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

Abstract

Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.

β‐Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents

“…For the optical ICSS experiment, DAT‐cre mice were injected with adeno‐associated virus carrying ChR2‐EGFP (AAV5‐EF1α‐DIO‐ChR2‐EGFP) and implanted with bilateral custom‐made optical fibres (200‐μm inner diameter, N.A. 0.22; Doric Lenses, Quebec, Canada) targeted at the VTA (AP − 3.1, ML ± 0.8, DV − 4.25; Han et al, ; Jordan, Humburg, et al, ; Newman et al, ).…”

“…Mice were gently connected to a cable attached to an optical swivel, which was in turn connected to a 473‐nm laser tuned for channelrhodopsin (ChR2) stimulation. Computer software controlled a pulse generator that controlled the lasers (Han et al, ; Jordan, Humburg, et al, ; Newman et al, ).…”

Monoamine transporters: structure, intrinsic dynamics and allosteric regulation

“…DAT and SERT are similar in terms of sequence and structure 2,6 and, not surprisingly, SERT also transport DA 48 , many drugs that bind SERT also bind DAT 49 , and there is a close correlation between the actions of DAT and those of SERT, as well as those of NET 91,92 . While SSRIs are successful in selectively targeting SERT over DAT and NET 48 , and atypical DAT inhibitors have proven useful against cocaine-abuse disorder 74,[93][94][95] , future challenges must still be addressed, some of which are briefly described below.…”

Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?

“…Indeed, all of these compounds were able to block and reduce DA uptake, an effect highly correlated to their affinity to DAT, as demonstrated by voltammetry studies in rats and mice (Keighron et al, 2019b;Newman et al, 2019). Moreover, their varying ability to enhance the stimulation of elicited DA release in voltammetry studies was unrelated to their affinity for DAT (Keighron et al, 2019b;Newman et al, 2019). These effects once more suggest that compounds that prefer or stabilize an inward facing conformation of DAT would produce limited, if any, cocaine-like effects (Keighron et al, 2019a,b;Giancola et al, 2020;Slack et al, 2020).…”

“…It is worth noting that the varying effects on stimulation of DA levels were not a result of an altered efficacy as DAT blockers. Indeed, all of these compounds were able to block and reduce DA uptake, an effect highly correlated to their affinity to DAT, as demonstrated by voltammetry studies in rats and mice (Keighron et al, 2019b;Newman et al, 2019). Moreover, their varying ability to enhance the stimulation of elicited DA release in voltammetry studies was unrelated to their affinity for DAT (Keighron et al, 2019b;Newman et al, 2019).…”