Doris Doudet

Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning.

J. Neurochem (2012) 120, 806–817.

Neuromodulation in a minipig MPTP model of Parkinson disease

Large animal neuroscience enables the use of conventional clinical brain imagers and the direct use and testing of surgical procedures and equipment from the human clinic. The greater complexity of the large animal brain additionally enables a more direct translation to human brain function in health and disease. Economical, ethical, scientific and practical issues may on the other hand hamper large animal neuroscience. Large animal neuroscience should therefore either be performed in order to examine large animal species dependent problems or to complement promising small animal basic studies by constituting an intermediate research system, bridging small animal CNS research to the human CNS. We have, accordingly, during the last ten years used the Göttingen minipig to examine neuromodulatory treatment modalities such as stem cell transplantation and deep brain stimulation directed towards Parkinson disease. This has been accomplished by the development of a MPTP-based large animal model of Parkinson disease in the Göttingen minipig and the development of stereotaxic and surgical approaches needed to manipulate the Göttingen minipig CNS. The instituted changes in the CNS can be evaluated in the live animal by brain imaging (PET and MR), cystometry, gait analysis, neurological evaluation and by post mortem examination based on histology and stereological analysis.

Pathological gambling: relation of skin conductance response to dopaminergic neurotransmission and sensation-seeking.

Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic mechanisms. We recruited equal numbers of PG subjects and healthy control (HC) subjects, and then tested the claim that SCR is less conditioned by dopaminergic activity in PG subjects. During active gambling, SCR differed in PG and HC subjects (P < 0.05), but positron emission tomography revealed the same dopamine receptor availability. However, highly sensation-seeking (HS) PG subjects had lower dopamine receptor availability (P < 0.0001) in the baseline, compared to normal sensation-seeking (NS) PG subjects. We find that HS versus NS controls had the same observation of significant increase of binding potential (BP(ND)) in high compared to normal sensation seekers. In both groups, PG and HC, highly sensation-seeking subjects had significant increase of receptor availability in striatum, compared to normally sensation-seeking subjects, separately (P < 0.05 and P = 0.02, respectively) and together (P < 0.0005). We conclude that SCR is less conditioned by dopaminergic activity in highly sensation-seeking subjects, regardless of PG status.

α2-adrenoceptor binding in Flinders-sensitive line compared with Flinders-resistant line and Sprague-Dawley rats.

Objectives Disturbances in the noradrenergic system, including alterations in the densities of α2-adrenoceptors, are posited to be involved in the pathophysiology of depression. In this study, we investigate the binding of α2-adrenoceptors in regions relevant to depression in an animal model of depression. Methods Using in vitro autoradiography techniques and the selective α2-ligand, [3H]RX 821002, we investigated the density of α2-adrenoceptors in female Flinders-sensitive line (FSL) rats, a validated model of depression, and in two traditional control groups – female Flinders-resistant line (FRL) and Sprague-Dawley (SD) rats. Results The α2-adrenoceptor density was increased in most regions of the FSL rat brain when compared with SD rats (10% across regions). Moreover, the α2-adrenoceptor density was further increased in the FRL rats compared with both FSL (10% across regions) and SD rats (24% across regions). Conclusions The increase in α2-adrenoceptor binding in cortical regions in the FSL strain compared with the SD control strain is in accord with α2-adrenoceptor post-mortem binding data in suicide victims with untreated major depression. However, the differences in binding observed in the two control groups were unexpected and suggest the need for further studies in a larger cohort of animals of both sexes.

Anesthesia in animal imaging: Differing effects of propofol versus isoflurane on dopamine 1 receptor binding in Göttingen minipig brain

The dopamine 1 (D1) receptor has in recent years become a site of interest for its involvement in a number of psychiatric conditions. Its characteristics and modulation are extensively studied in experimental models and pharmacological challenges using the in vivo capabilities of PET imaging. The role of anesthesia on the dopaminergic D2/3 receptors has been carefully examined but little data exist on its role on the D1 receptors. In this study, we evaluated the role of two routinely used anesthetics on the binding of a common tracer of the D1 receptor, SCH23390, using the Göttingen minipigs, which are attracting increasing interest for in vivo imaging due to their behavioral characteristics and large brain size. Under isoflurane (n=5) or propofol (n=3) as anesthesia, the minipigs underwent PET scanning in a High-Resolution Research Tomograph with the D1 receptor tracer, [11C]SCH23390. Using the Logan reference tissue model, we found higher binding potential in the isoflurane group compared with the propofol group in the striatum (59%), putamen (55%), caudate (63%), thalamus (39%), temporal cortex (53%), frontal cortex (60%) and globus pallidus (51%). The magnitude of the differences in these data brings to light the importance of the effects of anesthesia during animal experimentation and on the possible impact and interpretation of the data. It remains to be determined whether these distinct anesthetic sensitivities may play an even greater role during pharmacological or therapeutic challenges. Currently, such possibilities are being investigated.

Kinetics of yohimbine binding and displacement in porcine brain in vivo

In brain of Danish landrace pigs (n=6), volumes of distribution of the selective a2 adrenoceptor antagonist [C]yohimbine in 10,000 voxels were determined as ratios of voxel AUC over arterial plasma AUC. The volumes had a bimodal distribution. Inhibition plots of volumes obtained after displacement with unlabeled yohimbine, Vi=sVe+(1−s)Vh, revealed a non-displaceable partition coefficient of 0.91 ml/cm. Binding potentials were calculated as (Vh/Ve)−1. A second series of inhibitions slightly raised Ve to 1.23 ml/cm, with commensurate changes of the bimodal distributions of binding potentials before and after inhibition. However, the validity of the Ve calculation depends on the anatomical position of the voxels. Examination of the bimodal distribution revealed an extracerebral location of the voxels belonging to the lower peak. Inhibition plots of the intracerebral voxels revealed an average Ve of 1.51 ml/cm, as shown in the panel at the top left (Fig. 1). This average partition coefficient was consistent with the regional average obtained from regions of interest rather than voxels, with an average Ve of 1.57 ml/cm. Determined with the averageVeof 1.51 ml/cm, the intracerebral voxels hadbindingpotentials ranging from0.5 to 1.5. Theextracerebral voxels had apartition coefficientof 1.02 ml/cm consistent with the absent blood–brain barrier. In a different study of minipig brains (n=3) with Vagal Nerve Stimulation (VNS), volumes of distribution changed upon acute activation of the stimulation, as determined with Gjedde–Patlak plots. In pig #1, shown in the panel at bottom left (Fig. 2), the volumes of distribution declined in the three selected regions. The declinewas consistent with the average Ve of 1.51 ml/cm determined in landrace pigs. Binding potentials in these regions declined by 10–20% of the baseline during the acute VNS stimulation. In pig #2, volumes of distribution also declined in the three selected regions, consistentwith the average Ve of 1.51 ml/cm. During the acute VNS stimulation of this pig, the binding potentials in the selected brain regions declined by 20–30% of the baseline. In pig#3, however, the volumes of distribution rose in the three selected regions, andduring theacuteVNSstimulation, thebindingpotentials in the selectedbrain regions increased 10–20%of baseline. The changes of the bindingpotentials hence appeared to dependon thebaseline,withdeclines for baselineswith binding potentials above 2 and increases for the baseline below 2, implying that the change by VNS stimulation tended towards binding potentials averaging 1.75, as shown in the panel to the right (Fig. 3). Another way of stating the same observation is to conclude that the variability of binding potentials declined after the stimulation.