Adolescent marijuana use is a prominent public health concern. Indeed, exposure to marijuana during adolescence, a developmental period characterized by impulsivity, is correlated with maladaptive decision making in adulthood. The changing national attitudes on marijuana use and the resultant push for the reform of marijuana laws (21 states and the District of Columbia currently have legalized marijuana in some form) highlight a need to examine the long-term neurobiological consequences of cannabinoid exposure. Likewise, methylphenidate (MPH, Ritalin) prescription, a psychostimulant highly prescribed to impulsive adolescents, has significantly risen and therefore co-exposure with marijuana is now more likely to happen than ever before. Given that MPH interacts with the same neural substrates activated by marijuana, the question of whether exposure to THC (the main psychoactive component in marijuana), MPH, or their combination during adolescence promotes enduring neuroadaptations underlying compromised impulse control needs to be addressed. We will first define adolescent impulsivity phenotypes prior to pharmacological treatments and will utilize sophisticated microdialysis detection schemes and in vitro electrophysiology to determine whether endocannabinoid (eCB) mobilization from dopaminergic neurons of the ventral tegmental area (VTA) differs between impulsive and controlled animals. Next, real-time dopamine (DA) release and accumbal firing patterns observed at precise behavioral epochs, will be optogenetically characterized with a specialized sensor during a delay-discounting task in adult animals exposed to THC in adolescence (aim 1). Importantly, the effects of THC treatment in adolescence will be contrasted to those occurring following adult exposure.
In aim 2 we will examine how treatment with THC in adolescence modifies eCB signaling and whether these modifications change as a function of impulsive phenotype and age of exposure.
Aim 3 will build upon the prior two aims to determine if the effects of THC and MPH co-exposure on eCB signaling and dopaminergic encoding of decision making are greater compared to those of either drug alone. The complementary use of innovative recording methods is likely to elucidate changes in neural mechanisms governing DA neurotransmission and accumbal activity patterns that may explain differences in impulse control in adulthood following exposure to marijuana and/or Ritalin in adolescence. The proposed experiments respond to PA-14-163, ?Effects of Cannabis Use and Cannabinoids on the Developing Brain? by examining the behavioral, neurochemical and electrophysiological mediation of eCB signaling governing the dynamic control of mesolimbic DA processing in impulse control and its potential dysfunction following exposure to THC, MPH, or their combination in adolescence.
According to the NIDA-funded 2013 Monitoring the Future Study, approximately 34-45% of high school students have used cannabis at least once and 6.6% report daily use. Importantly, a growing body of literature links adolescent cannabinoid use with an increased incidence of psychiatric problems in adulthood. Likewise, over the past several years, methylphenidate or Ritalin, is becoming a public health concern due to its increased rate in clinical prescriptions for the treatment of ADHD as well as its misuse in adolescents. Clinical experience indicates that there are few effective approaches for use in crisis intervention, stabilization and harm reduction in these at-risk populations. By employing new neurobiological tools with promising therapeutic value in a broad spectrum of psychiatric conditions, a better understanding of the neurobiological mechanisms triggering maladaptive impulsive phenotypes in disorders of motivation will be gained.
