Medical Pharmacology Commons^™

Targeting The Endocannabinoid System To Reduce Nociception, Lamont Booker

Theses and Dissertations

Pain of various etiologies (e.g., visceral, inflammatory) can be a debilitating disorder that presents a problem of clinical relevance. While it is known that ∆9-tetrahydrocannabinol (THC) the primary psychoactive constituent found in marijuana produces analgesia in various rodent models of pain, its pharmacological properties are overshadowed by its psychomimetic effects. THC is the primary phytocannabinoid found in marijuana though other prevalent constituents such as the phytocannabinoids (e.g., cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), tetrahydrocannabivarin (THCV)) may possess antinociceptive actions without the psychomimetic effects associated with THC. Indeed, these phytocannabinoids act upon the endocannabinoid system (ECS) that is comprised of the …

Electrophysiological Characterization Of Enteric Neurons Isolated From The Immortomouse, Edward G. Hawkins

Theses and Dissertations

The availability of murine genetic models is extremely advantageous to studying gastrointestinal function, but the benefits afforded by studying enteric neurons in mice has been hindered by their accessibility. Fetal (E13) and 2 day post-natal (P2) enteric neuron cell lines (IM-FEN and IM-PEN, respectively) were recently developed from the H-2Kb-tsA58 immortomouse. Our goal was to identify the electrophysiological properties of these cell lines and clarify their utility as a model of enteric neurons. IM-PEN cells stained positively for the neuron specific markers βIII-tubulin and PGP9.5 and were negative for the glial cell marker S100. Detection of mRNA for TRPA1, TRPV1, …

Involvement Of P53 In The S-Phase Checkpoint During Nucleotide Deficiencies, Cortney Heyer

Theses and Dissertations

Several classes of antimetabolites have been developed for the treatment of cancer, including numerous inhibitors of nucleotide biosynthesis. N-(phosphonacetyl)-L-aspartate (PALA) and hydroxyurea (HU) are two antimetabolites that inhibit nucleotide biosynthesis; PALA inhibits de novo pyrimidine synthesis and HU inhibits the conversion of ribonucleotide diphosphates to deoxyribonucleotide diphosphates. Due to the similar mechanisms, it was thought that cancer cells would respond similarly to HU and PALA treatment. However, studies in this dissertation revealed strikingly different responses to either HU or PALA treatment in HCT116 cells. A cytoprotective S-phase arrest was activated upon HU treatment while PALA treatment failed to activate the …

Bionic Technologies Transforming The Science Of Healthcare Delivery, Scott A. Waldman , M.D., Ph.D, Andre Terzic , M.D., Ph.D

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Individualization of patient care is creating an envisioned future in which practitioners wield a new doctor’s bag deploying individual molecular, genetic, cellular, and systems profiles.  These emerging tools are refining traditional paradigms of disease palliation into nuanced patient management algorithms employing prognostic risk stratification, therapeutic response prediction, and adverse event avoidance. Advancing technologies are enabling a shift to more proximal nodes along the continuum of pathobiology. Innovations in biomarker platforms, genomic profiling, and molecular imaging reveal the earliest stages of pathophysiology, limiting systems disruption to cells and tissues while preserving integrated organ function, enabling risk mitigation and disease prevention.  At …

Revised Dose Schema Of Sublingual Buprenorphine In The Treatment Of The Neonatal Opioid Abstinence Syndrome., Walter K Kraft, Kevin Dysart, Jay S Greenspan, Eric Gibson, Karol Kaltenbach, Michelle E Ehrlich

Department of Pharmacology and Experimental Therapeutics Faculty Papers

AIMS: More than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS.

DESIGN: Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine.

SETTING: Large, urban, tertiary care hospital.

PARTICIPANTS: Twenty-four term infants requiring pharmacological treatment for NAS.

MEASUREMENTS: Outcomes were neonatal safety, length of treatment and length of hospitalization.

FINDINGS: Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of …

Year In Review, Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

If examination of journal performance is a surrogate for the vitality of a discipline, the continued ascension of Clinical Pharmacology and Therapeutics (CPT) bodes well for the evolution and practice of human therapeutics in this decade. CPT has excelled as the authoritative, cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy and evaluation of therapeutics in humans. Building on a foundation that established the core tenets, and a framework providing the structural integrity for the field, CPT was conceived by visionary precedent editors and editorial teams who were themselves leaders of …

Serum 25-Hydroxyvitamin D Level And Acute-Phase Reaction Following Initial Intravenous Bisphosphonate., Tarak Srivastava, Hongying Dai, Connie J. Haney, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Clinical Translational Science 2020: Disruptive Innovation Redefines The Discovery-Application Enterprise, Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Vaccines, analgesia, and antibiotics embody some of the most

enduring therapeutic breakthroughs that have transformed

medicine. Building on such fine paradigms of biomedical

innovation, the evolution of technologies has increasingly

sparked spectacular advances across the continuum of wellness

and disease-spanning medical and surgical specialties. Discovery

science—fueled by government and private sector resources—has

systematically instituted the principles of modern healthcare

delivery ensuring that medical practice is based on up-to-date

scientifi c evidence. Th e harmony between science, technology,

and resources has culminated in a golden age of discovery and

translation, eradicating infections, curing cancers, and palliating

endocrine and metabolic diseases. Indeed, …

Analysis Of The Proteome Of Human Airway Epithelial Secretions., Mehboob Ali, Erik P Lillehoj, Yongsung Park, Yoshiyuki Kyo, K Chul Kim

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Airway surface liquid, often referred to as mucus, is a thin layer of fluid covering the luminal surface that plays an important defensive role against foreign particles and chemicals entering the lungs. Airway mucus contains various macromolecules, the most abundant being mucin glycoproteins, which contribute to its defensive function. Airway epithelial cells cultured in vitro secrete mucins and nonmucin proteins from their apical surface that mimics mucus production in vivo. The current study was undertaken to identify the polypeptide constituents of human airway epithelial cell secretions to gain a better understanding of the protein composition of respiratory mucus.

RESULTS: …

Genomic Analysis Of Individual Differences In Ethanol Drinking: Evidence For Non-Genetic Factors In C57bl/6 Mice, Jennifer T. Wolstenholme, Jon A. Warner, Maria I. Capparuccini, Kellie J. Archer, Keith L. Shelton, Michael F. Miles

Pharmacology and Toxicology Publications

Genetic analysis of factors affecting risk to develop excessive ethanol drinking has been extensively studied in humans and animal models for over 20 years. However, little progress has been made in determining molecular mechanisms underlying environmental or non-genetic events contributing to variation in ethanol drinking. Here, we identify persistent and substantial variation in ethanol drinking behavior within an inbred mouse strain and utilize this model to identify gene networks influencing such “non-genetic” variation in ethanol intake. C57BL/6NCrl mice showed persistent inter-individual variation of ethanol intake in a two-bottle choice paradigm over a three-week period, ranging from less than 1 g/kg …

The Effects Of Laropiprant, A Selective Prostaglandin D₂ Receptor 1 Antagonist, On The Antiplatelet Activity Of Clopidogrel Or Aspirin., Aimee Dallob, Wen-Lin Luo, Julie Mabalot Luk, Lisa Ratcliffe, Amy O Johnson-Levonas, Jules I Schwartz, Victor Dishy, Walter K. Kraft, Jan N De Hoon, Anne Van Hecken, Inge De Lepeleire, Waldemar Radziszewski, John A Wagner, Eseng Lai

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time …

Preventing Mother-To-Child Transmission Of Human Immunodeficiency Virus-1 (Hiv-1): Effects Of Intrapartum And Neonatal Single-Dose Nevirapine Prophylaxis And Subsequent Hiv-1 Drug Resistance At Antiretroviral Treatment Initiation, Amanda L. Harmon

CMC Senior Theses

The prevention of mother-to-child transmission is one of the most powerful tools in human immunodeficiency virus type 1 (HIV-1) prevention and has huge potential to improve both maternal and child health. In the absence of any preventative measures, infants born to and breastfed by their HIV-positive mothers have roughly a one-in-three chance of acquiring the infection themselves. HIV can be passed on from mother-to-child during pregnancy, during labor and delivery, and even after during breastfeeding.

Intrapartum and neonatal single-dose nevirapine (sd-NVP) is the foundation of preventing mother-to-child transmission in lower resource settings where it has been used alone or as …

Transdermal And Oral Dl-Methylphenidate-Ethanol Interactions In C57bl/6j Mice, Guinevere Hannah Bell

MUSC Theses and Dissertations

The persistence of attention-deficit/hyperactivity disorder (ADHO) into adulthood has been increasingly recognized over the past few decades and the stimulant drug dl-methylphenidate (MPH) has remained a first-line pharmacotherapeutic agent in the treatment of ADHD. Many adult ADHD patients who are prescribed MPH report concomitant use with ethanol. In humans, coadministration of dl-MPH and ethanol results in pharmacokinetic and pharmacodynamic drug - drug interactions. Ethanol elevates biological concentrations of the pharmacologically active d-MPH isomer and yields the metabolic transesterification product ethylphenidate (EPH). EPH appears to be formed through the actions of carboxylesterase 1 (CES1) which exhibits I-MPH substrate enantioselectivity in both …

Serum Monocyte Chemoattractant Protein-1 In Pancreatic Cancer., Jennifer Sullivan, Qiaoke Gong, Terry Hyslop, Harish Lavu, Galina Chipitsyna, Charles Yeo, Hwyda A Arafat

Department of Surgery Faculty Papers

Background/Aims. Pancreatic ductal adenocarcinoma (PDA) has etiological association with chronic inflammation. Elevated circulating levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), are found in obese individuals. We hypothesized that serum MCP-1 levels are elevated in obese PDA patients. Methods. ELISA was used to analyze MCP-1 serum levels in PDA (n = 62) and intraductal papillary mucinous neoplasms (IPMN) (n = 27). Recursive partitioning statistical analysis investigated the relationship between log MCP-1 and clinicopathological parameters. Results. Log MCP-1 values were significantly (P < 0.05) elevated in patients with BMI ≥ 37.5. In patients with BMI < 37.5, average log MCP-1 values were significantly elevated in PDA patients when compared to IPMN patients. Within the IPMN group, higher log MCP-1 levels correlated with increased age. Recursive partitioning analysis of IPMN versus PDA revealed a strategy of predicting characteristics of patients who are more likely to have cancer. This strategy utilizes log MCP-1 as the primary factor and also utilizes smoking status, gender, and age. Conclusion. MCP-1 is a promising biomarker in pancreatic cancer. The potential of using MCP-1 to distinguish PDA from IPMN patients must be studied in larger populations to validate and demonstrate its eventual clinical utility.

Concurrent Validation Of The Dash And The Quickdash In Comparison To Neck-Specific Scales In Patients With Neck Pain, Saurabh Mehta, Joy Macdermid, Lisa Carlesso, Colleen Mcphee

Physical Therapy Faculty Research

Study Design. Concurrent validity study.

Objective. To examine the validity of the Disabilities of Arm, Shoulder, and Hand (DASH) and the QuickDASH in patients with neck pain in comparison with the Neck Disability Index (NDI), the Cervical Spine Outcome Questionnaire (CSOQ), and the Visual Analogue Scale (VAS) for pain. To examine the agreement between the DASH and the QuickDASH and assess whether the QuickDASH can be used instead of full DASH in patients with neck pain.

Summary of Background Data. NDI is commonly used for measuring neck-related disability in patients with neck pain; but it does not offer to assess …

Microrna-21 Dysregulates The Expression Of Mef2c In Neurons In Monkey And Human Siv/Hiv Neurological Disease., Sowmya V. Yelamanchili, A Datta Chaudhuri, L N. Chen, Huangui Xiong, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

MicroRNAs (miRNAs) play important roles in regulating a plethora of physiological and pathophysiogical processes including neurodegeneration. In both HIV associated dementia in humans and its monkey model SIV encephalitis we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. In situ hybridization of the diseased brain sections revealed induction of miR-21 in neurons. MiR-21 can be induced in neurons by prolonged N-methyl-D-aspartic acid receptor stimulation, an excitotoxic process active in HIV and other neurodegenerative diseases. Introduction of miR-21 into human neurons leads to pathological functional defects. Furthermore, we show that miR-21 …

Antifolate Modulators Of Amp-Activated Protein Kinase Signaling As Cancer Therapeutics, Scott Rothbart

Theses and Dissertations

Since its discovery, it was appreciated that the antifolate pemetrexed had multiple targets within folate metabolism. This laboratory was instrumental in showing that pemetrexed elicited its primary action as a thymidylate synthase inhibitor. Unusual for an antifolate, pemetrexed showed significant clinical activity against malignant pleural mesothelioma and non-small cell lung cancer. Accordingly, the FDA recently issued first-line approvals for pemetrexed in these diseases, leading us to question whether the effects of pemetrexed on other folate-dependent targets could explain this atypical clinical activity of the drug. Studies in this dissertation showed that in addition to thymidylate synthase inhibition, pemetrexed was also …

Identification Of Thioaptamer Ligand Against E-Selectin: Potential Application For Inflamed Vasculature Targeting., Aman P Mann, Anoma Somasunderam, René Nieves-Alicea, Xin Li, Austin Hu, Anil K Sood, Mauro Ferrari, David G Gorenstein, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Active targeting of a drug carrier to a specific target site is crucial to provide a safe and efficient delivery of therapeutics and imaging contrast agents. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. In this study, we identified a thiophosphate modified aptamer (thioaptamer, TA) against E-selectin (ESTA-1) by employing a two-step selection strategy: a recombinant protein-based …

Survival Associated Pathway Identification With Group Lp Penalized Global Auc Maximization., Zhenqiu Liu, Laurence S Magder, Terry Hyslop, Li Mao

Department of Pharmacology and Experimental Therapeutics Faculty Papers

It has been demonstrated that genes in a cell do not act independently. They interact with one another to complete certain biological processes or to implement certain molecular functions. How to incorporate biological pathways or functional groups into the model and identify survival associated gene pathways is still a challenging problem. In this paper, we propose a novel iterative gradient based method for survival analysis with group Lp penalized global AUC summary maximization. Unlike LASSO, Lp (p < 1) (with its special implementation entitled adaptive LASSO) is asymptotic unbiased and has oracle properties 1. We first extend Lp for individual gene identification to group Lp penalty for pathway selection, and then develop a novel iterative gradient algorithm for penalized global AUC summary maximization (IGGAUCS). This method incorporates the genetic pathways into global AUC summary maximization and identifies survival associated pathways instead of individual genes. The tuning parameters are determined using 10-fold cross validation with training data only. The prediction performance is evaluated using test data. We apply the proposed method to survival outcome analysis with gene expression profile and identify multiple pathways simultaneously. Experimental results with simulation and gene expression data demonstrate that the proposed procedures can be used for identifying important biological pathways that are related to survival phenotype and for building a parsimonious model for predicting the survival times.

Cannabinoid Receptors In The 3d Reconstructed Mouse Brain: Function And Regulation, Peter Nguyen

Theses and Dissertations

CB1 receptors (CB1R) mediate the psychoactive and therapeutic effects of cannabinoids including ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent in marijuana. However, therapeutic use is limited by side effects and tolerance and dependence with chronic administration. Tolerance to cannabinoid-mediated effects is associated with CB1R adaptations, including desensitization (receptor-G-protein uncoupling) and downregulation (receptor degradation). The objectives of this thesis are to investigate the regional-specificity in CB1R function and regulation. Previous studies have investigated CB1Rs in a subset of regions involved in cannabinoid effects, but an inclusive regional comparison of the relative efficacies of different classes of cannabinoids to activate G-proteins has not …

The Impact Of Adolescent Nicotine Exposure On Drug Dependence In Adulthood, Mai Alajaji

Theses and Dissertations

Nicotine is one of the first and most commonly abused drugs in adolescence. According to The Center for Disease Control, every day more than 6000 adolescents try their first cigarette and over 3000 of them become daily smokers. Smoking among adolescents is a strong predictor of future drug abuse and dependence in adulthood. A number of studies has suggests that adolescents pre-exposed to nicotine may suffer permanent disruption of the brain’s reward systems through changes in dopamine receptor function. We hypothesize that nicotine exposure during adolescence causes long lasting neurobiological alterations that increase the likelihood of cocaine use in adulthood. …

Cell Death And Sustained Senescence Arrest In Colon Carcinoma And Melanoma Tumor Cells In Response To The Novel Microtubule Poison, Jg-03-14, Jonathan Biggers

Theses and Dissertations

Previous studies from this and other laboratories have shown that the novel microtubule poison, JG-03-14, which binds to the colchicine binding site of tubulin, has the capacity to promote both autophagy and apoptosis in breast tumor cells, as well as interfering with endothelial cell function and potentially disrupting tumor vasculature. The current work was designed to investigate the interaction between JG-03-14 and cell culture models of colon carcinoma and melanoma, specifically HCT116 human colon carcinoma cells and B16F10 murine melanoma cells. In both cases, JG-03-14 promoted death in the bulk of the treated population. FACS analysis, DAPI and TUNEL staining …

Fenotipo Y Genotipo Del Virus De La Diarrea Viral Aislado De Bovinos En El Perú., Mariluz Araínga, Hermelinda Rivera G., Juan Carlos Huaman G., Alberto Manchego S.

Journal Articles: Pharmacology & Experimental Neuroscience

The aim of this study was to determine the phenotype and genotype of Bovine Viral Diarrhoea Virus (BVDV) in Peruvian cattle. During the period 1998-2007, tissues of aborted fetus, blood, serum or plasma samples of bovine with acute infection or persistently infected from dairy herds of various locations in the country were collected and the BVDV antigen was detected by immnunofluorescence or capture ELISA tests, and positive samples were inoculated en BVDV free BT cells and cultured until third passage to determine the biotype. Both animal tissues and third passage of positive samples were tested by a Real Time Reverse …

Biomarkers For Aging, Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen, Thomas S. Foster

Pharmacology and Nutritional Sciences Faculty Patents

A statistical and functional correlation strategy to identify changes in cellular pathways specifically linked to impaired cognitive function with aging. Analyses using the strategy identified multiple groups of genes expressed in the hippocampi of mammals, where the genes were expressed at different levels for several ages. The aging changes in expression began before mid-life. Many of the genes were involved in specific neuronal and glial pathways with previously unrecognized relationships to aging and/or cognitive decline. These identified genes and the proteins they encode can be used as novel biomarkers of brain aging and as targets for developing treatment methods against …

Sizing Up Pharmacotherapy For Obesity., Michael A. Valentino, Andre Terzic, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Obesity has increased over the last 20 years, from a condition affecting only a small portion of populations in developed countries, into a global pandemic. The impact of obesity can be appreciated in the context of the populations at risk, and it is estimated that >1 billion adults worldwide are overweight (BMI >25 kg/m2), 300 million of whom are clinically obese (BMI >30 kg/m2). In the United States, 65% of adults are overweight, and 32.2% of them are obese, a prevalence that has doubled over 20 years. In industrialized countries, obesity rates have tripled, coinciding with adoption of a Western …

Cip4 And Src In Promoting The Migration And Invasion Of Breast Cancers, Christina S. Pichot

Dissertations and Theses (Open Access)

Cellular invasion represents a critical early step in the metastatic cascade, and many proteins have been identified as part of an “invasive signature.” The non-receptor tyrosine kinase Src is commonly upregulated in breast cancers, often in conjunction with overexpression of EGFR. Signaling from this pathway stimulates cell proliferation, migration, and invasion and frequently involves proteins that regulate the cytoskeleton. My data demonstrates that inhibition of Src, using the small-molecule inhibitor dasatinib, impairs cellular migration and invasion. Furthermore, Src inhibition sensitizes the cells to the effects of the chemotherapeutic doxorubicin resulting in dramatic, synergistic inhibition of proliferation with combination treatments. The …

Tamoxifen: Mechanisms Of Resistance, Cyrus Mccoy Adams

Theses and Dissertations (ETD)

The role of estrogen in breast cancer has been recognized for decades. The selective estrogen receptor modulator tamoxifen was the first targeted therapy for the treatment of breast cancer. It was also the first drug approved by the FDA for the reduction of breast cancer risk. While tamoxifen has extended the lives of countless patients with breast cancer, resistance to tamoxifen remains a significant clinical problem. Work over the last two decades has greatly enhanced our understanding of the molecular mechanisms by which breast cancer cells may become resistant to tamoxifen treatment. Here I review our current understanding of the …

The Mechanism Of Mitochondrial Folate Transport By The Mitochondrial Folate Transporter, Scott Alan Lawrence

Theses and Dissertations

The mitochondrial folate transport protein (MFT) functions to transport folates into the mitochondrial matrix. The MFT is a member of a mitochondrial carrier family (MCF) of proteins that have a high degree of sequence and structural similarities, yet they transport vastly different substrates at high specificities. In this dissertation research, the folate-specific transport mechanism of the MFT was explored using experimental and computational techniques. MFT residues that differed from MCF consensus residues in conserved PxD/ExxK/R motifs and at a predicted substrate-binding site common to all MCF proteins were investigated. Site-directed mutagenesis of these anomalous residues in the MFT revealed that …

Differential Roles Of The Two Major Endocannabinoid Hydrolyzing Enzymes In Cannabinoid Receptor Tolerance And Somatic Withdrawal, Joel Schlosburg

Theses and Dissertations

While there is currently active debate over possible therapeutic applications of marijuana and cannabis-based compounds, consistently their primary drawbacks have been the psychoactive properties, dependence, and abuse potential. Prolonged administration of ∆9-tetrahydrocannabinol (THC), the primary psychoactive constituent in marijuana, demonstrates both tolerance and physical withdrawal in both preclinical and clinical studies. Repeated THC administration also produces CB1 receptor adaptations in the form of reduced activation of receptors, along with a downregulation of membrane surface receptors, in many brain regions involved in THC-associated behaviors. The increased need for drug to maintain therapeutic effects, and a withdrawal syndrome following discontinuation of use, …

Modulation Of Cocaine-Like Behavioural Activity By Serotonin Uptake Inhibition Relative To The Effects Of The Novel And Selective Dopamine Transporter Inhibitor, D-84, Angela Batman

Theses and Dissertations

Cocaine dependence is a major health concern worldwide, but despite this high rate of abuse there are currently no approved therapies for cocaine dependence. Replacement pharmacotherapies are one possible approach for treating cocaine dependence, and identification of such therapeutics for cocaine abuse is the long-term goal of this research. Cocaine binds to, and inhibits uptake at the dopamine (DAT), serotonergic (SERT) and noradrenaline (NET) uptake transporters, but studies have shown that cocaine produces its strong behavioural and positive reinforcing effects through inhibition of the DAT. To this end a great number of diverse, non-selective DAT-inhibiting compounds have been investigated as …