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Article ; Online: Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.

Barrett, James E / Shekarabi, Aryan / Inan, Saadet

2023 Volume 75, Issue 6, Page(s) 1062–1118

Abstract: Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been ... ...

Abstract	Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the
MeSH term(s)	Animals ; Humans ; Oxycodone/adverse effects ; Thebaine/therapeutic use ; Analgesics, Opioid/adverse effects ; Opioid-Related Disorders/drug therapy ; Morphine/therapeutic use ; Receptors, Opioid/therapeutic use
Chemical Substances	Oxycodone (CD35PMG570) ; Thebaine (2P9MKG8GX7) ; Analgesics, Opioid ; Morphine (76I7G6D29C) ; Receptors, Opioid
Language	English
Publishing date	2023-06-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	209898-2
ISSN	1521-0081 ; 0031-6997
ISSN (online)	1521-0081
ISSN	0031-6997
DOI	10.1124/pharmrev.121.000506
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Article ; Online: Energy drink produces aversive effects in planarians.

Mokkarala, Prateek / Shekarabi, Aryan / Wiah, Sonita / Rawls, Scott M

Physiology & behavior

2022 Volume 255, Page(s) 113933

Abstract: Energy drinks pose consumer and environmental risks. One of the few organisms suitable for investigating both risks are planarians, which display mammalian-like behavioral effects during drug exposure and reside in aquatic environments. We investigated ... ...

Abstract	Energy drinks pose consumer and environmental risks. One of the few organisms suitable for investigating both risks are planarians, which display mammalian-like behavioral effects during drug exposure and reside in aquatic environments. We investigated effects of Monster Energy® (0.001 - 10%) on planarian behaviors using established assays. For acute exposure, only higher concentrations reduced motility (>1%) and caused stereotypies (>1%). Lower concentrations (0.1-1%) enhanced light avoidance, a measure of defensive responding. In place conditioning experiments conducted with low concentrations (0.0001%-0.1%), planarians avoided the energy drink-paired side. These results suggest that Monster Energy® causes aversive effects in aquatic life such as planarians.
MeSH term(s)	Animals ; Energy Drinks ; Mammals ; Planarians ; Stereotyped Behavior
Language	English
Publishing date	2022-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2022.113933
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Article ; Online: Energy drink produces aversive effects in planarians

Mokkarala, Prateek / Shekarabi, Aryan / Wiah, Sonita / Rawls, Scott M.

Physiology & Behavior. 2022 Oct., v. 255 p.113933-

2022

Abstract	Energy drinks pose consumer and environmental risks. One of the few organisms suitable for investigating both risks are planarians, which display mammalian-like behavioral effects during drug exposure and reside in aquatic environments. We investigated effects of Monster Energy® (0.001 – 10%) on planarian behaviors using established assays. For acute exposure, only higher concentrations reduced motility (>1%) and caused stereotypies (>1%). Lower concentrations (0.1–1%) enhanced light avoidance, a measure of defensive responding. In place conditioning experiments conducted with low concentrations (0.0001%-0.1%), planarians avoided the energy drink-paired side. These results suggest that Monster Energy® causes aversive effects in aquatic life such as planarians.
Keywords	acute exposure ; aquatic organisms ; behavior ; drugs ; energy ; energy drinks ; physiology ; Planarians ; Monster Energy® ; Invertebrate ; Caffeine ; Sugar ; Environment ; anxiety ; motility
Language	English
Dates of publication	2022-10
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2022.113933
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Article ; Online: Cyanidin prevents MDPV withdrawal-induced anxiety-like effects and dysregulation of cytokine systems in rats.

Inan, Saadet / Meissler, Joseph J / Shekarabi, Aryan / Foss, Jeffrey / Wiah, Sonita / Eisenstein, Toby K / Rawls, Scott M

Brain research

2023 Volume 1806, Page(s) 148310

Abstract: Psychostimulant exposure and withdrawal cause neuroimmune dysregulation and anxiety that contributes to dependence and relapse. Here, we tested the hypothesis that withdrawal from the synthetic cathinone MDPV (methylenedioxypyrovalerone) produces anxiety- ...

Abstract	Psychostimulant exposure and withdrawal cause neuroimmune dysregulation and anxiety that contributes to dependence and relapse. Here, we tested the hypothesis that withdrawal from the synthetic cathinone MDPV (methylenedioxypyrovalerone) produces anxiety-like effects and enhanced levels of mesocorticolimbic cytokines that are inhibited by cyanidin, an anti-inflammatory flavonoid and nonselective blocker of IL-17A signaling. For comparison, we tested effects on glutamate transporter systems that are also dysregulated during psychostimulant free period. Rats injected for 9 d with MDPV (1 mg/kg, IP) or saline were pretreated daily with cyanidin (0.5 mg/kg, IP) or saline, followed by behavioral testing on the elevated zero maze (EZM) 72 h after the last MDPV injection. MDPV withdrawal caused a reduction in time spent on the open arm of the EZM that was prevented by cyanidin. Cyanidin itself did not affect locomotor activity or time spent on the open arm, or cause aversive or rewarding effects in place preference experiments. MDPV withdrawal caused enhancement of cytokine levels (IL-17A, IL-1β, IL-6, TNF=α, IL-10, and CCL2) in the ventral tegmental area, but not amygdala, nucleus accumbens, or prefrontal cortex, that was prevented by cyanidin. During MDPV withdrawal, mRNA levels of glutamate aspartate transporter (GLAST) and glutamate transporter subtype 1 (GLT-1) in the amygdala were also elevated but normalized by cyanidin treatment. These results show that MDPV withdrawal induced anxiety, and brain-region specific dysregulation of cytokine and glutamate systems, that are both prevented by cyanidin, thus identifying cyanidin for further investigation in the context of psychostimulant dependence and relapse.
MeSH term(s)	Rats ; Animals ; Synthetic Cathinone ; Interleukin-17 ; Cytokines ; Central Nervous System Stimulants/toxicity ; Anxiety/chemically induced ; Benzodioxoles/pharmacology ; Pyrrolidines/pharmacology
Chemical Substances	Synthetic Cathinone ; cyanidin (7732ZHU564) ; Interleukin-17 ; Cytokines ; Central Nervous System Stimulants ; Benzodioxoles ; Pyrrolidines
Language	English
Publishing date	2023-03-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2023.148310
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Zs.A 161: Show issues

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Article ; Online: Troriluzole inhibits methamphetamine place preference in rats and normalizes methamphetamine-evoked glutamate carboxypeptidase II (GCPII) protein levels in the mesolimbic pathway.

Wiah, Sonita / Roper, Abigail / Zhao, Pingwei / Shekarabi, Aryan / Watson, Mia N / Farkas, Daniel J / Potula, Raghava / Reitz, Allen B / Rawls, Scott M

Drug and alcohol dependence

2022 Volume 242, Page(s) 109719

Abstract: Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). ...

Abstract	Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ.
MeSH term(s)	Rats ; Animals ; Methamphetamine/pharmacology ; Central Nervous System Stimulants/pharmacology ; Glutamate Carboxypeptidase II/therapeutic use ; Riluzole/therapeutic use ; Amphetamine-Related Disorders/drug therapy ; Glutamates/therapeutic use
Chemical Substances	Methamphetamine (44RAL3456C) ; Central Nervous System Stimulants ; Glutamate Carboxypeptidase II (EC 3.4.17.21) ; Riluzole (7LJ087RS6F) ; Glutamates
Language	English
Publishing date	2022-12-05
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	519918-9
ISSN	1879-0046 ; 0376-8716
ISSN (online)	1879-0046
ISSN	0376-8716
DOI	10.1016/j.drugalcdep.2022.109719
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Article ; Online: Multi-chemokine receptor antagonist RAP-103 inhibits opioid-derived respiratory depression, reduces opioid reinforcement and physical dependence, and normalizes opioid-induced dysregulation of mesolimbic chemokine receptors in rats.

Bongiovanni, Angela R / Zhao, Pingwei / Inan, Saadet / Wiah, Sonita / Shekarabi, Aryan / Farkas, Daniel J / Watson, Mia N / Wimmer, Mathieu E / Ruff, Michael R / Rawls, Scott M

Drug and alcohol dependence

2022 Volume 238, Page(s) 109556

Abstract: Chemokine-opioid crosstalk is a physiological crossroads for influencing therapeutic and adverse effects of opioids. Activation of chemokine receptors, especially CCR2, CCR5 and CXCR4, reduces opioid-induced analgesia by desensitizing OPRM1 receptors. ... ...

Abstract	Chemokine-opioid crosstalk is a physiological crossroads for influencing therapeutic and adverse effects of opioids. Activation of chemokine receptors, especially CCR2, CCR5 and CXCR4, reduces opioid-induced analgesia by desensitizing OPRM1 receptors. Chemokine receptor antagonists (CRAs) enhance opioid analgesia, but knowledge about how CRAs impact adverse opioid effects remains limited. We examined effects of RAP-103, a multi-CRA orally active peptide analog of "DAPTA", on opioid-derived dependence, reinforcement, and respiratory depression in male rats and on changes in chemokine and OPRM1 (µ opioid) receptor levels in mesolimbic substrates during opioid abstinence. In rats exposed to chronic morphine (75 mg pellet x 7 d), daily RAP-103 (1 mg/kg, IP) treatment reduced the severity of naloxone-precipitated withdrawal responses. For self-administration (SA) studies, RAP-103 (1 mg/kg, IP) reduced heroin acquisition (0.1 mg/kg/inf) and reinforcing efficacy (assessed by motivation on a progressive-ratio reinforcement schedule) but did not impact sucrose intake. RAP-103 (1-3 mg/kg, IP) also normalized the deficits in oxygen saturation and enhancement of respiratory rate caused by morphine (5 mg/kg, SC) exposure. Abstinence from chronic morphine elicited brain-region specific changes in chemokine receptor protein levels. CCR2 and CXCR4 were increased in the ventral tegmental area (VTA), whereas CCR2 and CCR5 were reduced in the nucleus accumbens (NAC). Effects of RAP-103 (1 mg/kg, IP) were focused in the NAC, where it normalized morphine-induced deficits in CCR2 and CCR5. These results identify CRAs as potential biphasic function opioid signaling modulators to enhance opioid analgesia and inhibit opioid-derived dependence and respiratory depression.
MeSH term(s)	Analgesics, Opioid/pharmacology ; Animals ; Male ; Morphine/pharmacology ; Nucleus Accumbens ; Peptides/metabolism ; Peptides/pharmacology ; Rats ; Receptors, Chemokine/metabolism ; Receptors, Opioid ; Receptors, Opioid, mu ; Respiratory Insufficiency/chemically induced ; Respiratory Insufficiency/drug therapy
Chemical Substances	Analgesics, Opioid ; Peptides ; RAP-103 ; Receptors, Chemokine ; Receptors, Opioid ; Receptors, Opioid, mu ; Morphine (76I7G6D29C)
Language	English
Publishing date	2022-07-11
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	519918-9
ISSN	1879-0046 ; 0376-8716
ISSN (online)	1879-0046
ISSN	0376-8716
DOI	10.1016/j.drugalcdep.2022.109556
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Article ; Online: Purinergic P2X7 receptor antagonist inhibits methamphetamine-induced reward, hyperlocomotion, and cortical IL-7A levels in mice: A role for P2X7/IL-17A crosstalk in methamphetamine behaviors?

Potula, Raghava / Gentile, Taylor A / Meissler, Joseph J / Shekarabi, Aryan / Wiah, Sonita / Farkas, Daniel J / Inan, Saadet / Eisenstein, Toby K / Rawls, Scott M

Brain, behavior, and immunity

2022 Volume 107, Page(s) 47–52

Abstract: P2X7 receptors are dysregulated during psychostimulant exposure. Furthermore, P2X7 receptors enhance endogenous systems (e.g., cytokines, dopamine, and glutamate) that facilitate psychostimulant addiction. Therefore, using mouse locomotor, conditioned ... ...

Abstract	P2X7 receptors are dysregulated during psychostimulant exposure. Furthermore, P2X7 receptors enhance endogenous systems (e.g., cytokines, dopamine, and glutamate) that facilitate psychostimulant addiction. Therefore, using mouse locomotor, conditioned place preference (CPP), and intracranial self-stimulation (ICSS) assays, we tested the hypothesis that methamphetamine (METH) reward and acute locomotor activation requires P2X7 receptor activity. We also investigated effects of P2X7 blockade on METH-induced changes in cytokine levels in brain reward regions. A438079 (5, 10, 50 mg/kg), a P2X7 antagonist, did not affect spontaneous locomotor activity but reduced hyperlocomotion caused by acute METH (1 mg/kg) exposure. A438079 (10 mg/kg) also prevented expression of METH CPP without causing aversive or rewarding effects. For ICSS experiments, METH (1 mg/kg) facilitated brain reward function as interpreted from reductions in baseline threshold. In the presence of A438079 (50 mg/kg), METH-induced facilitation of ICSS was reduced. Repeated METH exposure (1 mg/kg × 7 d) caused enhancement of IL-17A levels in the prefrontal cortex (PFC) that was normalized by A438070 (10 mg/kg × 7 d). The present data suggest that P2X7 receptor activity contributes to rewarding and locomotor-stimulant effects of METH through a potential mechanism involving IL-17A, which has recently been implicated in anxiety.
MeSH term(s)	Animals ; Mice ; Methamphetamine/pharmacology ; Receptors, Purinergic P2X7 ; Purinergic P2X Receptor Antagonists ; Interleukin-17
Chemical Substances	Methamphetamine (44RAL3456C) ; Receptors, Purinergic P2X7 ; Purinergic P2X Receptor Antagonists ; Interleukin-17
Language	English
Publishing date	2022-09-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2022.09.012
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