Abstract
Triple reuptake inhibitors (TRIs) that block the dopamine transporter (DAT), norepinephrine transporter, and serotonin transporter are being developed as a new class of antidepressant that may have better efficacy and fewer side effects compared with traditional antidepressants. We describe a novel TRI, 2-[4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethylsulfanyl]-1-(3-methylpiperidin-1-yl)-ethanone (JZAD-IV-22), that inhibits all three monoamine transporters with approximately equal potency in vitro. (+/−)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride (DOV 216,303), a TRI shown to be an effective antidepressant in a clinical trial, shows reuptake inhibition similar to that of JZAD-IV-22 in vitro. Furthermore, both JZAD-IV-22 and DOV 216,303 increase levels of dopamine, norepinephrine, and serotonin in the mouse prefrontal cortex when administered by peripheral injection. JZAD-IV-22 and DOV 216,303 exhibited antidepressant-like efficacy in the mouse forced-swim and tail-suspension tests at doses that increased neurotransmitter levels. Because development of DAT inhibitors could be hindered by abuse liability, both JZAD-IV-22 and DOV 216,303 were compared in two assays that are markers of abuse potential. Both JZAD-IV-22 and DOV 216,303 partially substituted for cocaine in a drug discrimination assay in rats, and high doses of DOV 216,303 produced locomotor sensitization in mice. JZAD-IV-22 showed no evidence of sensitization at any dose tested. These results demonstrate that JZAD-IV-22 is a TRI with antidepressant-like activity similar to that of DOV 216,303. The striking feature that distinguishes the two TRIs is that locomotor sensitization, a common underlying feature of drugs of abuse, is seen with DOV 216,303 but is completely lacking in JZAD-IV-22. These findings may have implications for the potential for abuse liability in humans.
Footnotes
This work was supported by the National Institutes of Health National Institute of Mental Health [Grant MH078433].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.174011.
-
ABBREVIATIONS:
- TRI
- triple reuptake inhibitor
- JZAD-IV-22
- 2-[4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethylsulfanyl]-1-(3-methylpiperidin-1-yl)-ethanone
- DOV 216,303
- (+/−)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride
- DAT
- dopamine transporter
- NET
- norepinephrine transporter
- SERT
- serotonin transporter
- DA
- dopamine
- NE
- norepinephrine
- 5-HT
- serotonin
- PFC
- prefrontal cortex
- C57
- C57BL/6J
- BALB
- BALB/cJ
- D
- drug
- V
- vehicle
- HPLC
- high-performance liquid chromatography
- ANOVA
- analysis of variance.
- Received August 12, 2010.
- Accepted September 22, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|