Adolescent Exposure to WIN 55212-2 Render the Nigrostriatal Dopaminergic Pathway Activated during Adulthood

Abstract

Background: During adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood. Methods: Male Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72-78). Results: Repeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure. Conclusions: These results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum.