Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change

Abstract

Rationale Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT-inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change. Methods We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place-conditioning in rats among cocaine and four BZT analogs with Cl-substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring. Results Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, IP), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning. Conclusions The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.

Preference for Distinct Functional Conformations of the Dopamine Transporter Alters the Relationship between Subjective Effects of Cocaine and Stimulation of Mesolimbic Dopamine

“…The present study suggests a safer pharmacological profile for AHN2-005 compared to methylphenidate due to its reduced cocaine-like effects. The lower abuse-liability of BZT-analogs has been reported previously (16, 37, 40-45) which is consistent with the present findings.…”

“…In contrast, full cocaine-like subjective effects were not produced by atypical DUIs at any dose or pretreatment time producing that same increase. A previous study similarly found that increases in DA levels of 65% over basal DA values are sufficient for place conditioning by cocaine, though insufficient for several atypical DUIs (37), which produced maximal increases in DA levels from 138 to 277% over basal values. In the present study, AHN1-055 and AHN2-005 produced cocaine-like subjective effects in rats only sporadically at some pre-session treatment times at the highest doses, whereas JHW007 did not substitute for cocaine at any dose or pretreatment time.…”

Preclinical Efficacy of N-Substituted Benztropine Analogs as Antagonists of Methamphetamine Self-Administration in Rats

“…The differences between BZT analogs and standard DA indirect agonists were obtained in all subjects with each training drug. Combined with the absence of place conditioning with these (Li et al, 2005;Velázquez-Sánchez et al, 2009 or other BZT analogs (Li et al, 2011;Tanda et al, 2013), the results are consistent with reduced or minimal abuse liability of BZT analogs.…”

Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter

“…This decrease in potency is a “preference” only in as much as cocaine-like stimulants show a substantially greater decrease in potency with the closed conformation. Alternatively it could be said that the BZT and rimcazole analogs are more tolerant to DAT conformation than are the cocaine-like stimulants (Tanda et al, 2013). As discussed by Loland et al (2008) a reasonable interpretation is that none of these compounds stabilize a conformation identical to the most dominating conformation of Y335A, but rather stabilize conformations that are more similar to Y335A than those promoted by the cocaine analogs.…”