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The Neurobiology of Opioid Addiction:
Opioid-Related Learning & Memory
Opioid class drugs underlie the most dangerous and intractable forms of addiction. Globally, the opioid addiction crisis continues unabated and there is a desperate need for pre-clinical research to unravel the neuronal, behavioural and molecular substrates underlying the addictive properties of opioids. Our research program focuses on identifying the neurobiological mechanisms underlying the power of opioids to produce powerful associative memories linked to the drug-taking experience. With a special focus on the amygdala-prefrontal cortical circuitry, we are characterizing how chronic exposure to opioids induces 'molecular switching mechanisms' within these brain circuits, leading to compulsive opioid seeking, withdrawal memory formation and relapse. Our research suggests that rather than representing a permanent brain adaptation, the process of opioid addiction involves discrete, plastic processes within memory-related brain circuits that can be prevented or reversed with targeting of these molecular adaptations.
Neurodevelopmental Effects of Cannabinoids: Implications for Mental Health
Marijuana is the most widely consumed drug on the planet and a high percentage of adolescents are regular users of cannabis. In addition, increasing numbers of pregnant women are turning to cannabis for the alleviation of morning sickness and pregnancy-related anxiety. Given the extreme vulnerability of the adolescent and pre-natal brains to drug exposure, there is an urgent need to identify and characterize the effects of neurodevelopmental cannabis exposure on the development of brain circuitry associated with mental health. We are currently exploring these phenomena using pre-clincal, translational rodent models of THC exposure, to determine how exposure to THC, the primary psychoactive compound in cannabis, may alter neuronal, behavioural and molecular pathways linked to increased vulnerability to disorders like schizophrenia, anxiety, depression and addiction. These studies use a combination of in vivo exposure, as well as cerebral brain organoids in order to model prenatal brain development during the earliest phases of brain development.
UCLA Broad Stem Cell Research Center/Cell Reports
Development and Characterization of Phytocannabinoids as Treatments for Neuropsychiatric Disorders
Cannabis contains over 100 distinct phytochemicals. While the primary psychoactive component in cannabis, THC, has been associated with psychiatric symptoms in some individuals, the largest non-psychoactive compound in cannabis, cannabidiol (CBD), has been demonstrated in both clinical and pre-clinical studies to possess significant clinical potential in the treatment of various mental health disorders, including schizophrenia, anxiety, depression and PTSD. Research in our laboratory has identified the specific neuronal and molecular mechanisms by which CBD produces anti-psychotic effects in translational models of schizophrenia and PTSD. In addition, we are currently examining the mechanisms by which CBD may alleviate symptoms of anxiety, PTSD and depression, using a combination of pre-clinical modelling, molecular and neuronal assays. In addition, we are currently exploring the potential therapeutic potential of several lesser known phytocannabinoids, including cannabichromene and cannabigerol, as well as several monoterpene compounds.
Characterizing the Addictive and Neurodevelopmental Effects of Nicotine
Despite significant reductions in nicotine addiction prevalence, smoking remains the number one cause of preventable mortality worldwide. Currently, we are seeing a resurgence in nicotine addiction with the increasing popularity of new nicotine delivery systems like e-cigarettes, vaping and juuling. Notably, we are seeing dramatic increases in smoking behaviours among adolescents, a period of neurodevelopment wherein 95% of smokers first become dependent on tobacco.
Our research into nicotine addiction focuses on understanding the role of dopamine transmission during different phases of the nicotine addiction process. For example, we have found that during early nicotine exposure, blocking dopamine transmission actually increases the addictive liability of nicotine by dramatically increasing its rewarding properties. In contrast, once nicotine dependence has developed, we have reported that the addictive effects of nicotine switch to a dopamine-dependent signaling pathway, similar to the opioid addiction process. We are currently exploring the precise neuropharmacological mechanisms by which mesolimbic dopamine transmission can differentially control the nicotine addiction process during distinct phases of nicotine exposure.
More recently, we have begun looking at how adolescent neurodevelopmental exposure to nicotine may lead to long-term vulnerability to mood disorders such as anxiety and depression. We recently reported that adolescent nicotine exposure can cause long-term symptoms of anxiety and depression that persist into adulthood, via functional modulation of the prefrontal cortex and sub-cortical dopamine system. Using pre-clinical translational rodent models, we are currently mapping out the precise neuronal and molecular signaling pathways underlying these effects.
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