GFRα-1 is expressed in parvalbumin GABAergic neurons in the hippocampus

Glial cell line derived neurotrophic factor (GDNF) is a potent survival factor for several types of neurons. GDNF binds with high affinity to GDNF-family receptor α-1 (GFRα-1). This receptor is expressed in different areas of the brain, including the hippocampus and dentate gyrus. By using in situ hybridization and immunohistochemistry, we found that 19% to 37% of glutamic acid decarboxylase (GAD) expressing neurons co-expressed GFRα-1 in the hippocampus. GFRα-1/GAD co-expression was found mainly in the stratum (s) pyramidale (29–37%) and s. oriens (20–25%). Further characterization of GFRα-1 expressing interneurons, based on their calcium-binding protein immunoreactivity, demonstrated that many parvalbumin (PV) immunoreactive neurons express GFRα-1 in the s. pyramidale of CA1 (72%), CA2 (70%) and CA3 (70%) subfields of the hippocampus. GFRα-1/PV double labeled neurons were also detected in the s. oriens of CA1 (52%), CA2 (27%) and CA3 (36%) subfields. The expression of GFRα-1 in principal neurons and in a specific sub-population of GABAergic neurons (PV-containing neurons) suggest that GDNF might modulate, in a selective manner, functions of the entire adult hippocampus.     

γ-Aminobutyric acidA receptor regulation: heterologous uncoupling of modulatory site interactions induced by chronic steroid, barbiturate, benzodiazepine, or GABA treatment in culture

Prolonged administration of anxiolytic, sedative, and anticonvulsant drugs that act through the GABA_A receptor (GAB_AR) can evoke tolerance and dependence, suggesting the existence of an endogenous mechanism(s) for altering the ability of such agents to interact with the GABA_AR. Uncoupling appears to be one such mechanism. This is a decrease in the allosteric interactions between the benzodiazepine (BZD) recognition site and other agonist or modulator sites on the GABA_AR, as measured by potentiation of [³H]flunitrazepam ([³H]FNZ) binding. To investigate the mechanism(s) of uncoupling, neuronal cultures were treated chronically with 3α-hydroxy-5β-pregnan-20-one (pregnanolone), pentobarbital, flurazepam, or GABA, then tested for enhancement of [³H]FNZ binding by these substances. The results indicate that BZDs, barbiturates, and steroids, as well as GABA itself, are capable of inducing both heterologous and homologous uncoupling. Surprisingly, different chronic drug treatments produce different patterns of homologous and heterologous uncoupling. Chronic exposure to pregnanolone, GABA, flurazepam or pentobarbital induces complete uncoupling of barbiturate-BZD site interactions, partial uncoupling of GABA-BZD site interactions, but different amounts of uncoupling of steroid-BZD site interactions. In addition, the EC₅₀ for pregnanolone-induced homologous uncoupling (1.7 μM) is over an order of magnitude greater than that for heterologous uncoupling of GABA and BZD sites (82 nM). Moreover, heterologous uncoupling by pregnanolone is inhibited by the GABA site antagonist SR-95531, whereas homologous uncoupling by pregnanolone is resistant to SR-95531. Therefore, there are at least two distinct ways in which GABA_AR modulatory site interactions can be regulated by chronic drug treatment.     

Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress

The high-metabolic demand of neurons and their reliance on glucose as an energy source places them atrisk for dysfunction and death under conditions of metabolic and oxidative stress. Uncoupling proteins (UCPs) are mitochodrial inner membrane proteins implicated in the regulation of mitochondrial membrane potential (ΔΨ_m) and cellular energy metabolism. The authors cloned UCP4 cDNA from mouse and rat brain, and demonstrate that UCP4 mRNA is expressed abundantly in brain and at particularly high levels in populations of neurons believed to have high-energy requirements. Neural cells with increased levels of UCP4 exhibit decreased ΔΨ_m, reduced reactive oxygen species (ROS) production and decreased mitochondrial calcium accumulation. UCP4 expressing cells also exhibited changes of oxygen-consumption rate, GDP sensitivity, and response of ΔΨ_m to oligomycin that were consistent with mitochondrial uncoupling. UCP4 modulates neuronal energy metabolism by increasing glucose uptake and shifting the mode of ATP production from mitochodnrial respiration to glycolysis, thereby maintaining cellular ATP levels. The UCP4-mediated shift in energy metabolism reduces ROS production and increases the resistance of neurons to oxidative and mitochondrial stress. Knockdown of UCP4 expression by RNA interference in primary hippocampal neurons results in mitochondrial calcium overload and cell death. UCP4-mRNA expression is increased in neurons exposed to cold temperatures and in brain cells of rats maintained on caloric restriction, suggesting a role for UCP4 in the previously reported antiageing and neuroprotective effects of caloric restriction. By shifting energy metabolism to reduce ROS production and cellular reliance on mitochondrial respiration, UCP4 can protect neurons against oxidative stress and calcium overload. These authors made equal contributions to this research.     

Basic FGF attenuates amyloid β-peptide-induced oxidative stress, mitochondrial dysfunction, and impairment of Na/K-ATPase activity in hippocampal neurons

Basic fibroblast growth factor (bFGF) exhibits trophic activity for many populations of neurons in the brain, and can protect those neurons against excitotoxic, metabolic and oxidative insults. In Alzheimer's disease (AD), amyloid β-peptide (Aβ) fibrils accumulate in plaques which are associated with degenerating neurons. Aβ can be neurotoxic by a mechanism that appears to involve induction of oxidative stress and disruption of calcium homeostasis. Plaques in AD brain contain high levels of bFGF suggesting a possible modulatory role for bFGF in the neurodegenerative process. We now report that bFGF can protect cultured hippocampal neurons against Aβ25-35 toxicity by a mechanism that involves suppression of reactive oxygen species (ROS) accumulation and maintenance of Na⁺/K⁺-ATPase activity. Aβ25-35 induced lipid peroxidation, accumulation of H₂O₂, mitochondrial ROS accumulation, and a decrease in mitochondrial transmembrane potential; each of these effects of Aβ25-35 was abrogated in cultures pre-treated with bFGF. Na⁺/K⁺-ATPase activity was significantly reduced following exposure to Aβ25-35 in control cultures, but not in cultures pre-treated with bFGF. bFGF did not protect neurons from death induced by ouabain (a specific inhibitor of the Na⁺/K⁺-ATPase) or 4-hydroxynonenal (an aldehydic product of lipid peroxidation) consistent with a site of action of bFGF prior to induction of oxidative stress and impairment of ion-motive ATPases. By suppressing accumulation of oxyradicals, bFGF may slow Aβ-induced neurodegenerative cascades.     

The GDNF family members neurturin, artemin and persephin promote the morphological differentiation of cultured ventral mesencephalic dopaminergic neurons

Neurturin (NRTN), artemin (ARTN), persephin (PSPN) and glial cell line-derived neurotrophic factor (GDNF) form a group of neurotrophic factors, also known as the GDNF family ligands (GFLs). They signal through a receptor complex composed of a high-affinity ligand binding subunit, postulated ligand specific, and a common membrane-bound tyrosine kinase RET. Recently, also NCAM has been identified as an alternative signaling receptor. GFLs have been reported to promote survival of cultured dopaminergic neurons. In addition, GDNF treatments have been shown to increase morphological differentiation of tyrosine hydroxylase immunoreactive (TH-ir) neurons. The present comparative study investigated the dose-dependent effects of GFLs on survival and morphological differentiation of TH-ir neurons in primary cultures of E14 rat ventral mesencephalon. Both NRTN and ARTN chronically administered for 5 days significantly increased survival and morphological differentiation of TH-ir cells at all doses investigated [0.1–100 ng/ml], whereas PSPN was found to be slightly less potent with effects on TH-ir cell numbers and morphology at 1.6–100 ng/ml and 6.3–100 ng/ml, respectively. In conclusion, our findings identify NRTN, ARTN and PSPN as potent neurotrophic factors that may play an important role in the structural development and plasticity of ventral mesencephalic dopaminergic neurons.     

Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.Key Words: adeno-associated virus, bone morphogenetic protein, dopaminergic neurons, growth/differentiation factor 5, neurodegeneration, neuroprotection, neurotrophic factor, Parkinson''s disease, Smad signaling, α-synuclein     

Horseradish peroxidase histochemistry. A comparison between various methods used for identifying neurons labeled by retrograde axonal transport

Horseradish (HRP) histochemistry is widely used in neuroanatomical and neuropathological research. In this study the sensitivity of 6 methods commonly used for demonstration of HRP were compared mainly by observation on retrogradely labeled hypoglossal neurons found after injection of HRP into the tongue of adult mice. For this purpose groups of equivalent sections were obtained from the brainstem of each mouse. In one series, 3 diaminobenzidine techniques (Graham-Karnovsky; Malmgren-Olsson; Streit-Reubi), and Mesulam's tetramethyl benzidine procedure were compared. In a second series the groups of sections were incubated with DAB (Graham-Karnovsky; Malmgren-Olsson), p-phenylene diamine (Hanker) or TMB (Mesulam; Hardy-Heimer).All the new methods (Streit-Reubi; Malmgren-Olsson; Hanker, Mesulam; Hardy-Heimer) revealed many more labeled neurons per section than the original Graham-Karnovsky technique and Mesulam's TMB procedure was in this regard superior to all of the other tested methods. Particularly in sections from the tongue, disturbing precipitates were often obtained with the TMB methods and they are not as well suited as the new DAB procedures for observations on fine details at the light microscopical level. The new DAB methods (Streit-Reubi; Malmgren-Olsson), apart from their high sensitivity, can very well be used for electron microscopy also.Mesulam's TMB procedure should therefore be the method of choice in studies on retrogradely labeled neurons if highest possible sensitivity is needed. For studies on fine details in such neurons, i.e. when highest possible resolution is required, any one of the new DAB procedures should be chosen. Due to their lower tendency to form artefactual precipitates, they can be recommended for other HRP applications as well, such as vascular permeability studies, observations on vasogenic edema and perineurial permeability.     

Aluminum pretreatment impairs the ability of astrocytes to protect neurons from glutamate mediated toxicity

A number of laboratories have shown that astrocytes protect neurons from glutamate excitotoxicity. The experiments described in this paper were designed to address the question whether prior exposure of astrocytes to aluminum (in the form of aluminum citrate) interfered with the ability of astrocytes to protect neurons from glutamate excitotoxicity. Our culture paradigm consisted of highly enriched cultures of neurons and astrocytes grown on separate coverslips; this design enables one to subject either the neurons or the astrocytes to specific treatments and recombine the cells into the same petri dish simply by moving ceverslips from dish to dish. We have confirmed findings of other laboratories that astrocytes could protect from glutamate-induced death when glutamate (100 μM) is added to the culture medium. We have also demonstrated that prior treatment of astrocytes with 100 μM aluminum citrate impairs this ability of astrocytes to promote neuronal survival. No differences, however, were observed in the ability of control and aluminum-treated astrocytes to take up glutamate. These findings suggest that aluminum may cause astrocytes to: (i) secrete a factor that makes neurons more susceptible to glutamate-induced toxicity; (ii) secrete a neuronotoxic factor in the presence of glutamate; or (iii) reduce secretion of a factor that protects neurons from glutamate excitotoxicity.     

Astrocytes expressing Vitamin D‐activating enzyme identify Parkinson’s disease

IntroductionAstrocytes are involved in Parkinson''s disease (PD) where they could contribute to α‐Synuclein pathology but also to neuroprotection via α‐Synuclein clearance. The molecular signature underlying their dual role is still elusive. Given that vitamin D has been recently suggested to be protective in neurodegeneration, the aim of our study was to investigate astrocyte and neuron vitamin D pathway alterations and their correlation with α‐Synuclein aggregates (ie, oligomers and fibrils) in human brain obtained from PD patients.MethodsThe expression of vitamin D pathway components CYP27B1, CYP24A1, and VDR was examined in brains obtained from PD patients (Braak stage 6; n = 9) and control subjects (n = 4). We also exploited proximity ligation assay to identified toxic α‐Synuclein oligomers in human astrocytes.ResultsWe found that vitamin D‐activating enzyme CYP27B1 identified a subpopulation of astrocytes exclusively in PD patients. CYP27B1 positive astrocytes could display neuroprotective features as they sequester α‐Synuclein oligomers and are associated with Lewy body negative neurons.ConclusionThe presence of CYP27B1 astrocytes distinguishes PD patients and suggests their contribution to protect neurons and to ameliorate neuropathological traits.     

Uncoupling Protein 2 Inhibition Exacerbates Glucose Fluctuation-Mediated Neuronal Effects

Though glucose fluctuations have been considered as an adverse factor for the development of several diabetes-related complications, their impact in the central nervous system is still not fully elucidated. This study was conducted to evaluate the responses of neuronal cells to different glycemic exposures alongside to elucidate the role of uncoupling protein 2 (UCP2) in regulating such responses. To achieve our goals, primary cortical neurons were submitted to constant high (HG)/low (LG) or glucose level variations (GVs), and the pharmacological inhibition of UCP2 activity was performed using genipin. Results obtained show that GV decreased neuronal cells’ viability, mitochondrial membrane potential, and manganese superoxide dismutase activity and increased reactive oxygen species (ROS) production. GV also caused an increase in the glutathione/glutathione disulfide ratio and in the protein expression levels of nuclear factor E2-related factor 2 (NRF2), UCP2, NADH-ubiquinone oxidoreductase chain 1 (ND1), and mitochondrially encoded cytochrome c oxidase I (MTCO1), both mitochondrial DNA encoded subunits of the electron transport chain. Contrariwise, genipin abrogated all those compensations and increased the levels of caspase 3-like activity, potentiated mitochondrial ROS levels, and the loss of neuronal synaptic integrity, decreased the protein expression levels of NRF1, and increased the protein expression levels of UCP5. Further, in the control and LG conditions, genipin increased mitochondrial ROS and the protein expression levels of UCP4, postsynaptic density protein 95 (PSD95), ND1, and MTCO1. Overall, these observations suggest that UCP2 is in the core of neuronal cell protection and/or adaptation against GV-mediated effects and that other isoforms of neuronal UCPs can be upregulated to compensate the inhibition of UCP2 activity.     

Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF

Consistent with the notion that a defect in cellular energy metabolism is a cause of human neurodegenerative disease, systemic treatment with the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA) can model the striatal neurodegeneration seen in Huntington's disease. Previously, we have found that nerve growth factor (NGF), delivered biologically by the implantation of a genetically altered fibroblast cell-line, can protect locally against striatal degeneration induced by infusions of high doses of glutamate receptor agonists. We now report that implantation of NGF-secreting fibroblasts reduces the size of adjacent striatal 3-NPA lesions by an average of 64%. We conclude that biologically delivered NGF protects neurons against excitotoxicity and mitochondrial blockade—both energy-depleting processes—implying that appropriate neurotrophic support in the adult brain could protect against neurodegenerative diseases caused in part by energy depletion. © 1993 Wiley-Liss, Inc.     

Role of salt-induced kinase 1 in androgen neuroprotection against cerebral ischemia

Androgens within physiological ranges protect castrated male mice from cerebral ischemic injury. Yet, underlying mechanisms are unclear. Here, we report that, after middle cerebral artery occlusion (MCAO), salt-induced kinase 1 (SIK1) was induced by a potent androgen—dihydrotestosterone (DHT) at protective doses. To investigate whether SIK1 contributes to DHT neuroprotection after cerebral ischemia, we constructed lentivirus-expressing small interference RNA (siRNA) against SIK1. The SIK1 knockdown by siRNA exacerbated oxygen–glucose deprivation (OGD)-induced cell death in primary cortical neurons, suggesting that SIK1 is an endogenous neuroprotective gene against cerebral ischemia. Furthermore, lentivirus-mediated SIK1 knockdown increased both cortical and striatal infarct sizes in castrated mice treated with a protective dose of DHT. Earlier studies show that SIK1 inhibits histone deacetylase (HDAC) activities by acting as a class IIa HDAC kinase. We observed that SIK1 knockdown decreased histone H3 acetylation in primary neurons. The SIK1 siRNA also exacerbated OGD-induced neuronal death in the presence of trichostatin A (TSA), an HDAC inhibitor, and decreased histone H3 acetylation at 4 hours reoxygenation in TSA-treated neurons. Finally, we showed that DHT at protective doses prevented ischemia-induced histone deacetylation after MCAO. Our finding suggests that SIK1 contributes to neuroprotection by androgens within physiological ranges by inhibiting histone deacetylation.     

Time and dose dependencies of effects of nerve growth factor on sympathetic and sensory neurons in neonatal rats

Nerve growth factor (NGF) plays a role in the development of several components of the sympathetic and sensory nervous systems. The objectives of this study were to examine the time and dose dependencies of some of the well known effects of NGF on sympathetic ganglia and to examine qualitatively and quantitatively the recently described effects on sensory ganglia of neonatal rats. Single doses of NGF as low as 0.1 mg/kg produce increases in tyrosine hydroxylase (TOH) activity in superior cervical ganglia (SCG), and doses of 3 mg/kg produce maximal effects. Larger doses and longer treatments are required to see increases in protein content of the SCG. Larger doses are also required to affect TOH activity in the adrenal gland. Increases in TOH activity in SCG can be observed within 18 h of injection. Chronic NGF treatment for three weeks produces no change in blood pressure or heart rate in neonatal rats. Chronic administration of NGF (1 or 3 mg/kg/day) results in dose-related increases in the protein content of dorsal root ganglia (DRG). The increase in protein content of the DRG was associated with an increase in the diameter of smaller neurons (those<30 μm in diameter), but NGF caused no change in the number of neurons.     

Effects of systemic naloxone upon ventrobasal thalamus neuronal responses in arthritic rats

This study deals with the effect of various doses of systemic naloxone (10 μg, 300 μg, 1 mg/kg) upon activities of 21 ventrobasa thalamus neurons recorded in 20 rats rendered arthritic by injection of Freund's adjuvant into the tail. These neurons presented reproducible responses to movement and/or mild lateral pressure on a joint and a joint and were recorded for at least 30 min after naloxone administration. Several neurons (5) were tested with two doses.After intravenous injection of naloxone at the dose of 10 μg/kg (10 cases) there was a rapid decrease of the responses. The maximum effect occurred at 15 min when the mean value expressed as a percentage of the control was 46.20 ± 8.51% (n= 10, P < 0.001). Recovery could be considered as complete at 30 min.At the dose of 300 μg/kg (9 cases), the decrease in the responses was less important, variable from one neuron to another but significant between 5 and 20 min (mean= 67.43 ± 9.00%at20min, n= 7, P < 0.01).At the dose of 1 mg/kg (7 cases), there was no significant modification of the response.Spontaneous firing rate of the neurons was slightly significantly increased after injection of the two highest doses and unmodified after the lowest.The relationship between the depressive effect produced by low doses of naloxone upon the neuronal responses, and the ‘bi-directional’ analgesic-hyperalgesic action of the drug, demonstrated in these suffering rats, is discussed.     

Pre- or post-treatment with the mitochondrial uncoupler 2,4-dinitrophenol attenuates striatal quinolinate lesions

We have examined the neuroprotective efficacy of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) in animals receiving striatal injections of the neurotoxin quinolinic acid. Animals administered DNP either 1 h before or 3 h following QA infusion developed lesions that were 25% smaller than control animals. Animals treated with the DNP analogue 2,4,6-trinitrophenol, which does not possess uncoupling activity in intact mitochondria, showed no neuroprotection. These results indicate that DNP, and other compounds that diminish the mitochondrial membrane potential, might provide a novel approach to the treatment of acute neurological injury.     

Highly selective effects of nerve growth factor,brain-derived neurotrophic factor,and neurotrophin-3 on intact and injured basal forebrain magnocellular neurons

Cholinergic neurons of the basal nucleus complex (BNC) respond to nerve growth factor (NCF), the first member of a polypeptide gene family that also includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), NGF, BDNF, and NT-3 are enriched in hippocampus. In addition, NGF and, more recently, BDNF have been shown to stimulate the cholinergic differentiation and enhance the survival of BNC cells in vitro. The present investigation was designed to test, in a comparative fashion, the in vivo effects of human recombinant NGF, BDNF, and NT-3 with confirmed activities in vitro on cholinergic and γ-aminobutyric acid (GABA)-ergic BNC neurons. The specific questions asked were whether and, to what extent, biologically active recombinant neurotrophins stimulate the transmitter phenotypes of intact cholinergic and GABAergic neurons of the BNC, and whether, and to what extent, recombinant neurotrophins protect the transmitter phenotypes of axotomized cholinergic and GABAergic neurons of the BNC following complete transections of the fimbria-fornix (measured by ChAT mRNA hybridization). Our results confirm the profound stimulatory and p^75NGFR expression in both intact and axotomized cholinergic neurons and to exert minor effects on some cholinergic markers (e.g., ChAT immunoreactivity). NT-3 had no influence on GABAergic neurons. Taken together, these results indicate that, despite their significant sequence homologies and their shared abundance in target fields of BNC neurons, NGF, BDNF, and NT-3 show striking differences in their efficacies as cholinergic trophic factors. GABAergic neurons of the BNC are resistant to neurotrophins. The result of the present investigation establish that NGF excels among neurotrophins as a trophic factor for intact and injured basal forebrain cholinergic neurons. © 1994 Wiley-Liss, Inc.     

Haloperidol Prevents Ketamine- and Phencyclidine-Induced HSP70 Protein Expression but Not Microglial Activation

NoncompetitiveN-methyl- -aspartate (NMDA) receptor antagonists, including ketamine and phencyclidine (PCP), produce abnormal intracellular vacuoles in posterior cingulate and retrosplenial cortical neurons in the rat. Ketamine also induces 70-kDa heat shock protein (HSP70) expression in pyramidal neurons in the posterior cingulate and retrosplenial cortex and, as shown by this study, activates microglia in the retrosplenial cortex of the rat. Whereas HSP70 protein expression was induced with ketamine doses of 40 mg/kg (ip) and higher, doses of 80 mg/kg and higher were required to activate microglia. HSP70-positive neurons were observed in 30- to 90-day-old rats but not in younger, 10- to 20-day-old animals following ketamine (80 mg/kg, ip). Pretreatment with the antipsychotic drug haloperidol at doses of 1.0 mg/kg and above abolished all HSP70 immunostaining produced by ketamine (80 mg/kg). However, a single dose of haloperidol (5 mg/kg, im) did not decrease the number of microglia activated in retrosplenial cortex by ketamine (80–140 mg/kg). Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial activation in the posterior cingulate and retrosplenial cortex of adult rats was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP). These results suggest that ketamine and PCP injure neurons in the posterior cingulate and retrosplenial cortex of adult rats. Though haloperidol may afford some protection against this injury since it inhibits induction of HSP70 expression, the failure to prevent microglial activation suggests that single doses of haloperidol do not completely protect neurons from NMDA antagonist toxicity.     

Electrophysiological and pharmacological properties of putative A13 incertohypothalamic dopamine neurons in the rat

A13 incertohypothalamic dopamine (DA) neurons were labelled with antibodies raised to tyrosine hydroxylase in the male rat. Electrophysiologically, these neurons could be distinguished from their neighboring non-DA cells by their wide action potentials ( > 2 ms), slow firing rates (0–3.8 impulses/s) and by the ability of iontophoresed DA and systemically administered apomorphine to inhibit impulse flow. Low doses of the antipsychotic drug haloperidol attenuated DA's response and reversed the apomorphine-inhibition of impulse flow.