MDMA-induced impairment in primates: antagonism by a selective norepinephrine or serotonin, but not by a dopamine/norepinephrine transport inhibitor

Abstract

Human MDMA (R,S-3,4-methylenedioxymethamphetamine) users display selective cognitive deficits after acute MDMA exposure, frequently attributed to serotonin deficits. We postulated that MDMA will compromise executive function in primates and that an inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET) but not the dopamine (DAT) transporter, will prevent impairment. The potencies of DAT/NET, NET and SERT inhibitors to block transport of [(3)H]MDMA and [(3)H]monoamines were compared in vitro. Subsequently, cynomolgus monkeys (Macaca fasicularis) were trained to stable performance in a reversal learning task. Effects of once-weekly oral or i.m. dose of MDMA (1.5 mg/kg, n = 4) on performance were monitored, alone or after pretreatment with inhibitors of the SERT, DAT or NET (prior to i.m. MDMA). 1) Drug potencies for blocking [(3)H]MDMA or [(3)H]monoamine transport were not consistent; 2) Oral MDMA increased error rates in a cognitive task for up to three days following exposure, whereas intramuscular MDMA prevented subjects from performing the cognitive task on the day of administration, but not on subsequent days; 3) The SERT inhibitor citalopram and the NET inhibitor desipramine, but not the DAT/NET inhibitor methylphenidate, reversed the effects of MDMA on task performance and mandibular movements induced by i.m. MDMA and 4) MDMA altered sleep latency. Oral MDMA impairs executive function in monkeys for several days, a finding of potential relevance to MDMA consumption by humans. Reversal of impaired executive function by a NET inhibitor implicates the NET and norepinephrine in MDMA-induced cognitive impairment and may be relevant to therapeutic strategies.

A neurochemical yin and yang: does serotonin activate and norepinephrine deactivate the prefrontal cortex?

“…In aged rhesus monkeys performing a visual object discrimination task, guanfacine produced improvement in reversal learning at high but not low doses (Steere and Arnsten 1997). In cynomolgus monkeys performing a reversal learning task, pretreatment with citalopram or desipramine, but not methylphenidate, blocked MDMA-induced task impairment (Verrico et al 2008).…”

Interactions between Bupropion and 3,4-Methylenedioxymethamphetamine in Healthy Subjects

“…Specifically, we explored the modulatory role of DA in the psychotropic effects of MDMA by using bupropion pretreatment to block MDMA-induced DA release. Dopamine transporter inhibition prevents the release of DA through the DA transporter induced by MDMA or other amphetamines (Verrico et al, 2008;Simmler et al, 2013b). Dopamine mediates the reinforcing addictive effects of psychostimulants, but its role in the drug-induced subjective effects of different psychostimulants, such as euphoria, is less clear (Wise, 2008).…”

“…In contrast, the role of DA in the acute mechanism of action of MDMA is less clear. In preclinical studies, DA receptor gene deletion in mice had minimal effects on MDMA-induced behavioral changes (Risbrough et al, 2006), and DA transporter inhibition did not alter the acute response to MDMA in rhesus monkeys (Verrico et al, 2008). In contrast, 5-HT and NE have been well documented to mediate most of the acute psychotropic and physiologic effects of MDMA in humans Farre et al, 2007;Hysek et al, 2011Hysek et al, , 2012d.…”

Behavioral Effects and Pharmacokinetics of (±)-3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) after Intragastric Administration to Baboons

“…Structurally, MDMA is related to both amphetamine (Gold et al, 1989;Verrico et al, 2008) and the hallucinogen mescaline (Kovar, 1998). According to the National Survey on Drug Use and Health, lifetime MDMA use in the United States has increased significantly from 4.3% in 2002 to 6.3% in 2010 among people aged $12 years.…”

“…Moreover, differential behavioral and pharmacological profiles as a function of the route of administration for abused drugs are a focus of clinical research [e.g., see Kuramoto et al (2011)], and the pharmacokinetics of MDMA do differ across routes of administration in rats (Baumann et al, 2009). In nonhuman primates, oral MDMA administration increased body temperature while suppressing locomotion in rhesus monkeys (Crean et al, 2007) and increased error rates in a cognitive task in cynomolgus monkeys (Verrico et al, 2008). In human laboratory studies, oral administration of MDMA produced increases in heart rate and blood pressure as well as increases in subjective responses such as energy level, empathy (Kolbrich et al, 2008;Peiró et al, 2013), and feelings associated with increased social behavior (Bedi et al, 2010).…”