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 Centre for Addictionand Mental Health |
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Research
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Neuroimaging: Research Annual Report 2003Section Head: Dr. José N. Nobrega Research in the Neuroimaging section is aimed at mapping changes in specific brain areas, neuroanatomical pathways and chemical mechanisms in neuropsychiatric disorders, primarily through the use of appropriate animal models. In 2002, we focused on three broad areas. Models of Depression and Stress Reactions Learned Helplessness Model of Depression We continue to test genes identified by cDNA microarray analyses in brains of animals showing propensity to develop depressive-type symptoms in response to stress, using the learned helplessness model of depression. This behavioural model also allows us to identify subjects that are resistant to stress-induced reactions. Our current data indicate that different sets of genes may be associated with propensity versus resistance to stress-induced behavioural deficits. While a number of candidate genes have proved to be false positives in this model, our PhD student, Beatrice Setnik, using in situ hybridization, has identified the first clear changes in gene expression in the frontal cortex of susceptible animals. Because human females are more prone to depressive episodes than males, we have extended the behavioural model to include gender comparisons. Our initial behavioural evaluations of female animals at different points in the estrous cycle did not reveal significant differences. We have, however, uncovered a significant overall difference between males and females in effects of stress on plasma levels of homocysteine (Hcy), an amino acid that has been associated with symptoms of depression, stress effects and cardiovascular risk. We found that, while males have higher basal Hcy levels than females, females appear to be more vulnerable than males to stress-induced elevations in Hcy. Chronic Mild Stress Model of Depression Using the chronic mild stress model of depression, we began to examine possible changes in the GABA-benzodiazepine receptor complex, seeking to isolate anxiety-related components of this model. This work is being conducted in collaboration with Dr. Nylson Silveira-Filho's group at the Federal University of São Paulo, Brazil. An extensive autoradiographic mapping analysis, using [3H]Ro-154513 to label diazepam-insensitive benzodiazepines binding sites, suggested that behavioural changes in this model are not likely to be mediated by alterations in this binding site. Sleep Deprivation and Depression We continue to study sleep deprivation, seeking to identify mechanisms involved in its beneficial (antidepressant) effects as well as in its potentially harmful effects. In collaboration with Dr. Sergio Tufik's group at the Federal University of São Paulo, we found that sleep deprivation was followed by localized changes in the expression of b1 thyroid hormone receptors in brain, suggesting a potential involvement of these receptors in antidepressant effects. We also conducted the first detailed examination of the serotonin transporter in the brain after sleep deprivation, using [ 11C] DASB. In this collaboration with Dr. Alan Wilson from the PET Centre at CAMH, we developed and validated experimental protocols for the use of short-lived PET tracers in in vitro autoradiographic analyses. This overall approach is now being extended to other areas, such as the preclinical imaging of potential PET probes for markers of pathology in Alzheimer's disease. This extension is part of a larger effort led by Dr. Paul Verhoeff of the Baycrest Geriatric Centre. In 2002, we published evidence that sleep deprivation, unlike stressful procedures in general, has unexpected beneficial effects on blood levels of homocysteine. High blood levels of homocysteine (Hcy) are a risk factor for cardiovascular disease. Stress increases Hcy levels, but sleep deprivation decreases Hcy levels in blood. On the other hand, we confirmed that sleep deprivation negatively affects the acquisition of a simple avoidance learning task, an effect that was blocked by muscarinic agonists. A detailed autoradiographic analysis indicated that this behavioural effect was not mediated by changes in the muscarinic M1 receptor binding in the brain. We also completed an extensive examination of two receptors for orexin (hypocretin), a neuropeptide that has been identified a key element in narcolepsy. In situ hybridization analyses revealed that both orexin1 and orexin2 receptors are significantly altered after sleep deprivation. Changes in the expression of the two receptor subtypes were different in kind from each other and were noticed in different parts of the brain. These receptor expression changes were not seen immediately after deprivation, but were seen after the animals were allowed to recover lost sleep for one day. Brain Dopamine and Movement Disorders We continue to collaborate with investigators from Germany to build a comprehensive map of brain alterations in the dtsz mutant hamster model of paroxysmal dystonia. This year we have identified significant changes in the hamsters' expression of the mRNA encoding two important neuropeptides in the basal ganglia circuits controlling movement, namely enkephalin and dynorphin. Our study continues of the VCM model of tardive dyskinetic syndromes induced by long-term antipsychotic treatment. Work published
by Peter Turrone, a PhD candidate, in collabora-tion with Drs. Gary Remington and Shitij Kapur from the Schizophrenia Section,
shows that, after long-term haloperidol treatment, variables such as dose and of continual drug avail-ability affect the likelihood
that dyskinetic symptoms will emerge. Long-term treatment by single daily injections produces fewer motor side-effects than
are seen when the same daily doses are given by continuous release (e.g., via osmotic minipumps). Brain Mechanisms of Compulsive Drug-Taking Behavioural Sensitization to Alcohol We continue to study the brain mechanisms underlying differential susceptibility to behavioural sensitization to alcohol. This year, we found that alcohol-sensitized mice have higher [3H] flunitrazepam binding levels in the ventral tegmental area -- an important region of the mesocorticolimbic pathway -- than do non-sensitized animals. These binding differences may have functional correlates, because our sensitized mice also showed an enhanced locomotor response to a benzodiazepine challenge. In a separate study, we examined the relationship between ethanol sensitization and learning variables. The results show that the development of ethanol sensitization seems to be positively associated to contextual learning. This confirms that the expression of sensitization depends heavily on contextual cues. GABA Receptor Changes and Alcohol In collaboration with Drs. Denise Tomkins (Biobehavioural Pharmacology) and Rachel Tyndale (Pharmacogenetics), we began analyses of GABA receptor changes in brains of two types of rats: one that shows innate high preference for alcohol and one that shows innate low preference for alcohol. |
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Last updated: Aug 24, 2004 3:23 PM Published: Jul 01, 2011 5:56 AM ID#P5710 |