Publications by authors named "Kevin S Murnane"

31 Publications

Formulation and Characterization of Microcapsules Encapsulating PC12 Cells as a Prospective Treatment Approach for Parkinson's Disease.

AAPS PharmSciTech 2021 May 7;22(4):149. Epub 2021 May 7.

Center for Drug Delivery Research, Vaccine Nanotechnology Laboratory, Mercer University College of Pharmacy, Atlanta, Georgia, 30341, USA.

Parkinson's disease (PD) is the second most common neurological disorder, associated with decreased dopamine levels in the brain. The goal of this study was to assess the potential of a regenerative medicine-based cell therapy approach to increase dopamine levels. In this study, we used rat adrenal pheochromocytoma (PC12) cells that can produce, store, and secrete dopamine. These cells were microencapsulated in the selectively permeable polymer membrane to protect them from immune responses. For fabrication of the microcapsules, we used a modified Buchi spray dryer B-190 that allows for fast manufacturing of microcapsules and is industrially scalable. Size optimization of the microcapsules was performed by systematically varying key parameters of the spraying device. The short- and long-term stabilities of the microcapsules were assessed. In the in vitro study, the cells were found viable for a period of 30 days. Selective permeability of the microcapsules was confirmed via dopamine release assay and micro BCA protein assay. We found that the microcapsules were permeable to the small molecules including dopamine and were impermeable to the large molecules like BSA. Thus, they can provide the protection to the encapsulated cells from the immune cells. Griess's assay confirmed the non-immunogenicity of the microcapsules. These results demonstrate the effective fabrication of microcapsules encapsulating cells using an industrially scalable device. The microcapsules were stable, and the cells were viable inside the microcapsules and were found to release dopamine. Thus, these microcapsules have the potential to serve as the alternative or complementary treatment approach for PD.
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http://dx.doi.org/10.1208/s12249-021-02007-9DOI Listing
May 2021

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and uptake1 and uptake2 monoamine transporters.

Neuropharmacology 2021 Apr 20;190:108570. Epub 2021 Apr 20.

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria; AddRess Centre for Addiction Research and Science, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria. Electronic address:

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108570DOI Listing
April 2021

Young at heart? Drugs of abuse cause early-onset cardiovascular disease in the young.

Heart 2021 Apr 15;107(8):604-606. Epub 2021 Feb 15.

Departments of Pathology, Cellular Biology and Anatomy, and Molecular and Cellular Physiology, LSU Health Shreveport, Shreveport, Louisiana, USA

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http://dx.doi.org/10.1136/heartjnl-2020-318856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075271PMC
April 2021

MDPV "high-responder" rats also self-administer more oxycodone than their "low-responder" counterparts under a fixed ratio schedule of reinforcement.

Psychopharmacology (Berl) 2021 Apr 23;238(4):1183-1192. Epub 2021 Jan 23.

Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Atlanta, GA, 30341, USA.

Rationale: Oxycodone is one of the most commonly prescribed and most frequently abused opioid analgesics, yet little is known regarding individual vulnerabilities to oxycodone abuse. The synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) has been shown to produce a "high-responder" phenotype characterized by increased drug intake and responding during periods of signaled drug unavailability (e.g., during post-infusion timeouts) in ~ 40% of male Sprague-Dawley rats. This phenotype also transfers to other psychostimulants (e.g., cocaine and methamphetamine), but it is unknown whether this phenotype transfers to other (non-stimulant) drugs of abuse.

Objectives: The present study aimed to (1) reestablish the "high-responder" phenotype in male Sprague-Dawley rats (n = 11) that acquired self-administration of MDPV (0.032 mg/kg/inf) on a fixed ratio 1 (FR1) schedule of reinforcement and (2) compare full dose-response curves for MDPV and oxycodone self-administration under an FR5 schedule of reinforcement.

Results: MDPV was ~ 3-fold more potent at maintaining peak levels of behavior and resulted in greater overall drug intake than oxycodone. High levels of timeout responding were noted in a subset of rats that acquired MDPV self-administration ("high-responders", n = 5), and the FR5 dose-response curve for MDPV was shifted upward for these rats relative to their "low-responder" (n = 6) counterparts. "High-responders" also self-administered more infusions of oxycodone under an FR5 schedule of reinforcement than "low-responders"; however, this was not coupled with increased levels of timeout responding.

Conclusions: The present data suggest that a subset of individuals with a history of using synthetic cathinones may be particularly vulnerable to the abuse of oxycodone.
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http://dx.doi.org/10.1007/s00213-021-05764-4DOI Listing
April 2021

Examination of xylene exposure in the U.S. Population through biomonitoring: NHANES 2005-2006, 2011-2016.

Biomarkers 2021 Feb 17;26(1):65-73. Epub 2020 Dec 17.

Tobacco and Volatiles Branch, U.S. Centers for Disease Control and Prevention, Atlanta, GA, USA.

Xylenes are aromatic hydrocarbons used for industrial applications such as the production of petrochemicals and plastics. Acute xylene exposures can negatively impact health through neurotoxicity and irritation of respiratory and dermal tissues. We quantified urinary biomarkers of xylene exposure [2-methylhippuric acid (2MHA) and a mixture of 3- and 4-methylhippuric acids (34MH)] in a representative sample of the U.S. population. Spot urine obtained during the National Health and Nutrition Examination Survey 2005-2006 and 2011-2016 was analysed using ultra-high-performance liquid chromatography/tandem mass spectrometry. Exclusive smokers were distinguished from non-users using a combination of self-report and serum cotinine data. The median 2MHA and 34MH levels were higher for exclusive smokers (100 µg/g and 748 µg/g creatinine, respectively) than for non-users (27.4 µg/g and 168 µg/g creatinine, respectively). Participants who smoked cigarettes had significantly higher 2MHA and 34MH levels ( < 0.0001) than unexposed participants. Smoking 1-10, 11-20, and >20 cigarettes per day (CPD) was significantly associated with 181%, 339% and 393% higher 2MHA levels, respectively. For 34MH, smoking 1-10, 11-20, and >20 CPD was significantly associated with 201%, 398%, and 471% higher 34MH levels, respectively. We confirm that tobacco smoke is a significant source of xylene exposure as measured by urinary 2MHA and 34MH levels.
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http://dx.doi.org/10.1080/1354750X.2020.1861100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855382PMC
February 2021

Transdermal delivery of breakthrough therapeutics for the management of treatment-resistant and post-partum depression.

Int J Pharm 2020 Dec 22;591:120007. Epub 2020 Oct 22.

Center for Drug Delivery Research, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA. Electronic address:

For the first time in over three decades, the year 2019 saw the approval of two new classes of antidepressants: Spravato™ esketamine intranasal spray for treatment-resistant depression, and Zulresso® brexanolone infusion against post-partum depression. Although both therapies were granted "breakthrough" designations, topical application of both drugs could offer several advantages over their current routes of administration. However, delivery of their high therapeutic doses (0.5 mg/kg ketamine in 1 h; 90 µg/kg/h brexanolone over 52 h) is unachievable by conventional means. We evaluated physical enhancement techniques such as iontophoresis, microneedle-treatment, and ablative laser for the rapid delivery of ketamine. Additionally, the sustained delivery of brexanolone across microporated skin employing chemical enhancers and novel microemulsions was also accomplished. The target therapeutic flux of ketamine after skin pre-treatment with laser (534.51 ± 146.93 µg/cm), and the application of anodal iontophoresis (681.93 ± 74.35 µg/cm) on ablated skin, was observed within one hour. Microporation of skin using laser was more effective than microneedles, for the delivery of ketamine as well as brexanolone. The developed microemulsions resulted in significantly higher transdermal delivery across laser-treated skin. Although brexanolone demonstrated higher solubility in the w/o microemulsion (21.31 ± 0.14 mg/mL) than the o/w microemulsion (10.69 ± 0.09 mg/mL), percutaneous absorption from the o/w microemulsion (6.04 ± 0.16%) was significantly higher than the w/o microemulsion (1.92 ± 0.02%).
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http://dx.doi.org/10.1016/j.ijpharm.2020.120007DOI Listing
December 2020

Nanoparticle encapsulated oxytocin increases resistance to induced seizures and restores social behavior in Scn1a-derived epilepsy.

Neurobiol Dis 2021 01 25;147:105147. Epub 2020 Oct 25.

Department of Human Genetics, Emory University, Atlanta, GA, United States of America.

Oxytocin (OT) has broad effects in the brain and plays an important role in cognitive, social, and neuroendocrine function. OT has also been identified as potentially therapeutic in neuropsychiatric disorders such as autism and depression, which are often comorbid with epilepsy, raising the possibility that it might confer protection against the behavioral and seizure phenotypes in epilepsy. Dravet syndrome (DS) is an early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, and cognitive and behavioral deficits. De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A are the main cause of DS, while genetic epilepsy with febrile seizures plus (GEFS+), also characterized by early-life FSs and afebrile epilepsy, is typically caused by inherited mutations that alter the biophysical properties of SCN1A. Despite the wide range of available antiepileptic drugs, many patients with SCN1A mutations do not achieve adequate seizure control or the amelioration of associated behavioral comorbidities. In the current study, we demonstrate that nanoparticle encapsulation of OT conferred robust and sustained protection against induced seizures and restored more normal social behavior in a mouse model of Scn1a-derived epilepsy. These results demonstrate the ability of a nanotechnology formulation to significantly enhance the efficacy of OT. This approach will provide a general strategy to enhance the therapeutic potential of additional neuropeptides in epilepsy and other neurological disorders.
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http://dx.doi.org/10.1016/j.nbd.2020.105147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726060PMC
January 2021

Transdermal Delivery of the Free Base of 3-Fluoroamphetamine: In Vitro Skin Permeation and Irritation Potential.

AAPS PharmSciTech 2020 Mar 25;21(3):109. Epub 2020 Mar 25.

Center for Drug Delivery Research, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, Georgia, USA.

This work aimed to continue our effort in establishing the feasibility of 3-fluoroamphetamine (also known as PAL-353) to be a transdermal drug candidate by studying the delivery of the base form through the human cadaver skin in lieu of the previously investigated salt form, and for the first time using an EPIDERM™-reconstructed human epidermal model to predict the skin irritation potential of PAL-353, in support of development for a matrix-type transdermal delivery system. Passive and enhanced (with chemical permeation enhancers) transdermal delivery were investigated via in vitro permeation studies that were performed on Franz diffusion cells with dermatomed human cadaver skin. After 24 h, PAL-353 free base revealed high passive permeation of 417.49 ± 30.12, 1577.68 ± 165.41, and 4295.16 ± 264.36 μg/cm, with applied formulation concentrations of 5.5 (F1), 20 (F2), and 40 (F3) mg/mL, respectively. Oleyl alcohol produced an approximately threefold steady-state flux enhancement at 5% or 10% w/w but may not be needed as the free base alone provided therapeutically relevant permeation. Further, it was predicted that therapeutically relevant delivery would be unlikely to cause skin irritation using the EPIDERM™-reconstructed human epidermal model. In conclusion, the present study further supported the development of PAL-353 transdermal delivery systems.
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http://dx.doi.org/10.1208/s12249-020-01649-5DOI Listing
March 2020

The synthetic cathinone 3,4-methylenedioxypyrovalerone increases impulsive action in rats.

Behav Pharmacol 2020 06;31(4):309-321

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

A previous study from our laboratory has shown that the selective catecholamine reuptake inhibitor 3,4-methylenedioxypyrovalerone (MDPV) persistently alters impulsive choice as measured by delay discounting. To further understand the proimpulsive effects of MDPV, we examined its capacity to modulate a different impulsive measure - impulsive action - using a differential reinforcement of low rates of responding task with an inter-response time of 20 s. Three groups of male, Sprague-Dawley rats (n = 6) were first tested in daily sessions to understand the acute effects of cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline (1.0 ml/kg) on impulsive action. Both cocaine and MDPV increased impulsive action, most notably by decreasing timing error responses and response efficiency, but MDPV was more effective than cocaine. Additionally, MDPV suppressed operant responding in two of six animals at the highest dose tested. Next, the same animals received 10 postsession injections, once every other day, of either 30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or 1.0 ml/kg saline based on their treatment group. An acute dose-effect redetermination was completed following the repeated administration studies, and once again MDPV and cocaine demonstrated proimpulsive effects. Interestingly, timing error responses were decreased in both MDPV and cocaine groups after an acute saline injection, potentially indicating persistent impulsive changes following the repeated administration phase of the experiment. These studies indicate that MDPV increases impulsive action acutely and that this increase may be potentiated following a series of repeated administrations.
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http://dx.doi.org/10.1097/FBP.0000000000000548DOI Listing
June 2020

A Classroom Activity to Increase Student Pharmacists Confidence in Dealing with the Opioid Epidemic.

Am J Pharm Educ 2019 11;83(9):7199

Mercer University College of Pharmacy, Mercer University Health Sciences Center, Atlanta, Georgia.

To implement and assess the impact of a hybrid flipped-classroom activity designed to increase the motivation and confidence of Doctor of Pharmacy (PharmD) students in addressing the opioid crisis. Third-professional year student pharmacists were provided with reading material developed by federal agencies and professional pharmacy organizations, as well as Georgia-specific information covering medical amnesty and local resources for opioid-overdose prevention prior to class. They then attended a four-hour classroom session that included hearing a lecture on opioid pharmacology and opioid overdose, viewing training videos, and engaging in extensive discussion. The students voluntarily completed pre- and post-intervention assessments regarding opioid abuse and opioid overdose prevention. Seventy of the 107 third-year students enrolled in the course completed the pre-intervention assessment (65% response rate), and 33 of the 70 completed the post-intervention assessment (47% retention rate). The students exhibited a high baseline motivation to assist in combating the opioid crises, but less confidence in their ability to intervene. Significant increases were seen in areas related to student confidence on the post-intervention assessment. Fewer changes were seen in areas related to student motivation. A "hybrid" flipped classroom activity increased the confidence of student pharmacists in their understanding of the physical and adverse effects of opioids and the application of reversal agents. Increased confidence may support increased intervention.
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http://dx.doi.org/10.5688/ajpe7199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920645PMC
November 2019

Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders.

CNS Neurol Disord Drug Targets 2019 ;18(10):735-749

Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, Atlanta, GA, United States.

Neurodegenerative disorders are commonly associated with a complex pattern of pathophysiological hallmarks, including increased oxidative stress and neuroinflammation, which makes their treatment challenging. Omega-3 Fatty Acids (O3FA) are natural products with reported neuroprotective, anti-inflammatory, and antioxidant effects. These effects have been attributed to their incorporation into neuronal membranes or through the activation of intracellular or recently discovered cell-surface receptors (i.e., Free-Fatty Acid Receptors; FFAR). Molecular docking studies have investigated the roles of O3FA as agonists of FFAR and have led to the development of receptor-specific targeted agonists for therapeutic purposes. Moreover, novel formulation strategies for targeted delivery of O3FA to the brain have supported their development as therapeutics for neurodegenerative disorders. Despite the compelling evidence of the beneficial effects of O3FA for several neuroprotective functions, they are currently only available as unregulated dietary supplements, with only a single FDA-approved prescription product, indicated for triglyceride reduction. This review highlights the relative safety and efficacy of O3FA, their drug-like properties, and their capacity to be formulated in clinically viable drug delivery systems. Interestingly, the presence of cardiac conditions such as hypertriglyceridemia is associated with brain pathophysiological hallmarks of neurodegeneration, such as neuroinflammation, thereby further suggesting potential therapeutic roles of O3FA for neurodegenerative disorders. Taken together, this review article summarizes and integrates the compelling evidence regarding the feasibility of developing O3FA and their synthetic derivatives as potential drugs for neurodegenerative disorders.
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http://dx.doi.org/10.2174/1871527318666191114093749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204890PMC
October 2020

The pharmacokinetics of 3-fluoroamphetamine following delivery using clinically relevant routes of administration.

Drug Deliv Transl Res 2020 02;10(1):271-281

Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, 3001 Mercer University Dr., Atlanta, GA, 30341, USA.

3-Fluoroamphetamine (also called PAL-353) is a synthetic amphetamine analog that has been investigated for cocaine use disorder (CUD), yet no studies have characterized its pharmacokinetics (PK). In the present study, we determined the PK of PAL-353 in male Sprague Dawley rats following intravenous bolus injection (5 mg/kg). Plasma samples were analyzed using a novel bioanalytical method that coupled liquid-liquid extraction and LC-MS/MS. The primary PK parameters determined by WinNonlin were a C (ng/mL) of 1412.09 ± 196.12 and a plasma half-life of 2.27 ± 0.67 h. As transdermal delivery may be an optimal approach to delivering PAL-353 for CUD, we assessed its PK profile following application of 50 mg of transdermal gel (10% w/w drug over 5 cm). The 10% w/w gel resulted in a short lag time, sustained delivery, and a rapid clearance in plasma immediately after removal. The rodent PK data were verified by examining in vitro permeation through human epidermis mounted on Franz diffusion cells. An in vitro-in vivo correlation (IVIVC) analysis was performed using the Phoenix IVIVC toolkit to assess the predictive relationship between rodent and human skin absorption/permeation. The in vitro permeation study revealed a dose-proportional cumulative and steady-state flux with ~ 70% of drug permeated. The fraction absorbed in vivo and fraction permeated in vitro showed a linear relationship. In conclusion, we have characterized the PK profile of PAL-353, demonstrated that it has favorable PK properties for transdermal administration for CUD, and provided preliminary evidence of the capacity of rodent data to predict human skin flux.
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http://dx.doi.org/10.1007/s13346-019-00685-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982562PMC
February 2020

Effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice.

Psychopharmacology (Berl) 2019 Dec 15;236(12):3567-3578. Epub 2019 Jul 15.

Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, 3001 Mercer University Dr., Atlanta, GA, 30341, USA.

Rationale: Approximately 20 million adults in the USA have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD.

Objective: To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol.

Methods: The effects of DOI were examined using ethanol-induced place conditioning (1.8 g/kg ethanol) and 2-bottle choice ethanol drinking (20% v/v), using a dose of DOI (3 mg/kg) that produced the maximal response in the serotonin 2A (5-HT) receptor-dependent head-twitch assay. Interactions between DOI and ethanol (3 g/kg) were examined using the ethanol-induced loss of righting reflex procedure and blood-ethanol analysis. To examine additional mechanisms by which psychedelics may interact with ethanol, we determined whether DOI reverses ethanol-induced nitric oxide release in macrophages, a marker of inflammation.

Results: DOI significantly attenuated ethanol-induced place conditioning and ethanol drinking. DOI-induced suppression of alcohol drinking depended upon 5-HT receptors, was selective for alcohol over water, and was selective for high alcohol-preferring subjects. DOI had no apparent pharmacokinetic interactions with ethanol, and DOI reduced ethanol-induced nitric oxide release.

Conclusions: Our findings demonstrate that DOI blocks ethanol place conditioning and selectively reduces voluntary ethanol consumption. This may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both. Additional studies to elucidate the mechanisms through which psychedelics attenuate the effects of ethanol would inform the pathophysiology of AUD and potentially provide new treatment options.
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http://dx.doi.org/10.1007/s00213-019-05328-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895420PMC
December 2019

Repeated administration of synthetic cathinone 3,4-methylenedioxypyrovalerone persistently increases impulsive choice in rats.

Behav Pharmacol 2019 10;30(7):555-565

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

3,4-Methylenedioxypyrovalerone (MDPV) is a selective catecholamine reuptake inhibitor abused for its psychostimulant properties. This study examined if MDPV administration alters impulsive choice measured by delay discounting in rats. Three groups of rats were tested in daily delay discounting sessions to determine the effects of acute cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline on mean adjusted delay (MAD). Dose-dependent decreases in MAD were elicited only by acute MDPV, which also suppressed operant responding at the highest dose. Next, rats received post-session injections (30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or saline) every other day for a total of 10 injections. MAD increased during saline treatment, did not change during cocaine treatment, and was reduced during MDPV treatment. In dose-effect re-determinations, no acute drug effects on MAD were observed, but compared to the initial dose-effect determination, MDPV suppressed operant responding in more animals, with zero animals completing trials at the highest dose. All saline and MDPV-treated subjects were sacrificed, and striatal and cortical dopamine levels were quantified by HPLC. These studies indicate that administration of MDPV may increase impulsive choice acutely and persistently. These proimpulsive effects are possibly mediated by increases in striatal dopamine turnover.
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http://dx.doi.org/10.1097/FBP.0000000000000492DOI Listing
October 2019

Skin Delivery and Irritation Potential of Phenmetrazine as a Candidate Transdermal Formulation for Repurposed Indications.

AAPS J 2019 05 31;21(4):70. Epub 2019 May 31.

Center for Drug Delivery Research, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, Georgia, USA.

Phenmetrazine, a selective dopamine and norepinephrine releaser, previously available as an oral anorectic, is prone to be abused. This study aimed to assess the feasibility of delivering phenmetrazine via the transdermal route for a new indication, while also minimizing its abuse potential. The passive permeation of phenmetrazine through dermatomed human cadaver skin was evaluated using static Franz diffusion cells at 10 mg/mL for the fumarate salt, and at 20, 40, and 80 mg/mL for the free base in propylene glycol for 24 h. Further, oleic acid (5% w/w), oleyl alcohol (5% and 10% w/w), and lauric acid (10% w/w) were investigated as chemical permeation enhancers to enhance the delivery. Skin irritation potential was assessed using EpiDerm™ in vitro reconstructed human epidermal model. The free base showed superior 24-h delivery (8.13 ± 4.07%, 10.6 ± 2.5%, and 10.4 ± 1.4% for groups with 20, 40, and 80 mg/mL of the free base, respectively) to phenmetrazine fumarate salt (undetectable). The successful screening of effective chemical enhancers, oleyl alcohol (5% and 10% w/w), oleic acid (5% w/w), and lauric acid (10% w/w) resulted in significant enhancement of delivery. The calculated therapeutic relevant flux for the potential indication, attention deficit hyperactivity disorder, 20 μg/cm/h was met, where a 24-mg daily dose from a 50-cm patch was projected to be delivered to a 60-kg individual. Irritation study results suggest that formulations with therapeutically relevant delivery are likely to be non-irritant. In conclusion, it is feasible to deliver therapeutically relevant amounts of phenmetrazine via the transdermal route.
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http://dx.doi.org/10.1208/s12248-019-0335-9DOI Listing
May 2019

The synthetic cathinone psychostimulant α-PPP antagonizes serotonin 5-HT receptors: In vitro and in vivo evidence.

Drug Test Anal 2019 Jul 22;11(7):990-998. Epub 2019 Apr 22.

Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, USA.

Synthetic cathinones (SCs) are β-keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5-HT receptors (5-HT R) and muscarinic M receptors (M R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M R (minimal displacement of [~K ] [ H]scopolamine up to 10 μM). However, two SCs, α-pyrrolidinopropiophenone (α-PPP) and 4-methyl-α-PPP, had low μM K values at 5-HT R. In 5-HT R-phosphoinositide hydrolysis assays, α-PPP and 4-methyl-α-PPP displayed inverse agonist activity. We further assessed the 5-HT R functional activity of α-PPP, and observed it competitively antagonized 5-HT R signaling stimulated by the 5-HT R agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI; K  = 851 nM). To assess in vivo 5-HT R activity, we examined the effects of α-PPP on the DOI-elicited head-twitch response (HTR) in mice. α-PPP dose-dependently blocked the HTR with maximal suppression at 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α-PPP. To corroborate a 5-HT R mechanism, we also tested 3,4-methylenedioxy-α-PPP (MDPPP) and 3-bromomethcathinone (3-BMC), SCs that we observed had 5-HT R K s > 10 μM. Neither MDPPP nor 3-BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α-PPP has antagonist interactions at 5-HT R in vitro that may translate at physiologically-relevant doses in vivo. Considering 5-HT R antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α-PPPs unpopularity compared to other monoamine transporter inhibitors.
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http://dx.doi.org/10.1002/dta.2582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615953PMC
July 2019

The renaissance in psychedelic research: What do preclinical models have to offer.

Authors:
Kevin S Murnane

Prog Brain Res 2018 5;242:25-67. Epub 2018 Oct 5.

Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, Atlanta, GA, United States. Electronic address:

Human research with psychedelics is making groundbreaking discoveries. Psychedelics modify enduring elements of personality and seemingly reduce anxiety, depression, and substance dependence in small but well-designed clinical studies. Psychedelics are advancing through pharmaceutical regulatory systems, and neuroimaging studies have related their extraordinary effects to select brain networks. This field is making significant basic science and translational discoveries, yet preclinical studies have lagged this renaissance in human psychedelic research. Preclinical studies have a lot to offer psychedelic research as they afford tight control of experimental parameters, subjects with documented drug histories, and the capacity to elucidate relevant signaling cascades as well as conduct invasive mechanistic studies of neurochemistry and neural circuits. Safety pharmacology, novel biomarkers, and pharmacokinetics can be assessed in disease state models to advance psychedelics toward clinical practice. This chapter documents the current status of psychedelic research, with the thematic argument that new preclinical studies would benefit this field.
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http://dx.doi.org/10.1016/bs.pbr.2018.08.003DOI Listing
March 2019

The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice.

Eur J Pharmacol 2019 Jan 6;842:255-261. Epub 2018 Nov 6.

Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, Atlanta, GA, USA. Electronic address:

Anesthesia-Induced Hypothermia (AIH) has been reported to be the cause of many postoperative adverse effects, including increased mortality, decreased immune responses, cardiac events, and a greater prevalence of postoperative surgical wound infections. AIH can in some cases be minimized with pre-warming fluids and gases and forced-air heating systems, but such techniques are not always effective and can result in patient burns or other adverse effects. Stimulation of 5-HT receptors has been reported to increase body temperature through a variety of mechanisms, and as such, may be a viable target for pharmacologically minimizing AIH. In the present study, we examined the effects of 5-HT receptor stimulation on hypothermia induced by the injectable anesthetic ketamine in Swiss-Webster mice using rectal thermometry. We report that ketamine dose-dependently induced hypothermia, and mice did not become tolerant to this effect of ketamine over the course of three injections spaced at once per week. Ketamine-induced hypothermia was significantly attenuated by pretreatment with the selective 5-HT receptor agonist WAY-163909 but not by pretreatment with the mixed 5-HT receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Moreover, the blockade of ketamine-induced hypothermia by WAY-163909 was reversed by pretreatment with the selective 5-HT receptor antagonist SB-242084. These findings demonstrate that stimulation of 5-HT receptors can reduce AIH, at least for ketamine-induced hypothermia. They warrant further study of the pharmacological and neurobiological mechanisms underlying this interaction and its extension to other anesthetics. Furthermore, these findings suggest that the maintenance of body temperature during surgery may be a new clinical use for 5-HT receptor agonists.
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http://dx.doi.org/10.1016/j.ejphar.2018.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296880PMC
January 2019

Formulation and evaluation of 4-benzylpiperidine drug-in-adhesive matrix type transdermal patch.

Int J Pharm 2018 Oct 17;550(1-2):71-78. Epub 2018 Aug 17.

Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA. Electronic address:

The objective of our study was to develop a transdermal patch of 4-benzylpiperidine and to evaluate its in vitro transdermal permeation profile. Appropriate pressure sensitive adhesives and additives were selected based on solubility and slide crystallization studies. Release liners and backing membranes were selected based on their ability to peel without leaving a residue and their affinity to formulation respectively. Drug-in-adhesive patches developed were investigate for their in vitro drug permeation over 48 h across dermatomed human skin using Franz diffusion cells. Silicone based pressure sensitive adhesive along with colloidal silicon dioxide as viscosity builder, fluoropolymer coated membranes as the release liner and polyester based membranes as backing were chosen to develop a drug in silicone adhesive patch. Polyisobutylene adhesive based patch was developed with drug in polyisobutylene adhesive, along with oleic acid and oleyl alcohol as permeation enhancers, polyester for the release liner and polyethylene as backing. Among the patches developed, polyisobutylene adhesive based patch with higher drug concentration exhibited superior transdermal permeation (1608.5 ± 53.4 µg/cm over 48 h). The final patch was further tested for uniformity in coat weight, shear strength, tack and peel adhesion.
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http://dx.doi.org/10.1016/j.ijpharm.2018.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195313PMC
October 2018

Effects of chemical and physical enhancement techniques on transdermal delivery of 3-fluoroamphetamine hydrochloride.

Int J Pharm 2017 Aug 19;528(1-2):452-462. Epub 2017 Jun 19.

Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, 30341, USA. Electronic address:

The present study investigated the passive transdermal delivery of 3-fluoroamphetamine hydrochloride (PAL-353) and evaluated the effects of chemical and physical enhancement techniques on its permeation through human skin. In vitro drug permeation studies through dermatomed human skin were performed using Franz diffusion cells. Passive permeation of PAL-353 from propylene glycol and phosphate buffered saline as vehicles was studied. Effect of oleic acid, maltose microneedles, ablative laser, and anodal iontophoresis on its transdermal permeation was investigated. Infrared spectroscopy, scanning electron microscopy, calcein imaging, confocal laser microscopy, and histology studies were used to characterize the effects of chemical and physical treatments on skin integrity. Passive permeation of PAL-353 (propylene glycol) after 24h was found to be 1.03±0.17μg/cm. Microneedles, oleic acid, and laser significantly increased the permeation to 7.35±4.87μg/cm, 38.26±5.56μg/cm, and 523.24±86.79μg/cm (p<0.05), respectively. A 548-fold increase in drug permeation was observed using iontophoresis as compared to its passive permeation from phosphate buffered saline (p<0.05). The characterization studies depicted disruption of the stratum corneum by microneedles and laser treatment. Overall, transdermal permeation of PAL-353 was significantly enhanced by the use of chemical and physical enhancement techniques.
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http://dx.doi.org/10.1016/j.ijpharm.2017.06.041DOI Listing
August 2017

The serotonin 5-HT receptor and the non-addictive nature of classic hallucinogens.

J Psychopharmacol 2017 01 15;31(1):127-143. Epub 2016 Nov 15.

2 Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, Atlanta, USA.

Classic hallucinogens share pharmacology as serotonin 5-HT, 5-HT, and 5-HT receptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area-nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT receptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.
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http://dx.doi.org/10.1177/0269881116677104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445387PMC
January 2017

Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates.

J Neurosci 2013 Aug;33(33):13367-74

Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30322, USA.

Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways.
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http://dx.doi.org/10.1523/JNEUROSCI.1437-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742924PMC
August 2013

Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates.

J Sleep Res 2013 Oct;22(5):581-8

The objective of the present study was to further elucidate the mechanisms involved in the wake-promoting effects of psychomotor stimulants. Many previous studies have tightly linked the effects of stimulants to dopamine neurotransmission, and some studies indicate that serotonin 2A receptors modulate these effects. However, the role of dopamine in arousal is controversial, most notably because dopamine neurons do not change firing rates across arousal states. In the present study, we examined the wake-promoting effects of the dopamine-releaser amphetamine using non-invasive telemetric monitoring. These effects were evaluated in rhesus monkeys as a laboratory animal model with high translational relevance for human disorders of sleep and arousal. To evaluate the role of dopamine in the wake-promoting effects of amphetamine, we used in vivo microdialysis targeting the caudate nucleus, as this approach provides clearly interpretable measures of presynaptic dopamine release. This is beneficial in the present context because some of the inconsistencies between previous studies examining the role of dopamine in arousal may be related to differences between postsynaptic dopamine receptors. We found that amphetamine significantly and dose-dependently increased arousal at doses that engendered higher extracellular dopamine levels. Moreover, antagonism of serotonin 2A receptors attenuated the effects of amphetamine on both wakefulness and dopamine overflow. These findings further elucidate the role of dopamine and serotonin 2A receptors in arousal, and they suggest that increased dopamine neurotransmission may be necessary for the wake-promoting effects of amphetamine, and possibly other stimulants.
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http://dx.doi.org/10.1111/jsr.12045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808463PMC
October 2013

Effects of methamphetamine self-administration on actigraphy-based sleep parameters in rhesus monkeys.

Psychopharmacology (Berl) 2013 May 22;227(1):101-7. Epub 2012 Dec 22.

Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Atlanta, GA 30329, USA.

Rationale: Sleep disorders and substance abuse are highly comorbid. Although methamphetamine is a very commonly abused drug, to the best of our knowledge, no study has evaluated its effects on sleep during drug use and abstinence under well-controlled conditions in laboratory animals.

Objectives: The objective of this study was to examine the effects of methamphetamine self-administration on sleep-like measures in nonhuman primates.

Methods: Adult male rhesus monkeys (Macaca mulatta; n = 4) self-administered methamphetamine (0.01 and 0.03 mg/kg/injection, i.v.) under a fixed-ratio 20 schedule of reinforcement (60-min sessions once a day, 5 days per week) for 5 weeks. Sleep-like measures were evaluated with Actiwatch monitors before, during, and after each period of drug self-administration.

Results: Both doses of methamphetamine reliably maintained self-administration. Methamphetamine (0.03 mg/kg) increased derived measures of latency to sleep onset and sleep fragmentation, and decreased sleep efficiency compared to abstinence, and higher methamphetamine intake predicted worse sleep quality. However, sleep normalized immediately after the discontinuation of methamphetamine self-administration.

Conclusions: Methamphetamine markedly disrupted sleep-like measures; however, methamphetamine self-administration did not disrupt sleep quality during subsequent periods of drug abstinence.
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http://dx.doi.org/10.1007/s00213-012-2943-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622170PMC
May 2013

Neuroimaging and drug taking in primates.

Psychopharmacology (Berl) 2011 Jul 1;216(2):153-71. Epub 2011 Mar 1.

Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30329, USA.

Rationale: Neuroimaging techniques have led to significant advances in our understanding of the neurobiology of drug taking and the treatment of drug addiction in humans. Neuroimaging approaches provide a powerful translational approach that can link findings from humans and laboratory animals.

Objective: This review describes the utility of neuroimaging toward understanding the neurobiological basis of drug taking and documents the close concordance that can be achieved among neuroimaging, neurochemical, and behavioral endpoints.

Results: The study of drug interactions with dopamine and serotonin transporters in vivo has identified pharmacological mechanisms of action associated with the abuse liability of stimulants. Neuroimaging has identified the extended limbic system, including the prefrontal cortex and anterior cingulate, as important neuronal circuitry that underlies drug taking. The ability to conduct within-subject longitudinal assessments of brain chemistry and neuronal function has enhanced our efforts to document long-term changes in dopamine D2 receptors, monoamine transporters, and prefrontal metabolism due to chronic drug exposure. Dysregulation of dopamine function and brain metabolic changes in areas involved in reward circuitry have been linked to drug taking behavior, cognitive impairment, and treatment response.

Conclusions: Experimental designs employing neuroimaging should consider well-documented determinants of drug taking, including pharmacokinetic considerations, subject history, and environmental variables. Methodological issues to consider include limited molecular probes, lack of neurochemical specificity in brain activation studies, and the potential influence of anesthetics in animal studies. Nevertheless, these integrative approaches should have important implications for understanding drug taking behavior and the treatment of drug addiction.
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http://dx.doi.org/10.1007/s00213-011-2222-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232674PMC
July 2011

Acute brain metabolic effects of cocaine in rhesus monkeys with a history of cocaine use.

Brain Imaging Behav 2010 Dec;4(3-4):212-9

Division of Neuroscience, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.

Cocaine addiction involves an escalation in drug intake which alters many brain functions. The present study documented cocaine-induced changes in brain metabolic activity as a function of cocaine self-administration history. Experimentally naive rhesus monkeys (N = 6) were given increasing access to cocaine under a fixed-ratio schedule of intravenous (i.v.) drug self-administration. PET imaging with F-18 labeled fluorodeoxyglucose (FDG) was used to measure acute intramuscular (i.m.) cocaine-induced changes in brain metabolism in the cocaine-naïve state, following 60 sessions under limited-access conditions (1 h/day), following 60 sessions under extended-access conditions (4 h/day), and following 4 weeks of drug withdrawal. In the cocaine-naïve state, cocaine-induced increases in brain metabolism were restricted to the prefrontal cortex. As cocaine exposure increased from limited to extended access, metabolic effects expanded throughout the frontal cortex and were induced within the striatum. Conversely, cocaine-induced activation was far less robust following withdrawal. The results highlight a progressive expansion of the metabolic effects of cocaine to include previously unaffected dopamine innervated brain regions as a consequence of cocaine self-administration history. The identification of brain regions progressively influenced by drug exposure may be highly relevant toward efforts to develop treatments for cocaine addiction.
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http://dx.doi.org/10.1007/s11682-010-9100-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235327PMC
December 2010

Dopamine transporter-related effects of modafinil in rhesus monkeys.

Psychopharmacology (Berl) 2010 Jun 13;210(3):439-48. Epub 2010 Apr 13.

Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Atlanta, GA 30329, USA.

Rationale: Modafinil is currently used as a treatment for daytime sleepiness.

Objectives: The objectives of this study were to explore the dopamine transporter (DAT)-related effects of modafinil on behavior and in vivo neurochemistry in rhesus monkeys (Macaca mulatta).

Methods: The effects of modafinil (3.0-10 mg/kg, i.v.) were evaluated on locomotor activity, reinstatement of cocaine-maintained behavior, extracellular dopamine levels in the caudate nucleus, and DAT occupancy in the dorsal striatum. Eight subjects were fitted with a collar-mounted activity monitor to evaluate sleep-activity cycles, with 4 days of baseline recording preceding an injection of saline or modafinil (3.0-10 mg/kg). The effects of modafinil (3.0-10 mg/kg) and cocaine (0.3 mg/kg) on reinstatement of behavior that was previously maintained under a second-order schedule of i.v. cocaine delivery were tested in a separate group of subjects (n = 6). Finally, the effects of modafinil (3.0-10 mg/kg) on extracellular dopamine levels and DAT occupancy in vivo were characterized using microdialysis and positron emission tomography, respectively, in a within-subjects design (n = 4).

Results: Modafinil significantly increased nighttime locomotor activity and reinstated cocaine-maintained behavior but did not affect daytime locomotor activity. Modafinil significantly increased striatal extracellular dopamine levels at a dose that resulted in DAT occupancy of 64.4% (putamen) and 60.2% (caudate).

Conclusion: The behavioral and in vivo dopaminergic effects of modafinil are consistent with the profile of a low potency DAT inhibitor and may indicate potential for abuse at high doses.
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http://dx.doi.org/10.1007/s00213-010-1839-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874656PMC
June 2010

Behavioral and neurochemical effects of cocaine and diphenhydramine combinations in rhesus monkeys.

Psychopharmacology (Berl) 2009 Aug 9;205(3):467-74. Epub 2009 May 9.

Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Atlanta, GA 30329, USA.

Rationale: Diphenhydramine (DPH) is an over-the-counter medication used in the treatment of allergic symptoms. While DPH abuse is infrequent, recent preclinical evidence suggests that DPH and cocaine combinations may have enhanced reinforcing properties.

Objective: The aims were to assess the reinforcing effectiveness of cocaine and DPH alone or in combination under a second-order schedule of reinforcement and to examine the neurochemical basis of this interaction using in vivo microdialysis in awake rhesus monkeys.

Materials And Methods: Cocaine (0.03-0.3 mg/kg per injection), DPH (0.3-3.0 mg/kg per injection), or a combination was available under a second-order schedule of intravenous drug reinforcement (n = 3). In microdialysis studies, noncontingent cocaine (0.1-1.0 mg/kg, iv), DPH (1.7 and 3.0 mg/kg, iv), or a combination was administered and changes in extracellular dopamine levels in the caudate nucleus were examined (n = 3-5).

Results: Cocaine and DPH dose-dependently maintained operant responding. Dose combinations of 1.0 or 1.7 mg/kg per injection DPH and 0.03 mg/kg per injection cocaine maintained greater rates of operant responding than 0.03 mg/kg per injection cocaine alone in the second component of the behavioral session. In microdialysis studies, cocaine dose-dependently increased extracellular dopamine levels, but no dose of DPH tested significantly increased dopamine levels above baseline. Moreover, combining DPH with cocaine did not enhance cocaine-induced dopamine increases.

Conclusions: The results support previous evidence of enhanced reinforcement with cocaine and DPH combinations and extend this finding to operant behavior maintained under a second-order schedule. However, the reinforcing effects of DPH alone or in combination with cocaine do not appear to be mediated via changes in dopamine overflow.
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http://dx.doi.org/10.1007/s00213-009-1555-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233267PMC
August 2009

Escalation of food-maintained responding and sensitivity to the locomotor stimulant effects of cocaine in mice.

Pharmacol Biochem Behav 2009 Jul 17;93(1):67-74. Epub 2009 Apr 17.

Division of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30322, USA.

Escalation of drug self-administration is a consequence of extended drug access and is thought to be specifically related to addiction, but few studies have investigated whether intake of non-drug reinforcers may also escalate with extended-access. The goal of these studies was to determine the effects of limited and extended-access to food reinforcers on behavioral and pharmacological endpoints in mice. In distinct groups, responding on a lever was maintained by liquid reinforcement, or nose-poke responses were maintained by sucrose pellets or liquid food in sessions lasting 1 h (limited-access) or 10 h (extended-access). The reinforcing strength of each food, as well as reinforcer-associated cues, was tested before and after extended-access using a progressive ratio (PR) schedule, and locomotor activity in response to novelty and increasing doses of cocaine was assessed in an open field setting in all animals after access to food reinforcers. Escalation of lever-pressing behavior reinforced by liquid food, but not nose-poke behavior reinforced by liquid food or sucrose pellets, was observed across successive extended-access sessions. A concomitant increase in the reinforcing strength of liquid food and its associated cues was apparent in mice that escalated their responding, but not in mice that did not escalate. Finally, extended reinforcer access leading to behavioral escalation was accompanied by an increased sensitivity to the psychostimulant effects of cocaine compared to limited-access. These findings indicate that behavioral escalation can develop as a consequence of extended-access to a non-drug reinforcer, although both the nature of the reinforcer (liquid versus solid food) and the topography of the operant response (lever versus nose-poke) modulate its development. These data also suggest that some of the behavioral and pharmacological corrolaries of behavioral escalation observed following extended-access to drug self-administration may not be due to drug exposure, but rather, may result from basic behavioral processes which underlie operant responding maintained by appetitive stimuli.
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http://dx.doi.org/10.1016/j.pbb.2009.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523326PMC
July 2009

Nonhuman primate neuroimaging and the neurobiology of psychostimulant addiction.

Ann N Y Acad Sci 2008 Oct;1141:176-94

Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.

Neuroimaging techniques have led to significant advances in our understanding of the neurobiology and treatment of drug addiction in humans. The capability to conduct parallel studies in nonhuman primates and human subjects provides a powerful translational approach to link findings in human and animal research. A significant advantage of nonhuman primate models is the ability to use drug-naïve subjects in longitudinal designs that document the neurobiological changes that are associated with chronic drug use. Moreover, experimental therapeutics can be evaluated in subjects with well-documented histories of drug exposure. The in vivo distribution and pharmacokinetics of drug binding in brain have been related to the time-course of behavioral effects associated with the addictive properties of stimulants. Importantly, the characterization of drug interactions with specific protein targets in brain has identified potential targets for medication development. Neuroimaging has proven especially useful in studying the dynamic changes in neuronal function that may be associated with environmental variables. Last, neuroimaging has been used effectively in nonhuman primates to characterize both transient and long-lasting changes in brain chemistry associated with chronic drug exposure. Although there is some evidence to suggest neurotoxicity in humans with long histories of stimulant use, parallel studies in nonhuman primates have not identified consistent long-term changes in such neurochemical markers. Collectively, the results of these studies of nonhuman primates have enhanced our understanding of the neurobiological basis of stimulant addiction and should have a significant impact on efforts to develop medications to treat stimulant abuse.
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http://dx.doi.org/10.1196/annals.1441.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585996PMC
October 2008