Interactions between Cocaine and the Putative Allosteric Dopamine Transporter Ligand SRI-31142

Abstract

Drugs that inhibit the dopamine (DA) transporter (DAT) include both therapeutic agents and abused drugs. Recent studies identified a novel series of putative allosteric DAT inhibitors, but the in vivo effects of these compounds are unknown. This study examined the abuse-related behavioral and neurochemical effects produced in rats by SRI-31142 [2-(7-methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine], one compound from this series. In behavioral studies, intracranial self-stimulation (ICSS) was used to compare the effects produced by SRI-31142, the abused and nonselective DAT inhibitor cocaine, and the selective DAT inhibitor GBR-12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine]. In neurochemical studies, in vivo microdialysis was used to compare the effects of SRI-31142 and cocaine on levels of DA and serotonin in nucleus accumbens (NAc). The effects of SRI-31142 in combination with cocaine were also examined in both procedures. In contrast to cocaine and GBR-12935, SRI-31142 failed to produce abuse-related increases in ICSS or NAc DA; instead, SRI-31142 only decreased ICSS and NAc DA at a dose that was also sufficient to block cocaine-induced increases in ICSS and NAc DA. Pharmacokinetic studies suggested low but adequate brain penetration of SRI-31142, in vitro binding studies failed to identify likely non-DAT targets, and in vitro functional assays failed to confirm DA uptake inhibition in an assay of DAT-mediated fluorescent signals in live cells. These results indicate that SRI-31142 does not produce cocaine-like abuse-related effects in rats. SRI-31142 may have utility to block cocaine effects and may warrant further study as a candidate pharmacotherapy; however, the role of DAT in mediating these effects is unclear, and side effects may be a limiting factor.

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

“…These findings suggest that cocaine, DAT inhibitors, or D 1 R agonists each potentiate the rewarding effects of eICSS and imply that these drugs have rewarding effects of their own. In contrast, withdrawal from chronic cocaine or amphetamine administration is associated with depression‐like effects and deficits in brain reward function, as assessed by BSR threshold elevation or a rightward/downward shift of eICSS 56–59 . Based on these findings, if a test drug produces a cocaine‐like leftward or upward shift in ICSS curve, we interpret the drug to be rewarding or reward enhancing.…”

Synthetic Cathinone Analogues Structurally Related to the Central Stimulant Methylphenidate as Dopamine Reuptake Inhibitors

“…4-(4-(Dimethylamino)­phenyl)-1-methylpyridinium (APP + ) acts as a substrate at the monoamine transporters and therefore was used to examine the effects of the compounds on APP + -induced signals (3 μM) at hDAT as previously described . APP + does not fluoresce on its own but only when it is taken up by cells and undergoes interactions with intracellular components . The fluorescence intensity was measured in FlpIn-TRex HEK293 cells stably expressing hDAT and plated in 96-well imaging plates.…”

“…An epifluorescence microscope (Olympus IX70) equipped with a monochromator (Polychrome V), digital EMCCD camera (Andor), and a pressurized perfusion system (Automate Scientific) was used to monitor the activity of DAT in live cells which were exposed to APP + as described previously . The DsRed fluorescent signal was used to find the focal plane of the cell monolayer, and then the APP + signal was measured using wavelengths of 460 nm for excitation and 540 nm for emission at a 10 Hz acquisition rate. , The imaging solution (IS) used for the experiment consisted of 130 NaCl, 4 KCl, 1 MgCl 2 , 2 CaCl 2 , 5 glucose, 10 Hepes, in mM, and the pH was adjusted to 7.3 using NaOH. Cells were exposed to IS for 10 s, then exposed to the test compound for 30 s, and then exposed to the test compound plus APP + for 30 s. Each well was exposed to a single concentration of the test compound, and control wells without a test compound were run every experimental day to define the 100% APP + uptake.…”

“…In addition, we prepared and examined the des -keto analogue of 4 (i.e., 5 ) to determine if the keto group of 4 (or if the ester function of 1 ) is important for DAT transporter activity. The compounds were examined as DAT reuptake inhibitors competing for the uptake of the fluorescent nonselective DAT substrate APP + as previously reported . Additional testing confirmed that none behaved as releasing agents; all behaved as DAT reuptake inhibitors.…”

Cocaethylene: When Cocaine and Alcohol Are Taken Together

“…An appropriate number of dopamine molecules are needed at any given time to activate these receptors appropriately, and this dopamine balance is systematically regulated by the brain. Cocaine actively interferes with the brain’s efforts to achieve and maintain optimal dopamine levels by occupying the dopamine transporters, the proteins by which the brain’s dopamine-producing cells use to retrieve excess dopamine molecules [ 23 ]. By allowing these dopamine molecules to accumulate, the dopamine receptors become excessively stimulated [ 22 ].…”