Different glial response to methamphetamine- and methylenedioxymethamphetamine-induced neurotoxicity

Abstract

The consequences of the neurotoxic insult induced by 3,4-methylenedioxymethamphetamine (MDMA, an amphetamine derivative with specific action on the serotonergic system) were compared with those of methamphetamine (a derivative with specific action on dopaminergic system) in rats. Both drugs induced a very similar loss of body weight, especially evident 24 h after treatment. Their hyperthermic profile was also very similar and was dependent on ambient temperature, corroborating the thermo-dysregulatory effect of both substances. Methamphetamine (four injections of 10 mg kg(-1) s.c. at 2-h intervals) induced the loss of dopaminergic (35%) but not of serotonergic, terminals in the rat striatum and, simultaneously, a significant increase in striatal peripheral-type benzodiazepine receptor density, pointing to a glial reaction. Evidence for this drug-induced astrogliosis was the increased heat shock protein 27 (HSP27) expression in striatum, cortex and hippocampus. MDMA (20 mg kg(-1) s.c. b.i.d. for 4 days) induced a similar dopaminergic lesion in the striatum 3 days post-treatment, which reversed 4 days later. An important neurotoxic effect on serotonergic terminals was also observed in the cortex, striatum and hippocampus 3 days post-treatment, which partially reversed 4 days later in the striatum and hippocampus. No microglial activation was noticeable at either 3 or 7 days after MDMA treatment. This lack of effect on microglial cells was assessed by [(3)H]PK 11195 binding and OX-6 immunostaining, which were unchanged in the striatum and cortex after MDMA treatment. A non-significant tendency to increase was noted in the hippocampus 3 days after MDMA treatment. Furthermore, in MDMA-treated rats, neither HSP27 expression nor an increase in HSP27 immunoreactivity were detected. This result, together with the lack of increase in glial fibrilliary acidic protein (GFAP) immunoreactivity, indicate no astroglial activation at either 3 or 7 days post-treatment. Without microglial activation, an inflammatory process would not accompany the lesion induced by MDMA. The differences in glial activation between methamphetamine and MDMA observed in the present study could have implications for the prognosis of the injury induced by these drugs.

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

“…The previously reported failure to detect a loss of SERT protein in Western blot analyses is not the sole reason why some have questioned the 5-HT neurotoxic potential of substituted amphetamines. In particular, the fact that MDMA and structurally related drugs (PCA, FEN) do not typically produce signs of glial activation in the context of selective 5-HT deficits (Rowland et al, 1993;O'Callaghan and Miller, 1994;Pubill et al, 2003;Wang et al, 2004Wang et al, , 2005Rothman et al, 2004;Thomas et al, 2004; but see Wilson et al, 1993;Aguirre et al, 1999;Orio et al, 2004) has led some of these investigators to reconsider the notion that substituted amphetamines produce neurotoxic effects. When considering these data, however, it is important to bear in mind that the effects of established 5-HT neurotoxins (5,7-DHT and 5,6-DHT) on glial responses have also been largely negative, particularly in brain regions removed from the site of intracerebral toxin injection (Stagaard et al, 1987;Hardin et al, 1994;Rowland et al, 1993;Bendotti et al, 1994;Dugar et al, 1998; but see Frankfurt et al, 1991;Dugar et al, 1998).…”

Imaging Brain Inflammation with [11C]PK11195 by PET and Induction of the Peripheral-Type Benzodiazepine Receptor after Transient Focal Ischemia in Rats

“…[ 3 H]PK11195 Binding A separate group of rats (n = 18) was used to study [ 3 H]PK11195 binding following a method reported previously (Pubill et al, 2003). We studied controls (n = 4), and ROI-c2 correspond to the homologous contralateral region of infarction and periphery, respectively.…”

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

“…Newer markers, including Fluoro-Jade staining (Schmued and Bowyer, 1997, as well as microglial activation (Thomas et al, 2004, Thomas andKuhn, 2005), increased density of peripheral benzodiazepine receptors and increased expression of heat shock protein 27 (both markers of gliosis) (Pubill et al, 2003), are also in support of METH-induced neurotoxicity.…”

“…For example, MDMA appears to be relatively ineffective in producing reactive gliosis, as indicated by a lack of a pronounced increase in expression or immunoreactivity of GFAP , Pubill et al, 2003, Wang et al, 2004b, although in a single exception, Aguirre and colleagues report an increase in GFAP immunoreactivity in the hippocampus 7 days after MDMA administration (Aguirre et al, 1999). MDMA also does not produce an appreciable increase in the expression of heat shock protein 27, particularly when compared to responses evoked by METH (Pubill et al, 2003).…”