1. Alterations in rat striatal dopamine transporters produced by long-access cocaine self-administration. Our laboratory has been documenting the consequences of chronic, high-dose, long-access cocaine self-administration under a variety of schedules of reinforcement for over 15 years. We have focused on two major adaptation categories - hypodopaminergia and cocaine tolerance. Hypodopaminergia describes the reduced function of dopamine terminals in striatal regions, and cocaine tolerance refers to a marked reduction in cocaine's ability to inhibit dopamine uptake, which leads to escalating cocaine intake over time. We have used these metrics to focus on identifying populations that may show increased vulnerability to develop cocaine use disorder, and to test novel therapeutics that could counteract tolerance and hypodopaminergia as a putative treatment for cocaine use disorder. Within this project we have a number of sub-projects:
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Sex differences underlying individual vulnerability to cocaine use disorder. This project focuses on understanding how biological sex can influence behavioral and neurobiological vulnerability to cocaine use disorder, using both intravenous drug self-administration and fast scan cyclic voltammetry in rats. We find that females overall transition from initial cocaine exposure to regular usage more quickly, as well as showing increased motivation to take cocaine, when compared to males, and that this effect is particularly pronounced in female rats during the estrus stage of the estrous cycle. We also find that cocaine-naïve female rats show altered dopamine terminal function during the estrus stage that may drive vulnerability to future cocaine taking.
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Testing novel therapeutic targets that may mitigate cocaine use disorder. Our lab has focused on utilizing dopamine releasing drugs (such as phenmetrazine, a compound that acts similarly to amphetamine in dopamine neurons) to alleviate behavioral and neurobiological alterations driven by chronic cocaine exposure. Recently, we have turned to applying a combinatorial drug treatment strategy of phenmetrazine in combination with kappa opioid receptor antagonists in order to reduce required dose, side effects, and potential abuse liability of either drug alone. We have found that the kappa opioid receptor antagonist nBNI, in combination with phenmetrazine (PM), is able to reduce motivation for cocaine following chronic cocaine exposure to a greater degree than either drug alone.
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Identifying new molecular targets that may be involved in cocaine use disorder. Recently, our lab discovered that an under-studied protein involved in presynaptic cytoarchitecture of dopamine neurons, synaptogyrin-3 (SYG3) seems to be protective against cocaine-related behaviors. SYG3 levels were inversely correlated to motivation to take cocaine, and early investigation of SYG3 overexpression in dopamine neurons revealed decreased anxiety-like behavior, which has been postulated to predict future cocaine taking. Our future studies will examine naïve and cocaine-mediated changes in the dopamine system in animals with SYG3 overexpression and knockdown.
2. Chronic alcohol and stress exposure produces hypodopaminergia in the mesolimbic reward system of mice, rats and monkeys. We have documented that chronic alcohol and withdrawal or repeated stress alone cause a blunting of dopamine signaling, at least in part mediated by increased activity of kappa opioid receptors, in rodents. We have had the unique opportunity to measure dopamine in striatal slices from chronic alcohol drinking monkeys, which show remarkably similar adaptations in dopamine and kappa opioid receptor functioning following chronic alcohol exposure. This work is in a collaboration with the Integrative Neuroscience Initiative on Alcoholism (INIA) Stress consortium. Within this project we have a number of sub-projects:
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Identifying rapidly developing and long-lasting changes to the kappa opioid receptor system and anxiety-like behaviors following alcohol exposure. The goal of this project is to assess how alcohol rapidly induces alterations to kappa opioid receptor activity and signaling in the nucleus accumbens, and how alterations to this stress-related neuromodulator may drive increased vulnerability to relapse during protracted abstinence following chronic alcohol exposure. We find increased anxiety-like behavior long into abstinence, and that animals with a history of chronic alcohol exposure show altered dopamine response to kappa opioid agonists following stress or acute alcohol. This project is now turning to examine how downstream signaling by the kappa opioid receptor may be influenced by acute and chronic alcohol and stress in rodents and nonhuman primates.
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Determining stress paradigms that drive exacerbated phenotypes when combined with chronic alcohol, as well as novel behavioral output measures of anxiety- and depression-like behavior. The goal of this project is to determine whether early life stress (adolescent social isolation) and chronic intermittent alcohol interact to increase vulnerability to alterations in dopamine dynamics in male and female rats. Specifically, we are determining whether early life stress and withdrawal from 10 days of intermittent exposure to vaporized alcohol lead to pronounced changes in dopamine dynamics, kappa opioid receptor activity (responses to increasing concentrations of KOR agonist U50,488), and dopamine responses to phasic-like stimulation.
3. Some populations are at increased risk of developing substance use disorders when exposed to opioids, but there may be new pain treatment strategies that carry reduced abuse liability. As the world struggles with a worsening opioid epidemic, our lab has recently focused on how opioids alter behavior and the mesolimbic dopamine system, what populations may show increased vulnerability to opioid use disorder, and examining possible pain treatments that are as effective for pain management as those targeting the mu opioid receptor but without abuse and addiction liability. Within this project we have a number of side-projects:
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The interactions of the dopamine system on heroin vulnerability and withdrawal. We have recently expanded our lab's findings to evaluate how dopamine mediates heroin's rewarding and reinforcing properties and investigate how hypodopaminergic state during withdrawal drives increased vulnerability to heroin seeking. In addition, we are interested in parsing apart how early-life stress manifests long-lasting neural alterations that lead to increased heroin vulnerability in adulthood, and how females may have increased vulnerability to developing opioid use disorder.
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Identifying novel opioid pain treatments without abuse liability. This project examines biased kappa opioid receptor agonists for pain treatment. Biased kappa agonists have been developed to selectively activate either the G-protein or the beta-arrestin pathway; the former is linked to the antinociception effects while the latter is associated with the dysphoric effects. Here we test the ability of G-protein biased kappa opioid receptor agonists (such as Triazole 1.1) to mitigate pain without inducing dysphoria and negative affect with a combination of behavioral tests, microdialysis, and slice voltammetry.
4. Adolescent nicotine exposure alters adult alcohol consumption and dopamine dynamics in the nucleus accumbens. This project, funded by the Wake Forest Baptist Health Tobacco Control Center of Excellence (TCCOE) examines how adult alcohol consumption, dopamine kinetics, and kappa opioid receptor activity is altered by voluntary adolescent nicotine exposure. Our preliminary findings indicate that, while exposure to low levels of nicotine in adolescence does not change adult alcohol consumption, adolescent nicotine exposure does drive long-lasting changes in the dopamine system when combined with low levels of adult alcohol consumption. This indicates that the combination of these two substances of abuse may drive increased vulnerability to substance use disorder or aberrant dopamine system function.
Side Interests / Projects from Jones Lab Past (which we still think are really cool!)
The acute and chronic effects of amphetamine have been explored in our laboratory over 15 years. There is an ongoing controversy about whether a low-dose, long-lasting amphetamine formulation would make a viable therapeutic agent for the treatment of cocaine addiction. Our studies support this notion, and we have been exploring several different aspects of amphetamine action, from its acute effects on release vs uptake to its long term effects on cocaine self-administration.
Intermittent cocaine self-administration produces sensitization of dopamine and behavior. In contrast to the tolerance and low function of the dopamine system after long access paradigms (6+ hours), allowing only brief access for a few minutes at time increases motivation to seek cocaine and dopamine responses to cocaine. These manuscripts have challenged the dogma that long, continuous exposure to cocaine is required to create relevant translational models of drug addiction.
High fat diet-induced obesity is associated with dramatic changes in dopamine signaling that in some ways resemble drug and alcohol addiction. We have begun exploring the effects of chronic continuous access or limited binge-like access to a high fat diet in mice. We have found that neurochemical and behavioral effects of these paradigms modify responses to abused drugs such as amphetamine and produce a withdrawal syndrome similar to that produced by chronic ethanol exposure.
Methylphenidate self-administration produces opposite neurochemical, dopamine terminal and behavioral effects from cocaine. Methlyphenidate, or Ritalin, is a dopamine transporter blocker, in the same drug class as cocaine, but it has very different effects on the dopamine transporter and dopamine terminals in the striatum. We have published a series of well-cited manuscripts on methlyphenidate interactions with the dopamine system and continue to explore this topic.