Striatal and cortical NMDA receptors are altered by a neurotoxic regimen of methamphetamine

Abstract

Methamphetamine (m-AMPH) treatment produces long-lasting damage to striatal and cortical monoaminergic terminals and may also injure nonmonoaminergic cortical neurons. Evidence suggests that both dopamine (DA) and glutamate (GLU) play crucial roles in producing this damage. We used quantitative autoradiography to examine [3H]mazindol ([3H]MAZ) binding to striatal DA transporters and [3H]GLU binding to N-methyl-D-aspartate (NMDA) receptors in the striatum and cortex 1 week and 1 month after a neurotoxic regimen of m-AMPH. Rats received m-AMPH (4 mg/kg) or saline (SAL) (1 ml/kg) in four s.c. injections separated by 2 h intervals. One week after m-AMPH, the ventral and lateral sectors of the striatum showed the greatest decreases in both [3H]MAZ and [3H]GLU binding, while the nucleus accumbens (NA) showed no significant decreases. One month after m-AMPH, striatal [3H]MAZ binding was still significantly decreased, while NMDA receptor binding had recovered. Surprisingly, the parietal cortex showed a m-AMPH-induced increase in NMDA receptor binding in layers II/III and IV 1 week after m-AMPH and only in layers II/III 1 month after m-AMPH. The prefrontal cortex showed no m-AMPH-induced changes in NMDA receptor binding at either time point. This is the first demonstration that a regimen of m-AMPH that results in long-lasting damage to DA terminals can alter forebrain NMDA receptor binding. Thus, repeated m-AMPH treatments may produce changes in glutamatergic transmission in selected striatal and cortical regions.

Increases in cytoplasmic dopamine compromise the normal resistance of the nucleus accumbens to methamphetamine neurotoxicity

“…DA nerve endings in the NAc are much more resistant to the damaging effects of METH by comparison to the CPu. METH-induced reductions in NAc DA levels are 20-40% of what is seen in CPu (Morgan and Gibb 1980;O'Dell et al 1991;Sabol et al 2001;Wallace et al 2001;Davidson et al 2007) while DAT binding sites (Eisch et al 1992(Eisch et al , 1996 and TH activity (Haughey et al 1999) are not changed in the NAc. The METH-induced formation of high molecular weight DAT complexes that occurs in CPu (Baucum et al 2004) does not occur in the NAc (Hadlock et al 2009), and a non-toxic METH dosing regimen that induces behavioral sensitization lowers DAT density in CPu but not in the NAc (Bjorklund et al 2008).…”

Effect of single and repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat

“…It has been proposed that the long-term effects of Meth depend on the amount of overflow of DA induced by the drug (O'Dell et al 1991), and, in agreement, it has been shown that Meth-induced damage is prevented by inhibition of DA synthesis (Gibb and Kogan 1979;Hotchkiss and Gibb 1980;, DA transport Marek et al 1990), or even by DA receptor antagonism (Sonsalla et al 1986;O'Dell et al 1993). It has been argued, however, that Meth may also increase glutamate (Glu) overflow (Sonsalla et al 1989;Nash and Yamamoto 1992;Stephans and Yamamoto 1994), leading to the hypothesis that there is a synergism between both DA and Glu release, and that this is a requirement for Meth-induced neurotoxicity (Abekawa et al 1994;Eisch et al 1996).…”

“…This effect is perhaps due to a decrease in DA transport (Eisch et al 1996;Fleckenstein et al 1997), required for Meth to be taken up to elicit its effect on DA terminals (Marek et al 1990). The most striking effect of repeated Meth was, however, on K + -evoked inhibitory (GABA) and excitatory (Glu, Asp) amino acid levels, which were increased.…”

“…It has been proposed that not only DA, but also Glu levels have to be increased for Meth to produce neurotoxicity (Abekawa et al 1994;Eisch et al 1996), and that a repetitive regimen of Meth administration is required for producing long-term changes in basal ganglia function (Chapman et al 2001;Wallace et al 2001). Thus, we investigated the effect of repeated Meth doses on neurotransmitter release, evaluated under basal and K + -depolarizing conditions.…”

Running wheel exercise ameliorates methamphetamine‐induced damage to dopamine and serotonin terminals

“…Although Schwendt et al (2009) recently showed that repeated long-access self-administration of mAMPH led to a down-regulation of DAT rather than neurotoxicity, the single-day binge mAMPH regimen used in the present experiments has been shown to produce long-lasting decreases in striatal DA content (Eisch et al, 1992), binding of two different radioligands to striatal DAT (Belcher et al, 2005;Eisch et al, 1996;Schröder et al, 2003), and striatal TH immunoreactivity (Eisch et al, 1996). Thus, we interpret the present decreases in striatal DA markers as representing injury to DA terminals.…”