The most sensitive neurodevelopmental period for the effects of methamphetamine on creating predisposition to drug addiction in adulthood

Psychostimulants, including methamphetamine (MA), have neurotoxic effect, especially, if they are targeting CNS during its critical periods of development. Prenatal/neonatal MA exposure (5 mg/ml/kg) during gestation and/or lactation makes adult rats more sensitive to acute injection to the drug with the same mechanism of action. However, it is still not known which of gestation/lactation stage is the most sensitive to this effect. This study could clarify which of the gestational stage during human pregnancy is the most suited for the treatment of drug-addicted pregnant women. Drug-seeking behavior of adult male and female rats was tested in Conditioned Place Preference (CPP) test. Eight groups of male and eight groups of female rats were tested in adulthood: rats, whose mothers were exposed to MA (5 mg/ml/kg) or saline (SA, 1 ml/kg) during the first half of gestation period (GD 1-11), the second half of gestation period (GD 12-22) and neonatal period (PD 1-11) simulating 1^st, 2^nd and 3^rd trimester, respectively. In order to do so, we compared indirect neonatal applications via the exposed dams with the group of rat pups that received MA or SA directly by injections. Our data demonstrated that application of MA in dose 5 mg/ml/kg during conditioning resulted in increased drug-seeking behavior, but this effect was not affected by prenatal drug exposure. Only neonatal MA exposure influenced creating drug addiction in adulthood. Exposure during early lactation period caused the most significant changes in number of entries and the time spent in the chambers associated with drug administration. Finally, stage of later gestation and early neonatal development seems to be crucial for administration of MA. In conclusion, results suggest that the most significant neurotoxic effects of MA were precisely within the second and third trimester when underway development of monoaminergic nerve terminals in structures responsible for drug-induced alterations in drug-seeking behavior.

Audience take away:

• Correlations in human and rat neuro-ontogeny
• Effects of psychostimulants drugs on neurodevelopment
• Model of creating drug-seeking behavior in experimental studies
• Sex differences in drug abuse and drug-seeking behavior
• Sex differences in pharmacokinetics and pharmacodynamics of psychostimulants