Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity

Abstract

Major depressive disorder is a prevalent disease, and current pharmacotherapy is considered to be inadequate. It has been hypothesized that a triple reuptake inhibitor (TRI) that activates dopamine (DA) neurotransmission in addition to serotonin and norepinephrine (NE) circuitries may result in enhanced antidepressant effects. Here, we investigated the pharmacological effects of a serotonin-preferring TRI-amitifadine (EB-1010, formerly DOV 21947). The effects of amitifadine (10 mg/kg ip.) on extracellular concentrations of monoamines and their metabolites in rat brain regions were investigated using the in vivo microdialysis technique. The effects of amitifadine on locomotor activity and stereotyped behavior were also evaluated. A major metabolite of amitifadine, the 2-lactam compound, was investigated for inhibition of monoamine uptake processes. Amitifadine markedly and persistently increased extracellular concentrations of serotonin, NE, and DA in prefrontal cortex. The extracellular concentrations of DA were also increased in the DA-rich areas striatum and nucleus accumbens. The extracellular concentrations of the metabolites of serotonin, 5-hydroxyindoleacetic acid, and DA, 3,4-dihydroxyphenylacetic and homovanillic acid, were also markedly decreased in brain regions. Amitifadine did not increase locomotor activity or stereotypical behaviors over a broad dose range. The lactam metabolite of amitifadine weakly inhibited monoamine uptake. Thus, amitifadine increased extracellular concentrations of serotonin, NE, and DA, consistent with TRI. Although amitifadine significantly increased DA in the nucleus accumbens, it did not induce locomotor hyperactivity or stereotypical behaviors. The enhancement of serotonin, NE, and DA in rat brain regions associated with depression suggest that amitifadine may have novel antidepressant activity.

Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats

“…However, doses of amitifadine that increased NAc DA produced even larger increases in NAc 5HT levels. Similar results were obtained for effects of amitifadine on DA and 5HT levels in prefrontal cortex [20], and evidence suggests that 5HT can oppose and limit abuse-related effects of DA [22,32,36,51]. In the ICSS procedure, amitifadine doses up to 3.2 mg/kg had no effect on control ICSS despite the efficacy of 3.2 mg/kg amitifadine to alleviate acid-induced depression of ICSS.…”

“…Amitifadine is a triple uptake inhibitor that occupies this pharmacological niche. It blocks DAT with approximately 5- to 10-fold weaker potency than it blocks SERT and NET [45], and it increased microdialysis measures of DA<NE<5HT in prefrontal cortex of rats without producing significant locomotor activation [20]. The purpose of the present study was to evaluate effects of amitifadine on NAc DA and ICSS in the absence and presence of the IP acid noxious stimulus.…”

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Amitifadine is a novel monoamine uptake inhibitor with similar potencies to inhibit NET and SERT and slightly weaker potency to inhibit DAT (Skolnick et al, 2003;Golembiowska et al, 2012). The behavioral profile of amitifadine in ICSS resembles the profile of MDMA in that amitifadine facilitates low ICSS rates maintained by low frequencies of brain stimulation but also depresses high rates of ICSS maintained by high frequencies (Prins et al, 2012) (L. L. Miller and S. S. Negus, unpublished observations).…”

Amitifadine, a triple monoamine re-uptake inhibitor, reduces nicotine self-administration in female rats

“…Amitifadine has been found to have no appreciable direct effect on neurotransmitter receptors, including nicotinic receptors (Bymaster, unpublished observation). In vivo , amitifadine was active with minimal effective doses of 5 mg/kg in the rat forced swim test and mouse tail suspension antidepressant models (Golembiowska et al, 2012; Skolnick et al, 2003). Consistent with triple re-uptake blockade, amitifadine inhibited ex vivo binding to dopamine, norepinephrine and serotonin transporters and robustly increased these transmitters in prefrontal cortex and dopamine in the striatum of rats (Golembiowska et al, 2012; Lengyel et al, 2008).…”