Adolescent cannabinoid exposure attenuates adult female sexual motivation but does not alter adulthood CB1R expression or estrous cyclicity

Abstract

Adolescence is a developmental period characterized by neuronal remodeling and the maturation of adult emotionality, reproductive behavior and social behavior. We examined whether chronic cannabinoid exposure in adolescent rats alters female sexual motivation, estrous cyclicity, sucrose preference, and CB1R expression in adulthood. Female rats were administered with the synthetic cannabinoid agonist, CP-55,940 (0.4 mg/kg, intraperitoneal), daily during adolescent development (PND 35–45). In a subset of subjects, socio-sexual motivation was investigated in adulthood (PND 75–86) using a runway apparatus. Estrous cyclicity was tracked in adulthood via vaginal cytology and a single-mount test. A two-bottle sucrose preference test was also conducted to determine whether predicted changes in socio-sexual motivation might be linked to alterations in hedonic processing. CB1R expression was examined in two separate subsets of subjects, one sacrificed following drug treatment (PND 46) and one before behavioral testing (PND 74). Drug treatment significantly decreased adult preference for a male conspecific (sexual motivation), as assessed by both Run Time and Proximity Time, but did not affect estrous cyclicity or sucrose preference. CP-55,940 treatment also induced immediate, but transient, decreases in CB1R expression in the ventromedial nucleus of the hypothalamus and amygdala. Drug treatment did not affect CB1R expression in the nucleus accumbens (core or shell) or globus pallidus at either time point. We suggest that the endocannabinoid system may play a role in the maturation of neuroendocrine axes and adult female reproductive behavior, and that chronic exposure to cannabinoids during adolescence disrupts these neurodevelopmental processes.

Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia

“…63 Another study reports acute but transient reductions in CB1 expression following chronic administration of the synthetic cannabinoid agonist, CP-55940, during adolescence. 64 A similar pattern of CB1 transient downregulation is seen in human PET (positron emission tomography) imaging studies of the CB1 receptor in chronic cannabis, but, with abstinence, CB1 receptor density returned to normal levels. 65 It has also been proposed that adolescent CB1 receptors contribute to learning impairments in ACU mice by virtue of their functional properties.…”

Sex-Dependent Vulnerability to Cannabis Abuse in Adolescence

“…Not least, interactions of the endocannabinoid system with gonadal hormones may also play a part. Interestingly, it has been recently suggested that sex hormones and the endocannabinoid system might work in symphony to promote maturational processes within the adolescent brain, specifically in those circuits important for the emotional and motivational response to sexually relevant stimuli ( 46 ). However, the existence of a close interaction between the endocannabinoid system and sex hormones has long been known.…”

The Modulating Role of Sex and Anabolic-Androgenic Steroid Hormones in Cannabinoid Sensitivity

“…Due to the deep changes occurring during these periods of life, individuals of both sexes are particularly (although differentially) sensitive to many stimuli, vulnerable toward the development of psychopathological conditions and more prone to abuse drugs, including cannabis ( Wiley and Burston, 2014 ; Silva et al, 2016 ; Wagner, 2016 ). Exposure to cannabinoids during critical developmental periods alters several functions in adult animals ( Schneider, 2008 ; Rubino and Parolaro, 2016 ), including working ( Schneider and Koch, 2003 ; O’Shea et al, 2004 ) and spatial memory ( Rubino et al, 2009 ), sensorimotor gating ( Schneider and Koch, 2003 ), anxiety and anxiolytic-like responses ( Biscaia et al, 2003 ; O’Shea et al, 2004 ; Viveros et al, 2005b ), anhedonia, depressive-like states ( Schneider and Koch, 2003 ; Rubino et al, 2008 ) and sexual behavior ( Chadwick et al, 2011 ). Long-term alterations induced by cannabinoids in the developing organism are well known ( Gupta and Elbracht, 1983 ; Navarro et al, 1994 ; Pistis et al, 2004 ; Viveros et al, 2005a ; Spano et al, 2006 ; Ellgren et al, 2007 ; Renard et al, 2014 ; Rubino and Parolaro, 2016 ; Melas et al, 2018 ) and recent reports are pointing out epigenetic mechanisms underlying cannabis action ( Szutorisz and Hurd, 2016 , 2018 ; Prini et al, 2017 ).…”