Age-dependent effects of chronic amphetamine on prelimbic-nucleus accumbens circuit function and goal-directed behavior
Non-medial amphetamine (AMPH) use is prevalent in the adolescent population. Empirical evidence suggests that individuals starting using drugs during adolescence have a higher chance of developing drug-related problems. It is hypothesized that adolescents may have a heightened vulnerability to drug induced plasticity such as cognitive deficits and neuroadaptations. My pilot studies suggested that the high frequency stimulation (HFS)-induced long-term depression (LTD) in the prelimbic cortex (PL) is likely to be a target influenced by repeated AMPH in an age-of-exposure dependent manner, which results in abnormalities in the reward circuit function and goal-directed behavior. Using a rat model, this hypothesis was tested with three specific aims: (1) to investigate the ontogeny of this LTD function (Experiment 1), (2) to assess the effect of adolescent and adult amphetamine on HFS-induced LTD in the PL and the potential mechanisms underlying AMPH-induced changes (Experiment 2) and (3) to determine whether AMPH-induced changes in the PL and in the reward circuit are associated with impaired cognitive flexibility (Experiment 3). In Experiment 1, field potentials in brain slices from male naive rats were assessed to test the effect of age on the expression of this LTD. The role of GABA and dopamine receptors in the HFS-induced LTD was investigated using respective agonist or antagonist. In Experiment 2, brain slices from male rats pre-exposed to repeated 3.0 mg/kg AMPH i.p injections were used in field potential and patch-clamp recordings to assess AMPH’s effect on the expression of LTD and dopamine’s modulation of inhibition. In Experiment 3, male and female rats were treated as in Experiment 2 and subjected to a strategy set-shifting task to assess AMPH’s effect on cognitive flexibility. Upon finishing the behavioral testing, each rat was sacrificed for slice recordings to assess AMPH’s effect on HFS-induced plasticity in the PL-nucleus accumbens circuit. These studies revealed unique behavioral changes and neuroadaptations following adolescent AMPH exposure. Our results are consistent with the hypothesis that adolescent brain is more vulnerable to the detrimental effect of drugs.
Adolescence, amphetamine, prefrontal cortex, plasticity
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign