The Novel Triple Reuptake Inhibitor JZAD-IV-22 Exhibits an Antidepressant Pharmacological Profile without Locomotor Stimulant or Sensitization Properties

Caldarone, Barbara J.; Paterson, Neil E.; Zhou, Jia; Brunner, Daniela; Kozikowski, Alan P.; Westphal, Koen G.C.; Korte-Bouws, G.A.H.; Prins, Jolanda; Korte, S. Mechiel; Olivier, Berend; Ghavami, Afshin

doi:10.1124/jpet.110.174011

Cited by 25 publications

(22 citation statements)

References 38 publications

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“…No data are available on the sexual side effect profile of TRIs, but a recent trial with a TRI (the DOV 216,303 isomer amitifadine) showed no worsening of sexual functioning after chronic treatment of depressed patients [37]. The preclinical data (Figure 3 left column, middle) confirm the lack of sexual side effects of DOV 216,303 at doses that exert antidepressant effects in animal models of depression [36,[38][39][40]. This clearly suggests that 5-HT mediated inhibition of sexual behavior can be overcome by stimulating dopaminergic neurotransmission via dopamine transporter (DAT)-blockade, although a role for noradrenaline cannot be excluded.…”

Section: Sexual Dysfunctionsupporting

confidence: 49%

Sexual Dysfunction, Depression and Antidepressants: A Translational Approach

Olivier¹,

Franco²,

Waldinger³

et al. 2017

Sexual Dysfunction

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Major depression is frequently associated with sexual dysfunctions. Most antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), induce additional sexual side effects and, although effective antidepressants, deteriorate sexual symptoms, which are the main reason that patients stop antidepressant treatment. Many strategies have been used to circumvent the additional sexual side effects, but results are rather disappointing. Recently, new antidepressants have been introduced, vilazodone and vortioxetine, which seem to lack sexual side effects in the early registration trials. Much research with large numbers of depressed patients and adequate methodological tools still has to confirm in daily use the absence of sexual side effects of new antidepressants. Animal models that in an early phase of drug development may predict putative sexual side effects of new antidepressants are extremely useful and could speed up development of new antidepressants. A rat model of sexual behavior is described that has a very high predictive validity for sexual side effects in man. Several characteristics of present antidepressants with regard to sexual dysfunctions are also present in the rat model and establish its validity. The animal model can also be used in the search for new psychotropics without sexual side effects or for drugs with sexual stimulating activity.

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Section: Sexual Dysfunctionsupporting

confidence: 49%

Sexual Dysfunction, Depression and Antidepressants: A Translational Approach

Olivier¹,

Franco²,

Waldinger³

et al. 2017

Sexual Dysfunction

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“…Remarkably, neither noradrenaline (NRI), serotonin (SSRI) nor mixed NE/5-HT reuptake blockers (SNRI) were able to substitute for the tramadol DS, whereas NRIs, but not SSRIs were able to shift the dose-response curve to the left. It is well known that SSRIs are notoriously difficult to train as a DS in rats (Olivier 2015) whereas NRIs create trainable cues (Caldarone et al 2010;Dekeyne et al 2001). Tramadol, via its (-)-enantiomer and (-)-metabolite, has norepinephrine reuptake inhibiting effects that may contribute to its sexual inhibitory effects at higher doses.…”

Section: Discussionmentioning

confidence: 99%

Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects

Olivier¹,

Franco²,

Oosting

et al. 2017

Neuropharmacology

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Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs. Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its μ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties.

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“…[13]. Interestingly, DOV 216,303 exerted these addiction-like effects at doses higher than the effective doses in depression models (5-10 mg/kg versus 20-100 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent rat study showed that DOV 216,303 partially substituted for cocaine in a drug discrimination test and caused a sensitization response at high doses although the doses used in these experiments were higher than the effective doses in depression models [13]. To further explore and characterize the possible abuse potential of DOV 216,303, we compared its effects with cocaine in addiction-related mouse models: acute self-administration, conditioned place preference as well as drug-induced hyperlocomotion.…”

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confidence: 99%

Addiction‐Related Effects of DOV 216,303 and Cocaine: A Comparative Study in the Mouse

Sørensen

Husum

Brennum

et al. 2014

Basic Clin Pharma Tox

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DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking reuptake of dopamine, leading to increased extracellular concentrations of dopamine in the nucleus accumbens. Thus, DOV 216,303 and other triple reuptake inhibitors might be speculated to exhibit abuse potential, limiting their future therapeutic use. To further elucidate potential addictive properties of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216,303 than cocaine were needed to induce hyperlocomotion and increase extracellular accumbal dopamine with effective doses being higher than effective doses used in depression models. Moreover, DOV 216,303 displayed a pharmacokinetic profile with lower potential for addiction than cocaine. Thus, high levels of DAT occupancy were reached slower and decayed more slowly after DOV 216,303 than cocaine administration. The present study shows that acute administration of DOV 216,303 displays some addictive-like properties in mice, but these were less pronounced than cocaine, most likely due to different pharmacokinetic profiles.Triple reuptake inhibitors have been proposed as a novel type of antidepressant drugs that inhibit the reuptake of the three monoamines serotonin, noradrenaline and dopamine via inhibition of their respective transporters SERT, NAT and DAT [1,2]. DOV 216,303 is a prototype of the triple reuptake inhibitors that has shown antidepressant activity in animal models of depression [1,3,4] as well as in a clinical study in depressed patients [5]. However, drugs that block DAT may exert positive reinforcing effects that could lead to addiction [6,7]. Therefore, DOV 216,303 and other triple reuptake inhibitors could possess abuse potential that might seriously limit their use in future treatment of depression. For instance, the highly addictive drug cocaine is a triple reuptake inhibitor that is believed to exert its reinforcing effect via DAT blockade, leading to increase of mesolimbic extracellular dopamine levels [8,9].Several other DAT inhibitors have been found to be reinforcing in animal models of addiction, including GBR 12909, RTI-177, BTCP and AHN 1-005. For instance, GBR 12909 was self-administered in a manner similar to cocaine by rats [6]. RTI-177 maintained self-administration behaviour on a second-o...

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The Novel Triple Reuptake Inhibitor JZAD-IV-22 Exhibits an Antidepressant Pharmacological Profile without Locomotor Stimulant or Sensitization Properties

Cited by 25 publications

References 38 publications

Sexual Dysfunction, Depression and Antidepressants: A Translational Approach

Sexual Dysfunction, Depression and Antidepressants: A Translational Approach

Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects

Addiction‐Related Effects of DOV 216,303 and Cocaine: A Comparative Study in the Mouse

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