Adolescent Stress Reduces Adult Morphine-Induced Behavioral Sensitization in C57BL/6J Mice

Abstract

Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence–a critical period of frontal lobe development–influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex (PFC) miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the PFC compared to control mice. The specificity of the effects for C57BL/6J vs. BALB/cJ mice provides evidence of a gene-environment interaction influencing opioid behaviors. However, this conclusion is dampened by limited locomotor sensitization observed in BALB/cJ mice. It remains possible that results may differ to other doses of morphine or other behavioral responses. Long-term differences in stress reactivity or miRNA expression in C57BL/6J mice suggests two possible biological mechanisms to evaluate in future research.

The effect of stress on opioid addiction-related behaviors: A review of preclinical literature.

“…However, in this study, stress-exposed rats did drink more morphine after a period without the drug, which the authors termed “relapse drinking” (Marks-Kaufman & Lewis, 1984). Work from our lab showed that adolescent chronic variable social stress (which includes periods of social isolation and social reorganization—i.e., group-housed with novel partners), did not affect adult morphine consumption in male or female C57BL/6J or BALB/cJ mice (Kamens et al, 2021).…”

“…the drug, which the authors termed "relapse drinking" (Marks- Kaufman & Lewis, 1984). Work from our lab showed that adolescent chronic variable social stress (which includes periods of social isolation and social reorganization-i.e., group-housed with novel partners), did not affect adult morphine consumption in male or female C57BL/6J or BALB/cJ mice (Kamens et al, 2021). Data from operant self-administration studies have additionally yielded mixed results.…”

“…While these three studies indicate that stress increases morphine-induced locomotor activity, two studies found opposite results. In male and female BALB/cJ and C57BL/cJ exposed to social isolation and social reorganization during adolescence, there was no difference in locomotor stimulation to a high (100 mg/kg) dose of morphine (Kamens et al, 2021). Finally, male Hooded rats that were isolated during adolescence had less locomotor depression compared to group-housed animals (Katz & Steinberg, 1970).…”

“…Strain has also been an important variable when considering published locomotor sensitization studies, highlighting a genetic contribution to this behavior. Male C57BL/6J mice exposed to adolescent chronic variable social stress exhibited attenuated locomotor sensitization compared to control animals (Kamens et al, 2021). In contrast, the same stressor did not affect female C57BL/6J mice or male or female BALB/cJ mice, providing evidence of a Gene × Environment interaction.…”

MicroRNA Regulation of the Environmental Impact on Adolescent Neurobehavioral Development: A Systematic Review

“…The protocol proposed as a model of posttraumatic stress disorder (PTSD) included repeated inescapable foot shocks applied at early adolescence (PND-28) for 6 consecutive days (Li et al, 2016;Liu et al, 2016). Protocols for inducing social stress varied from isolation (McCreary et al, 2016) to physical aggression by unfamiliar male mice in the chronic social defeat stress (CSDS) (Torres-Berrío et al, 2021) and chronic variable social stress (CVSS) induced by repeated rehousing with unfamiliar cage mates (Kamens et al, 2021). All were applied during adolescence except two of them that explored the effect of prenatal stress induced by maternal restrain (Cattaneo et al, 2020) and individual housing (McCreary et al, 2016).…”