Age‐Dependent Differential Responses of Monoaminergic Systems to High Doses of Methamphetamine

Abstract

Abuse of methamphetamine (METH) by adolescents is a major public health issue in the U.S.A. Because of the neurotoxic potential of METH, we examined the response of CNS monoaminergic systems in young (adolescent) animals [postnatal day (PND) 40] to high-dose treatments (10 mg/kg, four injections, 2-h intervals) of this drug and contrasted these effects to those seen in older (young adult) rats (PND 90). Consistent with previous reports, we observed that PND 40 animals did not manifest the long-term (7-day) deficits in extrapyramidal dopamine (DA) parameters observed in PND 90 rats. In contrast, METH-induced rapid (1-h) reduction in the activity of striatal DA transporters occurred in both age groups. In addition, both persistent (7-day) and rapid (1-h) deficits in serotonergic systems (measured as reductions in tryptophan hydroxylase activity) were observed in PND 40 and 90 rats. Age-related differences in METH-induced hyperthermia did not appear to be a principal cause for our observations; however, age-dependent pharmacokinetics of this drug might have contributed to the differential METH monoaminergic responses by PND 40 and 90 animals. Key Words: Methamphetamine -Dopamine -Serotonin-NeurotoxicityDevelopmental-Pharmacokinetic.

Age-Dependent Methamphetamine-Induced Alterations in Vesicular Monoamine Transporter-2 Function: Implications for Neurotoxicity

“…; Spear, 2000), stress-induced gonadarche (Spear, 2000), and/or antioxidant systems (Kim et al, 2002). Changes in dopaminergic systems have also been reported (Araki et al, 1997;Cappon et al, 1997;Kokoshka et al, 2000), although this study is the first to evaluate the impact of methamphetamine on VMAT-2 function during this developmental period.…”

“…Similarly, this highdose methamphetamine regimen leads to a loss of tyrosine hydroxylase-positive terminals in postnatal day 60 and 80 rats but not in postnatal day 40 and younger rats (Pu and Vorhees, 1993). In addition, Kokoshka et al (2000) demonstrated that multiple high-dose administrations of methamphetamine lead to long-term decreases in dopamine transporter activity, tyrosine hydroxylase activity, and the binding of the dopamine transporter ligand WIN35498 in postnatal day 90 rats but not in postnatal day 40 rats. These studies suggest that the persistent dopamine deficits caused by methamphetamine are more apparent in older rats.…”

Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes

“…One possibility is that age differences in pharmacokinetics could account for reduced sensitivity to METH in adolescents, but findings are again mixed. Studies examining plasma and brain levels of stimulants have found that adolescents have lower (Spear and Brake 1983;Kokoshka et al 2000;McCarthy et al 2004;Craig et al 2014), higher (Caster et al, 2005), or similar levels (McCarthy et al, 2004;Caster et al, 2005) compared to adults. Based on the extensive changes occurring in the brain during adolescence (Andersen et al 1997(Andersen et al , 2000Dagher et al 2001;Koss et al 2014;Juraska and Willing 2017), another possibility is that differences in pharmacodynamics (e.g.…”

Escalating Dose Methamphetamine Pretreatment Alters the Behavioral and Neurochemical Profiles Associated with Exposure to a High-Dose Methamphetamine Binge

“…In addition, evidence suggests species-and age-differences in the vulnerability to METH and it appears that some indices may be permanently attenuated (ie only partially recover) depending on the extent and severity of the METH treatment (Ojeda et al, 1980;Lucot et al, 1982;Woolverton et al, 1989;Cappon et al, 1997;Cass and Manning, 1999;Kokoshka et al, 2000;Riddle et al, 2002a). However, when recovery has been demonstrated, the differential rates Escalating dose-binge methamphetamine exposure DS Segal et al apparent for the various markers could indicate that different underlying mechanisms are involved.…”