Assessment of adolescent neurotoxicity: Rationale and methodological considerations

Abstract

This introduction to the special issue of Neurotoxicology and Teratology on "Risk of neurobehavioral toxicity in adolescence" begins by broadly considering the ontogeny and phylogeny of adolescence, and the potential value of animal models of adolescence. Major findings from the emerging neuroscience of adolescence are then highlighted to establish the importance of studies of adolescent neurotoxicity. A variety of methodological issues that are of particular relevance to adolescent exposures are then discussed. These include consideration of pharmacokinetic factors, inclusion of other-aged comparison group(s), and issues involving timing, route of administration, and exposureinduced alterations in growth rate. Despite such methodological challenges, research to determine whether adolescence is a time of increased vulnerability (or greater resiliency) to specific drugs and environmental toxicants is progressing rapidly, as exemplified by the work presented in the articles of this special issue. Keywordsadolescence; neurotoxicity; behavior; animal models; brain sculpting; pharmacokinetics; drug metabolism; body weight; methodology Most of what we know about neural and behavioral consequences of developmental exposure to drugs and other chemicals is based on exposures during the prenatal and early postnatal period, with little emphasis on exposure periods that subsume adolescence. With the increasing recognition that adolescence is a time of considerable neural restructuring and sculpting of the brain (for review, see Spear, 2000), there likewise has been a growing interest in assessing whether this developmental transition is a vulnerable period for neurotoxicity. This special issue is designed to highlight research examining "the question of whether adolescence is a…. (time) of enhanced neurobehavioral toxic risk associated with exposure to drugs of abuse, therapeutic drugs, hormones and environmental toxicants." By presenting examples of the emerging research in this area, the goal of the special issue is to encourage additional high quality work in this area, and to draw attention to Neurotoxicology and Teratology as an outlet for this research.

Evidence of oxidative stress and mitochondrial dysfunctions in the testis of prepubertal diabetic rats

“…Although classification of experimental animals based on age is practically difficult, the age range from 28 to 42 days postnatal has been conservatively classified as adolescence. 42 Induction of diabetes resulted in significant reduction in testicular weights among both age groups, the degree being relatively higher among 4-week-old PP rats. This increased susceptibility could be related to the age and disturbances in the pituitary-gonadal axis.…”

The International Society for Developmental Psychobiology 39th Annual Meeting Symposium: Alcohol and Development: Beyond fetal alcohol syndrome

“…Effects of alcohol for which adolescents are relatively insensitive include alcohol-induced motor impairment (e.g., White, Bae, et al, 2002;White, Truesdale, et al, 2002), social impairment , dysphoria (Varlinskaya, Falkowitz, & Spear, 2006), and sedation (e.g., Moy, Duncan, Knapp, & Breese, 1998;Silveri & Spear, 1998). These adolescent-typical insensitivities to alcohol are not related simply to pharmacokinetic factors (see Spear, 2007, for further discussion), but instead may reflect, at least in part, the more rapid development of acute tolerance in immature animals relative to their adult counterparts (Silveri & Spear, 1998;Varlinskaya and Spear, 2006a).…”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…Rodents also undergo changes in neurobehavioural, physical and sexual characteristics which resemble those developmental changes in adolescent humans (Spear 2000;2007). Based on the timing of these 'adolescence-like' characteristics including puberty and its related changes, the adolescent period in experimental rodents (Figure 1-1(a)) is generally considered to span from postnatal day (PND) 28 to PND56 while this period can vary with sex and species (Brenhouse and Andersen 2011;McCutcheon and Marinelli 2009;Schneider 2013;Spear 2000;2007;Yetnikoff et al 2014). Other researchers have proposed that it can also be as early as PND21 and as late as PND70 (Burke and Miczek 2014;Schneider 2013;Tirelli et al 2003).…”

“…As outlined in the Section 1.1., adolescent brain maturation pathways are highly conserved across species (Spear 2000;2007). This enables researchers to model adolescent pharmacological 7 treatment in experimental rodents and investigate the effects of such administration in a strictlycontrolled manner.…”

“…In this section, I critically review and discuss the studies that subjected animals to APDs at postnatal ages corresponding to adolescent human brain development (Brenhouse and Andersen 2011;Burke and Miczek 2014;McCutcheon and Marinelli 2009;Schneider 2013;Spear 2007;Yetnikoff et al 2014). Studies that examined APD treatment in prenatal period or in animals older than PND60 or that did not clearly describe the age of the animals at the start of treatment were excluded from the review.…”