Sex-Specific Alterations in Dopamine Metabolism in the Brain after Methamphetamine Self-Administration

Abstract

Methamphetamine (METH) use disorder affects both sexes, with sex differences occurring in behavioral, structural, and biochemical consequences. The molecular mechanisms underlying these differences are unclear. Herein, we used a rat model to identify potential sex differences in the effects of METH on brain dopaminergic systems. Rats were trained to self-administer METH for 20 days, and a cue-induced drug-seeking test was performed on withdrawal days 3 and 30. Dopamine and its metabolites were measured in the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and hippocampus (HIP). Irrespective of conditions, in comparison to females, male rats showed increased 3,4-dihydroxyphenylalanine (DOPA) in the PFC, dSTR, and HIP; increased cys-dopamine in NAc; and increased 3,4-dihydroxyphenylethanol (DOPET) and 3,4-dihydroxyphenylacetic acid (DOPAC) in dSTR. Males also showed METH-associated decreases in DA levels in the HIP but increases in the NAc. Female rats showed METH-associated decreases in DA, DOPAL, and DOPAC levels in the PFC but increases in DOPET and DOPAC levels in the HIP. Both sexes showed METH-associated decreases in NAc DA metabolites. Together, these data document sex differences in METH SA-induced changes in DA metabolism. These observations provide further support for using sex as an essential variable when discussing therapeutic approaches against METH use disorder in humans.

Keywords: DA metabolites; dopamine; mesocorticolimbic; methamphetamine; sex differences.

Figure 1

Behaviors of female and male rats after METH SA and during METH-seeking tests. (A) Patterns of daily METH intake behaviors by female and male rats. (B) METH intake by female and male low and high METH takers. (C) Drug-seeking behaviors by female and male rats at WD3 and WD30. Key to statistics: * p < 0.05, ** p < 0.01, female and male METH groups compared with respective saline groups; ! p < 0.05, !!! p < 0.001, comparison of male METH group with female METH group; $ p < 0.05, $$ p < 0.01, $$$ p < 0.001, comparison of daily METH intake of female and male rats compared to METH intake on the first day of SA or comparison of active lever pressing on WD30 compared to WD3. # p < 0.05, ## p < 0.01, ### p < 0.001, comparison between female or male high METH takers vs. low METH takers. All values represent means ± SEM of number of animals indicated in the figure. CT, control saline rats; LT, low METH takers; HT, high METH takers.

Figure 2

Levels of dopamine and its metabolites in the prefrontal cortex (PFC). (A) DOPA, (B) cys_DOPA, (C) DA, (D) DOPAL, (E) DOPET, and (F) DOPAC in female and male METH rats compared to controls after 30 days of withdrawal from METH SA. Key to statistics: * p < 0.05, ** p < 0.01, **** p < 0.0001, comparison between controls vs. low and high METH-taker groups; # p < 0.05, ### p < 0.001, comparison between low and high METH-taker groups; ! p < 0.05, !! p < 0.01, !!!! p < 0.0001, comparison between female and male rats. All values represent means ± SEM of number of animals indicated in the figure. CT, control saline rats; LT, low METH takers; HT, high METH takers.

Figure 3

Content of dopamine and its metabolites in the nucleus accumbens (NAc) after 30 days of withdrawal from METH SA. (A) DOPA, (B) cys_DOPA, (C) DA, (D) cys_DA, (E) DOPAL, (F) DOPET, and (G) DOPAC in female and male rats. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. # p < 0.05, ## p < 0.01. ! p < 0.05, !! p < 0.01, !!! p < 0.001, !!!! p < 0.0001.

Figure 3

Content of dopamine and its metabolites in the nucleus accumbens (NAc) after 30 days of withdrawal from METH SA. (A) DOPA, (B) cys_DOPA, (C) DA, (D) cys_DA, (E) DOPAL, (F) DOPET, and (G) DOPAC in female and male rats. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. # p < 0.05, ## p < 0.01. ! p < 0.05, !! p < 0.01, !!! p < 0.001, !!!! p < 0.0001.

Figure 4

Effect of METH SA and withdrawal in the dorsal striatum (dSTR) dopamine and its metabolites level. (A) DOPA, (B) cys_DOPA, (C) DA, (D) cys_DA, (E) DOPAL, (F) DOPET, and (G) DOPAC in female and male rats. * p < 0.05, ** p < 0.01. # p < 0.05. ! p < 0.05, !! p < 0.01, !!! p < 0.001.

Figure 4

Effect of METH SA and withdrawal in the dorsal striatum (dSTR) dopamine and its metabolites level. (A) DOPA, (B) cys_DOPA, (C) DA, (D) cys_DA, (E) DOPAL, (F) DOPET, and (G) DOPAC in female and male rats. * p < 0.05, ** p < 0.01. # p < 0.05. ! p < 0.05, !! p < 0.01, !!! p < 0.001.

Figure 5

Level of dopamine and its metabolites in the hippocampus (HIP). (A) DOPA, (B) cys_DOPA, (C) DA, (D) DOPAL, (E) DOPET, and (F) DOPAC in female and male METH rats after 30 days of withdrawal from METH SA. * p < 0.05, ** p < 0.01, *** p < 0.001. # p < 0.05, ### p < 0.001. ! p < 0.05, !! p < 0.01, !!! p < 0.001.