Date of Presentation
5-5-2022 12:00 AM
College
School of Osteopathic Medicine
Poster Abstract
Opioids exert their abuse-related effects by enhancing dopamine (DA) neurotransmission within the brain’s mesolimbic reward system, a neural projection involving DA neurons in the ventral tegmental area (VTA) that project to medium spiny neurons within the nucleus accumbens (NAc). Mu (MOR) are expressed by several populations of GABAergic neurons that tonically inhibit VTA DA neurons. By inhibiting these GABAergic neurons in a MOR-dependent manner, opioids indirectly enhance DA neurotransmission via disinhibition of DAergic neurons. Accumulating evidence indicates that selective pharmacological antagonism of the dopamine D3 receptor (D3R) attenuates the abuse-related effects of several opioids, but the neurobiological mechanisms mediating this phenomenon remains unclear. This project sought to determine whether the NAc may represent one site of action within the mesolimbic DA system where D3R antagonists exert their anti-opioid behavioral effects. To address this question, we assessed whether intra-NAc microinfusion of a highly-selective D3R antagonist, VK4-40, alters morphine-induced hyperactivity in mice, a behavioral marker of increased DA neurotransmission within the mesolimbic VTA-NAc projection. Adult male and female C57Bl/6 mice (n=8) were surgically implanted with bilateral guide cannulae targeting the NAc. Mice were then tested weekly for the impact of VK4-40 administration (0, 100, 1000 ng/side) on hyperactivity induced by morphine (18 mg/kg, i.p.). Our preliminary data suggests that intra-NAc administration of VK4-40 attenuated morphine-induced hyperactivity at the highest concentration tested (1000 ng/side). These early results suggest that the NAc may be one brain region in which D3R antagonists act to reduce the abuse-related effects of opioids. Next phases of this ongoing research project include 1) determining whether intra-NAc VK4-40 administration perturbs basal locomotor activity, 2) studying the effects of VK4-40 infusion in other nodes of the mesolimbic DA system, and 3) examining whether VK4-40 disrupts opioid-induced increases in the activity of VTA DA neurons and/or opioid-induced increases in NAc DA levels. Collectively, these studies are poised to reveal the neurobiological mechanisms by which selective D3R antagonism disrupts the abuse-related effects of opioids.
Keywords
Dopamine Antagonists, Opioid-Related Disorders, Opioid Receptors, Dopamine D3 Receptors, Nucleus Accumbens, Neurochemistry
Disciplines
Disease Modeling | Medical Neurobiology | Medicine and Health Sciences | Molecular and Cellular Neuroscience | Molecular Biology | Neuroscience and Neurobiology | Substance Abuse and Addiction
Document Type
Poster
Included in
Disease Modeling Commons, Medical Neurobiology Commons, Molecular and Cellular Neuroscience Commons, Molecular Biology Commons, Substance Abuse and Addiction Commons
Morphine-Induced Hyperactivity is Attenuated by Intra-Accumbens Administration of the Highly-Selective Dopamine D3 Receptor Antagonist VK4-40
Opioids exert their abuse-related effects by enhancing dopamine (DA) neurotransmission within the brain’s mesolimbic reward system, a neural projection involving DA neurons in the ventral tegmental area (VTA) that project to medium spiny neurons within the nucleus accumbens (NAc). Mu (MOR) are expressed by several populations of GABAergic neurons that tonically inhibit VTA DA neurons. By inhibiting these GABAergic neurons in a MOR-dependent manner, opioids indirectly enhance DA neurotransmission via disinhibition of DAergic neurons. Accumulating evidence indicates that selective pharmacological antagonism of the dopamine D3 receptor (D3R) attenuates the abuse-related effects of several opioids, but the neurobiological mechanisms mediating this phenomenon remains unclear. This project sought to determine whether the NAc may represent one site of action within the mesolimbic DA system where D3R antagonists exert their anti-opioid behavioral effects. To address this question, we assessed whether intra-NAc microinfusion of a highly-selective D3R antagonist, VK4-40, alters morphine-induced hyperactivity in mice, a behavioral marker of increased DA neurotransmission within the mesolimbic VTA-NAc projection. Adult male and female C57Bl/6 mice (n=8) were surgically implanted with bilateral guide cannulae targeting the NAc. Mice were then tested weekly for the impact of VK4-40 administration (0, 100, 1000 ng/side) on hyperactivity induced by morphine (18 mg/kg, i.p.). Our preliminary data suggests that intra-NAc administration of VK4-40 attenuated morphine-induced hyperactivity at the highest concentration tested (1000 ng/side). These early results suggest that the NAc may be one brain region in which D3R antagonists act to reduce the abuse-related effects of opioids. Next phases of this ongoing research project include 1) determining whether intra-NAc VK4-40 administration perturbs basal locomotor activity, 2) studying the effects of VK4-40 infusion in other nodes of the mesolimbic DA system, and 3) examining whether VK4-40 disrupts opioid-induced increases in the activity of VTA DA neurons and/or opioid-induced increases in NAc DA levels. Collectively, these studies are poised to reveal the neurobiological mechanisms by which selective D3R antagonism disrupts the abuse-related effects of opioids.