Search

There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The α5-containing subtype is highly expressed in the hippocampus, and selective α5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the α1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the α5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the α1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the α5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

The brain circuitry of opiate craving was investigated with positron emission tomography (PET) imaging of regional cerebral blood flow (rCBF).Twelve abstinent opiate-dependent subjects listened to audiotaped autobiographical scripts of an episode of craving and a neutral episode while undergoing a PET scan with the tracer [(15)O]H(2)O. Statistical parametric mapping was used to analyze the PET images of rCBF changes.Comparison of the drug-related and neutral stimulus conditions revealed activation of rCBF in the left medial prefrontal and left anterior cingulate cortices and deactivation in the occipital cortex in response to the drug-related stimulus. A further statistical parametric mapping analysis with a subjective rating of craving as a covariate showed a positive association of between craving and rCBF in the left orbitofrontal cortex.The patterns of cerebral activation reflect the different brain regions mediating the salience of opiate-related stimuli and the subjective experience of craving for opiates.

The mapping of 5-HT2 receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands. Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-io do-2-methoxybenzamide (123I-5-I-R91150 or 123I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT2A receptors. This study reports on preliminary 123I-5-I-R91150 SPET, whole-body and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately 2% of total body counts at 180 min post injection (p.i. ). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice multi-detector system SME-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free from 5HT2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately 100-120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100 min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic data on the distribution of 5-HT2A receptors in humans (cerebral cortexstriatumcerebellum). These findings suggest that 123I-5-I-R91150 may be used for the imaging of 5-HT2A receptors in the living human brain with SPET.

The mapping of 5-HT2 receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands. Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150 or123I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT2A receptors. This study reports on preliminary123I-5-I-R91150 SPET, wholebody and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately 2% of total body counts at 180 min post injection (p.i.). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice multi-detector system SEM-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free from 5HT2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately 100–120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100 min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic data on the distribution of 5-HT2A receptors in (cerebral cortex>striatum>cerebellum). These findings suggest that123I-5-I-R91150 may be used for the imaging of 5-HT2A receptors in the living human brain with SPET.

Objective The endogenous opioid system (EOS) is involved in hedonic processing of reward, positive reinforcement, impulsivity, and potentially craving in alcohol dependence. Stress manifests in multiple stages of addiction, including early susceptibility to alcohol abuse, progression to dependence and risk of stress-related relapse. This literature review aims to collate evidence for the role of stress and opioid systems in alcohol addiction and identify novel interactions, with major importance in alcoholism treatment. Further, the actions of nalmefene and naltrexone, which may inform stress/opioid interaction in alcohol dependence, will be discussed. Method Published articles were identified with a MEDLINE search (January 1980 to March 2012). Key terms included: opioid, hypothalamic-pituitary-adrenal (HPA) axis, alcoholism, naltrexone, nalmefene. An initial review of titles preceded a second review of abstracts to identify articles meeting inclusion criteria. Results Alcohol addiction involves dysregulation of the EOS and stress systems, though precise abnormalities are uncertain. Normalisation of these systems in abstinence may occur, with inconsistent timings and degrees. The EOS has considerable interactions with stress at multiple levels of the HPA axis. Naltrexone, a relatively 1¼- specific opioid antagonist, paradoxically improves blunted 1 2 -endorphin activity in alcoholism. Naltrexone may also increase HPA responsiveness, with potential HPA normalisation, indicating an EOS-stress link. Nalmefene acts at all opioid receptors, especially K- which binds dynorphin. Dynorphin and stress interact in withdrawal, thus nalmefene may be effective in targeting relapse by negative reinforcement. Conclusion Stress and EOS abnormalities in alcoholism, and extent of normalisation of these systems in abstinence, require further investigation. There is evidence for multifaceted interactions between opioid and stress systems in alcoholism. Since naltrexone and nalmefene have differential activity at EOS receptors, comprehensive characterisation of naltrexone and nalmefene action on stress systems is critical. Delineation of the effect of these drugs on HPA normalisation in abstinence, potentially via the EOS, is timely. This could ensure targeted and evidence-based care in those with alcohol dependency.

Using a brain-dedicated triple-headed single-photon emission tomography (SPET) system, a sequential whole-volume imaging protocol has been devised to evaluate the regional distribution of iodine-123 iomazenil binding to GABAA receptors in the entire brain. The protocol was piloted in eight normal volunteers (seven males and one female; mean age, 24.8 +/- 3.9 years). The patterns obtained were largely compatible with the known distribution of GABAA receptors in the brain as reported in autoradiographic studies, with cerebral cortical regions, particularly the occipital and frontal cortices, displaying the highest 123I-iomazenil uptake. Measures of time to peak uptake and tracer washout rates presented with the same pattern of regional variation, with later times to peak and slower washout rates in cortical regions compared to other brain areas. Semiquantitative analysis of the data using white matter/ventricle regions as reference demonstrated a plateau of specific 123I-iomazenil binding in neocortical and cerebellar regions from 60-75 min onwards. These data demonstrate the feasibility of sequential, dynamic whole-volume 123I-iomazenil SPET imaging. The protocol may be particularly useful in the investigation of neuropsychiatric conditions which are likely to involve more than one focus of GABA abnormalities, such as anxiety disorders and schizophrenia.

Introduction: When assessed using Positron Emission Tomography(PET), opioid receptor availability was elevated in subjects inearly abstinence from dependent substance use compared withcontrols [1] and positively correlated with craving in alcoholdependent subjects [1,2]. It is unclear whether these findingspredate or are a consequence of substance dependence sinceevidence linking amount and duration of substance use withopioid receptor availability is limited. We therefore examined therelationship between personality traits in dependent subjects andcontrols with opioid receptor availability assessed by PET scans.Methods: We recruited ten opioid and ten alcohol dependentsubjects abstinent following detoxification and eleven healthycontrols. Subjects underwent one [11C]diprenorphine PET scanfollowing standard protocols. An analysis of tracer volume ofdistribution (VD) globally and in 21 a priori regions was producedusing an automated protocol. Personality traits were assessed inall subjects using the Eysenck personality inventory (EPQ-R).Results: There was no significant difference between thegroups’ scores on the ‘neuroticism’ (N) scale (ANOVA p = 0.325)although the control subjects tended to have lower scores. Significantpositive correlation was found between global VD andN scores across all 31 subjects (r = 0.55, p = 0.001), in controlsubjects (r = 0.70, p = 0.016) and in alcohol dependent subjects(r = 0.67, p = 0.037), but not in opioid dependent subjects(r = −0.178, p = 0.623). In all of the 21 a priori brain regions, Nscores showed a significant positive correlation with VD acrossall subjects (n = 31). When controls were analysed separately thispositive correlation remained in all 21 a priori regions. Significantcorrelations were found in the alcohol dependent subjects in 16of the 21 a priori regions but no regions showed significant correlationsin the opioid dependent subjects. There was significantdifference between the three groups’ scores on the ‘psychoticism’(P) scale (p

Dopamine release by drugs of abuse has frequently been hypothesizedto be one of the core neurobiological processes underpinningdependence. The ability of stimulant drugs to provoke dopaminerelease has been repeatedly demonstrated in animal models andin human stimulant users. For example, the amount of dopaminereleased by an injection of methylphenidate has been shown tocorrelate with the subjective experience (Volkow et al. 1999).Animal studies on dopamine release in response to opioids havebeen less consistent in their results (Hemby et al. 1999;Wise etal. 1995). In this study we used the PET tracer 11C-Racloprideto measure dopamine response to injected heroin in methadonemaintainedopioid users. 12 patients were recruited from the localtreatment services. Each underwent 2 PET scans one or two weeksapart. 5 minutes prior to each scan they received an injectionof 50mg heroin or saline placebo in a double-blind balanceddesign. Subjective measures of opioid intoxication and withdrawal,craving, and mood were recorded at regular intervals during thescan. Using an automated process, developed in house, measuresof Raclopride binding were derived for caudate, putamen andventral striatum bilaterally. When compared to placebo, the heroininjection provoked significant increases in subjective experienceof "rush" and "high". However, no measurable effect was found onRaclopride binding. Further experiments are planned to investigatethe potential effects of anticipation on the dopamine response toopioids.

Brain opioid receptors are involved in the reinforcing effectsof both opioids and alcohol. A neuroimaging study previouslyshowed increased levels of the mu opioid receptor in cocaineaddiction that was related to craving in early abstinence [Zubieta etal 1996]. We have therefore investigated whether early abstinencein heroin or alcohol dependence is also associated with increasedopioid receptor availability and craving. Two patient groups wererecruited: 1) heroin dependent patients in early abstinence frommethadone; 2) alcohol dependent patients who had been detoxifiedwith chlordiazepoxide. All underwent an PET scan with[11C]diprenorphine, a nonselective opioid receptor tracer, on abrain dedicated ECAT 953b scanner. An arterial input functioncorrected for radioactive metabolites was calculated. Spectralanalysis was used to generate a volume of distribution (VD)map of [11C]diprenorphine reflecting opioid receptor availability.In both the heroin and alcohol dependent groups, a significant[p < 0.05] increase in global VD was seen compared to the controlgroup. In the alcohol dependent group, 4 subjects were rescannedafter ~3 months abstinence and in 3 subjects, a reduction inglobal [11C]diprenorphine VD was seen and related to a changein reported craving. These results suggest that early abstinencefrom alcohol or heroin in dependence is associated with increasedavailability of opioid receptors in the brain. These findings areconsistent with those reported in early abstinence from cocaineand is further evidence for a generic role of the endogenous opioidsystem in substance dependence.

Background Over the last 30 years the number of people who drink alcohol at harmful levels has increased in many countries. There have also been large increases in rates of sexually transmitted infections. Available evidence suggests that excessive alcohol consumption and poor sexual health may be linked. The prevalence of harmful alcohol use is higher among people attending sexual health clinics than in the general population, and a third of those attending clinics state that alcohol use affects whether they have unprotected sex. Previous research has demonstrated that brief intervention for alcohol misuse in other medical settings can lead to behavioral change, but the clinical and cost-effectiveness of this intervention on sexual behavior have not been examined. Methods We will conduct a two parallel-arm, randomized trial. A consecutive sample of people attending three sexual health clinics in London and willing to participate in the study will be screened for excessive alcohol consumption. Participants identified as drinking excessively will then be allocated to either active treatment (Brief Advice and referral for Brief Intervention) or control treatment (a leaflet on healthy living). Randomization will be via an independent and remote telephone randomization service and will be stratified by study clinic. Brief Advice will comprise feedback on the possible health consequences of excessive alcohol consumption, written information about alcohol and the offer of an appointment for further assessment and Brief Intervention. Follow-up data on alcohol use, sexual behavior, health related quality of life and service use will be collected by a researcher masked to allocation status six months later. The primary outcome for the study is mean weekly alcohol consumption during the previous three months, and the main secondary outcome is the proportion of participants who report unprotected sex during this period. Discussion Opportunistic intervention for excessive alcohol use has been shown to be effective in a range of medical settings. The SHEAR study will examine whether delivering such interventions in sexual health clinics results in reductions in alcohol consumption and will explore whether this is associated with changes in sexual behavior.

BackgroundIt is unclear if research findings support clinical opinion that cannabis use leads to worse outcomes in people with psychosis, or whether this impression is confounded by other factors.AimsTo systematically review the evidence pertaining to whether cannabis affects outcome of psychotic disorders.MethodWe searched 10 relevant databases (to November 2006), reference lists of included studies and contacted experts. We included 13 longitudinal studies from 15 303 references. Data extraction and quality assessment were conducted independently and in duplicate.ResultsCannabis use was consistently associated with increased relapse and non-adherence. Associations with other outcome measures were more disparate. Few studies adjusted for baseline illness severity, and most made no adjustment for alcohol, or other potentially important confounders. Adjusting for even a few confounders often resulted in substantial attenuation of results.ConclusionsConfidence that most associations reported were specifically due to cannabis is low. Despite clinical opinion, it remains important to establish whether cannabis is harmful, what outcomes are particularly susceptible, and how such effects are mediated. Studies to examine this further are eminently feasible.

Craving is a major factor in addiction, predicting poorer outcome to treatment. To improve our understanding of craving for alcohol, we have compared in the laboratory the effects of inducting craving for alcohol by exposure to the sight and the smell of an alcoholic beverage, imagery of craving scripts, and recall of autobiographical memories of craving. We used subjective measures of craving, together with autonomic measures, in 14 abstinent alcohol-dependent individuals in the first month after detoxification. All subjects reported a significant increase in ratings of urges after exposure to alcoholic drinks, following the imagery of craving and after recalling autobiographical memories of craving. Physiological measures have shown that craving imagery as well as memory induction were equally effective as exposure to alcoholic drinks in modestly increasing autonomic arousal (indicated by systolic blood pressure). Our preliminary findings support the existing evidence in nicotine and opiate dependence that images and memories are as effective as in vivo exposure in eliciting craving for drugs.

In 2013, illegal drug use was responsible for 1.8% of years of life lost in the European Union, alcohol was responsible for 8.2% and tobacco for 18.2%, imposing economic burdens in excess of 2.5% of GDP. No single European country has optimal governance structures for reducing the harm done by nicotine, illegal drugs and alcohol, and existing ones are poorly designed, fragmented, and sometimes cause harm. Reporting the main science and policy conclusions of a transdisciplinary five-year analysis of the place of addictions in Europe, researchers from 67 scientific institutions addressed these problems by reframing an understanding of addictions. A new paradigm needs to account for evolutionary evidence which suggests that humans are biologically predisposed to seek out drugs, and that, today, individuals face availability of high drug doses, consequently increasing the risk of harm. New definitions need to acknowledge that the defining element of addictive drugs is ‘heavy use over time’, a concept that could replace the diagnostic artefact captured by the clinical term ‘substance use disorder’, thus opening the door for new substances to be considered such as sugar. Tools of quantitative risk assessment that recognize drugs as toxins could be further deployed to assess regulatory approaches to reducing harm. Re-designed governance of drugs requires embedding policy within a comprehensive societal well-being frame that encompasses a range of domains of well-being, including quality of life, material living conditions and sustainability over time; such a frame adds arguments to the inappropriateness of policies that criminalize individuals for using drugs and that continue to categorize certain drugs as illegal. A health footprint, modelled on the carbon footprint, and using quantitative measures such as years of life lost due to death or disability, could serve as the accountability tool that apportions responsibility for who and what causes drug-related harm.

In 2013, illegal drug use was responsible for 1.8% of years of life lost in the European Union, alcohol was responsible for 8.2% and tobacco for 18.2%, imposing economic burdens in excess of 2.5% of GDP. No single European country has optimal governance structures for reducing the harm done by nicotine, illegal drugs and alcohol, and existing ones are poorly designed, fragmented, and sometimes cause harm. Reporting the main science and policy conclusions of a transdisciplinary five-year analysis of the place of addictions in Europe, researchers from 67 scientific institutions addressed these problems by reframing an understanding of addictions. A new paradigm needs to account for evolutionary evidence which suggests that humans are biologically predisposed to seek out drugs, and that, today, individuals face availability of high drug doses, consequently increasing the risk of harm. New definitions need to acknowledge that the defining element of addictive drugs is ‘heavy use over time’, a concept that could replace the diagnostic artefact captured by the clinical term ‘substance use disorder’, thus opening the door for new substances to be considered such as sugar. Tools of quantitative risk assessment that recognize drugs as toxins could be further deployed to assess regulatory approaches to reducing harm. Re-designed governance of drugs requires embedding policy within a comprehensive societal well-being frame that encompasses a range of domains of well-being, including quality of life, material living conditions and sustainability over time; such a frame adds arguments to the inappropriateness of policies that criminalize individuals for using drugs and that continue to categorize certain drugs as illegal. A health footprint, modelled on the carbon footprint, and using quantitative measures such as years of life lost due to death or disability, could serve as the accountability tool that apportions responsibility for who and what causes drug-related harm.