Repeated amphetamine administration induces Fos in prefrontal cortical neurons that project to the lateral hypothalamus but not the nucleus accumbens or basolateral amygdala.

Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
Psychopharmacology (Impact Factor: 3.99). 05/2008; 197(2):179-89. DOI: 10.1007/s00213-007-1021-7
Source: PubMed

ABSTRACT The development of sensitization to amphetamine (AMPH) is dependent on increases in excitatory outflow from the medial prefrontal cortex (mPFC) to subcortical centers. These projections are clearly important for the progressive enhancement of the behavioral response during drug administration that persists through withdrawal.
The objective of this study was to identify the mPFC subcortical pathway(s) activated by a sensitizing regimen of AMPH.
Using retrograde labeling techniques, Fos activation was evaluated in the predominant projection pathways of the mPFC of sensitized rats after a challenge injection of AMPH.
There was a significant increase in Fos-immunoreactive cells in the mPFC, nucleus accumbens (NAc), basolateral amygdala (BLA), and lateral hypothalamus (LH) of rats treated repeatedly with AMPH when compared to vehicle-treated controls. The mPFC pyramidal neurons that project to the LH but not the NAc or BLA show a significant induction of Fos after repeated AMPH treatment. In addition, we found a dramatic increase in Fos-activated orexin neurons.
The LH, a region implicated in natural and drug reward processes, may play a role in the development and persistence of sensitization to repeated AMPH through its connections with the mPFC and possibly through its orexin neurons.

Download full-text


Available from: Gloria Evelyn Meredith, Aug 18, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) and amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA)/kainate receptors of the prelimbic (PL) division of the medial prefrontal cortex (MPFC) on the panic attack-like reactions evoked by γ-aminobutyric acid-A receptor blockade in the medial hypothalamus (MH). Rats were pretreated with NaCl 0.9%, LY235959 (NMDA receptor antagonist), and NBQX (AMPA/kainate receptor antagonist) in the PL at 3 different concentrations. Ten minutes later, the MH was treated with bicuculline, and the defensive responses were recorded for 10 min. The antagonism of NMDA receptors in the PL decreased the frequency and duration of all defensive behaviors evoked by the stimulation of the MH and reduced the innate fear-induced antinociception. However, the pretreatment of the PL cortex with NBQX was able to decrease only part of defensive responses and innate fear-induced antinociception. The present findings suggest that the NMDA-glutamatergic system of the PL is critically involved in panic-like responses and innate fear-induced antinociception and those AMPA/kainate receptors are also recruited during the elaboration of fear-induced antinociception and in panic attack-related response. The activation of the glutamatergic neurotransmission of PL division of the MPFC during the elaboration of oriented behavioral reactions elicited by the chemical stimulation of the MH recruits mainly NMDA receptors in comparison with AMPA/kainate receptors.
    Cerebral Cortex 01/2013; DOI:10.1093/cercor/bht001 · 8.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Behavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. Male Sprague-Dawley rats underwent unilateral intra-VTA infusion of the retrograde tracer Fluorogold (FG), followed by 5 daily injections of either amphetamine (2.5 mg/kg, i.p.) or saline vehicle. Four weeks later, rats were challenged with amphetamine (1.0 mg/kg, i.p.) or saline (1.0 mL/kg, i.p.). Repeated amphetamine treatment produced locomotor sensitization upon drug challenge. Two hours later, rats were euthanized, and mPFC sections were double-immunolabeled for either Fos-FG or Fos-BDNF. Tissue from the VTA was also double-immunolabeled for Fos-BDNF. Amphetamine challenge increased Fos and BDNF expression in the mPFC regardless of prior drug experience, and further augmented mPFC BDNF expression in sensitized rats. Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.
    Neuropharmacology 05/2011; 61(4):558-64. DOI:10.1016/j.neuropharm.2011.04.026 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Orexinergic projection originated from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) has an important role in the acquisition of morphine conditioned place preference (CPP). However, little if any is known about the function and/or effect of orexin on CPP in rats. In the present study, we investigated the direct effect of orexinergic neurons on acquisition of CPP by chemical stimulation of LH and involvement of orexin-A and CB1 receptors within the VTA in development of reward-related behaviors. 129 adult male albino Wistar rats weighing 220-320 g were unilaterally implanted by two separate cannulae into the LH and VTA. The CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The results showed that unilateral intra-LH administration of carbachol (62.5, 125 and 250 nmol/0.5 μl saline) as a cholinergic agonist, during conditioning phase, induced CPP in a dose-dependent manner. The maximal effect was shown at the dose of 250 nmol (P<0.001) compared to vehicle (saline) group. However, intra-VTA administration of SB334867 as a selective orexin-A receptor antagonist (0.1, 1 and 10 nmol/0.3 μl DMSO) and AM251 (5, 25 and 125 nmol/0.3 μl DMSO) as a CB1 receptor antagonist, just 5 min before carbachol during the 3-day conditioning phase, could dose-dependently inhibit the development of LH stimulation-induced CPP in the rats. It is supposed that the orexinergic projection from LH to VTA is involved in LH chemical stimulation-induced CPP and orexin-A receptor in the VTA has a substantial role in this phenomenon. Our findings also suggest the existence of cross-talk between cannabinoid and orexinergic systems within the VTA in conditioned place preference paradigm.
    Behavioural brain research 10/2010; 217(1):41-6. DOI:10.1016/j.bbr.2010.10.007 · 3.39 Impact Factor