Date of Presentation
5-6-2021 12:00 AM
College
School of Osteopathic Medicine
Poster Abstract
In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of OUD. More specifically, D3R antagonists have been shown by us and others to attenuate the abuse-related behavioral effects of opioids without producing adverse side effects associated with nonselective D2-like receptor antagonists.
We previously examined the effects of the selective D3R antagonist PG01037 (133-fold selectivity for D3R vs. D2R) using drug-induced hyperactivity as a behavioral proxy for DA release within the nucleus accumbens. Interestingly, we found that PG01037 enhances cocaine-induced hyperlocomotion while it attenuates morphine-induced hyperlocomotion in mice. The potentiation of psychostimulant effects could confound the potential use of D3R antagonists for the treatment of OUD, since many opioid users co-abuse stimulants such as cocaine. However, recent studies with more selective D3R antagonists found that they do not enhance certain effects of cocaine while still reducing opioid effects. It is currently unknown what impact these highly-selective D3R antagonists will have on cocaine-induced hyperactivity and/or dopamine neurotransmission.
The purpose of this study was to examine the impact of pretreatment with the novel and highly selective D3R antagonist VK4-40 (250-fold selectivity for D3R vs. D2R) on cocaine- and morphine-induced hyperlocomotion in mice.
Keywords
Cocaine, morphine, mice, Opioid-Related Disorders, Dopamine Antagonists
Disciplines
Cell Biology | Disease Modeling | Medical Cell Biology | Medicine and Health Sciences | Molecular and Cellular Neuroscience | Neurosciences | Substance Abuse and Addiction
Document Type
Poster
Included in
Cell Biology Commons, Disease Modeling Commons, Medical Cell Biology Commons, Molecular and Cellular Neuroscience Commons, Neurosciences Commons, Substance Abuse and Addiction Commons
The Dopamine D3 Receptor Antagonist VK4-40 Attenuates Morphine-Induced Hyperactivity But Not Cocaine-Induced Hyperactivity in Mice
In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of OUD. More specifically, D3R antagonists have been shown by us and others to attenuate the abuse-related behavioral effects of opioids without producing adverse side effects associated with nonselective D2-like receptor antagonists.
We previously examined the effects of the selective D3R antagonist PG01037 (133-fold selectivity for D3R vs. D2R) using drug-induced hyperactivity as a behavioral proxy for DA release within the nucleus accumbens. Interestingly, we found that PG01037 enhances cocaine-induced hyperlocomotion while it attenuates morphine-induced hyperlocomotion in mice. The potentiation of psychostimulant effects could confound the potential use of D3R antagonists for the treatment of OUD, since many opioid users co-abuse stimulants such as cocaine. However, recent studies with more selective D3R antagonists found that they do not enhance certain effects of cocaine while still reducing opioid effects. It is currently unknown what impact these highly-selective D3R antagonists will have on cocaine-induced hyperactivity and/or dopamine neurotransmission.
The purpose of this study was to examine the impact of pretreatment with the novel and highly selective D3R antagonist VK4-40 (250-fold selectivity for D3R vs. D2R) on cocaine- and morphine-induced hyperlocomotion in mice.