Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion

Abstract

Chronic abuse of methamphetamine leads to cognitive dysfunction and high rates of relapse, paralleled by significant changes of brain dopamine and serotonin neurotransmission. Previously, we found that rats with extended access to methamphetamine self-administration displayed enhanced methamphetamine-primed reinstatement of drug-seeking and cognitive deficits relative to limited access animals. The present study investigated whether extended access to methamphetamine self-administration produced abnormalities in dopamine and serotonin systems in rat forebrain. Rats self-administered methamphetamine (0.02-mg/i.v. infusion) during daily 1-h sessions for 7 to 10 days, followed by either short-(1-h) or longaccess (6-h) self-administration for 12 to 14 days. Lever responding was extinguished for 2 weeks before either reinstatement testing or rapid decapitation and tissue dissection. Tissue levels of monoamine transporters and markers of methamphetamine-induced toxicity were analyzed in several forebrain areas. Long-access methamphetamine self-administration resulted in escalation of daily drug intake (ϳ7 mg/kg/ day) and enhanced drug-primed reinstatement compared with the short-access group. Furthermore, long-, but not shortaccess to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex and dorsal striatum. In contrast, only minor alterations in the tissue levels of dopamine or its metabolites were found, and no changes in markers specific for dopamine terminals or glial cell activation were detected. Our findings suggest that persistent methamphetamine seeking is associated with region-selective changes in DAT levels without accompanying monoaminergic neurotoxicity. Greater understanding of the neuroadaptations underlying persistent methamphetamine seeking and cognitive deficits could yield targets suitable for future therapeutic interventions.Methamphetamine (Meth) abuse in humans can quickly develop into a chronic relapsing disorder, accompanied by a wide range of neuropsychological deficits. For example, Meth addicts display impairments in memory functions, cognitive and psychomotor performance, as well as increased impulsivity and aggressive behavior (for reviews, see Nordahl et al., 2003;Scott et al., 2007). Human brain imaging studies provide evidence that these neuropsychological deficits are paralleled by significant changes in brain dopaminergic and serotonergic neurotransmitter systems, as well as altered general metabolic activity in basal ganglia and frontal cortices (for review, see Chang et al., 2007). In particular, chronic Meth abuse reduces the density of dopamine transporters (DAT) in the striatum and (to a lesser extent) in the frontal Article, publication date, and citation information can be found at

Methamphetamine Self-Administration Causes Persistent Striatal Dopaminergic Alterations and Mitigates the Deficits Caused by a Subsequent Methamphetamine Exposure

“…Furthermore, and in contrast to effects of binge METH treatment (Hadlock et al, 2010), no increases in GFAP immunoreactivity, a marker of astrocytic activation and neuronal damage, were found after METH self-administration. This is consistent with previous reports that indicate self-administration produces adaptations that differ from the effects of binge METH treatment (Schwendt et al, 2009;Brennan et al, 2010).…”

“…The findings of the current study are generally consistent with the neuroadaptations reported in Schwendt et al (2009) after METH self-administration. In particular, METH exposure persistently decreased DAT, without altering GFAP, TH, or VMAT-2 immunoreactivity in the striatum.…”

“…In particular, METH exposure persistently decreased DAT, without altering GFAP, TH, or VMAT-2 immunoreactivity in the striatum. Similar to the findings of Schwendt et al (2009) and Brennan et al (2010), no significant decreases in DA content were seen 8 days after self-administration in animals when 0.12 or 0.06 mg per infusion was administered. In contrast, decreases in DA content were observed after self-administration of the higher dose (0.24 mg/infusion) of METH.…”

“…Some investigators (Schwendt et al, 2009;Krasnova et al, 2010), but not all (Stefanski et al, 2002;Shepard et al, 2006;Brennan et al, 2010), reported persistent dopaminergic deficits caused by self-administration. For example, Schwendt et al (2009) reported relatively small "neuroadaptations" that were specific to the DAT. In contrast, Krasnova et al (2010) reported larger deficits in several monoaminergic markers, including the DAT.…”

Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

“…However, there exists a large literature indicating methamphetamineglutamate interactions in mediating high-dose methamphetamine-induced neuronal toxicity within the forebrain (Abekawa et al, 1994;Battaglia et al, 2002;Burrows et al, 2000;Davidson et al, 2007;Golembiowska et al, 2003;Marshall et al, 1993;Simões et al, 2007Simões et al, , 2008Sonsalla et al, 1989;Tata and Yamamoto, 2007). Although these latter studies are relevant to cellular processes induced by very heavy methamphetamine use, they fail to assess the potential role for glutamate in the establishment of methamphetamine self-administration when drug intake is relatively low (eg, Gass et al, 2009;Schwendt et al, 2009;Shepard et al, 2006, Stefanski et al, 1999). …”