Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

Abstract

Rationale: Many animal models relevant to the persistent effects of drugs of abuse necessitate the application of interspecies dose scaling procedures to approximate drug administration regimens in humans, but drug self-administration procedures differ in that they allow animal subjects to control their own drug intake. Objectives: This report reviews the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA), its enantiomers, and several structural analogs in rhesus monkeys, paying particular attention to the pharmacological mechanisms of such reinforcing effects, the development of structure activity relationships among these compounds, the stability of MDMA self-administration behavior over time, and the persistent effects of selfadministered MDMA on monoamines. Results: The methylenedioxy amphetamine congeners MDMA, 3, 4-methylenedioxyamphetamine, N-ethyl-3,4-methylenedioxyamphetamine, and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine function as reinforcers in rhesus monkeys, maintaining self-administration behavior greater than that engendered by contingent saline but less than that engendered by traditional psychostimulants. These findings are remarkable as structurally distinct serotonergic hallucinogen-like drugs do not maintain reliable selfadministration in laboratory animals. During prolonged MDMA self-administration, MDMA-maintained responding progressively weakens, and MDMA eventually fails to maintain significant self-administration. The neurochemical correlates of this effect have not yet been identified. Conclusions: Procedures in which MDMA and related compounds are self-administered can be established in rhesus monkeys. These techniques can be used to engender contingent MDMA exposure without resorting to controversial methods of interspecies dose scaling. As such, further application of self-administration methods may provide important new insights into the persistent effects of MDMA on brain and behavior in nonhuman primates.

Estimating the relative reinforcing strength of (±)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine

“…This finding is consistent with previous reports from studies with rats (Ratzenboeck et al 2001;Schenk et al 2003), rhesus monkeys (Beardsley et al 1986;Fantegrossi et al 2002;Fantegrossi 2006;Lile et al 2005) and baboons (Lamb and Griffiths 1987), and with the well-established abuse liability of MDMA (Strote et al 2002;Yacoubian 2003). The study by Lile et al (2005) used a PR schedule similar to the one used in the present study, but with a different progression in response requirement and a shorter TO between injections.…”

Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges

“…The blunted responsiveness to MDMA shown here agrees with previous reports of tolerance to diverse effects of MDMA in rats, including anorexia (Zacny et al, 1990), discriminative stimulus properties (Schechter, 1991, Virden andBaker, 1999), hyperthermia (Shankaran andGudelsky, 1999, Piper et al, 2006) and locomotor activity Geyer, 1992, Brennan andSchenk, 2006). Tolerance to behavioral actions of MDMA is also well documented in non-human primates (Frederick et al, 1995, Frederick and Paule, 1997, Fantegrossi et al, 2004, Fantegrossi, 2007. On the other hand, a number of studies in rodents provide evidence for sensitized responsiveness after repeated MDMA exposure (Poland et al, 1997, Kalivas et al, 1998, Giorgi et al, 2005, suggesting tolerance development is not a universal outcome.…”

“…Tolerance to behavioral actions of MDMA is also well documented in non-human primates (Frederick et al, 1995, Frederick and Paule, 1997, Fantegrossi et al, 2004, Fantegrossi, 2007. On the other hand, a number of studies in rodents provide evidence for sensitized responsiveness after repeated MDMA exposure (Poland et al, 1997, Kalivas et al, 1998, Giorgi et al, 2005, suggesting tolerance development is not a universal outcome.…”

Endocrine and Neurochemical Effects of 3,4-Methylenedioxymethamphetamine and Its Stereoisomers in Rhesus Monkeys

“…Previous studies have used variants of allometric scaling to equilibrate the doses of MDMA administered to experimental animals to human consumption (Mueller et al, 2008). However, these allometric models are sensitive to the pharmacokinetic and corrective factors used and can thus yield highly variable estimates (Yates and Kugler, 1986;Baumann et al, 2007;Fantegrossi, 2007). Furthermore, previous studies have shown that the doses of MDMA voluntarily self-administered by rhesus monkeys (Fantegrossi et al, 2002;Banks et al, 2008) are within the range, on a mg/kg basis, that humans abuse (1-2 mg/kg) (Cole et al, 2002;Harris et al, 2002;Green et al, 2003).…”