2017 — 2021 |
Mackie, Kenneth P. [⬀] Manzoni, Olivier Jj (co-PI) |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex-Specific Critical Periods Determine the Effects of Cannabinoids On the Mesocorticolimbic System @ Indiana University Bloomington
Cannabis is the most frequently used illicit drug. Its widespread use in adolescents is associated with an increased risk for mental illness and is a major public health concern. For example, an increased rate of psychosis and an earlier onset of psychotic illness have been observed with heavy adolescent cannabis use. There is also a correlation between early cannabis use, the age at onset of psychotic disorders and the age at first hospitalization for 'pure' cannabis users. However, the pathophysiological mechanisms underlying the adverse effects of early cannabis use, such as perturbed social interactions, psychosis and addiction risk remain to be elucidated. A better understanding of these mechanisms is necessary to develop therapies & effective prevention programs, and to inform decisions on public policy, including cannabis legalization. Adolescence is a period of profound neurodevelopmental maturation, notably in the mesocortico-limbic system (MCS), an ensemble of interconnected structures involved in higher cognitive functions, emotions, reward and social behaviors. MCS development occurs at different rates in males and females. During adolescence, social play, an MCS-based behavior, guides the emergence and proper maturation of social interactions. Disruption of social play in the adolescent negatively affects adult behaviors. Impaired adolescent social play may also be a sign of emerging psychopathology. The main psychoactive ingredient of cannabis (i.e., THC) engages the abundant CB1 cannabinoid receptor (CB1R), competing with endogenous cannabinoids. CB1Rs are a core component of the endogenous cannabinoid system (ECS). The ECS is abundant throughout the MCS and modulates many neurodevelopmental, neuronal and synaptic processes, including adolescent social play. Recent discoveries from our laboratories fueled the concept that ECS dysfunction plays a key role in diverse neuropsychiatric diseases of environmental or genetic origin. Motivated by new, unpublished data, and using a rodent model, we propose a multi-disciplinary approach to establish the sex-specific development and distribution of ECS components in the MCS and how these affect the molecular, synaptic and behavioral consequences of adolescent cannabis (THC) exposure. Our 3 aims will: 1/ Characterize and compare the normal functional development of neuronal and synaptic responses in the MCS between male and female rats from pre-adolescence to adulthood. 2/ Establish the developmental patterns of expression and localization of key components of the ECS in the rat MCS in a sex and age-specific fashion. 3/ Determine the sex-specific functional (molecular, synaptic, and behavioral) consequences of THC exposure during critical periods of adolescence and adulthood. Together, the results of these studies will define new structural, molecular and functional synaptic substrates of the sex-specific effects of adolescent cannabis use on ECS function and behavior.
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0.895 |
2018 — 2021 |
Mackie, Kenneth P. [⬀] Manzoni, Olivier Jj (co-PI) |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Perinatal Cannabinoids Delay Kcc2 Expression and Lead to Neurodevelopmental Abnormalities @ Indiana University Bloomington
Cannabis is the most frequently used illicit drug. Maternal perinatal cannabis use has been associated with a range of adverse neurodevelopmental consequences in the offspring. The underlying mechanism(s) remain incompletely understood, but are consistent with impaired cortical neuronal circuit formation. A coordinated program of transcriptional and physiological events governs the assembly of cortical circuits. The evolutionary conserved switch of gamma amino butyric acid (GABA) from an excitatory to an inhibitory neurotransmitter is crucial to the normal development of cortical circuits and associated behaviors. The switch is primarily driven by increased expression of a potassium/chloride co-transporter, KCC2, which extrudes chloride from the cell. In our preliminary experiments, we have found that administration of a synthetic cannabinoid or THC for the first 10 days after birth to lactating rat and mice dams suppresses KCC2 expression in the PFC at postnatal days 10-15, prolonging the time during which GABA excites PFC networks. Perinatal exposure also impaired prefrontal cortex synaptic plasticity and cognitive or social behaviors in the adult progeny of both sexes. The proposed work will follow up these exciting preliminary data to determine the immediate and long-lasting effects of the cannabinoid-induced delay in KCC2 expression by addressing three specific aims. Aim 1. Identify the early molecular, functional and behavioral consequences of exposing dams to THC ± CBD during lactation on the progeny of both sexes. These experiments will characterize the early consequences on neuronal circuits in the PFC, determine THC's mechanism (and possible antagonism by cannabidiol (CBD)) to delay KCC2 expression, examine the localization and levels of components of the PFC endocannabinoid system and measure ecologically-relevant pup behaviors (ultrasonic vocalizations and homing following maternal separation) after maternal exposure to cannabinoids. Aim 2. Determine the long-term consequences of THC ± CBD exposure during lactation. These experiments will determine if THC ± CBD exposure during lactation has enduring effects on synaptic plasticity in adolescent and adult, on levels or localization of PFC endocannabinoid components, on naturalistic social behaviors, and cognitive function. Aim 3. Strategies to ameliorate the long-term deleterious consequences of THC exposure during lactation. These experiments will test the hypothesis that enhancing endocannabinoid signaling (CB1 positive allosteric modulators or inhibitors of eCB degradation) will rescue the behavioral and physiological deficits that are a consequence of PCE. Completion of these experiments will reveal the underpinnings of the impact of perinatal THC exposure on neuronal functions and behavior and provide new therapeutic strategies to ameliorate associated behavioral deficits.
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0.895 |