The hippocampal formation is thought to contribute to both addictive behaviors and to psychotic disorders, and the actions of the neurotransmitter dopamine are intimately involved with these disease states. We have used both whole-cell and extracellular recording techniques in hippocampal slices to investigate the actions of both cocaine and dopamine receptor agonists in the CA1 region. In the presence of cocaine (10 M), endogenously released dopamine decreased monosynaptic inhibitory postsynaptic currents (IPSCs) evoked from stratum radiatum but not from stratum oriens. This effect of cocaine was not blocked by the D 1/5 antagonist SCH 23390 ({R-(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine}) (3 M), whereas several D 2 -like dopamine receptor antagonists prevented the cocaine-induced decrease in the IPSC. The most selective of the effective antagonists tested was the D 3 antagonist, U 99194 ({5,6-dimethoxy-indan-2-yl dipropylamine}) maleate (1 M). An exogenously applied D 3 -selective dopamine receptor agonist, PD 128907 ({(ϩ)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano-[4,3-b]-1,4-oxazin-9-ol}) (1 M), also significantly inhibited the IPSC, providing further evidence that the activation of the D 3 subtype of dopamine receptor by endogenously released dopamine can modulate inhibition in the CA1 region. This disinhibitory action on pyramidal cells also increased synaptic excitability following Schaffer collateral stimulation, as demonstrated by either a decrease in paired-pulse inhibition of the population spike response or by an increase in the excitatory component of the mixed synaptic response evoked from stratum radiatum. These actions indicate that the activation of D 3 receptors by endogenously released dopamine, especially under conditions of transporter blockade, may significantly impact the processing of synaptic information through the stratum radiatum layer of the hippocampus.Functional imbalance of the dopamine neurotransmitter system in the brain is thought to be a key component underlying both schizophrenia and substance use disorders, and their comorbidity is increasingly being recognized in human populations (Negrete, 2003) and investigated using animal models (Chambers and Taylor, 2004). Data obtained from rats utilizing either the neonatal hippocampal lesion (schizophrenia) or self-administration (substance use) animal models have suggested that the hippocampus is likely to be involved in both schizophrenia (Harrison, 2004), and drug relapse (Vorel et al., 2001;Sun and Rebec, 2003). It is therefore important to determine the role of the endogenous dopamine transmitter system in normal and pathological hippocampal function.The understanding of the actions of dopamine as a neurotransmitter in the hippocampal formation has evolved over the past 3 decades, from the presumption that dopamine had no significant role (except as a precursor to norepinephrine), to the current appreciation that dopamine can act via multiple signaling pathways in ...
Aim: Variations in the clinical outcomes using mesenchymal stem cells (MSCs) treatments exist, reflecting different origins and niches. To date, there is no consensus on the best source of MSCs most suitable to treat a specific disease. Methods: Total transcriptome analysis of human MSCs was performed. MSCs were isolated from two adult sources bone marrow, adipose tissue and two perinatal sources umbilical cord and placenta. Results: Each MSCs type possessed a unique expression pattern that reflects an advantage in terms of their potential therapeutic use. Advantages in immune modulation, neurogenesis and other aspects were found. Discussion: This study is a milestone for evidence-based choice of the type of MSCs used in the treatment of diseases.
Norepinephrine has potent antiepileptic properties, the pharmacology of which is unclear. Under conditions in which GABAergic inhibition is blocked, norepinephrine reduces hippocampal cornu ammonis 3 (CA3) epileptiform activity through ␣ 2 adrenergic receptor (AR) activation on pyramidal cells. In this study, we investigated which ␣ 2 AR subtype(s) mediates this effect. First, ␣ 2 AR genomic expression patterns of 25 rat CA3 pyramidal cells were determined using real-time single-cell reverse transcription-polymerase chain reaction, demonstrating that 12 cells expressed ␣ 2A AR transcript; 3 of the 12 cells additionally expressed mRNA for ␣ 2C AR subtype and no cells possessing ␣ 2B AR mRNA. Hippocampal CA3 epileptiform activity was then examined using field potential recordings in brain slices. The selective ␣AR agonist 6-fluoronorepinephrine caused a reduction of CA3 epileptiform activity, as measured by decreased frequency of spontaneous epileptiform bursts. In the presence of AR blockade, concentration-response curves for AR agonists suggest that an ␣ 2 AR mediates this response, as the rank order of potency was 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14304) Ն epinephrine Ͼ6-fluoronorepinephrine Ͼ norepinephrine phenylephrine. Finally, equilibrium dissociation constants (K b ) of selective ␣AR antagonists were functionally determined to confirm the specific ␣ 2 AR subtype inhibiting CA3 epileptiform activity. Apparent K b values calculated for atipamezole (1.7 nM), MK-912 (4.8 nM), BRL-44408 (15 nM), yohimbine (63 nM), ARC-239 (540 nM), prazosin (4900 nM), and terazosin (5000 nM) correlated best with affinities previously determined for the ␣ 2A AR subtype (r ϭ 0.99, slope ϭ 1.0). These results suggest that, under conditions of impaired GABAergic inhibition, activation of ␣ 2A ARs is primarily responsible for the antiepileptic actions of norepinephrine in the rat hippocampal CA3 region.The noradrenergic system is a key modulator of numerous physiological and pathological processes. Within the central nervous system (CNS), noradrenergic neurons innervate copious neural networks and regulate a number of essential neurological functions, including attention and arousal, sleep, and learning and memory (Pupo and Minneman, 2001).
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