Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

Abstract

The current study examined whether adolescent rats are more vulnerable than adult rats to the lasting adverse effects of cannabinoid exposure on brain and behavior. Male Wistar rats were repeatedly exposed to D-9-tetrahydrocannabinol (D 9 -THC, 5 mg/kg i.p.) in a place-conditioning paradigm during either the adolescent (post-natal day 28 + ) or adult (post-natal day 60 + ) developmental stages. Adult rats avoided a D 9 -THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final D 9 -THC injection. In contrast, adolescent rats showed no significant place aversion. Adult D 9 -THC-treated rats produced more vocalizations than adolescent rats when handled during the intoxicated state, also suggesting greater drug-induced aversion. After a 10-15 day washout, both adult and adolescent D 9 -THC pretreated rats showed decreased social interaction, while only D 9 -THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last D 9 -THC injection, rats were euthanased and hippocampal tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual D 9 -THC being present in blood at this time. Proteomic analysis uncovered 27 proteins, many involved in regulating oxidative stress/mitochondrial functioning and cytoarchitecture, which were differentially expressed in adolescent D 9 -THC pretreated rats relative to adolescent controls. In adults, only 10 hippocampal proteins were differentially expressed in D 9 -THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated D 9 -THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippocampal alterations in adolescent than adult rats.

Adolescent Cannabinoid Exposure Permanently Suppresses Cortical Oscillations in Adult Mice

“…Chronic adolescent, but not adult, cannabinoid-induced oscillation suppression suggests that attenuated network synchrony is not merely a consequence of repeated cannabinoid exposure, but reflects a unique sensitivity of the adolescent brain to modification by cannabinoids. Our data are consistent with findings that adolescent, but not adult, cannabinoid exposure produces lasting cognitive impairments in rodents (Schneider and Koch, 2003;O'Shea et al, 2004;Quinn et al, 2008) and humans (Solowij et al, 2002;Meier et al, 2012).…”

“…We also report impaired novel object recognition behavior in adolescent WIN-treated mice, which is consistent with previous reports of cognitive impairments after persistent adolescent cannabis exposure in both rodents (Schneider and Koch, 2003;O'Shea et al, 2004;Quinn et al, 2008) and humans (Solowij et al, 2002;Meier et al 2012).…”

“…Persistent marijuana use before adulthood may permanently impair cognitive functioning (Solowij et al, 2002;Meier et al, 2012) and confer a higher risk of developing psychiatric diseases, such as schizophrenia, in susceptible individuals (Arseneault et al, 2004). Chronic adolescent, but not adult, cannabinoid exposure produces lasting working memory impairments and recapitulates other schizophrenia endophenotypes in rodents, including impaired sensorimotor gating, social avoidance, and anhedonia/avolition (Schneider and Koch, 2003;O'Shea et al, 2004;Quinn et al, 2008).…”

Chronic Δ9-Tetrahydrocannabinol During Adolescence Provokes Sex-Dependent Changes in the Emotional Profile in Adult Rats: Behavioral and Biochemical Correlates

“…However, we did not investigate whether a similar picture was produced as a long-term consequence after chronic THC treatment in adult rats, although recent papers support the idea of adolescents being specifically vulnerable to enduring adverse effects of cannabinoids (Quinn et al, 2007). Therefore, the potential problems arising in relation to marijuana consumption in adolescence suggest that this developmental phase is a vulnerable period for persistent adverse effects of cannabinoids.…”

Adolescent Exposure of JWH-018 “Spice” Produces Subtle Effects on Learning and Memory Performance in Adulthood

“…Further, some of the reported effects appear to last for a considerable period following drug exposure [12]. In rats, the timing of the exposure during the neurophysiological development of the organism appears to contribute to impairments in working memory when tested as adults while adult Δ-9-THC-treated rats does not produce persistent impairments [13,14]. Last, such adolescent exposure effects may, in part, be associated with the sex of the animal as well, with more severe effects reported in female rats [15].…”