Differential laminar effects of amphetamine on prefrontal parvalbumin interneurons

Abstract

The increase in excitatory outflow from the medial prefrontal cortex is critical to the development of sensitization to amphetamine. There is evidence that psychostimulant-induced changes in dopamine-GABA interactions are key to understanding the behaviorally sensitized response. The objective of this study was to characterize the effects of different amphetamine paradigms on the Fos activation of GABAergic interneurons that contain parvalbumin in the medial prefrontal cortex. Although a sensitizing, repeated regimen of amphetamine induced Fos in all cortical layers, only layer V parvalbumin-immunolabeled cells were activated in the infralimbic and prelimbic cortices. Repeated amphetamine treatment was also associated with a loss of parvalbumin immunoreactivity in layer V, but only in the prelimbic cortex. An acute amphetamine injection to naïve rats was associated with an increase in Fos, but in parvalbumin-positive neurons of the prelimbic cortex, where it was preferentially induced in layer III. These data indicate that distinct substrates mediate the response to repeated or acute amphetamine treatment. They also suggest that a sensitizing amphetamine regimen directs mPFC outflow, via changes in inhibitory neuron activation, towards subcortical centers important in reward.Keywords prelimbic cortex; infralimbic cortex; GABA; dopamine; Fos; behavioral sensitization Repeated amphetamine (AMPH) exposure in humans has been associated with long-lasting changes in behavior (Robinson and Berridge, 2000). In experimental animals, such treatment progressively augments locomotion (behavioral sensitization), an effect that persists after treatment and can be measured by a drug challenge (Wolf, 1998). Sensitization to AMPH appears to require changes in dopamine and excitatory amino acid transmission in the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) (Wolf et al., 1995;Li and Wolf, 1997;Tzschentke and Schmidt, 2000;Wolf et al., 2003). Lesions of the mPFC block the development of sensitization, whether AMPH is repeatedly injected systemically or intra-VTA (Wolf et al., 1995;Li and Wolf, 1997;Cador et al., 1999; but see Tzschentke and Schmidt, 2000). AMPH sensitization also induces region-specific increases in mPFC Fos expression (Hedou et al., 2002), although the active neurons have yet to be fully identifed.Correspondence should be addressed to Maud M. Morshedi, Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA, (maud.morshedi@students.rosalindfranklin.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could ...

Repeated Amphetamine Exposure Disrupts Dopaminergic Modulation of Amygdala–Prefrontal Circuitry and Cognitive/Emotional Functioning

“…This suggests that, after repeated AMPH treatment, the excitatory influence of BLA inputs on mPFC neurons was enhanced, while at the same time, the inhibitory influence of the BLA on populations of mPFC cells was reduced. This observation is consistent with previous reports that repeated psychostimulant exposure leads to (1) a general increase in excitability of mPFC pyramidal neurons (Peterson et al, 2000;Parsegian et al, 2011) and (2) a reduction in mPFC GABAergic interneurons in the mPFC (Morshedi and Meredith, 2007).…”

“…Conversely, recordings from AMPH-treated rats revealed that higher stimulation currents were required to induce a comparable duration of inhibition relative to controls. This latter effect may be attributable to a reduction in GABAergic interneurons, because treatment with a similar AMPH regimen is associated with a loss of parvalbumin immunoreactivity in the mPFC (Morshedi and Meredith, 2007).…”

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

“…D 1 activation increases the excitability of interneurons, which results in an enhancement of their output (Gorelova et al, 2002; González-Burgos et al, 2005). Thus, it is possible that repeated AMPH exposure induces changes in interneuron physiology such that they become less sensitive to D 1 stimulation and/or have a reduced output capacity (Morshedi and Meredith, 2007). However, the current study does not allow us to rule out the possibility that there are postsynaptic changes that may contribute to the reduced inhibition in the pyramidal cells.…”

Perturbations in different forms of cost/benefit decision making induced by repeated amphetamine exposure

“…Interestingly, repeated psychostimulant exposure reduces expression of dopamine receptors and related proteins in the prefrontal cortex (Bowers et al 2004;Briand et al 2008) and disrupts the electrophysiological actions of mesocortical dopamine (Peterson et al 2000(Peterson et al , 2006Orozco-Cabal et al 2008). Moreover, these treatments can also reduce the expression of prefrontal cortical GABAergic interneurons (Morshedi and Meredith 2007). Thus, it is plausible that enhanced mesoaccumbens dopamine activity, in combination with cellular and neurochemical disruptions in the prefrontal cortex, may contribute to the alterations in decision making induced by repeated AMPH treatments.…”