Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice

A novel animal model highlights the link between Akt dysfunction, reduced cortical dopamine function, norepinephrine transporters, and schizophrenia-like behaviors

Brief exposure to obesogenic diet disrupts brain dopamine networks.

OBJECTIVE:We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH). METHODS:We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET). RESULTS:We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals. CONCLUSION:These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding

HF diet blunts striatal insulin signaling and D2R availability.

<p>(A) Reduction of basal striatal Akt activity in HF- vs. LF-fed animals was determined by phosphorylation of the Akt substrate, exogenous, recombinant GSK3α. Representative phosphoimmunoblots of phospho-GSK3α for HF and LF striatal samples is shown (left panel). The bar graph (right panel) shows data for phospho-GSK3α with each sample normalized to LF control. *<i>p</i> < 0.05, Student’s <i>t</i>-test (<i>n</i> = 5 animals/group). (B) [¹⁸F]fallyride PET images (left panel) of coronal and axial views of striatal radiotracer binding in a representative LF animal show green pseudocolor (color bar range indicates 0–1%ID/g). The graph (right panel) represents group-averaged data and shows reduced striatal D2R availability <i>in vivo</i> (DVR’—distribution volume ratio) in HF (<i>n</i> = 3) vs. LF (<i>n</i> = 4) groups, determined by [¹⁸F]fallyride PET. *<i>p</i> < 0.05, one-tailed Student’s <i>t</i>-test (based on <i>a priori</i> test of HF < LF).</p

Inter-regional correlations in amphetamine-evoked CBV changes are reduced in HF- vs. LF-fed rats.

<p>(A) Correlation matrices identifying brain region pairs where time course profiles (TC; first row) and/or amplitudes (area under curve, AUC; second row) of response to AMPH represent Z-scores that were significantly correlated across animals in LF- and HF-fed rats (<i>p</i> < 0.01; first and second columns). For regions present in multiple slices, slice location (mm) relative to Bregma is shown. Significant differences between HF and LF diet groups were found through permutation analysis (LF vs. HF; <i>p</i> < 0.05; third column). Abbreviations: mPFC, medial prefrontal cortex; Cg, cingulum; Rs, retrosplenium; Hipp, hippocampus; V, visual cortex; S, somatosensory cortex; M, motor cortex; VPM/L, ventral posterior medial/lateral thalamus; MDTN, mediodorsal thalamic nuclei; Hypo, hypothalamus; CP, caudateputamen; NAc, nucleus accumbens.(B) The size of the effect of HF on inter-regional correlation is depicted by the thickness of the line connecting the region pair in the rat brain schematic. For all region pairs with significant differences between the two groups, the strengths of correlations were weaker in HF vs. LF groups. HF feeding had the strongest effect in region pairs with the largest ΔZ (embedded table) and thickest lines (rat brain schematic). The green font indicates region pairs with significant differences found by both AUC and TC methods.</p

HF diet blunts cortical and subcortical fMRI responses to amphetamine.

<p>(A) Blunted amphetamine (AMPH) evoked cerebral blood volume (CBV) changes in HF- vs. LF-fed rats. Group averaged CBV responses for HF- and LF-fed animals shown for three coronal slices centered on caudate putamen (Bregma -2.8, -0.8, +1.2) in both diet groups. Maps depict mean ËV change over baseline for 15 min post-AMPH. (B-G) Time courses of %∆CBV and associated mean %∆CBV (bar graphs) following AMPH- or saline vehicle- challenge in cortical and subcortical regions of interest. One-way ANOVA followed by post-hoc analyses to test for significant difference in post-AMPH and post-saline responses in HF- vs. LF-fed animals (bar graphs), <i>p</i> < 0.05 significant.</p

Role for mTOR Signaling and Neuronal Activity in Morphine-Induced Adaptations in Ventral Tegmental Area Dopamine Neurons

SummaryWhile the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knockout of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse