This Medications Development Center (MDC) for cocaine pharmacotherapy renewal has evaluated over 25 new medications, introduced many new technologies (fMRI, pharma MRI, SPECT, genetics), and facilitated multidisciplinary collaborations among clinical pharmacology, laboratory medicine, neuroimaging, and molecular genetics. We have 78 publications in the past 4 years, covering cocaine genetics (GABA transporter) to vaccines and opiate and nicotine research collaborations with the Chinese National Institute on Drug Dependence. In our continuation we will focus on medication development by modulating norepinephrine (NE) and dopamine (DA) and propose six Specific Aims. 1. To conduct human laboratory cocaine- and methamphetamine (MA)-administration studies with 4 new agents for safety and efficacy: RTI-336 (DA transporter blocker), SY117 (adenosine 2a inhibitor to increase DA activity), and two novel agents, YPK10A and JD-Tic (kappa opiate antagonist) (Proj 1). 2. To conduct two clinical trials of agents modulating NE activity through alpha 1-NE blockade (prazosin and carvedilol) or NE reduction by inhibiting dopamine beta hydroxylase (Proj 2 &3). 3. To test for NE genetic matching of patients to the 3 medications in our two clinical trials. 4. To continue pilot research focused on human genetics for matching new NE and other agents to effective cocaine &MA pharmacotherapies. 5. To attract and train new drug abuse pharmacotherapy investigators through our Center's Core facilities and projects. 6. To disseminate our findings through education and international collaborations.
Cocaine- and MA-dependence are major public health problems in the United States. No FDA-approved treatments for cocaine- or methamphetamine-dependence exist. A greater knowledge of the basic biology of cocaine- and methamphetamine dependence combined with genetic matching for medication response will lead to improved treatments for the disorder.
|Zhang, Xuefeng; Nielsen, David A; Domingo, Coreen B et al. (2018) Pharmacogenetics of Dopamine ?-Hydroxylase in cocaine dependence therapy with doxazosin. Addict Biol :|
|Patriquin, Michelle A; Hamon, Sara C; Harding, Mark J et al. (2017) Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes. Psychiatr Genet 27:178-186|
|Mahoney, James J; Kalechstein, Ari D; De Marco, Anthony P et al. (2017) The relationship between premorbid IQ and neurocognitive functioning in individuals with cocaine use disorders. Neuropsychology 31:311-318|
|Shorter, Daryl; Nielsen, David A; Hamon, Sara C et al. (2016) The ?-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals. Pharmacogenet Genomics 26:428-35|
|Azadeh, Shabnam; Hobbs, Brian P; Ma, Liangsuo et al. (2016) Integrative Bayesian analysis of neuroimaging-genetic data with application to cocaine dependence. Neuroimage 125:813-824|
|Li, Xiaofan; Shorter, Daryl; Kosten, Thomas R (2016) Buprenorphine Prescribing: To Expand or Not to Expand. J Psychiatr Pract 22:183-92|
|Ayanga, Daniel; Shorter, Daryl; Kosten, Thomas R (2016) Update on pharmacotherapy for treatment of opioid use disorder. Expert Opin Pharmacother 17:2307-2318|
|Cao, Bo; Bauer, Isabelle E; Sharma, Ajaykumar N et al. (2016) Reduced hippocampus volume and memory performance in bipolar disorder patients carrying the BDNF val66met met allele. J Affect Disord 198:198-205|
|Bauer, Isabelle E; Soares, Jair C; Nielsen, David A (2015) The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: A systematic review. Am J Addict 24:15-23|
|Liu, Shijing; Maili, Lorena; Lane, Scott D et al. (2015) Serotonin transporter gene promoter polymorphism predicts relationship between years of cocaine use and impulsivity. Psychiatr Genet 25:213-4|
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