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 Centre for Addictionand Mental Health |
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Research
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Clinical Neuroscience: Research Annual Report 2003Section Head: Dr. Usoa Busto The Clinical Neuroscience Section conducts human experimental research to better understand the different factors that influence substance use and dependence as well as other forms of compulsive or addictive behaviour such as gambling. These factors can relate to the drug, the host and the environment. Host Factors Contributing to Substance Use Disorders We continue our research into host factors contributing to substance use disorders, including multiple drug use, psychiatric comorbidity and genetics. Depression and Dopaminergic Pathways Ongoing studies in this area continue to examine the role of the brain reward system in major depressive disorder (with Drs. Claudio Naranjo, Helen Mayberg and Simon Graham). We have shown that the brain reward systems (mesocortico-limbic dopaminergic pathways) are altered in people who are severely depressed and that specific areas of the brain are involved in the response to a dopaminergic probe. The role of nicotine in modulating symptoms of depression in depressed smokers and non-smokers is another area under active research (with Drs. Laura Cardenas, Martin Zack, Sylvain Houle, Shitij Kapur and Helen Mayberg). Data from ongoing positron emission tomography (PET) studies show that dopamine release in depressed smokers is significantly lower compared to depressed non-smokers. This difference suggests the possibility of a hypofunctional mesocorticolimbic dopaminergic system (Cardenas et al.,2002). Dr. Peter Selby and colleagues have also received funding to train professionals to be more effective in treating nicotine dependence. We now have a protocol approved to examine the mechanisms of craving for nicotine in both current and abstinent smokers (with Drs. Selby and Laurie Zawertailo). Brain Responses to Amphetamine and Hydromorphone This year, we completed a neuroimaging study showing that changes occur in specific areas of the brain in the response to amphetamine (Tremblay et al., 2003, in preparation). Other research in humans has shown that oral d-amphetamine administration is associated with a prolonged displacement of [11C] raclopride, which is sustained at six hours post-drug (Cardenas et al., in press), even though the subjective effects of the drug dissipate within three hours. This finding demonstrates longer-term effects of d-amphetamine on dopamine release than has been previously demonstrated. We also completed a study using hydromorphone as a probe for the dopaminergic and opioid systems. Results suggest that hydromorphone acts differently from amphetamine on dopaminergic/opioid pathways -- in people with depression, hydromorphone caused a reported decrease in negative symptoms (e.g., sedation) and little change in positive symptoms. Hypnotic Medications in Older Adults We continue to study the effects of hypnotic medications in older adults (with Drs. Beth Sproule and Nathan Herrmann), in
the hope of learning more about age as a host factor for substance use problems. We have received approval for a novel adjunctive treatment for opioid dependence, using the NMDA antagonist dextromethorphan to alleviate withdrawal and tolerance. We also plan to further examine the mechanisms of craving in people who are opioid-dependent using functional magnetic resonance imaging (F-MRI) of brain activity (with Drs. Simon Graham and Laurie Zawertailo). The intrinsic pharmacological characteristics of drugs of abuse (such as potency, the ability to produce reinforcing effects and drug kinetics) are essential to drug-taking behaviour. One line of our research looks at the comparative abuse liability of available drugs and new compounds. We have recently completed a study examining the comparative pharmacology, behavioural effects and abuse potential of heroin and hydromorphone in human subjects (with Drs. Bruna Brands and David Marsh), and we have funding for another crossover study of hydromorphone in people who are opioid-dependent (with Drs. Brands and Marsh). We also plan to expand our research to study aspects of alcohol dependence, such as gender differences in cognitive effects of alcohol (with Drs. Denise Tomkins, Constantine Poulos, Martin Zack and Laurie Zawertailo). Pharmacological Modulation of Addiction-Related Cognitive Networks and Related Processes The main focus of our research is to learn how addiction-related memory structures are activated, and how this activation underlies and interacts with the motivation or craving to engage in addictive behaviour, comorbidity factors (e.g., concurrent addiction and mental health problems), environmental factors (e.g., stress) and, in some cases, measures of addictive behaviour itself. As we examine the key processes of activation and inhibition, we look at ways in which medications, alcohol, other drugs and addictive reinforcers like gambling alter semantic memory structures in healthy people and in people with addictive disorders. We are trying to determine if addiction-related disturbances contribute to deficits in self-regulation by activating or by inhibiting the cognitive processes that maintain regulation under normal circumstances. Activation of semantic memory networks is important for three reasons. 1) It occurs involuntarily and, in some cases, without conscious awareness. 2) It can bias decisions and overt behaviour toward addictive reinforcers and away from adaptive alternatives. 3) It can be measured simply and accurately, using response time tasks administered by computer. For these reasons, studying the activation of semantic memory networks is a useful way to define the motivation behind addictive behaviour. We have developed a procedure, called The Lexical Salience Task, to assess the effect of a pharmacological prime rather than a verbal prime on substance use or other addictive behaviour. For example, if activation of brain catecholamines contributes to the motivation to gamble, this procedure can show us if the difference in reading speed to gambling words (e.g., wager) versus neutral words (e.g., window) is greater under a dose of the catecholamine agonist, amphetamine, than under placebo. Similarly, if activation of brain GABA transmission contributes to motivation to drink, the difference in reading speed to alcohol words (e.g., beer) versus neutral words (e.g., board) should be greater under a dose of the GABA agonist, diazepam, than under placebo. We have investigated these two areas in the research projects outlined below. The Role of Dopamine in Gambling In a previous study, we found that, in people who have gambling problems, amphetamine: primes gambling cognitions; inhibits neutral cognitions; increases urge to gamble; and decreases confidence to avoid gambling. Amphetamine had no such effects in controls. Although dopamine is the primary neurochemical activated by amphetamine, amphetamine also activates other neurochemicals, including norepinephrine and serotonin. In our current study, we hope to isolate the role of dopamine in motivation to gamble, gambling-related cognitions and actual betting behaviour in people who have gambling problems. We will assess the ability of the selective dopamine antagonist, haloperidol, to reduce desire to gamble and gambling-related semantic activation induced by a brief gambling episode in problem gamblers and in age- and gender-matched controls. We will also investigate the effects of dopamine blockade on patterns of betting behaviour during the gambling episode. We predict that, relative to placebo, haloperidol will reduce post-gambling desire to gamble as well as activation of gambling cognitions on The Lexical Salience Task. If dopamine also influences patterns of gambling behaviour, haloperidol should dampen the overall escalation in bet size and reactivity to wins and losses that characterize problem gambling behaviour. This project is funded by a grant from The Ontario Problem Gambling Research Centre. Priming Effects of Benzodiazepines on Alcohol-Related Cognitions and Drinking Behaviour This project examines the priming effects of two benzodiazepines on automatic alcohol-related cognitions and drinking behaviour in people who have drinking problems. We will compare the effects of diazepam, a drug with high abuse liability, with those of clonazepam, a drug with low abuse liability. We will also examine how drug dose, severity of alcohol problems and the degree of co-existing anxiety affect cognitive and behavioural responses to these drug probes. Our findings will lay the foundation for future research with other pharmacological probes to better characterize the specific neurochemical substrates of motivation to drink in people who have drinking problems and varying degrees of anxiety. Preliminary data indicate that low-dose diazepam (5 mg) primes alcohol-related cognitions on The Lexical Salience Task. The degree of lexical priming also predicts the volume of beer consumed in a taste-test drinking procedure (cf. Marlatt et al., 1973). In addition, the degree of priming correlates with the severity of alcohol use, as measured by drinks per week. Drinks per week did not mediate the correlation between lexical priming and taste-test drinking. Consistent with a previous study (Zack et al., 1999), high-dose diazepam (15 mg) significantly reduced the ability of negative-affect words (e.g., tense) to prime alcohol-related cognitions (e.g., beer) in a conventional lexical decision semantic priming task in drinkers with no history of benzodiazepine use. Notably, diazepam had no effect on neutral, categorical priming (e.g., cat-dog), and negative-affect alcohol priming was clearly evident under placebo. Together, these diazepam data indicate a homeostatic priming and satiety process, moderated by dose, in people who have drinking problems. The findings corroborate the utility of drug priming of addiction-related memory networks as a means of assessing medications that may reduce problem drinking. This procedure may be especially useful for investigating individual differences in the neurochemical basis of alcohol priming to predict which medication(s) will be beneficial to a particular profile of drinking problem. Effects of Alcohol on Stress-Induced Cognitive Activation in Young Drinkers This project is being carried out in collaboration with Dr. Colin M. MacLeod of the Department of Psychology at the University of Toronto. We are building on previous grant-funded research to evaluate the effects of alcohol on automatic alcohol- and anxiety-related cognitions, induced by a stressor, in university undergraduates with high or low anxiety sensitivity. People who have high anxiety sensitivity are more likely to use alcohol to cope with negative mood states; they have higher rates of drinking problems than do people who have low anxiety sensitivity. The current study will determine the possible mediating role of semantic network dampening in the negative reinforcing effects of alcohol in high-anxiety-sensitive drinkers. Initial data indicate that, relative to placebo, a moderate dose of alcohol (BAC =.06%) primes alcohol-related cognitions in low-anxiety-sensitive but not in high-anxiety-sensitive drinkers. Relative to a soft drink, placebo alcohol (de-alcoholized beer) reduces activation of anxiety-related and alcohol-related cognitions in both low- and high-anxiety-sensitive subjects. If these preliminary results persist when the sample is complete, they will provide a basis for examining interventions to modify alcohol-induced and expectancy-related memory activation in young people at risk for alcohol problems (cf. Breslin, Zack & McMain, 2002). This project is funded by a grant from The Alcoholic Beverage Medical Research Foundation. Deficient Inhibitory Control and MDMA This study is being carried out in collaboration with Dr. Paul Fletcher of the Biopsychology Section. Dr. Stephen Kish (Human Neurochemical Pathology Laboratory) and Dr. Constantine X. Poulos (Clinical Neuroscience Department) are consultants. Chronic use of 3, 4-methylenedioxymethamphetamine (MDMA, ecstasy) has been linked with lasting damage to brain serotonin (5-HT) neurons in rodents and non-human primates. People who use MDMA consistently display deficits in memory, which correlate with deficits in 5-HT function. Although some research has found impulsivity in chronic MDMA users, these previous findings are of limited value, as study participants used a variety of other psychoactive drugs as well as MDMA. In this study, we are trying to assess fully the cognitive inhibitory processes involved in impulsivity in MDMA users and to determine the impact on impulsivity of prior MDMA versus other drug use. We have assessed three groups of subjects: (1) people who use MDMA plus low levels of other substances (the normative pattern
of MDMA use), (2) people who use marijuana-only and (3) drug-free controls. We are also testing a fourth group (4) people
who use MDMA plus marijuana-only (a minority of MDMA users). The data in hand suggest that, across a range of tasks, people in the marijuana-only group show as much or more impulsivity as do the people who use MDMA plus other drugs. Both of these groups tended to be more impulsive than controls, although the differences were not consistent. In contrast to these group mean results, correlational analyses indicated a consistent positive correlation between lifetime use of MDMA (tablets) and impairment on the various tasks, whereas level of marijuana use was unrelated to impairment on any task. These results suggest that, in chronic MDMA users, prior use of marijuana may contribute to some observed deficits in impulse control, but also that heavier MDMA use is associated with poorer impulse control. Because levels of MDMA and marijuana use were not inter-correlated, these substances may exert separate adverse effects on impulse control. However, marijuana is retained in the body long after ingestion, so the results may be affected by residual or hangover effects of recent use (i.e., one week pre-testing). We plan to assess prior users of MDMA and marijuana-only users with at least six months abstinence to clarify the lasting effects of these drugs on impulse control. This project is funded by the CAMH Grants in Psychiatry program. |
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Last updated: Aug 24, 2004 3:22 PM Published: Dec 09, 2009 8:19 PM ID#P5699 |