Publications from the Medication Development Program.
2024 |
Xi, Zheng-Xiong; Bocarsly, Miriam E; Galaj, Ewa; Hempel, Briana; Teresi, Catherine; Shaw, Marlisa; Bi, Guo-Hua; Jordan, Chloe; Linz, Emily; Alton, Hannah; Tanda, Gianluigi; Freyberg, Zachary; Alvarez, Veronica A; Newman, Amy Hauck Presynaptic and Postsynaptic Mesolimbic Dopamine D Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice Journal Article In: Biol Psychiatry, vol. 96, no. 9, pp. 752–765, 2024, ISSN: 1873-2402. @article{pmid38838841b,BACKGROUND: Past research has illuminated pivotal roles of dopamine D receptors (DR) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear.nnMETHODS: We employed Cre-LoxP techniques to selectively delete DR from presynaptic dopamine neurons or postsynaptic dopamine D receptor (DR)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic DR in cocaine and opioid actions.nnRESULTS: Our results revealed DR expression in ∼25% of midbrain dopamine neurons and ∼70% of DR-expressing neurons in the nucleus accumbens. While dopamine D receptors (DR) were expressed in ∼80% dopamine neurons, we found no DR and DR colocalization among these cells. Selective deletion of DR from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of DR from DR-expressing neurons attenuated locomotor responses to D-like and D-like agonists. Strikingly, deletion of DR from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these DR deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, DR knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from DR-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia.nnCONCLUSIONS: We dissected presynaptic versus postsynaptic DR function in the mesolimbic dopamine system. DR and DR are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic DR are critically involved in the actions of opioids but not cocaine. |
Hersey, Melinda; Mereu, Maddalena; Jones, Claire S; Bartole, Mattingly K; Chen, Andy Y; Cao, Jianjing; Hiranita, Takato; Chun, Lauren E; Lopez, Jessica P; Katz, Jonathan L; Newman, Amy Hauck; Tanda, Gianluigi Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats Journal Article In: Eur J Neurosci, vol. 59, no. 10, pp. 2436–2449, 2024, ISSN: 1460-9568. @article{pmid38444104,Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine. |
Hersey, Melinda; Tanda, Gianluigi Modafinil, an atypical CNS stimulant? Journal Article In: Adv Pharmacol, vol. 99, pp. 287–326, 2024, ISSN: 1557-8925. @article{pmid38467484,Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an "atypical" CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders. |
2023 |
Hersey, Melinda; Chen, Andy Y; Bartole, Mattingly K; Anand, Jayati; Newman, Amy Hauck; Tanda, Gianluigi In: ACS Chem Neurosci, vol. 14, no. 15, pp. 2802–2810, 2023, ISSN: 1948-7193. @article{pmid37466616,Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many psychostimulants, like cocaine, inhibit the dopamine transporter (DAT), which is largely thought to account for actions related to their misuse and dependence. Cocaine-like, typical DAT inhibitors preferentially bind DAT in an outward-facing conformation, while atypical DAT inhibitors, like modafinil, prefer a more inward-facing DAT conformation. Modafinil and -modafinil have emerged as potential therapeutic options for selected populations of individuals affected by PSUD. In addition, analogs of modafinil (JJC8-088 and JJC8-091) with different pharmacological profiles have been explored as potential PSUD medications in preclinical models. In this work, we employ fast scan cyclic voltammetry (FSCV) to probe nucleus accumbens shell (NAS) dopamine (DA) dynamics in C57BL/6 male and female mice. We find that cocaine slowed DA clearance in both male and female mice but produced more robust increases in evoked NAS DA in female mice. -Modafinil produced mild increases in evoked NAS DA and slowed DA clearance across the sexes. The modafinil analog JJC8-088, a typical DAT inhibitor, produced increases in evoked NAS DA in female and male mice. Finally, JJC8-091, an atypical DAT inhibitor, produced limited increases in evoked NAS DA and slowed DA clearance in both sexes. In this work we begin to tease out how sex differences may alter the effects of DAT targeting and highlight how this may help focus research toward effective treatment options for PSUD. |
Hersey, Melinda; Bartole, Mattingly K; Jones, Claire S; Newman, Amy Hauck; Tanda, Gianluigi In: Molecules, vol. 28, no. 13, 2023, ISSN: 1420-3049. @article{pmid37446929,Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents. |
Keighron, Jacqueline D; Bonaventura, Jordi; Li, Yang; Yang, Jae-Won; DeMarco, Emily M; Hersey, Melinda; Cao, Jianjing; Sandtner, Walter; Michaelides, Michael; Sitte, Harald H; Newman, Amy Hauck; Tanda, Gianluigi Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release Journal Article In: Transl Psychiatry, vol. 13, no. 1, pp. 202, 2023, ISSN: 2158-3188. @article{pmid37311803,Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKIIα in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine's neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder. |
Keighron, Jacqueline D; Bonaventura, Jordi; Li, Yang; Yang, Jae-Won; DeMarco, Emily M; Hersey, Melinda; Cao, Jianjing; Sandtner, Walter; Michaelides, Michael; Sitte, Harald H; Newman, Amy Hauck; Tanda, Gianluigi Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release Journal Article In: Transl Psychiatry, vol. 13, no. 1, pp. 202, 2023, ISSN: 2158-3188. @article{pmid37311803b,Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKIIα in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine's neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder. |
Hersey, Melinda; Bacon, Amanda K; Bailey, Lydia G; Lee, Mary R; Chen, Andy Y; Leggio, Lorenzo; Tanda, Gianluigi Oxytocin receptors mediate oxytocin potentiation of methylphenidate-induced stimulation of accumbens dopamine in rats Journal Article In: J Neurochem, vol. 164, no. 5, pp. 613–623, 2023, ISSN: 1471-4159. @article{pmid36420597,While the illicit use and misuse of stimulants like cocaine and methylphenidate (MP) has increased, there remains no FDA-approved treatments for psychostimulant use disorders (PSUD). Oxytocin (OT) has shown promise as a potential pharmacotherapy for PSUD. Dopamine (DA) neurotransmission plays a significant role in PSUD. We have recently shown that OT blunts the reinforcing effects of MP but, surprisingly, enhanced MP-induced stimulation of DA levels. Such effects have been suggested as a result of activation of OT receptors or, alternatively, could be mediated by direct actions of OT on MP blockade of the DA transporter. Here, we employed fast scan cyclic voltammetry (FSCV) to investigate the effects of systemic OT on MP-induced changes in the dynamics of DA, phasic release and uptake, in the nucleus accumbens shell (NAS) of Sprague-Dawley rats. We also tested the systemic effects of an antagonist of OT receptors, atosiban, to counteract the OT enhancement of dopaminergic effects of MP under microdialysis procedures in the NAS in rats. Administration of OT alone (2 mg/kg; i.p.) did not significantly modify evoked NAS DA dynamics measured by FSCV, and when administered 10 min before MP (0.1, 0.3, 1.0 mg/kg; i.v.), OT did not potentiate MP-induced increases in phasic DA release and did not alter DA clearance rate, suggesting no direct interactions of OT with the MP-induced blockade of DA uptake. Also, OT alone did not elicit significant changes in tonic, extracellular NAS DA levels measured by microdialysis. However, consistent with previous studies, we observed that OT pretreatments (2 mg/kg; i.p.) potentiated MP-induced (0.1, 0.3, 1.0 mg/kg; i.v.) efflux of extracellular NAS DA levels. This effect was abolished when rats were pretreated with atosiban (2 mg/kg; i.p.), suggesting that OT receptors mediate this OT action. Overall, our results suggest that OT receptors mediated OT potentiation of MP-induced stimulation of extracellular NAS DA levels, likely driven by modulation of DA receptor signaling pathways, without affecting MP blockade of DAT. |
2021 |
Gomez, Juan L; Bonaventura, Jordi; Keighron, Jacqueline; Wright, Kelsey M; Marable, Dondre L; Rodriguez, Lionel A; Lam, Sherry; Carlton, Meghan L; Ellis, Randall J; Jordan, Chloe J; Bi, Guo-Hua; Solis, Oscar; Pignatelli, Marco; Bannon, Michael J; Xi, Zheng-Xiong; Tanda, Gianluigi; Michaelides, Michael Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior Journal Article In: Transl Psychiatry, vol. 11, no. 1, pp. 570, 2021, ISSN: 2158-3188. @article{pmid34750356b,Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn were dependent on the Zn transporter 3 (ZnT3), a neuronal Zn transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn deficiency in mice resulted in decreased striatal Zn content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn release and turnover/metabolism in the striatum, and that synaptically released Zn potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine's pharmacological mechanism of action and suggest that Zn may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders. |
Fu, Xiuping; Shah, Aparna P; Keighron, Jacqueline; Mou, Ta-Chung M; Ladenheim, Bruce; Alt, Jesse; Fukudome, Daisuke; Niwa, Minae; Tamashiro, Kellie L; Tanda, Gianluigi; Sawa, Akira; Cadet, Jean-Lud; Rais, Rana; Baraban, Jay M Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity Journal Article In: Transl Psychiatry, vol. 11, no. 1, pp. 427, 2021, ISSN: 2158-3188. @article{pmid34392304,Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients. |
