Intrastriatal grafts of mesenchymal stem cells in adult intact rats can elevate tyrosine hydroxylase expression and dopamine levels

MSCs (mesenchymal stem cells) derived from the bone marrow have shown to be a promising source of stem cells in a therapeutic strategy of neurodegenerative disorder. Also, MSCs can enhance the TH (tyrosine hydroxylase) expression and DA (dopamine) content in catecholaminergic cells by in vitro co‐culture system. In the present study, we investigated the effect of intrastriatal grafts of MSCs on TH protein and gene levels and DA content in adult intact rats. When MSCs were transplanted into the striatum of normal rats, the grafted striatum not only had significantly higher TH protein and mRNA levels, but also significantly higher DA content than the untransplanted striatum. Meanwhile, the grafted MSCs differentiated into neurons, astrocytes and oligodendrocytes; however, TH‐positive cells could not be detected in our study. These experimental results offer further evidence that MSCs are a promising candidate for treating neurodegenerative diseases such as Parkinson's disease.     

Spatial reference learning deficits in absence of dysfunctional working memory in the TgF344-AD rat model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by cognitive disorders and alterations of behavioral traits such as anhedonia and anxiety. Contribution of nonphysiological forms of amyloid and tau peptides to the onset of neurological dysfunctions remains unclear because most preclinical models only present one of those pathological AD-related biomarkers. A more recently developed model, the TgF344-AD rat has the advantage of overexpressing amyloid and naturally developing tauopathy, thus making it close to human familial forms of AD. We showed the presence of a learning dysfunction in a reference memory test, without spatial working memory impairment but with an increase in anxiety levels and a decrease in motivation to participate in the test. In the sucrose preference test, TgF344-AD rats did not show signs of anhedonia but did not increase the volume of liquid consumed when the water was replaced by sucrose solution. These behavioral phenomena were observed at an age when tau accumulation are absent, and where amyloid deposits are predominant in the hippocampus and the entorhinal cortex. Within the hippocampus itself, amyloid accumulation is heterogenous between the subiculum, the dorsal hippocampus and the ventral hippocampus. Thus, our data demonstrated heterogeneity in the appearance of various behavioral and neurochemical markers in the TgF344-AD rat. This multivariate analysis will therefore make it possible to define the stage of the pathology, to measure its evolution and the effects of future therapeutic treatments.     

Biotransformation of dopamine to norlaudanosoline by Aspergillus niger

Norlaundanosoline is a key intermediate in the synthesis of the benzylisoquinoline alkaloids providing the upper isoquinoline portion of the morphinan skeleton. This study evaluates the feasibility of using Aspergillus niger as an in situ biotransformation system to produce norlaudanosoline from dopamine. A. niger was chosen because monoamine oxidase can be readily induced in this organism. Monoamine oxidase catalyzes the conversion of dopamine to 3,4-dihydroxyphenylacetaldehyde. In the presence of dopamine, this aldehyde will then undergo a spontaneous Picket-Spengler condensation to form norlaudanosoline. Fermentation condition to form norlaudanosoline. Fermentation conditions were optimized for the production monoamine oxidase by using a two-stage process consisting of a growth stage and an induction stage. pH control was found to be important, and at pH 4.5 dopamine accumulation in the cells was high as was the level of monoamine oxidase. With pH control at 4.5, up to 21% of the cellular dopamine was converted to norlaudanosoline. It is proposed that with further protein engineering improvements, this system may prove suitable for the in situ bio-transformation of dopamine to norlaudanosoline.     

Paradoxical modulation of short-term facilitation of dopamine release by dopamine autoreceptors

Electrophysiological studies have demonstrated that dopaminergic neurons burst fire during certain aspects of reward-related behavior; however, the correlation between dopamine release and cell firing is unclear. When complex stimulation patterns that mimic intracranial self-stimulation were employed, dopamine release was shown to exhibit facilitated as well as depressive components (Montague et al. 2004). Understanding the biological mechanisms underlying these variations in dopamine release is necessary to unravel the correlation between unit activity and neurotransmitter release. The dopamine autoreceptor provides negative feedback to dopamine release, inhibiting release on the time scale of a few seconds. Therefore, we investigated this D(2) receptor to see whether it is one of the biological mechanisms responsible for the history-dependent modulation of dopamine release. Striatal dopamine release in anesthetized rats was evoked with stimulus trains that were designed to promote the variability of dopamine release. Consistent with the well established D(2)-mediated autoinhibition, the short-term depressive component of dopamine release was blocked by raclopride, a D(2) antagonist, and enhanced by quinpirole, a D(2)-receptor agonist. Surprisingly, these same drugs exerted a similar effect on the short-term facilitated component: a decrease with raclopride and an increase with quinpirole. These data demonstrate that the commanding control exerted by dopamine autoreceptors over short-term neuroadaptation of dopamine release involves both inhibitory and paradoxically, facilitatory components.     

Caffeine and accumbens shell dopamine

It has been reported that caffeine (1.5-30 mg/kg i.p.) as well as specific A1 (DPCPX, 8-cyclopentyl-1,3-dipropylxanthine) receptor antagonists fail to increase extracellular dopamine (DA) in the shell of the nucleus accumbens (NAc). However, it has also been reported that caffeine (10 and 30 mg/kg i.p.) and the A1 antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) increases NAc shell DA. To clarify this issue rats were implanted with microdialysis probes at different sites in the NAc shell, in the medial prefrontal cortex (PFCX, infralimbic cortex), and at the border between those areas. Irrespective of probe placement within the NAc shell and of the use of different surgical anesthetics (chloral hydrate and ketamine), we failed to observe changes in dialysate DA after 10 and 30 mg/kg i.p. of caffeine. Similarly negative results were obtained with DPCPX and CPFPX, two potent and selective A1 receptor antagonists. A significant increase of DA was obtained after caffeine when probes were located at the border between the NAc shell and the PFCX (10 and 30 mg/kg) or in the PFCX (10 mg/kg). In view of this and of our previous report that caffeine increases dialysate DA in the medial PFCX, we conclude that the increase in dialysate DA by caffeine observed by others arises from the medial PFCX rather than from the NAc shell as a result of placement of microdialysis probes at the border between the NAc shell and the PFCX.     

Nicotine increases dopamine clearance in medial prefrontal cortex in rats raised in an enriched environment

Environmental enrichment results in differential behavioral and neurochemical responsiveness to nicotine. The present study investigates dopamine clearance (CL_DA) in striatum and medial prefrontal cortex (mPFC) using in vivo voltammetry in rats raised in enriched (EC) or impoverished conditions (IC) and administered nicotine (0.4 mg/kg) or saline. Baseline CL_DA in striatum or mPFC was not different between EC and IC. Across repeated DA application, striatal CL_DA increased in saline-control EC and IC. CL_DA increased in mPFC in saline-control IC; CL_DA did not change in saline-control EC. Thus, enrichment differentially alters dynamic responses of the dopamine transporter (DAT) to repeated DA application in mPFC, but not in striatum. In EC, nicotine increased mPFC CL_DA compared to saline-control, but had no effect on CL_DA in IC; nicotine had no effect in striatum in EC or IC. Compared to respective saline-controls, nicotine increased dihydroxyphenylacetic acid content in striatum and mPFC in EC, but not in IC. Nicotine also had no effect on DA content in striatum or mPFC in EC or IC. Results indicate that enrichment eliminated the dynamic response of mPFC DAT to repeated DA application in saline-control and augmented the nicotine-induced increase in DAT function in mPFC, but not in striatum.