CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

Abstract

Agonist-replacement therapies have been successfully used for treatment of opiate and nicotine addiction, but not for cocaine addiction. One of the major obstacles is the cocaine-like addictive potential of the agonists themselves. We report here an atypical dopamine (DA) transporter (DAT) inhibitor, CTDP-32476, that may have translational potential for treating cocaine addiction. In vitro ligand-binding assays suggest that CTDP-32476 is a potent and selective DAT inhibitor and a competitive inhibitor of cocaine binding to the DAT. Systemic administration of CTDP-32476 alone produced a slow-onset, long-lasting increase in extracellular nucleus accumbens DA, locomotion, and brain-stimulation reward. Drug-naive rats did not self-administer CTDP-32476. In a substitution test, cocaine self-administration rats displayed a progressive reduction in CTDP-32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine. Pretreatment with CTDP-32476 inhibited cocaine self-administration, cocaineassociated cue-induced relapse to drug seeking, and cocaine-enhanced extracellular DA in the nucleus accumbens. These findings suggest that CTDP-32476 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.

Optogenetic brain‐stimulation reward: A new procedure to re‐evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter‐Cre mice

“…Therefore, in the present study, we determined whether cocaine produces a similar effect in oICSS. Consistent with our previous finding with eICSS, 27,49 systemic administration of cocaine produced a significant dose‐dependent increase in the number of lever responses for oICSS and upward shifted the stimulation–response curve compared with vehicle (Figure 1G). Two‐way ANOVA with repeated measures for cocaine dose and stimulation frequency revealed significant main effects for cocaine treatment ( F 2,10 = 64.13, p < 0.001) and frequency ( F 5,25 = 21.2, p < 0.001), and a dose × frequency interaction ( F 10,50 = 6.7, p < 0.001).…”

Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders

“…After stable cocaine self-administration was achieved as defined in the SI Materials and methods, the effects of JJC8-088 or JJC8-091 on cocaine (0.5 mg/kg/infusion) self-administration under FR2 or PR were evaluated. This dose of cocaine is located in the middle of the descending limb of the selfadministration dose-response curve [17,18], which is important for evaluating whether a test compound produces an enhancement or inhibition of cocaine's action. Additional groups were used to evaluate the reinforcing efficacy of JJC8-088 or JJC8-091 alone in drug-naive rats or in rats with a cocaine selfadministration history.…”

“…1a, b, right panels). Of note, compounds that are either cocaine-like or block the effects of cocaine can produce a similar reduction in cocaine self-administration under low FR (FR1, FR2) reinforcement by reinforcer substitution [18] or attenuated drug reward [27], respectively. Therefore, we further evaluated the effects of these two compounds on break-point for cocaine self-administration under a PR schedule of reinforcement, an index of drug reinforcing strength and/or motivation to seek drug [28].…”

Computational Systems Pharmacology-Target Mapping for Fentanyl-Laced Cocaine Overdose

“…For example, dopamine transporter (DAT) inhibitors, D3 receptor (D3R) antagonists, and μOR antagonists all have been reported to be effective in the therapeutic treatment of cocaine and opioid addiction. [6][7][8][9][10][11] Of note, D3R and μOR belong to class A of G-protein coupled receptors (GPCRs), which is the largest family of trans-membrane proteins, targeted by 30−40% of marketed drugs. 12 Moreover, ligands of other GPCRs are also reported to show potential therapeutic effects regarding drug abuse, including muscarinic acetylcholine receptor M4, 13 γ-amino-butyric acid type B receptor (GABAB), [14][15][16][17] metabotropic glutamate receptor 2 (mGluR2), [18][19][20] metabotropic glutamate receptor 5 (mGlu5), [21][22][23][24][25] trace amine-associated receptor 1 (TAAR1), [26][27][28][29] adenosine A2A receptor (A2aR), [30][31][32] cannabinoid 1-receptor (CB1R), 33,34 and cannabinoid 2-receptor (CB2R).…”