Department of Psychology

Department of

Psychology

Department of

Psychology

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Mary C. Olmstead, PhD
Professor
Department of Psychology
Centre for Neuroscience Studies
Queen's University, Kingston, ON K7L 3N6
T: 613-533-6208  F: 613-533-2499 
E: olmstead@queensu.ca

Research

International Innovations

Influenced by Impulse in International Innovation (PDF, 182 KB)

Opium poppies

Drug addiction is characterized by two behavioural traits: compulsion to take the drug (drug-seeking) and loss of control in limiting drug intake (impulsivity). Based on decades of research, we have a detailed understanding of the environmental and physiological factors that influence compulsive drug use. We know far less about the impulsive aspects of drug addiction although our research (and that of many colleagues around the world) is helping to uncover the mechanisms that underlie this maladaptive behaviour. The details of how we are approaching this question are outlined under the individual projects listed below.

Sucrose Bingeing as a Model of Addiction

The dramatic rise in obesity and eating disorders highlights a need to uncover the etiology of dysfunctional eating. Binge eating contributes substantially to these problems but there are few effective treatments for this condition, partly because behavioural and neural consequences of binge eating are unknown. Humans and animals binge selectively on highly palatable food suggesting that the behaviour is driven by hedonic, rather than metabolic, properties. As part of this work, therefore, Amanda Maracle investigated alterations in brain reward systems following sucrose bingeing in rats. We have also studied male/female differences in sucrose bingeing as a means to understanding the large discrepancy in the rate of eating disorders across the sexes. Finally, in collaboration with Dr. Katia Befort in the Laboratoire de Neurosciences Cognitive et Adaptatives at the Université de Strasbourg, we are investigating the epigenetic changes in the endocannabinoid system following sucrose bingeing. This will allow us to identify commonalities in neuroplasticity mechanisms that underlie maladaptive responding for abused drugs and palatable food.

Learning to Inhibit a Response

Effective interaction with the world around us depends on the ability to modify behaviour in response to environmental cues. These cues provide information on appropriate cues, not only which responses are correct but when they should be initiated. Standing at the intersection in any major city makes this point obvious: failing to wait for the green light can have disastrous consequences. My research group has focused on understanding these impulsive actions which we describe as ‘right move, wrong time’. To facilitate this work, Scott Hayton designed the Response Inhibition (RI) task in which rats withhold lever pressing for sucrose until a signal is presented. Responses prior to the signal are a measure of impulsive action. Advantages of the RI task include the fact that it is acquired rapidly, it provides measures of individual differences across rats, and both increases and decreases in performance can be observed following experimental manipulations. The RI task allowed Scott Hayton and Matt Lovett-Barron to test the novel hypothesis that impulse control requires new learning. We confirmed this idea in a collaboration with Eric Dumont (Dept. of Molecular and Biomedical Sciences), by showing that impulsive action is encoded as enhanced glutamate transmission in projections from the prelimbic (PL) region of the medial prefrontal cortex (mPFC) to the ventral striatum (VS). A follow up study revealed increased membrane excitability in the same neurons, providing further support for a specific mechanism underlying the acquisition of impulse control. An unexpected and intriguing outcome of this study was that plasticity in the adjacent infralimbic (IL) cortex encodes learning about cues predicting reward availability. Thus, there may be a functional dissociation across IL and PL cortices in the control of impulsive action.

Publications:

Hayton, S.J., Olmstead, M.C., & Dumont, E.C. (2011). Shift in the intrinsic excitability of medial prefrontal cortex neurons following training in impulse control and cued responding tasks. Public Library of Science (PLoS) One, 6, e23885.

Hayton, S.J., Lovett-Barron, M., Dumont, E.C. & Olmstead, M.C. (2010). Target-specific encoding of response inhibition: Increased contribution of AMPA to NMDA receptors at excitatory synapses in the prefrontal cortex. Journal of Neuroscience, 30, 11493-11500.

Olmstead, M.C. (2006). Animal models of drug addiction: Where do we go from here? Quarterly Journal of Experimental Psychology, 59, 625-53.

Pharmacology of Impulsive Action

Impulsive action, defined as the inability to inhibit a response (in lay terms ‘acting without thinking’) is linked to a number of neurotransmitter systems.  These include dopamine, serotonin, glutamate, and cannabinoids among others.  In collaboration with Prof. Brigitte Kieffer’s team at the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) in Strasbourg France, we provided the first evidence for an opioid contribution to impulsive action. In this study, deletion of mu opioid receptors in mice decreased impulsive action whereas deletion of delta opioid receptors had the opposite effect. We extended these findings by showing that opioid drugs alter impulsive action in rats, but the data were not consistent with the genetic knockout studies. This led us reconsider the role of other neurotransmitters in impulsive action, leading to the idea that inhibition of a motor response is controlled by different cognitive processes, depending on the task demands. Scott Hayton, Amanda Maracle and Megan Mahoney helped to verify this conjecture by showing that amphetamine and morphine have distinct effects on impulsive action when rats can and cannot predict the delay to reward availability. To understand the role of timing in this dissociation, we examined the probability of responding across sessions, revealing unique patterns of time-dependent errors under different task conditions. We are now examining whether differences in the cognitive processes that inhibit responding help to explain individual differences in trait impulsivity.

Publications:

Mahoney, M.K., Barnes, J.H., Wiercigroch, D., & Olmstead, M.C. (2016). Pharmacological investigations of a yohimbine-impulsivity interaction in rats. Behavioural Pharmacology, 27, 585-595..

Mahoney, M.K., Silveira, M.M., & Olmstead, M.C. (2013). Increased impulsive action in rats: Effects of morphine in a short and long fixed-delay response inhibition task. Psychopharmacology, 230, 569-577.

Hayton, S.J., Maracle, A.C., & Olmstead, M.C. (2012).  Opposite effects of amphetamine on impulsive action with fixed and variable delays to respond.  Neuropsychopharmacology, 37, 651-659.

Befort, K., Mahoney, M.K., Chow, C., Hayton, S.J., Kieffer, B.L. & Olmstead, M.C. (2011). Effects of delta opioid receptor activation on a response inhibition task in rats. Psychopharmacology, 214, 967-976.

Olmstead, M.C., Ouagazzal, A. & Kieffer, B.L. (2009). Mu and delta opioid receptors oppositely regulate motor impulsivity in the signaled nose poke task. Public Library of Science (PLoS) One, 4, e4410.

Paine, T.A. & Olmstead, M.C. (2004). Cocaine disrupts both behavioural inhibition and conditional discrimination in rats. Psychopharmacology, 175, 443-450.

Binge Drinking

Our work with animal models of addiction and impulsivity is used to test hypotheses regarding the relationship between the two.  Iris Balodis directed a complementary line of research, translating this preclinical work to humans. We focused on university students, a population that exhibits high rates of drug use and risky behaviours (related to impulsivity).  To date, we have shown that self-reported levels of impulsivity correlate with both recreational drug use and hazardous drinking; the latter is also associated with enhanced conditioning to reward-paired cues. Recently we reported that hormonal responses to stress are blunted by an alcohol placebo, and that initial hormonal reactions to the lab predict later responses to alcohol.  On the other hand, contrary to lay assumptions, alcohol intoxication does not increase risky choices in a gambling task or alter reward-related learning.  In contrast, stress-responses (both subjective and biochemical) are markedly reduced by alcohol.  Moreover, initial hormonal reactions to a laboratory setting predict subsequent responses to alcohol, which may be a biomarker for stress-related responses. The work furthers our understanding of how intoxication leads to impulsive behaviours, such as drinking and driving or unprotected sex.  This research has many practical implications because it furthers our understanding of why intoxication leads to dysfunctional behaviours; this information may then be applied to social interventions designed to reduce the incidence of problems associated with alcohol intoxication. The ultimate goal of this work is to identify factors which predict individuals who will develop maladaptive drinking and drug use during their undergraduate years.

Publications:

Magrys, S.A., & Olmstead, M.C. (2015). Acute stress increases voluntary consumption of alcohol in undergraduates. Alcohol and Alcoholism, 50, 213-218.

Magrys, S.A., & Olmstead, M.C. (2014). Alcohol intoxication alters cognitive skills mediated by frontal and temporal brain regions. Brain and Cognition, 85, 271-276.

Mahoney, M.K., & Olmstead, M.C. (2013). Neurobiology of an endophenotype: Modelling the progression of alcohol addiction in rodents. Current Opinions in Neurobiology, 23, 607-614.

Magrys, S.A., Wynne-Edwards, K.E., Olmstead, M.C., & Balodis, I.S. (2013). Biochemical responses to alcohol intoxication in healthy males: relationship with impulsivity, drinking behaviour and subjective effects.  Psychophysiology, 50, 204-209.

Balodis, I.S., Wynne-Edwards, K.E. & Olmstead, M.C. (2011). The stress-response-dampening effect of placebo. Hormones & Behavior, 59, 465-472.

Balodis, I.M., Wynne-Edwards, K.E. & Olmstead, M.C. (2010). The other side of the curve: examining the relationship between pre-stressor physiological responses and stress reactivity. Psychoneuroendocrinology, 35, 1363-1373.

Balodis, I.M. Lockwood, K.L. Magrys, S.A. & Olmstead, M.C. (2010). Preference conditioning in healthy individuals correlates with hazardous drinking. Alcoholism: Clinical and Experimental Research, 34, 1006-1012.

Balodis, I.M., Potenza, M.N. & Olmstead, M.C. (2010). Recreational drug use and impulsivity in a population of Canadian undergraduate drinkers. Frontiers in Psychiatry, 1, 1-7.

Balodis, I.M., Potenza, M.N. & Olmstead, M.C. (2009). Binge drinking in undergraduates: Binge drinking in undergraduates: Relationships with gender, drinking behaviors, impulsivity and the perceived effects of alcohol. Behavioural Pharmacology, 20, 518-526.

Balodis, I.M., Johnsrude, I.S. & Olmstead, M.C. (2007). Intact preference conditioning in acute intoxication despite deficient declarative knowledge and working memory. Alcoholism: Clinical and Experimental Research, 31, 1800-1810.

Balodis, I.M., MacDonald, T.K. & Olmstead, M.C. (2006). Instructional cues modify performance in the Iowa Gambling Task. Brain and Cognition, 60, 109-17.

Neural Pathways of Chronic Pain and Drug Reward

Chronic pain affects up to 1/3 of Canadian adults, rates that are similar to those in other developed countries.  Chronic pain is notoriously difficult to treat, partly because the effectiveness of most analgesics declines with use (tolerance).  In addition, chronic pain often leads to severe emotional disturbances including clinical states of anxiety and depression. This suggests that chronic pain produces alterations in emotional brain circuits, many of which are involved in the rewarding properties of abused drugs.  If this is true, analgesic drugs may engage different neural mechanisms in chronic pain and pain naïve states.  This could explain differences in the abuse liability of analgesics that are used recreationally and those that are used for pain relief.  We are studying this issue in collaboration with Dr. Cathy Cahill at University of California, Irvine by examining commonalities in the neural mechanisms that mediate analgesia and drug reward.

Publications:

Taylor, A.M.W., Castonguqy, A., Ghogha, A., Vayssiere, P., Pradhan, A.A., Xue, L., Wu, J, Levitt, P., Olmstead, M.C., De Koninck, Y., Evans, C.J., & Cahill, C. M. (2016). Neuroimmune regulation of GABergic neurons within the ventral tegmental area during withdrawal from chronic morphine. Neuropsychopharmacology, 41, 949-959.

Taylor, A., Castonguay, A., Taylor, A.J., Murphy, N.P., Ghogha, A., Cook, C., Xue, L, Olmstead, M.C., De Konick, Y., Evans, C.J., & Cahill, C.M. (2015). Microglial disrupt mesolimbic reward circuitry in chronic pain. Journal of Neuroscience, 35, 8442-8450.

Cahill, C.M., Xue, L., Holdridge, S., Grenier, P., Magnussen, C., Metcalfe, S., LeCourse, S., & Olmstead, M.C. (2013). Changes in morphine reward in a model of neuropathic pain. Behavioural Pharmacology, 24, 207-213.

Paradoxical Effects of Opioid Antagonists

Opiates are powerful analgesics, but their clinical use is hindered by side effects, tolerance, and concerns about dependence and addiction. A resolution to this problem may be provided by the paradoxical effects of ultra-low-dose opioid antagonists.  In standard doses, opioid antagonists, such as naloxone or naltrexone, block the effects of morphine and other opiates.  In contrast, ultra-low doses (log units lower than standard doses) block the development of tolerance and reverse established tolerance in animal models. These effects are not confined to analgesia: ultra low dose naltrexone also extends the duration of morphine's rewarding effect in the conditioned place preference paradigm.  The effect may be a general property of G-protein coupled receptors in that ultra-low doses of a noreadrenergic alpha 2 receptor antagonist inhibits morphine-induced tolerance and enhances morphine-induced analgesia.  One hypothesis we are investigating is whether these effects are mediated through inhibition of microglial activation.  Taken together, these studies have important implications for long-term pain management. Indeed, these paradoxical effects could help those with chronic pain who require prolonged opiate therapy..

Publications:

Tuerke, K.J., Paquette, J.J., Beninger, R.J. & Olmstead, M.C. (2011). Dissociable effects of ultra-low dose naltrexone on tolerance to the antinociceptive and cataleptic effects of morphine. Behavioural Pharmacology, 22, 558-563.

Burns, L.H., Leri, F. & Olmstead, M.C. (2006). Ultra-low-dose naltrexone reduces dependence and addictive properties of opioids. In: Dean, R., Bilsky, 

E., Negus, S. & Wickens J. (Eds.). Opioid Receptors and Antagonists: From Bench to Clinic. Volume in Contemporary Neuroscience Series.

Olmstead, M.C. & Burns, L.H. (2005). Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats. Psychopharmacology, 181, 576-581.

Wang, H.-Y., Friedman, E., Olmstead, M.C. & Burns, L.H. (2005). Ultra-low-dose naloxone attenuates chronic morphine-induced changes in Mu opioid receptor – G protein coupling and G βγ signalling. Neuroscience, 135, 247-261.

Powell, K.J., Abul-Husn, N.S., Jhamandas, A., Olmstead, M.C., Beninger, R.J. & Jhamandas, K. (2002). Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance and reward. Journal of Pharmacology and Experimental Therapeutics, 300, 588-596.

Cannabinoid Mechanisms in Pain and Analgesia

Building on our work with ultra-low dose opioid antagonists, Jay Paquette examined ways to improve the analgesic effects of cannabinoid drugs, which are approved for pain treatment in Canada. These drugs act at the CB1 receptor and exert effects similar to opioid drugs. This drug interaction may be explained by the fact that µ opioid and CB1 receptors are co-localized on spinal and supra-spinal neurons and have similar neural signal-transduction mechanisms. 
The work of our colleagues Khem Jhamandas and Catherine Cahill, among others, has shown that opioids have biphasic effects: ultra-low doses (i.e., pM to nM range) of opioid agonists stimulate, rather than inhibit, cellular activity, and this effect can be blocked by ultra-low doses of an opioid antagonist. Ultra-low doses of opioid antagonists also enhance the analgesic effect of opioid agonists, extend the duration of opioid-induced analgesia, prevent the development of tolerance, and reverse established tolerance. Because of the interaction between cannabinoid and opioid systems, Jay Paquette investigated whether the interaction is also expressed at the ultra-low dose level. Using rats and the tail-flick test of antinociception, we showed that ultra-low doses of an opioid antagonist dose dependently enhance cannabinoid-induced antinociception. In a second set of experiments, ultra-low doses of a CB1 receptor antagonist paradoxically enhanced the duration of cannabinoid-induced antinociception. In collaboration with colleagues in New York, we uncovered a molecular mechanism of these ultra-low dose cannabinoid effects, which involves a shift from an inhibitory to a stimulatory G-protein coupled mechanism. These findings suggest that the paradoxical effects of opiate antagonists (see previous project description) may extend to other pharmacological systems.

Publications:

Paquette, J.J. Wang, H-Y., Bakshi, K. & Olmstead, M.C. (2007). Cannabinoid-induced tolerance is associated with a CB-1 receptor G-protein coupling switch that is prevented by ultra-low dose rimonabant. Behavioural Pharmacology, 18, 767-776.

Paquette, J.J. & Olmstead, M.C. (2005). Ultra-Low Dose Naltrexone Enhances Cannabinoid-Induced Antinociception. Behavioural Pharmacology, 16, 597-603.