Elsevier

Biological Psychiatry

Volume 57, Issue 6, 15 March 2005, Pages 640-646
Biological Psychiatry

Original articles
The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects

https://doi.org/10.1016/j.biopsych.2004.12.007Get rights and content

Background

(2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that blocks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. Using positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce >50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT blockade by radafaxine in human brain.

Methods

PET and [11C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o) in 8 controls. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel.

Results

DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. Blockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No behavioral or cardiovascular effects were observed.

Conclusions

The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have reinforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict abuse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics.

Section snippets

Subjects

Eight healthy male subjects, 31 ± 6 years of age (mean ± SD), were studied. Written informed consent was obtained from all subjects after a complete description of the study and following the guidelines set by the institutional review board at Brookhaven National Laboratory (Upton, New York).

PET scan

The PET studies were carried out with an HR+ tomograph (resolution 4.5 × 4.5 × 4.5 mm full width half-maximum, 63 slices), with [11C]cocaine used as a DAT ligand (Fowler et al 1989). Methods for positioning

Results

Radafaxine significantly blocked DAT, as assessed by significant differences in the Bmax/Kd measures in caudate [F(4,28) = 8.7; p = .0001], putamen [F(4,28) = 13.7; p < .0001], and ventral striatum [F(4,28) = 6.6; p = .0007] (Figure 1,Table 1). Post hoc Dunnett test at the experimentwise error rate of .05 showed that with respect to baseline the differences were significant for all but the 1-hour measure in caudate and ventral striatum and were significantly different for all time points in

Discussion

This study shows that radafaxine has a relatively low potency for blocking the DAT and exhibits slow kinetics in the human brain. At the proposed therapeutic dose, it blocked an average of 20%–22% of the DAT after a single dose. Moreover, the maximal blockade in any one subject was 33%. The low levels of DAT blockade achieved with radafaxine contrast markedly with the levels of DAT blockade induced by the DAT blocker methylphenidate (MP), which at the oral doses used therapeutically occupies on

References (39)

  • R.C. Kessler et al.

    Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey

    Arch Gen Psychiatry

    (1994)
  • R.W. Lam et al.

    Combining antidepressants for treatment-resistant depressionA review

    J Clin Psychiatry

    (2002)
  • F.R. Levin et al.

    Bupropion treatment for cocaine abuse and adult attention-deficit/hyperactivity disorder

    J Addict Dis

    (2002)
  • K.P. Lindsey et al.

    Effects of dopamine transporter inhibitors on cocaine self-administration in emission tomography neuroimaging

    J Pharmacol Exp Ther

    (2004)
  • J. Logan et al.

    Distribution volume ratios without blood sampling from graphical analysis of PET data

    J Cereb Blood Flow Metab

    (1996)
  • J. Logan et al.

    Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects

    J Cereb Blood Flow Metab

    (1990)
  • J. Logan et al.

    Effects of blood flow on [11C]raclopride binding in the brainmodel simulations and kinetic analysis of PET data

    J Cereb Blood Flow Metab

    (1994)
  • L. Miller et al.

    A comparison of bupropion, dextroamphetamine, and placebo in mixed-substance abusers

    Psychopharmacology (Berl)

    (1983)
  • I.D. Montoya et al.

    Open-label pilot study of bupropion plus bromocriptine for treatment of cocaine dependence

    AM J Drug and Alcohol Abuse

    (2002)
  • Cited by (47)

    • Characterizing the environmentally benign nature of chemical processes: green chemistry metrics

      2022, Contemporary Chemical Approaches for Green and Sustainable Drugs
    • Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons

      2017, Neuropharmacology
      Citation Excerpt :

      JHW 007 exhibits an association rate for DAT that is ∼10 × slower than that of cocaine (Desai et al., 2005), and can take hours to produce maximal enhancement of nucleus accumbens DA following an i.p. injection (Tanda et al., 2009). Consistent with the behavioral effects of these DAT inhibitors, slow onset of action can generally be associated with reduced abuse liability (Volkow et al., 2005). Additionally, R-modafinil and JHW 007 have sustained effects on extracellular DA levels (Loland et al., 2012; Tanda et al., 2009), in contrast with cocaine which produces a rapid increase in DA followed by a rapid decrease back to baseline (Tanda et al., 2009).

    • Serotonin-dopamine interactions: implications for the design of novel therapeutic agents for psychiatric disorders

      2008, Progress in Brain Research
      Citation Excerpt :

      Indeed bupropion has not been shown to demonstrate any reinforcing properties (Volkow et al., 2005). A slow and long lasting DAT blockade, such as that observed with radafaxine in PET studies (Volkow et al., 2005), may indeed avoid the potential for abuse liability. DOV and the Mayo foundation have suggested that triple re-uptake inhibitors, which display a reduced activity at DAT compared to that at SERT and NET, may possess a reduced potential for abuse liability (Shaw et al., 2007).

    View all citing articles on Scopus
    View full text