Sex-Dependent Alterations in the mRNA Expression of Enzymes Involved in Dopamine Synthesis and Breakdown After Methamphetamine Self-Administration

Abstract

Sex differences have been reported in methamphetamine (METH) use disorder in humans and in animal models of METH exposure. Specifically, animals that self-administer METH show sex-related dissimilarities in dopamine (DA) metabolism. To better understand the molecular bases for the differences in DA metabolism, we measured the levels of mRNAs of enzymes that catalyze DA synthesis and breakdown in the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and hippocampus (HIP) of rats that had self-administered METH. There were significant sex differences in control rats, with males having higher basal levels of Th in the PFC and dSTR, Ddc in the NAc, and MaoB in the HIP. In contrast, female controls showed higher basal levels of Comt in the HIP. Male and female METH SA rats also showed some distinct responses to the drug. Specifically, female METH rats exhibited increased expression of Ddc and MaoB, whereas male METH animals showed higher levels of Comt mRNA in the PFC compared to their respective controls. In the NAc, male METH rats displayed decreased Th and Ddc mRNA levels. Together, our results identified sex-dependent and region-specific changes in the mRNA expression of several enzymes involved in DA synthesis and breakdown in response to METH SA, with the majority of differences being observed in the mesocorticolimbic dopaminergic system. These findings are of significant translational importance providing further support for the inclusion of sex as an important variable when planning and evaluating therapeutic interventions against METH use disorder in human clinical studies.

Keywords: Catechol-O-methyltransferase; Dopa-decarboxylase; Dopamine metabolism; Methamphetamine; Monoamine oxidase; Tyrosine hydroxylase.

Fig. 1

(A) Total number of infusions by female and male rats. (B) Infusions by low and high METH takers. (C) METH-seeking behaviors by females and males at withdrawal day 3 (WD3) and at WD30. Key to statistics: *P < .05, **P < .01, ***P < .001, comparison of control vs METH groups; #P < .05, ##P < .01, ###P < .001, comparison between low and high METH takers; !P < .05, !!P < .01, !!!P < .001, comparison between females and males; $P < .05, $ $P < .01, $ $P < .001 comparison of 1st week of METH or withdrawal day 3. CT, controls; METH, Methamphetamine; LT, low METH takers; HT, high METH takers

Fig. 2

Pathways of Dopamine Metabolism. Solid lines denote the primary pathway for dopamine synthesis and breakdown, whereas dotted lines denote alternate pathways. The red color denotes reactions, metabolites, and reactive oxygen species that are neurotoxic. The figure was created using ACD/ChemSketch (Freeware) 2021.1.3

Fig. 3

Effects of METH SA on the mRNA expression of Tyrosine hydroxylase (Th) and Dopa decarboxylase (Ddc) in the prefrontal cortex (PFC) (A and E), nucleus accumbens (NAc) (B and F), dorsal striatum (dSTR) (C and G) and hippocampus (HIP) (D and H). Key to statistics: * p < .05, ** p < .01, *** p < .001, comparison of control vs METH groups of same sex; # p < .05, ## p < .01, ### p < .001, comparison between low and high METH takers of same sex; ! p < .05, !! p < .01, !!! p < .001, comparison between females and males; CT, controls; LT, low METH takers; HT, high METH takers

Fig. 4

Correlations between total METH intake and mRNA levels (arbitrary unit) for Th in the NAc (A) and dSTR (B), Ddc in the PFC (C) and NAc (D), MaoA in the PFC (E), MaoB in the PFC (F), Aldh1a1 in the dSTR (G) and HIP (H), Comt in the PFC (I) and NAc (J)

Fig. 5

Effects of METH SA on the mRNA levels of monoamine oxidase A (MaoA) and monoamine oxidase B (MaoB) in the PFC (A and E), NAc (B and F), dSTR (C and G) and HIP (D and H). Key to statistics is as in Figure 3

Fig. 6

Effects of METH SA on the levels of Aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA in the PFC (A), NAc (B), dSTR (C) and HIP (D). Key to statistics is as in Figure 3

Fig. 7

Effects of METH SA on the levels of catechol-O-methyltransferase (Comt) mRNA in the PFC (A), NAc (B), dSTR (C) and HIP (D). Key to statistics is as in Figure 3