Synthetic cannabinoid, WIN 55212-2, leads to changes of proBDNF/BDNF ratio levels in the periaqueductal gray and blood concentrations in the adolescent rat

Abstract

Background: The hemp plant Cannabis sativa—marijuana and hashish are among the most commonly used illicit substances in adolescents and young adults. The synthetic CB1 agonist WIN 55212-2 (WIN) administration to rats and mice during adolescence leads to long-lasting deficits. Endocannabinoids and neurotrophins, particularly brain-derived neurotrophic factors (BDNF), are potent neuromodulators that play critical roles in many behavioral and physiological processes. Disruption of either BDNF or endocannabinoid signaling is associated with an overlapping set of neurologic and psychiatric diseases. The key to understanding the relationship between stress/anxiety and the endocannabinoid system may not lie in the anxiolytic or anxiogenic properties of various CB1 receptor ligands but in the ability of the endocannabinoid system to modulate the reactivity of affective or hypothalamic-pituitary-adrenal (HPA) processes. Hence, the periaqueductal gray (PAG), a midbrain structure that regulates anxiety, is key to understanding the relationship between stress/anxiety and the endocannabinoid system. Also, neurons within the PAG are a release-site for BDNF and are involved in analgesic agents, including opioids. This neurotrophin plays a role in synaptic plasticity and neuroprotection.

Furthermore, BDNF has well-established pro-survival effects, whereas its precursor protein, proBDNF, induces apoptosis. Thus, it has been suggested that the proBDNF/BDNF ratio could indicate neuronal health; however, the roles of the mBDNF/proBDNF after synthetic cannabinoids during this critical period is not clearly understood. Therefore, the present study aimed to evaluate the effect of adolescent exposure to WIN on the proBDNF/BDNF ratio levels in the PAG and blood concentrations in the adolescent rat.

Methods: Adolescent rats received five daily injections of either vehicle (1 mL/kg i.p.) or the cannabinoid (CB1 and CB2 receptor) agonist, WIN 55212-2 (0.2 mg/kg i.p. every other day). The PAG and nucleus accumbens were dissected and truncal blood samples were collected to analyze. Brain tissue and serum were used in an ELISA immunoassay to determine the concentrations for pro and mature BDNF.

Results: Chronic exposure of the synthetic CB1 agonist modified the proBDNF/BDNF ratio drastically, increasing 33% proBDNF levels and 47% BDNF in the dorsal PAG. Interestingly, only proBDNF blood concentrations were significantly increased (47%) compared to drug-naïve rats.

Conclusions: Our study revealed that synthetic CB1 receptors during adolescence significantly increased proBDNF levels in brain tissue and blood, demonstrating that the PAG and proBDNF/BDNF ratio are involved in endocannabinoid mediated neurotransmission.