meta-analysis

Background

Brain stimulation interventions are increasingly used to reduce craving and consumption in individuals with drug addiction or excessive eating behavior. However, the efficacy of these novel treatments and whether effect sizes are affected by the length of the intervention has not been comprehensively evaluated.

Sensitivity to naloxone of the behavioral signs of morphine withdrawal and c-Fos expression in the rat CNS: a quantitative dose-response analysis

Several studies have used c-Fos expression to delineate the neural substrate underlying naloxone-precipitated morphine withdrawal (MW). However, because behavioral manifestations of MW depend on both the degree of dependence and the doses of naloxone (NAL), a comprehensive study would require examining c-Fos expression in relation with the degree of MW. Here, changes in behavior and in c-Fos-like immunoreactivity (FLI) were studied in the same rats after injection of three doses of NAL to precipitate various degrees of MW. Fifteen established signs of MW were examined for 1 hour after NAL injection, and FLI was quantified in 52 regions of the brain and in the lumbosacral spinal cord. Linear regression analyses were used to examine changes in numbers of signs and FLI neurons with the doses of NAL, and data were considered dose-related for a statistical level of significance of P < 0.05. In summary, autonomic signs of MW increased in a dose-related manner, whereas somatomotor signs did not. After MW, 33 central nervous system regions exhibited significant increases in FLI and were, thus, considered as important neural correlates of MW. Twenty of them displayed dose-related increases in c-Fos expression and correspond to regions related to autonomic functions. Low c-Fos expression was detected in some regions involved in motor control or in reward, suggesting either their minor role in MW or a limitation of the technique. This dose-response analysis suggests that the increase in the severity of autonomic manifestations of MW is associated with a gradual activation of major structures of the autonomic nervous system.     

Phosphorylation of glutamate receptors: a potential mechanism for the regulation of receptor function and psychostimulant action

Ionotropic glutamate receptors, N-methyl-d-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), are densely distributed in the mammalian brain and actively regulate a variety of cellular activities. Expression and function of these receptors are also under a tight regulation by many molecular mechanisms. Protein phosphorylation represents one of the important mechanisms for the posttranslational modulation of these receptors. Constitutive and regulatory phosphorylation occurs at distinct sites (serine, threonine, or tyrosine) on the intracellular C-terminal domain of almost all subunits capable of assembling a functional channel. Several key protein kinases, such as protein kinase A, protein kinase C, Ca(2+)/calmodulin-dependent protein kinases, and tyrosine kinases are involved in the site-specific catalyzation and regulation of NMDAR and AMPAR phosphorylation. Through the phosphorylation mechanism, these protein kinases as well as protein phosphatases control biochemical properties (biosynthesis, delivery, and subunit assembling), subcellular distribution, and interactions of these receptors with various synaptic proteins, which ultimately modify the efficacy and strength of excitatory synapses containing NMDARs and AMPARs and many forms of synaptic plasticity. Emerging evidence shows that psychostimulants (cocaine and amphetamine) are among effective agents that profoundly alter the phosphorylation status of both receptors in striatal neurons in vivo. Thus, psychostimulants may modulate NMDAR and AMPAR function through the phosphorylation mechanism to shape the excitatory synaptic plasticity related to additive properties of drugs of abuse.     

Alcohol consumption in the elderly and risk of dementia related death - a Norwegian prospective study with a 17-year follow-up

Purpose: The aim of this study was to determine the association between alcohol intake and risk of dementia related death, taking into account relevant confounding and mediating factors. Materials and Methods: Data was obtained from a Norwegian prospective study with a 17-year follow-up. The study population comprised 25,635 participants aged between 60 and 80 years at the time of examination from the Cohort of Norway (CONOR). Cox regression was used to investigate the association between alcohol use and dementia related death. Results: Nearly half (12,139) of the study population died during follow-up, of which 1,224 had a diagnosis of dementia on their death certificate. The risk of dementia related death was significantly higher among abstainers than among individuals that drank alcohol once per month (HR = 1.33, 95% CI = 1.14–1.56, p < 0.001, in a fully adjusted model). Respondents with missing information regarding alcohol consumption (representing 5% of the study population) had the highest risk of dementia related death (HR = 1.60, 95% CI = 1.28–2.00, p < 0.001) and also significantly higher mortality rates due to alcohol-related causes (HR = 1.41, 95% CI = 1.03–1.93, p = 0.031) and other causes (HR = 1.32, 95% CI = 1.21–1.43, p < 0.001), all compared to those drinking alcohol no more than once per month. Conclusion: These findings suggest that the risk of dementia related death is significantly higher among elderly abstainers than among those who drink alcohol, after adjusting for relevant confounders. However, care should be taken in interpretation of data due to missing information on drinking frequency, as this missing-group might have a large share of the heavy drinkers in the study cohort.     

Smoking cessation in primary care - a randomized controlled trial of bupropione, nicotine replacements, CBT and a minimal intervention

Background/aims: Smoking cessation has been shown to be effective in randomized controlled trials. It is unclear though, whether interventions also work in routine primary care. Methods: In 167 primary care settings we conducted a randomized four‐armed smoking cessation trial to examine the efficacy of a minimal intervention (MI; n = 81), cognitive‐behavioral therapy (CBT; n = 175), bupropion (BUP; n = 108) and nicotine replacements (NRT; n = 103). Overall, 467 current smokers were enrolled. Abstinence rates at the end of treatment (12 weeks) were 32.8% for MI patients, 34.8% for CBT, 35.3% for NRT, and 46.5% for BUP patients (ITT, intention to treat) (no differential effects). Retention rates were highest in the BUP group (59.3%) and lowest in the NRT group (50.5%). Completer findings were: MI, 56.4%; CBT, 64%; BUP, 79.3%; NRT, 69.2% (LOCF, lost to follow‐up). No serious adverse events occurred during or after the medication phase. At 12‐month follow‐up continuous abstinence rates were: BUP, 29.0%; CBT, 20.9%; NRT, 29.6%; MI, 29.6%. Conclusion: Our findings suggest that established smoking cessation treatments are effective when applied by non‐specialist primary care physicians. Our data supports a structured, multimodal treatment structure as core ingredient of successful smoking cessation in primary care. Copyright © 2011 John Wiley & Sons, Ltd.     

Common and distinct networks underlying reward valence and processing stages: a meta-analysis of functional neuroimaging studies

To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC), as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore take distributed and interrelated representations of reward valuation and valence assessment into account.