Adolescent drug use: altered dopamine feedback control

Abstract

Neurotransmitter(NT)-receptor binding is regulated by a homeostatic process that involves feedback control loops. Normally, if NT concentration is altered relative to baseline, the free NT concentration and, hence, the amount receptor-bound recovers to basal levels. That is, the organism's intrinsic control system, via autoreceptor or other feedback, operates to maintain equilibrium at homeostasis (basal state). Exogenous substances such as abused drugs not only perturb NT basal level, but, as we have previously shown, also alter the homeostatic ‘set-point’. Alteration of the set-point results in abnormal NT levels and maladaptive adjustments to perturbations. We postulate such maladaptations help explain aberrant risk-taking behavior in young drug abusers, and vulnerability to transitioning into adult drug abuse. We determined the dopamine (DA) control function (cF) in adult rats and demonstrated that morphine induces alterations in cF sensitivity. The goal of this work is the extension to adolescent rats and other abused drugs. We use standard microdialysis/HPLC techniques to measure DA from the nucleus accumbens – a region still undergoing development during adolescence – of non-anesthetized naïve rats, then induce a perturbation away from the equilibrium set-point and follow the time-course of return to the altered equilibrium state. The derived data set provides the parameter values for the feedback control equations and how abused drugs alter them. The analysis does not require the molecular mechanisms of the feedback. Because many adolescents are poly-drug users, we also evaluate drug combinations using mathematically rigorous joint-action analysis. The intent is insight into adolescent drug use and neurobiological mechanisms underlying transition from use, to abuse, to dependence in adulthood and possible novel targets for prevention or treatment.