Methamphetamine exposure during pregnancy at pharmacological doses produces neurodevelopmental and behavioural effects in rat offspring

Abstract

In recent years methamphetamine (MA) use has become more prevalent, and of particular concern is its growing popularity of MA among women of childbearing age. However, to date, studies examining MA effects on the developing offspring in laboratory animals are limited. Thus, the aim of this study was to determine if in utero MA exposure in rats at pharmacological doses can have a negative impact on neonatal neurodevelopment and behaviour. Pregnant Sprague-Dawley dams (n=10 dams/group) received MA (0, 0.625, 1.25, 2.5mg/kg) once daily via oral gavage from gestational day 7 to 21. Maternal body weight, food and water consumption were recorded daily. A range of standard neurodevelopment parameters was examined in the offspring during the neonatal period. There were no neurodevelopmental deficits observed with offspring exposed to 0.625mg/kg MA, in fact, there were enhancements of neurodevelopment in some parameters at this low dose. However, exposure to the 1.25mg/kg MA dose resulted in significant impairments in surface righting reflex and forelimb grip in both sexes. Exposure to the 2.5mg/kg MA dose resulted in a significant reduction in ano-genital distance in males, and in both sexes resulted in delayed fur appearance and eye opening, impairments in surface righting reflex and negative geotaxis, and a reduction in body length. In conclusion, this study demonstrates that pharmacologically relevant doses of MA can have profound dose-related effects on neonatal outcome. If extrapolated to the clinical scenario this will give cause for concern regarding the risks associated with this drug of abuse at relatively low doses.

Detrimental effects of self-administered methamphetamine during pregnancy on offspring development in the rat

“…This observation is in contrast to the human (Good et al, 2010; Smith et al, 2006) and rodent literature (Acuff-Smith et al, 1996, Cho et al, 1991, McDonnell-Dowling et al, 2014, 2015b, 2016) showing that METH use/administration during pregnancy can lead to inadequate weight gain seen in the present study. Multiple reasons could account for the similarities in weight gain.…”

“…The latter results are in contrast to the human literature, where in utero METH-exposed newborns were found to be small for their gestational age (Minnes et al, 2012; Smith et al, 2003) and similar findings of decreased birthweight have been reported in other rodent studies (McDonnell-Dowling et al, 2014, 2015b; Slamberova et al, 2005). While this lack of difference can likely be explained by factors already described (e.g., daily dose, mode of administration, maternal health), it also suggests that moderate doses of METH throughout pregnancy, provided that it is self-administered, do not hinder appropriate growth and weight development of offspring after birth.…”

“…Starting on PND1, pups and dams were weighed daily and their overall health was assessed (i.e., fur appearance of dam, lack of chromodacryorrhea in dam, milk visible in pup’s stomach, pups age-appropriately active and warm to the touch). Daily, each pup was assessed for achievement of species-specific developmental milestones as described in Table 1 (adapted from McDonnell-Dowling et al, 2014). Maternal pup-directed and self-directed behavior (see Table 2) was assessed from PND1–14 for one hour, twice daily - immediately before the transition to the light portion of the cycle (7:00–8:00 hrs) and at the usual start time of the self-administration session (12:00–13:00 hrs) – using the scan sampling method described in Rüedi-Bettschen et al, (2004).…”

“…Notably, repeated administration of more moderate METH doses (e.g., 2.5 – 5mg/kg), before and throughout pregnancy, also has been shown to have profound effects on dams and offspring. For instance, daily, non-contingent administration of METH at moderate doses (5mg/kg) throughout pregnancy has been shown to reduce pup-directed maternal care (Slamberova et al, 2005) and delay pup development (McDonnell-Dowling et al, 2014, 2015b). As adults, METH-exposed offspring demonstrated increased impulsivity (Lloyd et al, 2013), increased nociception (Hruba et al, 2010a), increased disposition to drug abuse (Slamberova et al, 2012) and disruptions in learning and memory (Hruba et al, 2010b).…”

Effect of the environmental enrichment on the severity of psychological dependence and voluntary methamphetamine consumption in methamphetamine withdrawn rats

“…Although, previous studies have shown that EE reduced selfadministration and seeking behaviors of amphetamine and cocaine [11,12], MDMA (Ecstasy)-induced CPP [1]. Therefore, relatively low doses of oral METH in our study causes rewarding effects in the METH/SE rats, similar to human and animal studies [8,19]. In this study, the rats had free access to water and METH which preferred METH to water, reflecting an incentive demand for the drug in TBC model.…”