Increased mRNA levels of tyrosine hydroxylase and dopamine transporter in the VTA of male rats after chronic food restriction

Dieting as a strategy to reduce body weight often fails as it causes food cravings leading to bingeing and weight regain. Evidence from several lines of research suggests the presence of shared elements for neural regulation of food and drug craving. We quantified the expression of eight genes involved in dopamine signalling in brain regions related to the mesolimbic and nigrostriatal dopamine system in male rats subjected to chronic food restriction using quantitative real-time polymerase chain reaction. Food restriction strongly increased mRNA levels of tyrosine hydroxylase and the dopamine transporter in the ventral tegmental area. Quantitative autoradiography indicated that the dopamine transporter was also upregulated at the protein level in the shell of the nucleus accumbens. However, these effects were not observed after acute food deprivation. We suggest that the results reflect a sensitization of the mesolimbic dopamine pathway characterized by increased clearance of extracellular dopamine in the nucleus accumbens shell. Such sensitization of the mesolimbic dopamine system may be one of the underlying causes for the food cravings that interfere with dietary compliance.     

MDMA‐evoked changes in the binding of dopamine D2 receptor ligands in striatum of rats with unilateral serotonin depletion

We earlier reported an anomalous 50% decrease in [¹¹C]N‐methylspiperone ([¹¹C]NMSP) binding to dopamine D₂‐like receptors in living pig striatum after challenge with 3,4‐methylenedioxymethamphetamine (MDMA, “Ecstasy”), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [¹¹C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [¹²⁵I]RTI‐55 autoradiography. Baseline [¹¹C]NMSP microPET recordings were followed by either saline or MDMA‐HCl (4 mg/kg) injections (i.v.), and a second [¹¹C]NMSP recording, culminating with injection of [³H]raclopride for autoradiography ex vivo. Neither MDMA‐challenge nor serotonin lesion had any detectable effect on [¹¹C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [³H]raclopride ex vivo (relative to the B_max in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding‐site model, the increased [³H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo (K), revealing a 2‐fold increase in competition from endogenous dopamine at [³H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [¹¹C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent. Synapse 64:70–82, 2010. © 2009 Wiley‐Liss, Inc.     

A high-fat diet exacerbates depressive-like behavior in the Flinders Sensitive Line (FSL) rat, a genetic model of depression

Major depressive disorder (MDD) and diabetes mellitus type II (T2DM) are two of the major health challenges of our time. It has been shown that MDD and T2DM are highly co-morbid, and recent work has proposed a bi-directional connection between the diseases. The aim of the current study was to investigate the effect of a high-fat diet (HFD) on behavior and metabolism in a genetic rat model of depression, the Flinders Sensitive and Resistant Line (FSL/FRL) rats. Age and weight matched rats were fed a HFD or control diet for 10 weeks and subjected to behavioral testing and metabolic assessment. We found that HFD exacerbated the depressive-like behavior of the FSL rat in the Forced Swim Test (FST), a depression screening tool, although it did not affect the non-depressed FRL rat despite a higher caloric intake. Moreover, the depressive-like phenotype was associated with reduced anxiety and impairment in novel object recognition memory, while HFD consumption led to diminished object recognition memory as well. In both strains HFD increased insulin levels during an oral glucose tolerance test, although fasting blood glucose levels were only significantly increased by HFD in the FSL rat, suggesting a greater metabolic susceptibility in this rat strain. We conclude that compared with the FRL rat, the FSL rat is more susceptible to developing aberrant behaviors related to depression following metabolic stress induced by HFD. Further studies with a mechanistic focus could potentially lead to a better understanding of a possible pathophysiological link between T2DM and MDD.     

The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson's disease

Objective: One of the most frequent psychiatric symptoms in patients with Wilson's disease (WD) is depression. It has been suggested that depression is associated with deficits in serotonergic neurotransmission, but, hitherto, no measurements have been performed in WD. Methods: We prospectively examined 23 adult patients (12 women, 11 men, mean age 40 years) with WD for symptoms of depression using the Hamilton rating scale for depression (HAMD). We correlated the data with the presynaptic serotonin transporter density (SERT density) in the thalamus–hypothalamus and the midbrain–pons regions measured with high resolution single-photon emission computed tomography (SPECT) 24 hours after the application of 180 MBq 2β-carbomethoxy-3β-(4 [¹²³I]iodophenyl)tropane ( [¹²³I]b-CIT). The regions of interest were determined by coregistration with a standard MRI dataset. Results: A significant negative correlation was found between HAMD and SERT density in the thalamus–hypothalamus region (r = −0.49, p = 0.02), but not in the midbrain–pons (r = −0.31, p = 0.15). Conclusions: We conclude that depression in patients with Wilson's disease is correlated with alterations of serotonergic neurotransmission in the thalamus–hypothalamus region. Received: 24 July 2002, Received in revised form: 20 November 2002, Accepted: 28 November 2002 Correspondence to Wieland Hermanns, MD     

Effects of different frequencies of transcranial magnetic stimulation (TMS) on the forced swim test model of depression in rats.

BACKGROUND: Repetitive transcranial magnetic stimulation has been demonstrated in humans as well as in animal models to have an antidepressant effect, but the optimal frequency of stimulation is not known. We examined this question in a rat model of depression. METHODS: Young male Sprague-Dawley rats were allocated to two placebo (restraint and sham transcranial magnetic stimulation), one active control (imipramine), and four transcranial magnetic stimulation groups at 1, 5, 15 and 25 Hz and 1000 stimuli each. The Porsolt Swim Test was performed on day 1 (experiment 1). In an extension (experiment 2), the treatments were repeated on days 2 through 5, and the Swim Test repeated on days 3, 5, and 7. RESULTS: After one treatment session, all transcranial magnetic stimulation groups had significantly reduced immobility times compared with sham stimulation (p =.000), but the higher frequencies (15 and 25 Hz) did not differ significantly from lower (1 and 5 Hz) frequencies. After three sessions, all transcranial magnetic stimulation groups were different from placebo, and the rapid transcranial magnetic stimulation groups had lower immobility times than the slow transcranial magnetic stimulation groups (p =.035). After five sessions, only 15- and 25-Hz groups were different from control, and on day 7, only the 25-Hz group had reduced immobility. There was an overall difference between fast and slow transcranial magnetic stimulation (p =.010), and 1 Hz was different from the other three transcranial magnetic stimulation conditions (p =.016). CONCLUSIONS: Repetitive transcranial magnetic stimulation reduces immobility time in the Forced Swim Test model of depression, suggesting an antidepressant effect, which is evident at a range (1-25 Hz) of frequencies. With repeated administration, the findings suggest that the antidepressant effect of the higher frequencies, as for imipramine, is likely to be sustained, although the model used for this (i.e., repeating the Swim Test) requires further validation.