Pharmacological Specificity of Effects of N‐Substituted Benztropine Analogs on Cocaine Self Administration in Rats
Authors: Hiranita Takato , Kopajtic Theresa A. , Newman Amy H. , Katz Jonathan L. 
Published: November 2023

Several N‐substituted benztropine (BZT) analogs as atypical dopamine‐uptake inhibitors have been developed as leads for stimulant‐abuse treatments. Among them, N‐allyl (AHN 2‐005), and N‐butyl (JHW 007) analogs of 3α‐[bis(4′‐fluorophenyl)methoxy]‐tropane were reported as more potent in decreasing self‐administration of cocaine or d‐methamphetamine than in decreasing food‐maintained responding, suggesting relative specificity of the N‐substituted BZT analogs as a cocaine antagonist. Further the effects resembled those of pretreatments with a standard DA‐uptake inhibitor combined with a sigma receptor (σR) antagonist. Curiously, these BZT analogs were shown previously to bind to the dopamine transporter (DAT) and σRs. The present study examined selectivity of the BZT analogs by comparing their effects on self‐administration of cocaine, the σ1/2R agonist, DTG, and several other compounds in rats to assess specificity of their effects. Rats were trained to self‐administer cocaine (0.032–1.0 mg/kg/injection, i.v.) and other drugs were substituted for cocaine with and without pretreatments. AHN 2‐005 and JHW 007 produced a dose‐dependent insurmountable antagonism of cocaine (0.032–1.0 mg/kg/injection, 1.0–10 mg/kg, i.p. for the BZTs) and DTG (0.1–3.2 mg/kg/injection, 0.32–3.2 mg/kg, i.p. for the BZTs) self administration. Both AHN 2‐005 and JHW007 were approximately three‐fold more potent in decreasing DTG self administration than in decreasing cocaine self administration. No doses of the BZT analogs that were active against self‐administration of cocaine or DTG (1.0–10 mg/kg, i.p. for the BZTs) were also active against self administration of direct agonists at D1‐like [R(+)‐SKF 81297, (±)‐SKF 82958 (0.00032–0.01 mg/kg/injection, each)], D2‐like [R(−)‐NPA (0.0001–0.0032 mg/kg/injection), (−)‐quinpirole (0.0032–0.1 mg/kg/injection)] dopamine, or μ‐opioid (remifentanil, 0.0001–0.0032 mg/kg/injection) receptors. However, self administration of these direct‐acting agonists was dose‐dependently and selectively antagonized by their known antagonists [SCH 39166 (0.0032–0.032 mg/kg, i.p., a dopamine D1‐like receptor antagonist), L‐741,626 (0.1–1.0 mg/kg, i.p., a dopamine D2‐like receptor antagonist), and (−)‐naltrexone (0.1–3.2 mg/kg, i.p., an opioid receptor antagonist)]. Further, DTG self administration was insensitive to (−)‐naltrexone (3.2–32 mg/kg, i.p.). The present results indicate that the antagonist effects of several N‐substituted BZT analogs are not entirely specific for the reinforcing effects of stimulants, having effects also on DTG self administration. Further the present results suggest σR antagonist effects of the N‐substituted BZT analogs. That the BZT analogs were three‐fold more potent against DTG than cocaine self administration indicates a more complex pharmacology of cocaine compared to DTG self administration, and that cocaine self administration is however sensitive to the activity of the BZT analogs. Thus the present results further support a role of σRs in the abuse liability of cocaine.Support or Funding InformationThis work was supported by NIDA/NIH.