Intravenous self-administration of delta-9-THC in adolescent rats produces long-lasting alterations in behavior and rece
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ORIGINAL INVESTIGATION
Intravenous self-administration of delta-9-THC in adolescent rats produces long-lasting alterations in behavior and receptor protein expression Sierra J. Stringfield 1,2 & Mary M. Torregrossa 1,2 Received: 22 April 2020 / Accepted: 19 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale Initial exposure to cannabinoids, including Δ-9-tetrahydrocannabinol (THC), often occurs during adolescence. Considerable neurodevelopmental alterations occur throughout adolescence, and the environmental insult posed by exogenous cannabinoid exposure may alter natural developmental trajectories. Multiple studies suggest that long-lasting deficits in cognitive function occur as a result of adolescent cannabis use, but considerable variability exists in the magnitude of these effects. Objectives We sought to establish a novel procedure for achieving intravenous THC self-administration in adolescent rats in order to determine if volitional THC intake in adolescence produced indices of addiction-related behavior, altered working memory performance in adulthood, or altered the expression of proteins associated with these behaviors across several brain regions. Methods Male and female adolescent rats learned to operantly self-administer escalating doses of THC intravenously from PD 32–51. Upon reaching adulthood they were tested in abstinence for cued reinstatement of THC-seeking and working memory performance on a delayed-match-to-sample task. In a separate cohort, glutamatergic, GABAergic, and cannabinoid receptor protein expression was measured in multiple brain regions. Results Both male and female adolescents self-administered THC and exhibited cue-induced lever pressing throughout abstinence. THC-exposed males exhibited slightly enhanced working memory performance in adulthood, and better performance positively correlated with total THC self-administered during adolescence. Adolescent THC-exposed rats exhibited reductions in CB1, GABA, and glutamate receptor protein, primarily in the prefrontal cortex, dorsal hippocampus, and ventral tegmental area. Conclusions These results suggest that THC exposure at self-administered doses can produce moderate behavioral and molecular alterations, including sex-dependent effects on working memory performance in adulthood. Keywords Adolescent . Δ-9-Tetrahydrocannabinol . Self-administration . Cannabinoid . Sex differences . GABA . Glutamate . Reinstatement . Prefrontal cortex
Introduction Cannabis is the most widely used illicit substance among adolescents in the USA, and initiation of cannabis use often occurs during adolescence (SAMHSA 2019; Johnston et al. 2020). The growing trend toward legalization of cannabis for * Mary M. Torregrossa [email protected] 1
Department of Psychiatry, University of Pittsburgh, 450 Technology Drive, Suite 223, Pittsburgh, PA 15219, USA
2
Center for Neuroscience, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA 15213, USA
recreational or medical use, combined with a reduced percepti
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