D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence

Abstract

Amphetamine (AMPH) exposure leads to changes in behavior and dopamine receptor function in the prefrontal cortex (PFC). Since dopamine plays an important role in regulating GABAergic transmission in the PFC, we investigated if AMPH exposure induces long-lasting changes in dopamine’s ability to modulate inhibitory transmission in the PFC as well as whether the effects of AMPH differed depending on the age of exposure. Male Sprague–Dawley rats were given saline or 3 mg/kg AMPH (i.p.) repeatedly during adolescence or adulthood and following a withdrawal period of up to 5 weeks (Experiment 1) or up to 14 weeks (Experiment 2), they were sacrificed for in vitro whole-cell recordings in layer V/VI of the medial PFC. We found that in brain slices from either adolescent- or adult-exposed rats, there was an attenuation of dopamine-induced increases in inhibitory synaptic currents in pyramidal cells. These effects did not depend on age of exposure, were mediated at least partially by a reduced sensitivity of D1 receptors in AMPH-treated rats, and were associated with an enhanced behavioral response to the drug in a separate group of rats given an AMPH challenge following the longest withdrawal period. Together, these data reveal a prolonged effect of AMPH exposure on medial PFC function that persisted for up to 14 weeks in adolescent-exposed animals. These long-lasting neurophysiological changes may be a contributing mechanism to the behavioral consequences that have been observed in those with a history of amphetamine abuse.

High frequency stimulation-induced plasticity in the prelimbic cortex of rats emerges during adolescent development and is associated with an increase in dopamine receptor function

“…This hypothesized mechanism is based on the following. First, it is well established that dopamine elevates inhibitory tone in adult mPFC and the increase in inhibitory function could last over 30-40 min (Seamans et al, 2001;Kroner and Lavin, 2012;Paul et al, 2013;Kang et al, 2016). This prolonged action of dopamine on inhibition seems consistent with the post-HFS changes found in the current study.…”

Timing of amphetamine exposure in relation to puberty onset determines its effects on anhedonia, exploratory behavior, and dopamine D1 receptor expression in young adulthood

“…We recently found that repeated AMPH exposure during adolescence induced a long lasting reduction in D 1 R function in the mPFC (Kang et al, 2016). A primary aim of the current study was to determine if this functional change was associated with a reduction in D 1 R expression in the mPFC and one of its major targets, the NAc.…”

“…A 2-mm diameter punch was used to extract samples containing both shell and core of the NAc and both infralimbic and prelimbic regions of the mPFC. The subregions within each brain region were combined as our previous study (Kang et al, 2016) showed no differential effect of AMPH exposure on D 1 function in the infralimbic compared to prelimbic regions. After storage at −80 °C for up to 8 weeks, brain tissue from individual rats was homogenized in lysis buffer containing (in mM) 50 Tris-HCl (pH 7.4), 150 NaCl, 30 EDTA, 1.5% Triton-X, and 0.1% sodium dodecyl sulfate.…”

“…These developmental changes in dopamine receptor expression and function are thought to be critical for the maturation of the mesocortical circuit and its role in mediating various cognitive and affective behaviors (Tseng and O’Donnell, 2007; Casey et al, 2008; Naneix et al, 2012). We recently used in vitro, whole-cell recordings to demonstrate that adult rats exposed to AMPH during adolescence had reduced function of D 1 Rs in the mPFC (Kang et al, 2016). A potential mechanism for this effect is an AMPH-induced change in the typical developmental shift in the expression of D 1 R. A primary goal of the current study was to investigate if adolescent AMPH exposure induces changes in D 1 R expression in the mPFC and in one of the target structures whose ontogeny it influences, the NAc (Casey et al, 2008).…”

“…Using the same adolescent drug exposure paradigm that we have used previously to demonstrate changes in behavior and neurophysiology that last well into adulthood (Hankosky and Gulley, 2013; Hankosky et al, 2013; Sherrill et al, 2013; Hammerslag et al, 2014; Kang et al, 2016; Paul et al, 2016), we injected male and female rats with 3 mg/kg AMPH every other day starting well before puberty onset (P27) or near female puberty onset (P37). We then assessed withdrawal associated anhedonia and anxiety-related behavior in these pre-pubertal (Pre-P) and peri-pubertal (Peri-P) groups of rats using tests of sucrose preference and measures of activity in open-field arena and an elevated plus maze.…”