The mouse brain after foot shock in four dimensions: Temporal dynamics at a single-cell resolution.

Acute stress leads to sequential activation of functional brain networks. A biologically relevant question is exactly which (single) cells belonging to brain networks are changed in activity over time after acute stress across the entire brain. We developed a preprocessing and analytical pipeline to chart whole-brain immediate early genes' expression-as proxy for cellular activity-after a single stressful foot shock in four dimensions: that is, from functional networks up to three-dimensional (3D) single-cell resolution and over time. The pipeline is available as an R package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal, and finally, thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others-like the dentate gyrus-dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this "strategy" changed after foot shock in half of the brain areas. One of the strengths of our approach is that single-cell data were simultaneously examined across all of the 90 brain areas and can be visualized in 3D in our interactive web portal.

Comparative Analysis of Anticonvulsant Activity of Trans and Cis 5,5'-Diphenylhydantoin Schiff Bases.

Recently, the four 5,5'-diphenylhydantoin Schiff bases, possessing different aromatic species (SB1-Ph, SB2-Ph, SB3-Ph and SB4-Ph) were synthesized, characterized, and evaluated for anticonvulsant activity in combination with phenytoin. In the present study, the SB1-Ph and SB4-Ph compounds were selected, based on their anticonvulsant potency, and compared with their cis isomers, prepared after a one-hour exposure to the UV source, for their anticonvulsant potency in the maximal electroshock (MES) test and the kainate (KA)-induced status epilepticus (SE) test in mice. In the MES test, the cisSB1-Ph compound exhibited superior to phenytoin and trans isomer activity in the three tested doses, while the cisSB4-Ph compound entirely suppressed the electroshock-induced seizure spread at the highest dose of 40 mg/kg. Pretreatment with the cisSB1-Ph compound and the cisSB4-Ph at the doses of 40 mg/kg, respectively, for seven days, significantly attenuated the severity of KA SE compared to the matched control group pretreated with a vehicle, while phenytoin was ineffective in this test. The cisSB4-Ph but not the cisSB1-Ph demonstrated an antioxidant effect against the KA-induced SE in the hippocampus. Our results suggest that trans-cis conversion of 5,5'-diphenylhydantoin Schiff bases has potential against seizure spread in the MES test and mitigated the KA-induced SE. The antioxidant potency of cisSB4-Ph might be associated with its efficacy in mitigating the SE.

Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals.

Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal "go" circuit and a decreased prelimbic cortex-ventrolateral striatal "stop" circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, "shock-resistant" rats showed strengthening of this negative connectivity after shock exposure. In contrast, "shock-sensitive" rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs.

How Antidepressant Drugs Affect the Antielectroshock Action of Antiseizure Drugs in Mice: A Critical Review.

Depression coexists with epilepsy, worsening its course. Treatment of the two diseases enables the possibility of interactions between antidepressant and antiepileptic drugs. The aim of this review was to analyze such interactions in one animal seizure model-the maximal electroshock (MES) in mice. Although numerous antidepressants showed an anticonvulsant action, mianserin exhibited a proconvulsant effect against electroconvulsions. In most cases, antidepressants potentiated or remained ineffective in relation to the antielectroshock action of classical antiepileptic drugs. However, mianserin and trazodone reduced the action of valproate, phenytoin, and carbamazepine against the MES test. Antiseizure drug effects were potentiated by all groups of antidepressants independently of their mechanisms of action. Therefore, other factors, including brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) modulation, should be considered as the background for the effect of drug combinations.

Anti-epileptic activity, toxicity and teratogenicity in CD1 mice of a novel valproic acid arylamide derivative, N-(2-hydroxyphenyl)-2-propylpentanamide.

N-(2-hydroxyphenyl)-2-propylpentamide (HO-AAVPA) is a novel arylamide derivative of valproic acid (VPA) designed in silico, with better antioxidant and antiproliferative effect on cancer cell lines than VPA. This study was aimed to evaluate the anticonvulsant activity, the toxicity and teratogenicity produced in HO-AAVPA-treated CD1 mice using VPA as positive control. With the maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizure models, HO-AAVPA reduced the time of hind limb extension, stupor and recovery, the number of clonic and tonic seizures and the mortality rate in a dose-dependent manner, obtaining an ED50 of 370 and 348 mg/kg for MES and PTZ, respectively. On the rotarod test, mice administered with 600 mg/kg HO-AAVPA manifested reduced locomotor activity (2.78%); while HO-AAVPA at 300 mg/kg and VPA at 500 mg/kg gave a similar outcome (∼60%). The LD50 of 936.80 mg/kg herein found for HO-AAVPA reflects moderate toxicity. Concerning teratogenicity, the administration of HO-AAVPA to pregnant females at 300 and 600 mg/kg on gestation day (GD) 8.5 generated less visceral and skeletal alterations in the fetuses, as well as, minor rate of modifications in the expression pattern of the neuronal marker Tuj1 and endothelial marker PECAM1 in embryos, that those induced by VPA administration. Altered embryonic development occurred with less frequency and severity with HO-AAVPA at 600 mg/kg than VPA at 500 mg/kg. In conclusion, the protective effect against convulsions provided by HO-AAVPA was comparable to that of VPA in the MES and PZT seizure models, showed lower toxicity and less damage to embryonic and fetal development.

The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure-Synthesis and In Vivo/In Vitro Studies.

Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.

Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis.

The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia.

Dopamine is Required for Activity-Dependent Amplification of Arc mRNA in Developing Postnatal Frontal Cortex.

The activity-regulated gene Arc/Arg3.1 encodes a postsynaptic protein crucially involved in glutamatergic synaptic plasticity. Genetic mutations in Arc pathway and altered Arc expression in human frontal cortex have been associated with schizophrenia. Although Arc expression has been reported to vary with age, what mechanisms regulate Arc mRNA levels in frontal cortex during postnatal development remains unclear. Using quantitative mRNA analysis of mouse frontal cortical tissues, we mapped the developmental profiles of Arc expression and found that its mRNA levels are sharply amplified near the end of the second postnatal week, when mouse pups open their eyes for the first time after birth. Surprisingly, electrical stimulation of the frontal cortex before eye-opening is not sufficient to drive the amplification of Arc mRNA. Instead, this amplification needs both electrical stimulation and dopamine D1-type receptor (D1R) activation. Furthermore, visual stimuli-driven amplification of Arc mRNA is also dependent on D1R activation and dopamine neurons located in the ventral midbrain. These results indicate that dopamine is required to drive activity-dependent amplification of Arc mRNA in the developing postnatal frontal cortex and suggest that joint electrical and dopaminergic activation is essential to establish the normal expression pattern of a schizophrenia-associated gene during frontal cortical development.

Systematic evaluation of skeletal fractures caused by induction of electroconvulsive seizures in rat state a need for attention and refinement of the procedure.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most efficient treatments for major depression. Electroconvulsive seizures (ECS), the animal model of ECT, is widely used to study both mechanisms of action and adverse effects of ECT. As the treatment itself serves as an instant anaesthetic and anaesthetic agents may affect memory functions and behaviour, ECS is traditionally administered without muscle relaxation and anaesthesia. A major problem of unmodified ECS, which has only been addressed peripherally in the literature, is that some animals sustain spinal fractures and subsequent hind leg paralysis (paraplegia). This phenomenon leads to a higher degree of suffering and these animals need to be excluded from the studies. To reach sufficient statistical power, the group sizes are therefore often increased and this may lead to a pre-selected study group in risk of skewing the results. Moreover, the study design of the experiments do not comply with the 3R principles, which advocate for both refinement and reduction of animal experiments. The objective of this study is to systematically evaluate injuries caused by ECS. METHODS: We summarise the incidence of spinal fractures from 24 studies conducted during 2009-2015 in six different rat strains and report preliminary findings on scapular fractures following auricular ECS. RESULTS: In total, 12.8% of all tested animals suffered from spinal fractures and we find an increase in spinal fracture incidence over time. Furthermore, X-ray analyses revealed that some animals displayed scapular fractures. CONCLUSION: We discuss consequences of and possible explanations for ECS-induced fractures. Modifications of the method are highly warranted and we furthermore suggest that all animals are thoroughly examined for discrete fractures.

Effects of Tripeptide Gly-His-Lys in Pain-Induced Aggressive-Defensive Behavior in Rats.

We studied the effect of Gly-His -Lys tripeptide administered intraperitoneally in doses of 5, 15, 50 and 150 µg/kg on pain-induced aggressive-defensive behavior. A foot-shock model of aggression in rats grouped in pairs in an electrified chamber was used. Analgesic and antiaggresiogenic effects of the peptide were demonstrated. It was found the L-lysine residue plays the key role in these effects, because they were observed under the influence of L-lysine administration in doses close to its equimolar content in the studied tripeptide.

Pharmacogenetic excitation of dorsomedial prefrontal cortex restores fear prediction error.

Pavlovian conditioning involves encoding the predictive relationship between a conditioned stimulus (CS) and an unconditioned stimulus, so that synaptic plasticity and learning is instructed by prediction error. Here we used pharmacogenetic techniques to show a causal relation between activity of rat dorsomedial prefrontal cortex (dmPFC) neurons and fear prediction error. We expressed the excitatory hM3Dq designer receptor exclusively activated by a designer drug (DREADD) in dmPFC and isolated actions of prediction error by using an associative blocking design. Rats were trained to fear the visual CS (CSA) in stage I via pairings with footshock. Then in stage II, rats received compound presentations of visual CSA and auditory CS (CSB) with footshock. This prior fear conditioning of CSA reduced the prediction error during stage II to block fear learning to CSB. The group of rats that received AAV-hSYN-eYFP vector that was treated with clozapine-N-oxide (CNO; 3 mg/kg, i.p.) before stage II showed blocking when tested in the absence of CNO the next day. In contrast, the groups that received AAV-hSYN-hM3Dq and AAV-CaMKIIα-hM3Dq that were treated with CNO before stage II training did not show blocking; learning toward CSB was restored. This restoration of prediction error and fear learning was specific to the injection of CNO because groups that received AAV-hSYN-hM3Dq and AAV-CaMKIIα-hM3Dq that were injected with vehicle before stage II training did show blocking. These effects were not attributable to the DREADD manipulation enhancing learning or arousal, increasing fear memory strength or asymptotic levels of fear learning, or altering fear memory retrieval. Together, these results identify a causal role for dmPFC in a signature of adaptive behavior: using the past to predict future danger and learning from errors in these predictions.

[Treatment of psychiatric disorders during pregnancy and the breast feeding : Psychotherapy and other nondrug therapies]. / Behandlung psychischer Störungen in Schwangerschaft und Stillzeit : Psychotherapie und andere nichtmedikamentöse Therapien.

The majority of women suffering from psychiatric disorders in pregnancy and the breast feeding prefer psychotherapy and other nonpharmacological treatment over psychopharmacological treatment although the risk of malformations and postnatal complications in children exposed to psychopharmacological drugs must be regarded as acceptable in moderate to severely ill patients. Data are lacking, but several psychotherapeutic and biological treatments as well as noninvasive brain stimulation procedures have been investigated to treat depressive episodes and anxiety disorders in pregnancy and the breast feeding. In mild to moderate depressive episodes different psychotherapy treatments and counseling are significantly more effective in reducing depressive symptoms than no treatment.The same seems to be true for anxiety disorders; however, studies on this are sparse. Treatment by telephone and internet also seems to improve symptoms, which is of interest especially in the less flexible group of breast feeding women and for the development of future health care structures. Noninvasive stimulation treatment has been shown to be an effective nonpharmacological therapeutic option. Data for other recent noninvasive brain stimulation treatments and biological treatments as well as exercise therapy are sparse. In severe and delusional cases as well as treatment-resistant depressive episodes, electroconvulsive therapy should be considered in pregnant women. Because several patients prefer nonpharmacological therapy during this period, those should be applied if available and feasible. Regarding nonpharmacological treatment of obsessive-compulsive disorder, bipolar disorder and schizophrenia during pregnancy and the breast feeding, no recommendation can currently be given.

[Long-Term Contextual Memory in Mice: Persistence and Associability with Reinforcement].

Animals can associate memory of a context with unconditioned stimuli even if there is a long time in- terval between acquisition of contextual memory and its subsequent reinforcement. This phenomenon of context preexposure effect was first described and investigated in rats. Here we studied the possibility of associating previously acquired memory about a context with unconditioned stimulus (immediate shock) in mice. We showed that fear memory in this model was specific for the previously explored context but not for the context of immediate shock. Associative learning was possible when acquisition of contextual memory and presentation unconditioned stimulus (immediate shock) were spaced in the range of 30 min-30 days interval. Resulting memory was stable and persisted for at least 30 days. Our results open new avenues for studies of neuronal mechanisms of associative memory using transgenic re- porter mice.

Electroconvulsive seizures (ECS) do not prevent LPS-induced behavioral alterations and microglial activation.

BACKGROUND: Long-term neuroimmune activation is a common finding in major depressive disorder (MDD). Literature suggests a dual effect of electroconvulsive therapy (ECT), a highly effective treatment strategy for MDD, on neuroimmune parameters: while ECT acutely increases inflammatory parameters, such as serum levels of pro-inflammatory cytokines, there is evidence to suggest that repeated ECT sessions eventually result in downregulation of the inflammatory response. We hypothesized that this might be due to ECT-induced attenuation of microglial activity upon inflammatory stimuli in the brain. METHODS: Adult male C57Bl/6J mice received a series of ten electroconvulsive seizures (ECS) or sham shocks, followed by an intracerebroventricular (i.c.v.) lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) injection. Brains were extracted and immunohistochemically stained for the microglial marker ionized calcium-binding adaptor molecule 1 (Iba1). In addition, a sucrose preference test and an open-field test were performed to quantify behavioral alterations. RESULTS: LPS induced a short-term reduction in sucrose preference, which normalized within 3 days. In addition, LPS reduced the distance walked in the open field and induced alterations in grooming and rearing behavior. ECS did not affect any of these parameters. Phenotypical analysis of microglia demonstrated an LPS-induced increase in microglial activity ranging from 84 to 213 % in different hippocampal regions (CA3 213 %; CA1 84 %; dentate gyrus 131 %; and hilus 123 %). ECS-induced alterations in microglial activity were insignificant, ranging from -2.6 to 14.3 % in PBS-injected mice and from -20.2 to 6.6 % in LPS-injected mice. CONCLUSIONS: We were unable to demonstrate an effect of ECS on LPS-induced microglial activity or behavioral alterations.

Genetic background of mice strongly influences treatment resistance in the 6 Hz seizure model.

OBJECTIVE: The 6 Hz model of focal seizures has been increasingly used to identify anticonvulsant compounds with potential activity against therapy-resistant epilepsy, but the protective response to anticonvulsants in this model could be dependent on experimental conditions and selection of mouse strains. METHODS: Seizure thresholds in the 6 Hz model were compared in CF-1, NMRI, and C57Bl/6J male mice with two different electrical stimulators (Ugo Basile 5780 and Grass S48). Dose-response curves for phenytoin and levetiracetam were generated in the three strains at 32 and 44 mA current intensities using both devices. Plasma and brain exposure to the two drugs were measured in all three strains. RESULTS: CF-1 mice had the lowest seizure threshold and responded to phenytoin at 32 mA stimulation intensity, but not at 44 mA. NMRI and C57Bl/6J mice had nearly identical threshold values, but NMRI mice responded well to phenytoin at 32 mA and showed limited responsiveness to this drug at 44 mA, whereas C57Bl/6J mice were nearly completely resistant to phenytoin. Furthermore, levetiracetam showed limited efficacy and low potency in CF-1 and C57Bl/6J mice, particularly at 44 mA, whereas in NMRI mice the drug showed much higher potency in all experimental conditions. No obvious difference in the pharmacokinetics of both phenytoin and levetiracetam was detected between the mouse strains that would have explained these unexpected variations in potency. We have also found that the protective effects of both drugs may be influenced by the device type. SIGNIFICANCE: Collectively these observations clearly indicate that treatment resistance of 6 Hz seizures should be interpreted with strain and experimental conditions in mind. Furthermore, it is important to note that strain differences, much like human genetic differences, may explain why some mice and patients respond to a given treatment and others do not.

Maximal electroshock-induced seizures are able to induce Homer1a mRNA expression but not pentylenetetrazole-induced seizures.

OBJECTIVE: Homer1a is a protein that regulates metabotropic glutamate receptors involved in neural plasticity processes. Recently, we demonstrated that Homer1a mRNA is enhanced after pilocarpine-induced status epilepticus. Here, we investigated whether a single acute seizure triggered by means of pentylenetetrazole (PTZ) injection or maximal electroshock (MES) stimulation (2 different seizure models) would alter Homer1a expression in the hippocampus. METHODS: Male Wistar rats subjected to the PTZ or MES model were analyzed 2h, 8h, 24h, and 7days after seizure induction. Homer1a, mGluR1, and mGluR5 mRNA expression levels in hippocampal extracts were analyzed by quantitative PCR. RESULTS: Quantitative PCR revealed Homer1a overexpression at 2h after MES-induced tonic-clonic seizures compared to control, but the overexpression did not remain elevated after 8h. Pentylenetetrazole-induced seizures, in contrast, were not able to change Homer1a mRNA expression. No differences were observed at these time points after seizures for mGluR1 and mGluR5 mRNA expression in any of the models. SIGNIFICANCE: Our data indicate that the levels of Homer1a mRNA were transiently increased only after MES-induced tonic-clonic seizures (and not after PTZ-induced seizures). We suggest that Homer1a expression may be dependent on seizure intensity or on specific brain circuit activation. We suggest that Homer1a may contribute to counteract hyperexcitability processes.

Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise.

Voluntary exercise is known to have an antidepressant effect. However, the underlying mechanism for this antidepressant action of exercise remains unclear, and little progress has been made in identifying genes that are directly involved. We have identified macrophage migration inhibitory factor (MIF) by analyzing existing mRNA microarray data and confirmed the augmented expression of selected genes under two experimental conditions: voluntary exercise and electroconvulsive seizure. A proinflammatory cytokine, MIF is expressed in the central nervous system and involved in innate and adaptive immune responses. A recent study reported that MIF is involved in antidepressant-induced hippocampal neurogenesis, but the mechanism remains elusive. In our data, tryptophan hydroxylase 2 (Tph2) and brain-derived neurotrophic factor (Bdnf) expression were induced after MIF treatment in vitro, as well as during both exercise and electroconvulsive seizure in vivo. This increment of Tph2 was accompanied by increases in the levels of total serotonin in vitro. Moreover, the MIF receptor CD74 and the ERK1/2 pathway mediate the MIF-induced Tph2 and Bdnf gene expression as well as serotonin content. Experiments in Mif(-/-) mice revealed depression-like behaviors and a blunted antidepressant effect of exercise, as reflected by changes in Tph2 and Bdnf expression in the forced swim test. In addition, administration of recombinant MIF protein produced antidepressant-like behavior in rats in the forced swim test. Taken together, these results suggest a role of MIF in mediating the antidepressant action of exercise, probably by enhancing serotonin neurotransmission and neurotrophic factor-induced neurogenesis in the brain.

Synthesis and evaluation of anticonvulsant activity of N-(2,5-dimethylphenoxy)- and N-[(2,3,5-trimethylphenoxy)alkyl]aminoalkanols.

A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity. Pharmacological tests included maximal electroshock (MES) and subcutaneous pentetrazole seizure threshold (scMet) assays as well as neurotoxicity (TOX) evaluation in mice after intraperitoneal (i.p.) administration and/or in rats after oral (p.o.) administration. The most active compound was R-2N-[(2,3,5-trimethylphenoxy)ethyl]aminobutan-1-ol, which exhibited 100% activity in MES at the dose of 30 mg/kg body weight (mice, i.p.) and 75% activity in MES at 30 mg/kg b.w. (rats, p.o.) without neurotoxicity at the active doses.

Electroconvulsive therapy (ECT) in Parkinson's disease: ECS and dopamine enhancement.

INTRODUCTION: In addition to its effects in major psychiatric illness, electroconvulsive therapy (ECT) is known to have a beneficial effect on the core motor symptoms of Parkinson's disease (PD). This effect is believed to be mediated via dopamine in the striatum. Electroconvulsive shock (ECS), the animal analogue of ECT, is the model in which investigators have sought to elucidate the specific dopaminergic mechanisms by which ECT exerts its therapeutic effect in PD. Electroconvulsive shock has been given to intact animals as well as to animals with neurotoxic lesions that create parkinsonism. METHODS: In this paper, we selectively review the electroconvulsive shock literature on dopamine in the striatum. RESULTS: Electroconvulsive shock, and by extension, ECT, is associated with increased dopamine release and modulation of dopamine receptors. CONCLUSION: Better understanding of how ECT works to enhance dopaminergic systems in the brain could help to make it a more accepted treatment for PD.

Cone restraining and head-only electrical stunning in broilers: effects on physiological responses and meat quality.

Two experiments were conducted to evaluate a new electrical stunning system for broilers. The objective of the first experiment was to evaluate the behavioral, neural, and physiological responses of 27 broilers after head-only electrical stunning while their bodies were restrained in cone-shaped holders. In the second experiment, quality of meat from 30 broilers after head-only electrical stunning in a cone-shaped restrainer was compared with that from 30 broilers stunned in a conventional water bath. Broilers were restrained in the cone with their heads positioned to facilitate a correct stun, followed by a neck cut by hand. After stunning, each broiler displayed a tonic phase, followed by minimal brain activity during bleeding. On average, heart rate was 258 ± 51 beats/min before stunning. The heart was observed to malfunction after cutting. According to the correlation dimension analyses, the score remained low. Within a confidence limit of 95%, taking into account the number of birds with a reliable electroencephalogram (n = 27), the chance of an effective stun and exsanguination with all broilers lies between 0.90 and 1.00 using a sinusoidal AC current of 264 ± 29 mA (∼130 V). After a brief learning period, operators were able to easily position the broilers in the cone in a commercial setting. The pH after chilling was 0.5 units lower (P < 0.05) in the head-only stunned group compared with the group stunned in a conventional water bath. After head-only stunning, 60% of breast fillets showed no blood splashes and 3% showed severe blood splashes compared with 20 and 27% after conventional water bath stunning. No differences in temperature and color were observed between the 2 groups. It is concluded that broilers could be restrained in a cone, followed by correct head-only stunning, neck-cutting, and unconscious shackling afterward under laboratory and commercial slaughterhouse conditions. When this procedure was used, meat quality was better compared with broilers stunned in the conventional water bath.