Review article Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal Lindsay Silva a , Rita Black a , Michael Michaelides c , Yasmin L. Hurd c , Diana Dow-Edwards a,b, ⁎ a School of Graduate Studies, SUNY Downstate Medical Center, 450 Clarkson Ave, MSC 41, Brooklyn, 11203, NY, USA b Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave, Mail Stop 29, Brooklyn, 11203, NY, USA c Icahn School of Medicine at Mount Sinai, Department of Psychiatry and Neuroscience, Hess Center for Science and Medicine Building, 1470 Madison Avenue, New York, NY 11029, USA abstract article info Article history: Received 21 August 2015 Received in revised form 9 February 2016 Accepted 15 February 2016 Available online xxxx Adolescents who use marijuana are more likely to exhibit anxiety, depression, and other mood disorders, includ- ing psychotic-like symptoms. Additionally, the age at onset of use and the stress history of the individual can af- fect responses to cannabis. To examine the effect of early life experience on adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we exposed adolescent (postnatal day (P) 29–38) male and female rats, either shipped from a supplier or born in our vivarium, to once daily injections of 3 mg/kg THC. Our findings suggest that males are more sensitive to the anxiolytic and antidepressant effects of THC, as measured by the elevated plus maze (EPM) and forced swim test (FST), respectively, than females. Exposure to the FST increased plasma corticoste- rone levels, regardless of drug treatment or origin and females had higher levels than males overall. Shipping in- creased THC responses in females (acoustic startle habituation) and in males (latency to immobility in FST). No significant effects of THC or shipping on pre-pulse inhibition were observed. Due to differences in timing of puberty in males and females during the P29–38 period of THC treatment, we also dosed female rats between P21–30 (pre-puberty) and male rats between P39–48 (puberty). Pre-pubertal animals showed reductions in anxiety on the EPM, an effect that was not seen in animals treated during puberty. These results suggest that both sexes are more susceptible to changes in emotional behavior when THC exposure occurs just prior to the onset of puberty. Within the animals dosed from P29–38, THC increased cannabinoid receptor 1 (CB1R) mRNA expression and tended to decrease CP55,940 stimulated [ 35 S]GTPγS binding in the central amygdala only of females. Therefore, early stress enhances THC responses in males (in FST) and females (ASR habituation), THC alters CB1R expression and function in females only and prepubescent rats are generally more responsive to THC than pubertal rats. In summary, THC and stress interact with the developing endocannabinoid system in a sex specific manner during the peri-pubertal period. © 2016 Published by Elsevier Inc. Keywords: Delta-9-tetrahydrocannabinol Sex differences Puberty Emotionality CB1 receptor expression Corticosterone Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1. Experiment 1: Early life experience affects responses to adolescent THC: Measures of anxiety-, depression-, and psychosis-like behavior, and HPA axis activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1.1. Subjects and drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1.2. Elevated plus maze (EPM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1.3. Forced swim test (FST) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1.4. Pre-pulse inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1.5. Corticosterone ELISA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Neurotoxicology and Teratology xxx (2016) xxx–xxx ⁎ Corresponding author at: School of Graduate Studies, SUNY Downstate Medical Center, 450 Clarkson Ave, MSC 41, Brooklyn, 11203, NY, USA. E-mail address: diana.dow-edwards@downstate.edu (D. Dow-Edwards). NTT-06609; No of Pages 13 http://dx.doi.org/10.1016/j.ntt.2016.02.005 0892-0362/© 2016 Published by Elsevier Inc. Contents lists available at ScienceDirect Neurotoxicology and Teratology journal homepage: www.elsevier.com/locate/neutera Please cite this article as: Silva, L., et al., Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility..., Neurotoxicol Teratol (2016), http://dx.doi.org/10.1016/j.ntt.2016.02.005