Sex-Dependent Changes in Striatal Dopamine Transport in Preadolescent Rats Exposed Prenatally and/or Postnatally to Methamphetamine

Abstract

Methamphetamine (MA) is the most commonly used psychostimulant drug, the chronic abuse of which leads to neurodegenerative changes in the brain. The global use of MA is increasing, including in pregnant women. Since MA can cross both placental and haematoencephalic barriers and is also present in maternal milk, children of chronically abused mothers are exposed prenatally as well as postnatally. Women seem to be more vulnerable to some aspects of MA abuse than men. MA is thought to exert its effects among others via direct interactions with dopamine transporters (DATs) in the brain tissue. Sexual dimorphism of the DAT system could be a base of sex-dependent actions of MA observed in behavioural and neurochemical studies. Possible sex differences in the DATs of preadolescent offspring exposed to MA prenatally and/or postnatally have not yet been evaluated. We examined the striatal synaptosomal DATs (the activity and density of surface expressed DATs and total DAT expression) in preadolescent male and female Wistar rats (31-35-day old animals) exposed prenatally and/or postnatally to MA (daily 5 mg/kg, s.c. to mothers during pregnancy and lactation). To distinguish between specific and nonspecific effects of MA on DATs, we also evaluated the in vitro effects of lipophilic MA on the fluidity of striatal membranes isolated from preadolescent and young adult rats of both sexes. We observed similar changes in the DATs of preadolescent rats exposed prenatally or postnatally (MA-mediated drop in the reserve pool but no alterations in surface-expressed DATs). However, prenatal exposure evoked significant changes in males and postnatal exposure in females. A significant decrease in the activity of surface-expressed DATs was found only in postnatally exposed females sensitized to MA via prenatal exposure. MA applied in vitro increased the fluidity of striatal membranes of preadolescent female but not male rats. In summary, DATs of preadolescent males are more sensitive to prenatal MA exposure via changes in the reserve pool and those of preadolescent females to postnatal MA exposure via the same mechanism. The combination of prenatal and postnatal MA exposure increases the risk of dopaminergic deficits via alterations in the activity of surface-expressed DATs especially in preadolescent females. MA-mediated changes in DATs of preadolescent females could be still enhanced via nonspecific disordering actions of MA on striatal membranes.

Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice

“…There are known differences in dopamine reuptake control, responses to amphetamines and DAT function between male and female rodents [37][38][39] . Furthermore, there are reports of sex differences in the behavioral and physiological effects of different DAT dysfunctions [40][41][42][43] . The strongest difference we observed was in the response to amphetamine of female DAT-Cre KI mice, which not only did not display amphetamine-induced hyperlocomotion, but indeed reduced their activity in response to the stimulant.…”

Methamphetamine Consumption during Pregnancy – Effects on Child Health

“…Methamphetamines are transported directly into the cell, and thus, neurotoxicity of methamphetamine is observed to be much higher as compared to cocaine. Furthermore, female animals seem to be more vulnerable to some aspects of methamphetamine abuse than males [32,33]. Recent human data seem to confirm the higher vulnerability of women as compared to men [34,35].…”

The Adverse Effects of Prenatal METH Exposure on the Offspring: A Review

“…Sirova indicated that the combination of prenatal and postnatal METH exposure increases the risk of dopaminergic deficits by altering the activity of surface-expressed DATs, and that male mice were more sensitive. Additionally, changes in the fluidity of striatal membranes may significantly reduce the activity of surfaceexpressed DATs in female mice (Sirova et al, 2016). It should be noted that degeneration of dopaminergic neurons and monoamine neurotransmitter deficiency was observed in METH-exposed offspring (Salisbury et al, 2009).…”