Carl R. Lupica, Ph.D.

@article{pmid39155312,

title = {Basal forebrain-lateral habenula inputs and control of impulsive behavior},

author = {Eun-Kyung Hwang and Agustin Zapata and Vivian Hu and Alexander F Hoffman and Hui-Ling Wang and Bing Liu and Marisela Morales and Carl R Lupica},

url = {https://pubmed.ncbi.nlm.nih.gov/39155312/},

doi = {10.1038/s41386-024-01963-7},

issn = {1740-634X},

year  = {2024},

date = {2024-08-01},

urldate = {2024-08-01},

journal = {Neuropsychopharmacology},

abstract = {Deficits in impulse control are observed in several neurocognitive disorders, including attention deficit hyperactivity (ADHD), substance use disorders (SUDs), and those following traumatic brain injury (TBI). Understanding brain circuits and mechanisms contributing to impulsive behavior may aid in identifying therapeutic interventions. We previously reported that intact lateral habenula (LHb) function is necessary to limit impulsivity defined by impaired response inhibition in rats. Here, we examine the involvement of a synaptic input to the LHb on response inhibition using cellular, circuit, and behavioral approaches. Retrograde fluorogold tracing identified basal forebrain (BF) inputs to LHb, primarily arising from ventral pallidum and nucleus accumbens shell (VP/NAcs). Glutamic acid decarboxylase and cannabinoid CB1 receptor (CB1R) mRNAs colocalized with fluorogold, suggesting a cannabinoid modulated GABAergic pathway. Optogenetic activation of these axons strongly inhibited LHb neuron action potentials and GABA release was tonically suppressed by an endogenous cannabinoid in vitro. Behavioral experiments showed that response inhibition during signaled reward omission was impaired when VP/NAcs inputs to LHb were optogenetically stimulated, whereas inhibition of this pathway did not alter LHb control of impulsivity. Systemic injection with the psychotropic phytocannabinoid, Δ-tetrahydrocannabinol (Δ-THC), also increased impulsivity in male, and not female rats, and this was blocked by LHb CB1R antagonism. However, as optogenetic VP/NAcs pathway inhibition did not alter impulse control, we conclude that the pro-impulsive effects of Δ-THC likely do not occur via inhibition of this afferent. These results identify an inhibitory LHb afferent that is controlled by CB1Rs that can regulate impulsive behavior.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36730201,

title = {Persistent binding at dopamine transporters determines sustained psychostimulant effects},

author = {Marco Niello and Spyridon Sideromenos and Ralph Gradisch and Ronan O Shea and Jakob Schwazer and Julian Maier and Nina Kastner and Walter Sandtner and Kathrin Jäntsch and Carl R Lupica and Alexander F Hoffman and Gert Lubec and Claus J Loland and Thomas Stockner and Daniela D Pollak and Michael H Baumann and Harald H Sitte},

url = {https://pubmed.ncbi.nlm.nih.gov/36730201/},

doi = {10.1073/pnas.2114204120},

issn = {1091-6490},

year  = {2023},

date = {2023-02-01},

urldate = {2023-02-01},

journal = {Proc Natl Acad Sci U S A},

volume = {120},

number = {6},

pages = {e2114204120},

abstract = {Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow ) of -enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Nakamura:2019aa,

title = {Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion.},

author = {Yoki Nakamura and Dilyan I Dryanovski and Yuriko Kimura and Shelley N Jackson and Amina S Woods and Yuko Yasui and Shang-Yi Tsai and Sachin Patel and Daniel P Covey and Tsung-Ping Su and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/31596232},

doi = {10.7554/eLife.47209},

issn = {2050-084X (Electronic); 2050-084X (Linking)},

year  = {2019},

date = {2019-10-09},

journal = {Elife},

volume = {8},

address = {Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States.},

abstract = {Cocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue, we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine causes dissociation of the Sig-1R from ADP-ribosylation factor (ARF6), a G-protein regulating EV trafficking, leading to activation of myosin light chain kinase (MLCK). Blockade of Sig-1R function, or inhibition of ARF6 or MLCK also prevented cocaine-induced EV release and cocaine-stimulated 2-AG-modulation of inhibitory synapses in DA neurons. Our results implicate the Sig-1R-ARF6 complex in control of EV release and demonstrate that cocaine-mediated 2-AG release can occur via EVs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hwang:2019aa,

title = {Altered Corticolimbic Control of the Nucleus Accumbens by Long-term Delta(9)-Tetrahydrocannabinol Exposure.},

author = {Eun-Kyung Hwang and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/31543247},

doi = {10.1016/j.biopsych.2019.07.024},

issn = {1873-2402 (Electronic); 0006-3223 (Linking)},

year  = {2019},

date = {2019-08-06},

journal = {Biol Psychiatry},

address = {Electrophysiology Research Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.},

abstract = {BACKGROUND: The decriminalization and legalization of cannabis and the expansion of availability of medical cannabis in North America have led to an increase in cannabis use and the availability of high-potency strains. Cannabis potency is determined by the concentration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), a psychoactive constituent that activates cannabinoid CB1 and CB2 receptors. The use of high-potency cannabis is associated with cannabis use disorder and increased susceptibility to psychiatric illness. The nucleus accumbens (NAc) is part of a brain reward circuit affected by Delta(9)-THC through modulation of glutamate afferents arising from corticolimbic brain areas implicated in drug addiction and psychiatric disorders. Moreover, brain imaging studies show alterations in corticolimbic and NAc properties in human cannabis users. METHODS: Using in vitro electrophysiology and optogenetics, we examined how Delta(9)-THC alters corticolimbic input to the NAc in rats. RESULTS: We found that long-term exposure to Delta(9)-THC weakens prefrontal cortex glutamate input to the NAc shell and strengthens input from basolateral amygdala and ventral hippocampus. Further, whereas long-term exposure to Delta(9)-THC had no effect on net strength of glutamatergic input to NAc shell arising from midbrain dopamine neurons, it alters fundamental properties of these synapses. CONCLUSIONS: Long-term exposure to Delta(9)-THC shifts control of the NAc shell from cortical to limbic input, likely contributing to cognitive and psychiatric dysfunction that is associated with cannabis use.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lupica:2018aa,

title = {Cannabinoid disruption of learning mechanisms involved in reward processing.},

author = {Carl R Lupica and Alexander F Hoffman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30115765},

doi = {10.1101/lm.046748.117},

issn = {1549-5485 (Electronic); 1072-0502 (Linking)},

year  = {2018},

date = {2018-08-16},

journal = {Learn Mem},

volume = {25},

number = {9},

pages = {435--445},

address = {Electrophysiology Research Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.},

abstract = {The increasing use of cannabis, its derivatives, and synthetic cannabinoids for medicinal and recreational purposes has led to burgeoning interest in understanding the addictive potential of this class of molecules. It is estimated that approximately 10% of marijuana users will eventually show signs of dependence on the drug, and the diagnosis of cannabis use disorder (CUD) is increasing in the United States. The molecule that sustains the use of cannabis is Delta(9)-tetrahydrocannabinol (Delta(9)-THC), and our knowledge of its effects, and those of other cannabinoids on brain function has expanded rapidly in the past two decades. Additionally, the identification of endogenous cannabinoid (endocannabinoid) systems in brain and their roles in physiology and behavior, demonstrate extensive involvement of these lipid signaling molecules in regulating CNS function. Here, we examine roles for endogenous cannabinoids in shaping synaptic activity in cortical and subcortical brain circuits, and we discuss mechanisms in which exogenous cannabinoids, such as Delta(9)-THC, interact with endocannabinoid systems to disrupt neuronal network oscillations. We then explore how perturbation of the interaction of this activity within brain reward circuits may lead to impaired learning. Finally, we propose that disruption of cellular plasticity mechanisms by exogenous cannabinoids in cortical and subcortical circuits may explain the difficulty in establishing viable cannabinoid self-administration models in animals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Wright:2017aa,

title = {Enduring Loss of Serotonergic Control of Orbitofrontal Cortex Function Following Contingent and Noncontingent Cocaine Exposure.},

author = {Andrew M Wright and Agustin Zapata and Michael H Baumann and Joshua S Elmore and Alexander F Hoffman and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27733540},

doi = {10.1093/cercor/bhw312},

issn = {1460-2199 (Electronic); 1047-3211 (Linking)},

year  = {2017},

date = {2017-12-01},

journal = {Cereb Cortex},

volume = {27},

number = {12},

pages = {5463--5476},

address = {Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.},

abstract = {Clinical descriptions of cocaine addiction include compulsive drug seeking and maladaptive decision-making despite substantial aversive consequences. Research suggests that this may result from altered orbitofrontal cortex (OFC) function and its participation in outcome-based behavior. Clinical and animal studies also implicate serotonin in the regulation of OFC function in addiction and other neuropsychiatric disorders. Here we test the hypothesis that exposure to cocaine, through self-administration (CSA) or yoked-administration (CYA), alters the regulation of OFC function by 5-HT. Using whole-cell electrophysiology in brain slices from naive rats we find that 5-HT1A receptors generate hyperpolarizing outward currents in layer-V OFC pyramidal neurons, and that 5-HT2A receptors increase glutamate release onto these cells. Following extended withdrawal from CSA or CYA, this 5-HT regulation of OFC activity is largely lost. In-situ hybridization of 5-HT receptor transcripts reveals that 5-HT1A receptor mRNA is unaffected and 5-HT2A receptor mRNA is significantly elevated after CSA or CYA. These results demonstrate that 5-HT control of OFC neurons is disrupted for extended periods following cocaine exposure. We hypothesize that this dysregulation of 5-HT signaling leads to enduring disruptions of OFC network activity that this is involved in impaired decision-making associated with cocaine addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lupica:2017aa,

title = {Cannabinoids as hippocampal network administrators.},

author = {Carl R Lupica and Yuhan Hu and Orrin Devinsky and Alexander F Hoffman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28392266},

doi = {10.1016/j.neuropharm.2017.04.003},

issn = {1873-7064 (Electronic); 0028-3908 (Linking)},

year  = {2017},

date = {2017-09-15},

journal = {Neuropharmacology},

volume = {124},

pages = {25--37},

address = {U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Electrophysiology Research Section, Baltimore, MD, USA. Electronic address: clupica@mail.nih.gov.},

abstract = {Extensive pioneering studies performed in the hippocampus have greatly contributed to our knowledge of an endogenous cannabinoid system comprised of the molecular machinery necessary to process endocannabinoid lipid messengers and their associated cannabinoid receptors. Moreover, a foundation of knowledge regarding the function of hippocampal circuits, and its role in supporting synaptic plasticity has facilitated our understanding of the roles cannabinoids play in the diverse behaviors in which the hippocampus participates, in both normal and pathological states. In this review, we present an historical overview of research pertaining to the hippocampal cannabinoid system to provide context in which to understand the participation of the hippocampus in cognition, behavior, and epilepsy. We also examine potential roles for the hippocampal formation in mediating dysfunctional behavior, and assert that these phenomena reflect disordered physiological activity within the hippocampus and its interactions with other brain regions after exposure to synthetic cannabinoids, and the phytocannabinoids found in marijuana, such as Delta(9)-THC and cannabidiol. In this regard, we examine contemporary hypotheses concerning the hippocampal endocannabinoid system's participation in psychotic disorders, schizophrenia, and epilepsy, and examine cannabinoid-sensitive cellular mechanisms contributing to coherent network oscillations as potential contributors to these disorders. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hoffman:2017aa,

title = {Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with Delta(9) -tetrahydrocannabinol.},

author = {Alexander F Hoffman and Matthew D Lycas and Jakub R Kaczmarzyk and Charles E Spivak and Michael H Baumann and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/26732435},

doi = {10.1111/adb.12334},

issn = {1369-1600 (Electronic); 1355-6215 (Linking)},

year  = {2017},

date = {2017-03-01},

journal = {Addict Biol},

volume = {22},

number = {2},

pages = {390--399},

address = {Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.},

abstract = {There has been a marked increase in the availability of synthetic drugs designed to mimic the effects of marijuana. These cannabimimetic drugs, sold illicitly as 'Spice' and related products, are associated with serious medical complications in some users. In vitro studies suggest that synthetic cannabinoids in these preparations are potent agonists at central cannabinoid CB1 receptors (CB1Rs), but few investigations have delineated their cellular effects, particularly in comparison with the psychoactive component of marijuana, Delta(9) -tetrahydrocannabinol (Delta(9) -THC). We compared the ability of three widely abused synthetic cannabinoids and Delta(9) -THC to alter glutamate release and long-term potentiation in the mouse hippocampus. JWH-018 was the most potent inhibitor of hippocampal synaptic transmission (EC50 ~15 nM), whereas its fluoropentyl derivative, AM2201, inhibited synaptic transmission with slightly lower potency (EC50 ~60 nM). The newer synthetic cannabinoid, XLR-11, displayed much lower potency (EC50 ~900 nM) that was similar to Delta(9) -THC (EC50 ~700 nM). The effects of all compounds occurred via activation of CB1Rs, as demonstrated by reversal with the selective antagonist/inverse agonist AM251 or the neutral CB1R antagonist PIMSR1. Moreover, AM2201 was without effect in the hippocampus of transgenic mice lacking the CB1R. Hippocampal slices exposed to either synthetic cannabinoids or Delta(9) -THC exhibited significantly impaired long-term potentiation (LTP). We find that, compared with Delta(9) -THC, the first-generation cannabinoids found in Spice preparations display higher potency, whereas a recent synthetic cannabinoid is roughly equipotent with Delta(9) -THC. The disruption of synaptic function by these synthetic cannabinoids is likely to lead to profound impairments in cognitive and behavioral function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zapata:2017aa,

title = {Lateral Habenula Involvement in Impulsive Cocaine Seeking.},

author = {Agustin Zapata and Eun-Kyung Hwang and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28025973},

doi = {10.1038/npp.2016.286},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2016},

date = {2016-12-27},

journal = {Neuropsychopharmacology},

volume = {42},

number = {5},

pages = {1103--1112},

address = {Electrophysiology Research Section, Cellular Neurobiology Branch, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.},

abstract = {The lateral habenula (LHb) is a brain structure receiving inputs from limbic forebrain areas and innervating major midbrain monoaminergic nuclei. Evidence indicates LHb involvement in sleep control, reward-based decision making, avoidance of punishment, and responses to stress. Additional work has established that the LHb mediates negative feedback in response to aversive events. As a hallmark of drug addiction is the inability to limit drug use despite negative consequences, we hypothesize that LHb dysfunction may have a role in the lack of control over drug seeking. Here we examine the effects of LHb inactivation in control over drug seeking in several cocaine self-administration (SA) paradigms in rats. We find that inhibition of the LHb with GABAergic agonists did not alter cocaine SA under progressive ratio or seeking/taking chained reinforcement schedules, or during punishment-induced suppression of cocaine-reinforced responding. In contrast, LHb inhibition increased cocaine seeking when the drug was not available in rats trained to discriminate its presence using an environmental cue. This effect of LHb inhibition was selective for cocaine, as it did not impair responding for sucrose reinforcement. The effect of LHb injection of GABA agonists was mimicked by intra-LHb muscarinic cholinergic (mACh) antagonist injection, and activation of mACh receptors excited a majority of LHb neurons in in vitro electrophysiology experiments. These results indicate that the LHb participates in the suppression of impulsive responding for cocaine through the activation of a cholinergic circuit, and they suggest that LHb dysfunction may contribute to impaired impulse control associated with drug addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Wang2015e,

title = {Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.},

author = {Huikun Wang and Tyler Treadway and Daniel P Covey and Joseph F Cheer and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/26365195},

doi = {10.1016/j.celrep.2015.08.041},

issn = {2211-1247 (Electronic)},

year  = {2015},

date = {2015-09-10},

journal = {Cell Rep},

volume = {12},

number = {12},

pages = {1997--2008},

address = {Electrophysiology Research Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, 251 Bayview Boulevard, Suite 200, Baltimore, MD 21224, USA.},

abstract = {Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and alpha1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Root2014,

title = {Single rodent mesohabenular axons release glutamate and GABA.},

author = {David H Root and Carlos A Mejias-Aponte and Shiliang Zhang and Hui-Ling Wang and Alexander F Hoffman and Carl R Lupica and Marisela Morales},

url = {https://www.ncbi.nlm.nih.gov/pubmed/25242304},

doi = {10.1038/nn.3823},

issn = {1546-1726 (Electronic); 1097-6256 (Linking)},

year  = {2014},

date = {2014-11-01},

journal = {Nat Neurosci},

volume = {17},

number = {11},

pages = {1543--1551},

address = {Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.},

abstract = {The lateral habenula (LHb) is involved in reward, aversion, addiction and depression through descending interactions with several brain structures, including the ventral tegmental area (VTA). The VTA provides reciprocal inputs to LHb, but their actions are unclear. Here we show that the majority of rat and mouse VTA neurons innervating LHb coexpress markers for both glutamate signaling (vesicular glutamate transporter 2; VGluT2) and GABA signaling (glutamic acid decarboxylase; GAD, and vesicular GABA transporter; VGaT). A single axon from these mesohabenular neurons coexpresses VGluT2 protein and VGaT protein and, surprisingly, establishes symmetric and asymmetric synapses on LHb neurons. In LHb slices, light activation of mesohabenular fibers expressing channelrhodopsin2 driven by VGluT2 (Slc17a6) or VGaT (Slc32a1) promoters elicits release of both glutamate and GABA onto single LHb neurons. In vivo light activation of mesohabenular terminals inhibits or excites LHb neurons. Our findings reveal an unanticipated type of VTA neuron that cotransmits glutamate and GABA and provides the majority of mesohabenular inputs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}