Amphetamine neurotoxicity (or the opposite)

[Alex K Chen]

https://onlinelibrary.wiley.com/doi/10.1111/acel.14087

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Pairwise comparisons (with Sidak corrections) further revealed that cortical spine density was significantly reduced in untreated aged rats compared to the density in untreated young animals (p = 1.694e-6). Comparisons of the two AMPH-treated groups with the untreated groups revealed that the drug increased cortical spine density significantly in aged rats (p = 6.541e-10), resulting in a spine density in aged rats that was similar to the density in the young rats. In contrast, AMPH did not increase spine density in the young rats (Figure 5b).

FIGURE 5

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Chronic amphetamine treatment augments dendritic spine density and favors a morphological shift toward mature spines in aged Fischer 344 rats. (a) Representative example of Golgi staining of basal dendrites in layers II/III of the prelimbic cortex (PL) and in the hippocampal dentate gyrus (DG) of control and amphetamine (AMPH)-treated groups. (b, c) Spine density in layer II/III of the PL and in the DG of the hippocampus. Each individual point represents the mean of three randomized dendritic segments from each rat for density analyses (n = 5–6 rats per group). Each animal is represented by a different color. ****p < 0.0001. (d, e) Analysis of shifts in the relative abundance of long thin and mushroom spines (classified as described in Section 2) after AMPH treatment in layer II/III of the PL (d) and in the DG of the hippocampus (e) **p < 0.01 compared with the corresponding vehicle control groups and young versus aged.

Similarly, in the hippocampus (Figure 5c), a mixed model analysis revealed a significant main effect of age [F_(1,88.885) = 16.021, p = 1.30e-4], and a significant interaction between age and drug [F_(1,88.885) = 25.591, p = 2.25e-6]. As in the cortex, pairwise comparisons (with Sidak corrections) revealed that hippocampal spine density was significantly reduced in untreated aged rats compared to untreated young rats (p = 2.317e-8). Comparisons between the AMPH treatment groups with the untreated control groups revealed that AMPH increased spine density significantly in the aged rats (p = 1.359e-9) but not in the young rats.

Morphological analyses of spines in the prelimbic cortex (Figure 5d) revealed that AMPH treatment induces spine remodeling characterized by a decrease in long thin (immature/transient) spines and an increase in mushroom (stable mature) spines in aged rats. A three-way ANOVA (spine subtype × age × treatment) analyzing the percentage of spines within each experimental group indicated a significant main effect between spine subtype × age interaction [F_(1,38) = 8.839; p = 0.0051] and significant main effect between all three factors (subtype × age × drug) [F_(1,38) = 35.82; p < 0.0001]. Post hoc comparisons indicated that in comparison with young rats, aged rats displayed a significant decrease in mushroom spines (p = 0.0012) concomitant with an upregulation in long thin immature spines (p = 0.004). These findings are consistent with previous studies demonstrating structural reorganization occurring in normal aging (Dickstein et al., 2007). Importantly, chronic AMPH upregulated the number of mushroom spines in comparison with untreated aged controls (p = 0.0012), a phenomenon that was not observed in the young rats.

Similarly, in the hippocampus (Figure 5e), a three-way ANOVA analyzing spine distribution revealed a significant effect between spine subtype and age [F_(1,20) = 5.73; p = 0.0266] and a significant main effect between all three factors [spine subtype × drug × age; F_(1,16) = 17.19; p = 0.0008]. Similar to the findings in the prelimbic cortex, post hoc comparisons revealed that untreated aged animals displayed a decrease in mushroom spine density compared to young controls (p = 0.0084) that is rescued by AMPH treatment (p = 0.0012). Together, these data indicate that the unfavorable loss of dendritic mushroom spines associated with normal aging can be improved by AMPH treatment (Figure 5e and Figure S2).

 

 

Edited June 3 by Alex K Chen