We had previosuly shown that our lead proof-of-concept slow-onset long-acting dopamine transporter (DAT) inhibitor - CTDP30640 - enhances electrical brain-stimulation reward, enhances extracellular dopamine in the reward-related nucleus accumbens locus in the brain, stimulates locomotor activity, and significantly reduces intravenous cocaine self-administration in laboratory rats - all with a very pronounced slow-onset long-acting profile of action. During this same period, we extended our research in this area to include two additional compounds that we designed and synthesized de novo using computer-assisted molecular drug design and a pharmacophore DAT model that we ourselves developed - CTDP31345 and CTDP31346. Because of the high degree of similarity between the chemical structures of CTDP31345 and CTDP31346, a decision was made to run only one of those two compounds through a full range of preclinical animal screening paradigms - namely, CTDP31345. We found that CTDP31345 enhances electrical brain-stimulation reward, enhances extracellular dopamine in the reward-related nucleus accumbens locus in the brain, stimulates locomotor activity, and significantly reduces intravenous cocaine self-administration in laboratory rats - all with a very pronounced slow-onset long-acting profile of action. On a less promising note, we found that CTDP31345 generalizes to cocaine in the drug-discrimination animal behavioral paradigm, produces dramatic locomotor sensitization, and triggers relapse to cocaine-seeking behavior in laboratory rats who have been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. We further found that CTDP31345 itself supports intravenous self-administration, albeit at a much lower rate than cocaine. As we had previously seen with compound CTDP30640, the effects of compound CTDP31345 are additive with those of cocaine. This prompted us to explore the relationship between the fast-onset short-acting opiate heroin and the slow-onset long-acting opiate methadone, the latter of which is well-known to have clinical efficacy as an anti-addiction medication for patients addicted to opiates. We reasoned that investigating the heroin-methadone relationship in our preclinical animal models might shed light on medication development stratgies for cocaine and other psychostimulants. We found that - in contrast to the relationship between cocaine and CTDP30640 or CTDP31345 - methadone pretreatment: 1) dose-dependently inhibited intravenous heroin self-administration with a clear behavioral extinction pattern, 2) dose-dependently inhibited heroin-enhanced brain-stimulation reward, and 3) dose-dependently inhibited heroin-enhanced nucleus accumbens levels of the reward-related and relapse-related neurotransmitter dopamine as measured by in vivo brain microdialysis. This suggests a functional antagonism by methadone of heroin's actions, which may be explained by methadone's ability to produce cellular internalization of the mu opioid receptor. These data suggest that in order to be fully successful, potential anti-cocaine medications should more fully emulate methadone's action - i.e., functionally antagonizing cocaine's actions (perhaps by inducing conformational changes in the dopamine transporter) while at the same time blocking the transporter in a cocaine-like manner (but with slow-onset long-lasting pharmacokinetics) so as to substitute for cocaine and remediate the brain chemical deficiency believed to underlie cocaine hunger and cocaine craving. In addition, we believe that the facts that our compounds CTDP30640 and CTDP31345 show much slower onsets and much longer durations of action (e.g., 96 hours following a single injection) than other DAT inhibitors developed as potential anti-addiction pharmacotherapies (e.g., GBR12909) demonstrate the validity of our pharmacophore drug design model, our molecular drug design procedures, and our medication development strategy. On a purely molecular drug design level, during the reporting period we successfully designed and synthesized new slow-onset long-duration piperidine analogs with increased selectivity for the dopamine transporter, resulting in a new test compound - CTDP32476. During the present reporting period, we found the following: 1) that in vitro ligand binding assays show CTDP32476 to be a potent and selective DAT inhibitor; 2) that CTDP32476 is a competitive inhibitor of cocaine binding to the DAT; 3) that systemic administration of CTDP32476 alone produced a slow-onset, long-lasting increase in nucleus accumbens extracellular dopamine; 4) that systemic administration of CTDP32476 alone produced a slow-onset, long-lasting increase in locomotion; 5) that systemic administration of CTDP32476 alone produced a slow-onset, long-lasting increase in electrical brain-stimulation reward; 6) that drug-naive rats do not self-administer CTDP32476; 7) that, in substitution testing, cocaine self-administration rats display a progressive reduction in CTDP32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine; 8) that pretreatment with CTDP32476 inhibits cocaine self-administration; 9) that pretreatment with CTDP32476 inhibits cocaine-associated cue-induced relapse to drug-seeking; 10) that pretreatment with CTDP32476 inhibits cocaine-enhanced extracellular nucleus accumbens dopamine. These findings suggest that CTDP32476 is a unique DAT inhibitor that not only could satisfy drug hunger through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual - thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction. In addition, during the present reporting period we studied modafinil as a potential anti-addiction pharmacotherapeutic compound. Specifically, we used animal models of self-administration and in vivo brain microdialysis to study the pharmacological actions of R-modafinil and S-modafinil on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-modafinil is more potent and effective than S-modafinil in attenuating nicotine self-administration in laboratory rats. Further, we found that R-modafinili: 1) inhibits intravenous nicotine self-administration; 2) inhibits nicotine-induced relapse to nicotine-seeking behavior; and 3) inhibits nicotine-associated cur-induced drug-seeking behavior. R-modafinil alone neither sustained self-administration in rats previously self-administering nicotine not reinstated extinguished nicotine-seeking behavior. In vivo brain microdialysis experiments showed that R-modafinil alone produced a slow-onset moderate increase in nucleus accumbens dopamine. Pretreatment with R-modafinil dose-dependently blocked nicotine-enhanced nucleus accumbens dopamine in both naive and nicotine self-administering rats, suggesting a dopamine-dependent mechanism underlying mitigation of nicotine's effects. These findings support further investigation of R-modafinil for treatment of nicotine dependence in humans.
| Zhang, Hai-Ying; Bi, Guo-Hua; Yang, Hong-Ju et al. (2017) The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic. Neuropsychopharmacology 42:1871-1883 |
| Xi, Zheng-Xiong; Song, Rui; Li, Xia et al. (2016) CTDP-32,476: A Promising Agonist Therapy for Treatment of Cocaine Addiction. Neuropsychopharmacology : |
| Wang, Xiao-Fei; Bi, Guo-Hua; He, Yi et al. (2015) R-modafinil attenuates nicotine-taking and nicotine-seeking behavior in alcohol-preferring rats. Neuropsychopharmacology 40:1762-71 |
| Xi, Zheng-Xiong; Gardner, Eliot L (2008) Hypothesis-driven medication discovery for the treatment of psychostimulant addiction. Curr Drug Abuse Rev 1:303-27 |
| Gardner, Eliot L (2008) Use of animal models to develop antiaddiction medications. Curr Psychiatry Rep 10:377-84 |
