Profiles of visuospatial memory dysfunction in opioid-exposed and dependent populations.

BACKGROUND: Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. METHODS: We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. RESULTS: As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.

Neuropsychological functioning and chronic methadone use: A systematic review and meta-analysis.

INTRODUCTION: There is a presumption that neurocognition is commonly impaired in chronic methadone exposed individuals (CM) when compared with healthy controls (HP). Additionally, it remains unclear if short term (<1year) abstinence (AP) is associated with an altered cognitive profile when compared with CM. METHOD: A random effect model approach was used on data assembled into the Comprehensive Meta-Analysis programme. Cohen's d effect sizes and a significance levels of p<0.01 were calculated for each domain. RESULTS: Data from a total cohort of 1063 CM, 412 AP and 879 HP participants, from 23 independent studies indicate global impairments in neurocognitive function in CM relative to HP participants. The smaller body of evidence comparing CM to AP participants is inconclusive. CONCLUSION: Methodological issues such as small sample sizes, heterogeneity and poor quality limited the interpretation of the results and does not address whether the observed impairments reflect co-morbid functioning, methadone-related sedation and/or other factors. Only higher quality longitudinal studies will permit confident interpretation of the results observed in this meta-analysis.

The effect of dietary intervention on the metabolic and behavioural impairments generated by short term high fat feeding in the rat.

Previous studies have shown that rats fed a high calorie diet rich in saturated fat for 12weeks exhibit peripheral insulin resistance and impairments of behavioural flexibility when switched from an operant delayed matching to place (DMTP) schedule to a delayed non-matching to place (DNMTP) schedule. However, the metabolic changes evoked by feeding a high fat (HF) diet can be observed within two weeks of commencing the diet. The current study has confirmed that 4weeks exposure to an HF diet resulted in increased body weight, peripheral insulin resistance and plasma leptin. Studies performed during weeks 3 and 4 on the HF diet revealed suppressed lever pressing rates and impaired behavioural flexibility in the operant DMTP/DNMTP task. When animals fed the HF diet were then returned to a standard chow (SC) diet for 5weeks their weight and blood biochemistry no longer differed from those measured in animals that had never been exposed to the HF diet. The animals restored to the SC diet exhibited a clear ability to acquire the DNMTP schedule of reinforcement although these animals continued to lever press at a lower rate when compared with animals that received the SC diet throughout. The data suggest that exposure to an HF diet diminishes the motivation to respond for a reward and, thus, the capacity to adapt behavioural performance. This deficit was ameliorated, but not totally reversed, by the dietary intervention. If also true for humans, the results suggest that deficits in behavioural flexibility develop after only a short period on a high calorie diet but may be largely reversible through simple dietary intervention, at least in the early stages of deficit development. However, the putative effects of short-term exposure to an HF diet on behavioural motivation may persist for some time after switching to a healthier low fat diet and remain a problem for those seeking to adopt a healthier diet.

Impulsivity and opioid drugs: differential effects of heroin, methadone and prescribed analgesic medication.

BACKGROUND: Previous studies have provided inconsistent evidence that chronic exposure to opioid drugs, including heroin and methadone, may be associated with impairments in executive neuropsychological functioning, specifically cognitive impulsivity. Further, it remains unclear how such impairments may relate of the nature, level and extent of opioid exposure, the presence and severity of opioid dependence, and hazardous behaviours such as injecting. METHOD: Participants with histories of illicit heroin use (n = 24), former heroin users stabilized on prescribed methadone (methadone maintenance treatment; MMT) (n = 29), licit opioid prescriptions for chronic pain without history of abuse or dependence (n = 28) and healthy controls (n = 28) were recruited and tested on a task battery that included measures of cognitive impulsivity (Cambridge Gambling Task, CGT), motor impulsivity (Affective Go/NoGo, AGN) and non-planning impulsivity (Stockings of Cambridge, SOC). RESULTS: Illicit heroin users showed increased motor impulsivity and impaired strategic planning. Additionally, they placed higher bets earlier and risked more on the CGT. Stable MMT participants deliberated longer and placed higher bets earlier on the CGT, but did not risk more. Chronic opioid exposed pain participants did not differ from healthy controls on any measures on any tasks. The identified impairments did not appear to be associated specifically with histories of intravenous drug use, nor with estimates of total opioid exposure. CONCLUSION: These data support the hypothesis that different aspects of neuropsychological measures of impulsivity appear to be associated with exposure to different opioids. This could reflect either a neurobehavioural consequence of opioid exposure, or may represent an underlying trait vulnerability to opioid dependence.

A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin.

AIMS/HYPOTHESIS: We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity. METHODS: Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. RESULTS: HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. CONCLUSIONS/INTERPRETATION: Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet.

Neuropsychological consequences of chronic opioid use: a quantitative review and meta-analysis.

INTRODUCTION: It is widely assumed within the accumulated literature that neuropsychological function is commonly impaired as a consequence of chronic opioid use. METHOD: Quantitative and systematic review of the literature on the neuropsychology of chronic opioid use using the meta-analysis of observational studies in epidemiology (MOOSE) and the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. RESULTS: This meta-analysis suggests that chronic opioid exposure is associated with deficits across a range of different neuropsychological domains. However, the only domains where meta-analysis suggests robust impairment were those of verbal working memory, cognitive impulsivity (risk taking) and cognitive flexibility (verbal fluency). The magnitude of effect across these cognitive domains was medium according to Cohen's benchmark criteria. DISCUSSION: This analysis highlighted methodological problems present in the literature used and the value of utilising meta-analytic techniques to help further elucidate the neuropsychological consequences of chronic opioid use from 'core' addiction phenotypes.

Influence of 5,7-dihydroxytryptamine lesions of the rat fornix-fimbria and cingulum bundles on spontaneous activity in an aversive maze.

Exposure to aversive environmental stimuli stimulates the serotonergic neurones that project to the forebrain and inhibit spontaneous activity when studied in a simple maze. This study explored the putative role of the principal 5-hydroxytryptamine (5-HT) neurones that project to the hippocampus from the median raphe nucleus in this response to an aversive environment by lesioning the 5-HT fibres that project through the fornix/fimbria and cingulum bundles. The effects of the lesions were investigated in independent groups of animals tested in an enclosed four-arm maze and a more aversive elevated maze of the same dimensions composed entirely of four open arms. The rats were significantly less active in the open maze, the principal effect of maze design being observed during the first 5 min sub-trial of a 15 min trial. This response to the more aversive environment was totally abolished by the lesion. It is concluded that exposure to an explicitly aversive environment elicits a brief stimulation of the 5-HT neurones that project to the hippocampus from the median raphe nucleus and that this stimulation inhibits the initial burst of exploratory activity that is observed in animals placed in a less aversive novel environment.

Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform.

Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials. Repeated exposure to the stressor for 5 or 10 occasions increased 5-HT turnover in the hippocampus. By contrast, 5-HT turnover in frontal cortex was increased by acute exposure to the stressor. Microdialysis studies showed that acute stress increased 5-HT overflow in prefrontal cortex but not dorsal hippocampus whereas repeated daily (10 days) exposure to the stressor increased basal extracellular 5-HT in the dorsal hippocampus, but not the prefrontal cortex. Prior exposure to the stressor on up to 10 occasions enhanced the plasma corticosterone response to a challenge in an elevated plus-maze performed 24h later whereas repeated, but not acute, exposure to the stressor, elicited anxiolytic-like behavioural responses in this test. It is concluded that acute exposure to this form of inescapable stress selectively stimulates the 5-HT projections to the frontal cortex; repeated stress elicits a sustained increase in 5-HT release and turnover in the hippocampus. The data are consistent with the hypothesis that increased 5-HT release in the hippocampus may be implicated in the mechanisms underlying habituation to inescapable stress.

Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress.

It has been suggested that physiological resistance to repeated stress is associated with increased 5-hydroxytryptamine (5-HT) release in the dorsal hippocampus and that dysregulation of this neuroadaptation may be implicated in the psychopathology of depression. This study used 5,7-dihydroxytryptamine lesions to investigate the role of 5-HT projections to the hippocampus in physiological responses to repeated stress and putative changes in corticosteroid receptor immunoreactivity in the brain. Repeated exposure to elevated open platform stress (1 h/day) caused regionally selective changes in glucocorticoid and mineralocorticoid receptor immunoreactivity in the dorsal hippocampus that were not observed in ventral hippocampus, frontal cortex, hypothalamus or parietal cortex. Glucocorticoid receptor immunoreactivity in the dorsal hippocampus was decreased after 5 days but increased after 20 days of stress. Mineralocorticoid receptor immunoreactivity was increased after 5 or 10 days of stress. The increases in glucocorticoid and mineralocorticoid receptor immunoreactivity, evoked by repeated stress, were abolished by lesions of the principal 5-HT projections to the hippocampus. The lesions abolished the increased defecation observed in stressed animals, but had no effects on the plasma corticosterone response to the stressor or the habituation of this response observed following repeated stress. The experiments have revealed a dissociation in the regulation of corticosteroid receptor expression in the dorsal and ventral hippocampus by repeated stress and 5-HT. The data suggest that adaptation to inescapable stress is associated with regionally selective changes in corticosteroid receptor expression in dorsal hippocampus that are largely 5-HT-dependent, although these changes do not mediate habituation of the pituitary adrenocortical response to the stressor.

Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain.

RATIONALE: Sensitisation of the mesoaccumbens dopamine response to nicotine has been implicated in the development of nicotine dependence. This study explored the doses of nicotine that elicit the response in two strains of rats that differ in their baseline levels of activity. METHODS: Male Sprague-Dawley and Lister hooded rats were pretreated with daily subcutaneous injections of (-)-nicotine for 7 days at doses ranging from 0.03 mg/kg to 0.90 mg/kg. Microdialysis studies were performed on day 9 in conscious freely moving rats, placed in an activity box and challenged with 0.4 mg/kg nicotine. RESULTS: The acute administration of nicotine to drug-naive rats stimulated dopamine overflow in the accumbal shell but not the core. Sprague-Dawley rats, pretreated with nicotine (0.03 mg/kg/day and 0.10 mg/kg/day) showed increased basal overflow of dopamine in the accumbal core. Pretreatment with 0.10 mg/kg/day or 0.30 mg/kg/day, but not 0.03 mg/kg/day or 0.90 mg/kg/day, also caused sensitisation of the response to a nicotine challenge on the test day. Sensitisation of the locomotor response to nicotine exhibited a simple dose-response relationship, with the largest sensitisation being observed in animals pretreated with 0.90 mg/kg/day. In Lister hooded rats, pretreatment with nicotine reduced basal dopamine overflow in the accumbal core and did not cause sensitisation to a subsequent challenge with nicotine. CONCLUSIONS: Sensitisation of the mesoaccumbens dopamine response to nicotine is influenced by pre-treatment dose and the strain of rats used. It is not related directly to the expression of sensitised locomotor responses to the drug and, therefore, may be implicated in other psychopharmacological properties of the drug, including dependence.

The pharmacology underlying pharmacotherapy for tobacco dependence: a focus on bupropion.

Tobacco dependence remains the major preventable cause of early mortality and morbidity in the developed world. The primary reinforcer of the dependence is the nicotine present in tobacco smoke and, for many smokers, successful treatment depends upon breaking this dependence. Until recently, the only specific pharmacotherapy available for tobacco dependence was nicotine replacement therapy (NRT). Although this approach does significantly increase long-term cessation rates, it is by no means a panacea for the many smokers who require help to quit. Recently, a new drug, bupropion (Zyban), has been licensed as an additional pharmacological aid for smoking cessation. This commentary discusses the mechanisms that may account for its efficacy in this indication and considers the impact its introduction may have on the approach of healthcare systems to the treatment of tobacco dependence.

The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence.

A majority of habitual tobacco smokers find it very difficult to quit the habit because they become addicted to the nicotine present in tobacco smoke. Nicotine, like other psychostimulant drugs of abuse, increases dopamine release in the principal terminal field of the mesolimbic system, the nucleus accumbens, and there is evidence that this mediates the 'rewarding' properties of the drug, which reinforce its self-administration. This review focuses on the working hypothesis that addiction to nicotine, and other psychostimulant drugs, depends upon their ability to evoke a sustained increase in dopamine release directly into the extracellular space which lies between the cells in the nucleus accumbens where it stimulates extra-synaptic dopamine receptors. It is suggested that increased stimulation of these receptors is associated with increased incentive learning or the attribution of increased incentive salience to the cues associated with acquisition and delivery of the drug. The hypothesis proposes that these cues can become conditioned reinforcers of drug-taking behaviour. The receptors, which mediate the effects of nicotine on mesoaccumbens dopamine neurones, are desensitised by sustained exposure to nicotine at concentrations commonly found in the plasma of habitual smokers. It is proposed that, at times when the plasma nicotine concentration is sufficiently high to cause desensitisation of the receptors, tobacco smoking is maintained by the conditioned reinforcers present in the tobacco smoke. The hypothesis predicts, therefore, that conditioned reinforcement may play a more important role in the addiction to tobacco than for most other addictive behaviours. As a result, studies with nicotine have the potential to contribute to our understanding of the neurobiology of addiction which cannot easily be explored using drugs, such as cocaine and amphetamine, which invariably increase dopamine overflow in the forebrain.

The effects of nicotine on neural pathways implicated in depression: a factor in nicotine addiction?

The prevalence of tobacco smoking varies considerably between different groups within the community, tobacco smoking being particularly prevalent in patients with depressive disorder. This review will focus on results, derived from animal studies, which suggest that, in addition to its primary reinforcing properties, nicotine also exerts effects in stressful environments, which may account for its enhanced addictive potential in depressed patients. It focuses on the evidence that depression sensitises patients to the adverse effects of stressful stimuli, and that this can be relieved by drugs that stimulate dopamine release in the forebrain. This mechanism, it is proposed, contributes to the increased craving to smoke in abstinent smokers exposed to such stimuli, because they become conditioned to use this property of nicotine to produce rapid alleviation of the adverse effects of the stress. The review also explores the possibility that chronic exposure to nicotine elicits changes in 5-HT formation and release in the hippocampus which are depressogenic. It is postulated that smokers are protected from the consequences of these changes, while they continue to smoke, by the antidepressant properties of nicotine. However, they contribute to the symptoms of depression experienced by many smokers when they first quit the habit.

The influence of lobeline on nucleus accumbens dopamine and locomotor responses to nicotine in nicotine-pretreated rats.

In vivo brain microdialysis was used to investigate the influence of lobeline on dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) overflow in the core of the nucleus accumbens of freely-moving rats pretreated with nicotine (0.4 mg x kg(-1), s.c., once per day for 5 days). Locomotion was also recorded. Lobeline, at doses of 0.7, 4.0 and 10.0 mg x kg(-1), i.p., failed to elicit any significant changes in extracellular dopamine or dihydroxyphenylacetic acid levels during the 60 min following its administration and did not stimulate locomotor. The dopamine responses to nicotine (0.4 mg x kg(-1), s.c.), were abolished (P<0.01) if the nicotine challenge was administered 10 min but not 60 min, after lobeline doses of 4.0 and 10.0 mg kg(-1), i.p., but were unaffected following lobeline at the lowest dose tested (0.7 mg x kg(-1), i.p.) at either time. The increase in locomotor activity was significantly attenuated (P<0.01), to a similar extent, when the nicotine was injected 10 min, but not 60 min, after all three doses of lobeline (0.7, 4.0 and 10.0 mg kg(-1), i.p.) when compared with the saline-treated rats. The results suggest that lobeline is a short-acting antagonist of the nicotinic AChRs which mediate the effects of nicotine on mesolimbic dopamine activity and locomotor stimulation.

The influence of nicotine pretreatment on mesoaccumbens dopamine overflow and locomotor responses to D-amphetamine.

Pretreatment with psychostimulant drugs causes sensitisation of their effects on locomotor activity and dopamine (DA) overflow in the nucleus accumbens (NAcc) and there is evidence for similarities in the mechanisms involved. This study used in vivo microdialysis in conscious freely moving rats to investigate the extent to which pretreatment with nicotine causes sensitisation to D-amphetamine. Pretreatment with nicotine (0.4 mg/kg s.c. daily for 5 days) caused sensitisation of the locomotor responses to D-amphetamine (0.1-0.5 mg/kg s.c.) but not cocaine (15 mg/kg i.p.). Nicotine pretreatment did not influence the increase in DA overflow into dialysis probes, located in the core of the NAcc, evoked by systemic injections of D-amphetamine or cocaine (15 mg/kg i.p.) but decreased the overflow evoked by the administration of D-amphetamine (1 x 10(-6) M) through the dialysis probe. The results provide further evidence for a dissociation between the expression of sensitised locomotor responses to psychostimulant drugs and sensitisation of their stimulatory effects on DA overflow in the core of the NAcc. The results suggest that the sensitisation of the effects of nicotine on DA overflow in this subdivision of the NAcc may be pharmacologically specific to nicotinic drugs.

Sensitization of the mesoaccumbens dopamine response to nicotine.

This article reviews the evidence that pretreatment with nicotine causes a regionally selective sensitization of its stimulatory effects on a pathway, the mesoaccumbens dopamine (DA) system, which has been implicated in the locomotor stimulant response to nicotine and its ability to reinforce self-administration. The sensitization evoked by daily injections of nicotine is associated with a regionally selective downregulation of the control of mesoaccumbens DA neurons by inhibitory autoreceptors and depends upon co-stimulation of NMDA glutamatergic receptors. It is suggested that the sensitization is related to enhanced burst firing of mesoaccumbens neurons, which results in an enhancement of DA release into the extracellular space between the cells where it acts upon putative extrasynaptic dopamine receptors. The studies with NMDA receptor antagonists revealed a dissociation between the expression of sensitized mesoaccumbens DA and locomotor responses to nicotine. It is proposed, therefore, that the sensitized mesoaccumbens DA responses to nicotine may be implicated in psychopharmacological responses to drug concerned more closely with nicotine dependence.

Society for Research on Nicotine and Tobacco.

The proceedings of the second annual scientific conference of the Society for Research on Nicotine and Tobacco are summarized. The goal of the annual conference was to disseminate information about ongoing nicotine research from biological, behavioral and social perspectives. Data were presented describing our current understanding of the structure and function of neuronal nicotinic acetylcholine receptors, by which nicotine exerts most, if not all, of its effects in the brain. The conformational complexity of receptor subunits expressed in different brain areas contributes significantly to the complexity of responses observed to nicotinic agonists. Nicotine is being developed as a medication that might be used to maintain smoking cessation and to treat various medical diseases. The potential toxicity of nicotine, apart from cigarette smoking, is an important variable in assessing the benefits and risks of such therapeutic applications. The risks of nicotine-containing medications appear to be far less than those associated with tobacco use. Recent data indicate that cigarette smoking is increasing among young in the United States. Adolescent smokers are interested in quitting and make frequent quit attempts, but are usually not successful. Effective methods are needed to manage adolescent smokers before they become heavily addicted. Nicotine replacement as a pharmacological treatment for smoking cessation has made a significant contribution in improving quit rates. New medications have been developed that target specific populations of smokers.