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PubMed1985

Dysfunction of the midbrain angular complex can accentuate or attenuate circling behaviour in the rat.

The role of the midbrain angular complex (AC) in the execution of motor behaviours was investigated in the rat. In an automated holeboard apparatus bilateral AC electrolesions attenuated exploration and increased locomotor performance of drug-free rats on the first and second test occasions respectively; the latter result may signify a retarding of between-session habituation. Apomorphine also decreased locomotion and almost abolished head dipping and rearing in the holeboard; bilateral AC lesions reinstated locomotion to a normal level without modifying the other behavioural parameters. An electrolesion of one AC did not affect the animal's posture or spontaneous locomotion in the open field, but gave rise to pronounced ipsiversive circling when coupled with systemic administration of apomorphine. In unilaterally 6-hydroxydopamine (6-OHDA) treated rats subcutaneous injection of apomorphine evoked robust contraversive circling. A concomitant lesion of the ipsilateral AC introduced an additional ipsilateral bias to these animals' movements; contraversive circling was initially curtailed and posture reduced (or reversed), while stereotyped activities (particularly grooming) were suppressed. Contralateral orientation and circling were restored by subsequently lesioning the contralateral AC as well; bilateral AC lesions significantly potentiated circling to systemic apomorphine. Contralateral locomotor asymmetry was also produced by depositing apomorphine stereotaxically into the supersensitive caudate, or by microinjecting one substantia nigra zona reticulata with muscimol (in naive rats). Both rotational responses were facilitated by injury to the ipsilateral AC. The effects of electrocoagulating the AC were generally duplicated by discrete microinjection of muscimol or gamma-vinyl GABA into this area, suggesting GABA-mediated synapses are normally operative in this part of the brain. These results do not support the claim that the AC is specifically engaged in mediating postural asymmetry in the unilaterally 6-OHDA denervated rat. Instead, we believe that impairment of neurotransmission through one AC imposes an independent and reciprocal tendency to move towards that side of the brain, as well as attenuating stereotypy and facilitating locomotion. The resultant behavioural response to systemic apomorphine shown by animals bearing these two types of lesion embodies these separate actions.

Animals↗

PubMed1997

Functional and anatomical aspects of prefrontal pathology in schizophrenia.

Clinical and experimental research have provided anatomical, pharmacological, and behavioral evidence for a prominent prefrontal dysfunction in schizophrenia. Negative symptoms and behavioral disorganization in the disorder can be understood as a failure in the working memory functions of the prefrontal cortex by which information is updated on a moment-to-moment basis or retrieved from long-term stores, held in mind, and used to guide behavior by ideas, concepts, and stored knowledge. This article recounts efforts to dissect the cellular and circuit basis of working memory with the goal of extending the insights gained from the study of normal brain organization in animal models to an understanding of the clinical disorder; it includes recent neuropathological findings that indicate that neural dystrophy rather than cell loss predominates in schizophrenia. Evidence from a variety of studies is accumulating to indicate that dopamine has a major role in regulating the excitability of the cortical neurons upon which the working memory function of the prefrontal cortex depends. Interactions between monoamines and a compromised cortical circuitry may hold the key to the salience of frontal lobe symptoms in schizophrenia, in spite of widespread pathological changes. We outline several direct and indirect intercellular mechanisms for modulating working memory function in the prefrontal cortex based on the localization of dopamine receptors on the distal dendrites and spines of glutamatergic pyramidal cells and on gamma-aminobutyric acid (GABA) ergic interneurons in the prefrontal cortex. Understanding the interactions between the major cellular constituents of cortical circuits-pyramidal and nonpyramidal cells-is a necessary step in unraveling the receptor mechanisms, which could lead to an effective pharmacological treatment of negative and cognitive symptoms, as well as improved insight into the pathophysiological basis of the disorder.

Attention↗

PubMed1994

Chronic treatment with a classical neuroleptic alters excitatory amino acid and GABAergic neurotransmission in specific regions of the rat brain.

The purpose of the following experiments was to describe some of the neurochemical changes that occur in the basal ganglia of rats exposed chronically to a classical neuroleptic, fluphenazine, and to relate these changes to extrapyramidal motor dysfunction. For these studies a combination of behavioural, receptor autoradiographic and in situ hybridization methods were employed. Preliminary pharmacological studies on GABA receptors showed that incubation in Tris-acetate rather than Tris-citrate buffer increased the number of binding sites labelled by [3H]muscimol by over 120% without affecting binding affinity or selectivity. The results of experiments with fluphenazine showed that treatment for six months increased the frequency of vacuous chewing movements compared to controls. In the striatum, changes in GABA transmission were observed in fluphenazine-treated rats with increases in glutamate decarboxylase mRNA levels in the caudate nucleus, dorsal shell and core of the accumbens and decreases in [3H]muscimol binding in the caudate and dorsal shell regions. These data suggest that fluphenazine treatment increased GABA transmission in specific subregions of the caudate and accumbens nuclei. In addition, glutamate decarboxylase mRNA levels were elevated in the entopeduncular nucleus of fluphenazine-treated animals. Autoradiographic analysis of excitatory amino acid binding showed that fluphenazine exposure decreased [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding in entopeduncular nucleus and in the ventrolateral thalamic nucleus and decreased [3H]dizocilpine maleate binding in the medial geniculate nucleus. These experiments show that in addition to altering GABA transmission, chronic neuroleptic exposure alters excitatory amino acid transmission in specific regions of the basal ganglia-thalamocortical motor system. The neuroleptic dependent increases in glutamate decarboxylase mRNA levels in the entopeduncular nucleus may reflect changes in neurotransmission in the indirect pathway connecting the major input and output nuclei of the basal ganglia. Changes in some of these brain regions may be related to the occurrence of extrapyramidal motor disturbances.

Animals↗

PubMed2005

Modulation of striatal dopamine release by glycine transport inhibitors.

Traditional models of schizophrenia have focused primarily upon dopaminergic (DA) dysregulation. In contrast, more recent models focus on dysfunction of glutamatergic systems, acting particularly through N-methyl-D-aspartate (NMDA) receptors. NMDA receptors in brain are regulated by glycine, acting via a strychnine-insensitive regulatory site, and by glycine (GlyT1) transporters that maintain low glycine levels in the immediate vicinity of the NMDA receptor complex. The present study investigates the role of NMDA receptors in the modulation of striatal dopamine release in vitro, and of glycine transport inhibitors (GTIs) as potential psychotherapeutic agents in schizophrenia. In striatum, NMDA receptors exert dual excitatory/inhibitory effects, with inhibition reflecting activity of local GABAergic feedback regulation. We have previously demonstrated effectiveness of glycine in regulating [3H]DA release both in vivo and in vitro, consistent with its beneficial clinical effects. In the present study, similar effects were observed for the high-affinity GTI (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy-)propyl]sarcosine (NFPS), and for a range of high-affinity GTIs with appropriate rank order of potency. In addition, (+)NFPS significantly stimulated NMDA-induced [3H]GABA release. Effects, of GTIs, were blocked by the glycine-site antagonists L689,560 and HA-966, and the GABA(B) antagonists phaclofen and CGP 52432, confirming the roles of both the NMDA-associated glycine-site and presynaptic GABA(B) receptors in NMDA receptor-mediated regulation of striatal DA release in vitro. Endogenous DA hyperactivity is associated with prominent positive symptoms in schizophrenia. The present results are consistent with recent clinical studies showing significant effectiveness of glycine-site agonists and GTIs in reduction of persistent positive, as well as negative, symptoms in schizophrenia.

Amino Acid Transport Systems, Neutral↗

PubMed2006

Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder.

OBJECTIVES: Schizophrenia is associated with dysfunction of glutamatergic neurotransmission, and several studies have suggested glutamatergic abnormalities in bipolar disorder. Recent data suggest involvement of the NMDA receptor signaling complex, which includes NMDA receptor subunits as well as associated intracellular interacting proteins critical for NMDA receptor assembly, trafficking, and activation; the most well-characterized being PSD93, PSD95, SAP102, and NF-L. Previously, studies from our laboratories have described changes in glutamate receptor subunit transcript and binding site expression in schizophrenia and changes in NMDA receptor binding site expression in bipolar disorder in postmortem brain tissue. In the present work, we focus on the expression of these molecules in hippocampus in schizophrenia and bipolar affective disorder I. METHODS: We performed in situ hybridization to assess hippocampal expression of the transcripts encoding NMDA receptor subunits NR1, 2A, 2B, 2C and 2D, and the transcripts for the NMDA receptor associated PSD proteins PSD95, PSD93, NF-L, and SAP102 in subjects with schizophrenia, bipolar affective disorder I, and a comparison group. We also measured [(3)H]CGP39653 and [(3)H]MK-801 binding site expression in the hippocampus in schizophrenia. RESULTS: There was a significant decrease in the expression of transcripts for NR1 and NR2A subunits and SAP102 in bipolar disorder. We did not detect any changes in these transcripts or in binding site expression in the hippocampus in schizophrenia. CONCLUSIONS: We propose that the NMDA receptor signaling complex, including the intracellular machinery that is coupled to the NMDA receptor subunits, is abnormal in the hippocampus in bipolar disorder. These data suggest that bipolar disorder might be associated with abnormalities of glutamate-linked intracellular signaling and trafficking processes.

Binding Sites↗

PubMed2004

The principal features and mechanisms of dopamine modulation in the prefrontal cortex.

Mesocortical [corrected] dopamine (DA) inputs to the prefrontal cortex (PFC) play a critical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symptoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose-response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks.

Animals↗

PubMed1994

Interactions between the eye and hand motor systems: disruptions due to cerebellar dysfunction.

1. We tested the hypothesis that interactions occur between eye and hand movements produced in conjunction. This was accomplished by having human subjects with cerebellar dysfunction and age-matched controls perform two tasks: 1) tracking a moving target with the hand and 2) performing a pointing movement to intercept the target. Our prediction was that the inaccuracies that are characteristic of eye and hand movements generated in isolation by cerebellar subjects would be accentuated in each system during combined eye-hand tasks. 2. The cerebellar subjects took longer to respond to the onset of target motion in both tasks. This was true for both the eyes and hand, regardless of whether the eye and hand movements were generated in isolation or in conjunction with each other. 3. The cerebellar subjects also displayed a larger degree of error and/or variability in their hand movements than the control subjects. A significant amount of this increased variability was due to systematic changes in the trajectory of the hand during the critical periods leading up to and after each ocular saccade. These systematic changes were consistent with an overestimation of target velocity in the perifoveal visual field. 4. The increased variability of the cerebellar subjects' hand movements was markedly reduced by restricting eye movements. A similar reduction in variability occurred when vision of the hand was restricted in the tracking task. This effect was accompanied by improved eye movements. 5. For both sets of subjects the eye movements were affected by the hand movements produced in the tracking task. In particular, eye movement accuracy was improved in the controls and degraded in the cerebellar subjects when compared with the eye movements generated in isolation. In contrast, no changes were observed in the interception task. 6. Taken together, these results imply that a reciprocal interaction occurs between the eye and hand motor systems and/or that common "upstream" sites influence each of these systems in a similar manner. The functional anatomy and neurophysiological characteristics of several sites where such interactions may take place are discussed.

Adult↗

PubMed1992

Interictal behavioral disturbances: a search for molecular substrates.

Postictal symptoms can be disabling in themselves, but their underlying substrates may endure, giving rise to epilepsy-induced interictal behavioral disorders. Chronic temporal lobe epilepsy is reported to be associated with a variety of interictal behavioral changes which often take the form of affective disturbances. Depression, among the more common interictal psychological dysfunctions suffered by patients with temporal lobe seizures, could reflect epilepsy-induced alterations in normal opioid peptide mechanisms. In experimental animal models, certain postictal behaviors have been shown to be opioid-mediated. Furthermore, an experimental model of interictal behavioral disturbance resembles stimulation-induced defensive rage, which can be relieved by intracerebral administration of opioid peptides. Defensive rage is a species-specific behavior encountered in cats. Its correlate in humans would be difficult to predict in view of the stronger cortical control; however, it may manifest rather as insecurity, irritability, and perhaps depression. Extrapolation of animal experiments would suggest that depression and certain other common postictal and interictal affective disturbances seen in patients with temporal lobe seizures reflect mechanisms more related to opiate withdrawal, than to direct opiate actions. The activity-induced plasticity associated with recurrent temporal lobe seizures, therefore, should result in changes in opioid function that predispose to withdrawal phenomena. Limbic seizures induce enhanced enkephalin synthesis lasting for up to 2 weeks. Recurrent seizures in experimental animals, however, cause paradoxical up-regulation of mu opiate receptors. Patients with temporal lobe epilepsy demonstrate enhanced mu receptor binding in the neocortex of the epileptogenic temporal lobe on PET. The reasons for this enduring interictal effect are not clear. Nevertheless, if animals or patients become dependent on enhanced endogenous opioid activity as a result of seizures, and also have up-regulation of mu receptors, then severe withdrawal effects, such as defensive rage in cats or depression in humans, might be expected when seizures do not recur frequently. Plotting the time course of mRNAenk and enkephalin expression after seizures, and the time course of symptoms of interictal behavioral disturbances, may demonstrate a temporal relationship that supports this hypothesis. For instance, depression or other withdrawal symptoms might only occur when the interval between seizures is greater than the duration of seizure-induced enkephalin synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1996

L-2-chloropropionic acid-induced neurotoxicity is prevented by MK-801: possible role of NMDA receptors in the neuropathology.

We have demonstrated that following a single oral dose of L-2-chloropropionic acid (L-CPA) to rats (750 mg/kg; pH 7) there was a marked and widespread loss of granule cells in the cerebellum as assessed by neuropathology by 48 hr. There also appeared to be limited damage to Purkinje cells, whereas stellate, Golgi, and basket cells were not affected by L-CPA administration. The L-CPA-mediated cerebellar neuropathology was accompanied by a significant increase in the cerebellar water content and sodium concentration, 48 hr following L-CPA administration, suggesting an edematous reaction. After 36 hr, the animals displayed marked locomotor dysfunction and had to be terminated at 54 hr due to marked weight loss. We did not observe any neuropathology in forebrain regions nor was the water content in the forebrain significantly different from controls in animals which had been treated with L-CPA. Cerebellar aspartate concentrations were reduced 48 hr following L-CPA administration becoming marked at 54 hr and accompanied by a significant reduction in cerebellar glutamate concentrations. The density of N-methyl-D-aspartate (NMDA) receptors in the granular layer of the cerebellar cortex was also significantly reduced at 48 and 54 hr following L-CPA administration. Prior administration of MK-801 (dizocilpine) (5 mg/kg/i.p.), an irreversible NMDA receptor antagonist, 30 min before an oral dose of L-CPA (750 mg/kg) prevented the loss of both granule and Purkinje cells. There was no abnormal locomotor activity in the L-CPA rats treated with MK-801 except for the first 4 hr following dosing when animals were severely sedated. Animals which received L-CPA plus MK-801 were normal 96 hr post dosing showing that MK-801 did not delay the onset of L-CPA toxicity. There was no alteration in cerebellar water content or sodium concentrations in rats which had been administered MK-801 with L-CPA. The reductions in cerebellar aspartate and glutamate concentrations were totally prevented by administration of MK-801, as was the reduction in L(-)[3H]glutamate binding to cerebellar NMDA receptors. Administration of MK-801 alone (5 mg/kg/i.p.) did not alter the water content, sodium concentrations, aspartate or glutamate concentrations, or the density of NMDA receptors in the cerebellum. In conclusion, we suggest that L-CPA-induced neurotoxicity leading to loss in granule cells and an accompanying cerebellar edema can be prevented by MK-801, suggesting that a subpopulation of NMDA receptors found on cerebellar granule cells play a pivotal role in mediating the toxicity of this compound.

Administration, Oral↗

PubMed1999

Effects of antihypertensive therapies on the sympathetic nervous system.

The sympathetic nervous system is a major modulator of cardiovascular function. Over the past three decades, numerous studies, using various methodologies, have reported the existence of a variety of pre- and postsynaptic sympathetic dysfunctions in essential hypertension. Most of these abnormalities facilitate sympathetic neurotransmission, resulting in a chronic increase in the sympathetic tone and reactivity in a significant proportion of hypertensive patients. Chronic sympathetic activation is also associated with major alterations in the balance among postsynaptic adrenergic receptors in cardiovascular tissues. Indeed, an attenuation of beta-adrenergic function and a potentiation of alpha1-adrenergic function has been demonstrated in cardiovascular tissues in hypertensive patients, suggesting the development of a sympathetic postsynaptic alpha1 dominance during the development and evolution of hypertension. Chronic activation of the sympathetic system is deleterious and could contribute to the development of most cardiovascular complications associated with hypertension. One of the major aims of antihypertensive therapy should thus be to attenuate pre- or postsynaptic sympathetic tone. Most antihypertensive drugs have been found to improve either pre- or postsynaptic sympathetic function in hypertensive patients. At the presynaptic level, diuretics were found to increase the liberation of noradrenalin, presumably through baroreflex sympathetic activation. In contrast, beta-blockers were shown to attenuate noradrenalin release from sympathetic nerves by blocking presynaptic facilitatory beta-receptors, thus reducing the sympathetic tone on postsynaptic receptors. Similarly, angiotensin-converting enzyme inhibitors or angiotensin II type 1 (AT1) receptor antagonists have been found to reduce sympathetic reactivity by acting on the central nervous system, but also by blocking AT1-mediated facilitatory mechanisms located on sympathetic fibres and in the adrenal medulla. Short acting dihydropyridine calcium channel blockers (CCBs) were found to enhance noradrenalin release from sympathetic nerves, but longer acting CCBs seems to have variable effects. Indeed, while the chronic slow release formulation of nifedipine gastrointestinal therapeutic system (GITS) did not raise circulating noradrenalin levels, treatment with amlodipine increased circulating noradrenalin levels, suggesting that nifedipine GITS is neutral on the sympathetic tone but that amlodipine chronically activates the sympathetic system. At the postsynaptic level, however, dihydropyridine CCBs were shown to attenuate the sympathetic tone on alpha1-adrenoceptors. In conclusion, it appears that most antihypertensive drugs interfere with pre- or postsynaptic sympathetic mechanisms and that these mechanisms could contribute to their hypotensive effects.

Adrenergic Antagonists↗

PubMed2006

DARPP-32 is a robust integrator of dopamine and glutamate signals.

Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca(2+) signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca(2+) signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but that its response also depends on the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute effect on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the influence of the delay between dopamine and glutamate, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca(2+) regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons.

Basal Ganglia↗

PubMed1993

Effects of aging on the intrinsic membrane properties of medial NTS neurons of Fischer-344 rats.

1. Recent studies have demonstrated that the arterial baroreflex is imparied with aging and have implicated central components of the baroreflex arc in this autonomic dysfunction. Neurons in the medial portion of the nucleus tractus solitarius (mNTS) receive a major input from the arterial baroreceptors. The present study was undertaken to characterize the intrinsic membrane properties of mNTS neurons in young rats and to test the hypothesis that these properties are altered with aging. An in vitro brain stem slice preparation was used to record intracellularly from mNTS neurons; passive membrane properties, action potential characteristics, and repetitive firing properties were examined and compared. 2. Neurons in the mNTS of young (3-5 mo old) Fischer-344 rats (F-344; n = 35) had a resting membrane potential of -57 +/- 6.9 mV (mean +/- SD), a membrane time constant of 18 +/- 9.0 ms, and an input resistance of 110 +/- 60 m omega. Action potential amplitude was 81 +/- 7.5 mV with a duration at half-height of 0.83 +/- 0.15 ms. The spontaneous firing rate in 24 cells was 4.3 +/- 2.9 Hz. The amplitude and duration of the action potential afterhyperpolarization (AHP) were 6.6 +/- 3.0 mV and 64 +/- 34 ms, respectively. All neurons expressed spike frequency adaptation, action potential AHP, and posttetanic hyperpolarization. Delayed excitation and postinhibitory rebound were present in 34 and 14% of neurons tested, respectively. Neurons from adult (10-12 mo old) F-344 rats (n = 34) were similar to the young F-344 rats with respect to all of these variables. 3. Neurons from aged (21-24 mo old) F-344 (n = 32) were similar to those from young and adult rats, but there were two potentially important differences: the mean input resistance of the aged neurons was higher (170 +/- 150 M omega), with a larger proportion (46% of aged neurons vs. 20% of young neurons and 21% of adult neurons) having input resistances > 150 M omega; and there was a tendency for a smaller percentage of aged neurons (16% of aged neurons vs. 34% of young neurons and 29% of adult neurons) to express delayed excitation. 4. The potential significance of a high input resistance was tested by comparing the steady-state current-voltage (I-V) relationships and the frequency-current (f-I) relationships among low-resistance (1-100 M omega), medium-resistance (101-200 M omega).(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

PubMed1996

Immunolesion by 192IgG-saporin of rat basal forebrain cholinergic system: a useful tool to produce cortical cholinergic dysfunction.

Cholinergic lesion paradigms have been used to study the role of the cholinergic system in cortical arousal and cognitive function, and its implication in cognitive deficits that occur in Alzheimer's disease. In the last few years an increasing number of studies have applied neurotoxins including excitotoxins or cholinotoxins (e.g. AF64A) by stereotaxic injection into the Nbm to produce reductions in cortical cholinergic activity. One of the most serious limitations of these lesion paradigms is the fact that basal forebrain cholinergic neurons are always intermingled with populations of noncholinergic cells and that the cytotoxins used are far from being selective to cholinergic cells. Excitoxins when infused directly into the Nbm destroy non-specifically cell bodies but spare axons passing the injection site, whereas the specificity of AF64A to destroy cholinergic neurons depends on both the dosage applied and the site of injection. Recently, a monoclonal antibody to the low-affinity nerve growth factor (NGF) receptor, 192IgG, coupled to a cytotoxin, saporin, has been described as an efficient and selective immunotoxin for the NGF-receptor bearing cholinergic neurons in rat basal forebrain. Intraventricular administration of the 192IgG-saporin conjugate appears to induce a nearly complete and specific lesion of neocortical and hippocampal cholinergic afferents. Other neuronal systems in the basal forebrain are spared by the immunotoxin. Electrolytic, ibotenic acid, and cholinergic immunotoxic lesions of cholinergic basal forebrain nuclei resulted in slightly different effects on cortical cholinergic markers: Electrolytic lesion of the Nbm did not change M1-mAChR but resulted in reduced M2-mAChR in frontal and parietal cortices 1 week after lesion. Ibotenic acid lesion of the nucleus basalis did not alter M1-mAChR in any cortical region but led to enhanced M2-mAChR binding in the parietal cortex only. When applying the cholinergic immunotoxin 192IgG-saporin, both M1- and M2-mAChR binding sites were increased in a number of cortical areas 1 week after lesion. This comparison suggests that possibly the destruction of non-cholinergic basal forebrain cells by ibotenic acid and electrolytic lesion, might partly contribute to these different cortical effects. NMDA receptor binding was markedly reduced and AMPA, kainate, and GABAA receptor binding has been significantly increased in cortical regions displaying a reduced activity of AChE and decreased levels of high-affinity choline uptake sites due to immunolesion of the basal forebrain cholinergic system. Equivalent changes in cortical glutamate and GABA receptor subtype levels have been observed 7 days after electrolytic or ibotenic acid lesion of the Nbm. The data suggest that cholinergic immunolesion by 192IgG-saporin exhibits a valuable tool to produce specific cholinergic deficits in rats, which can be used as a model to study the effect of treatment with various drugs for compensating the impaired cortical cholinergic input.

Acetylcholine↗

PubMed1999

[Neuromuscular recovery following mivacurium is predictable in patients with severe systemic disease prognoses].

OBJECTIVES: Fast recovery from mivacurium-induced neuromuscular blockade is impaired in patients with decreased plasma cholinesterase activity which is often associated with dysfunction of different organs. Nevertheless, predictability of neuromuscular recovery may be given. Thus, this study evaluates parameters to predict individual neuromuscular recovery in patients with uncommon diseases. METHODS: 84 male or female patients (18-70 years of age) were allocated to one of two groups according to their ASA risk profile (without severe systemic diseases: ASA 1 and 2; with severe systemic diseases: ASA 3 and 4). Plasma cholinesterase activity (PChE) had been determined preoperatively. Anaesthesia was performed with propofol and fentanyl. Neuromuscular transmission was monitored by electromyography. The ulnar nerve was stimulated by train-of four stimuli and neuromuscular transmission was measured at the hypothenar. After mivacurium 0.1 mu mg/kg, an infusion of mivacurium was adjusted to maintain T1/T0 at approximately 5% for at least 60 min. Duration from application of the initial bolus until recovery to T1/T0 = 5% (dur 5), the mean mivacurium infusion rate (IR), infusion time, the early recovery time from cessation of infusion to T1/T0 = 25% (rec 25) and the final recovery time from T1/T0 = 25% to T4/T1 = 75% (final rec) was measured. Statistical analysis of data was performed using t-tests. (alpha = 0.05). Predictability of the recovery times (rec 25 and final rec) was tested by multiple linear least-squares regressions. Dependent variables were PChE, dur 5, IR, infusion time, and rec 25, respectively. To test for predictability of neuromuscular blockade by mivacurium with respect to severe systemic diseases, the ASA risk score was defined to be the second independent variable at each regression, the respective interaction was defined to be the third independent variable (variable 1 x group). Variables entered multiple regression analysis in a forward stepwise manner (F > 4.0). RESULTS: PChE was significantly lower in patients with severe systemic diseases (3.7 +/- 1.2 kU/l vs. 4.5 +/- 0.9 kU/l), dur 5 significantly prolonged (17.3 +/- 7.3 min vs. 11.0 +/- 3.0 min), IR significantly lower (4.6 +/- 2.6 micrograms/kg/min vs. 6.5 +/- 2.8 micrograms/kg/min), and rec 25 (8.7 +/- 4.0 min vs. 6.0 +/- 1.7 min) as well as final rec (23.0 +/- 16.3 min vs. 13.0 +/- 3.7 min) significantly prolonged compared to patients without severe systemic diseases. Both recovery intervals correlated significantly with PChE, dur 5, or IR, but not with the ASA risk score. Multiple regression analysis revealed a close correlation between rec 25 and final rec very closely (R2 = 0.875). Prolonged mivacurium infusion time and additionally high ASA risk score were correlated with a prolonged neuromuscular recovery (R2 = 0.130). DISCUSSION: Prolonged neuromuscular recovery could be predicted from a reduced PChE, a prolonged duration of action of the initial mivacurium bolus and a decreased mivacurium-infusion rate required to maintain a 95% neuromuscular blockade. Measurement of plasma cholinesterase and monitoring of mivacurium induced neuromuscular blockade can avoid resting neuromuscular blockade postoperatively despite of prolonged neuromuscular recovery.

Adolescent↗

PubMed2006

Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women.

CONTEXT: There is extensive evidence implicating dysfunctions in stress responses and adaptation to stress in the pathophysiological mechanism of major depressive disorder (MDD) in humans. Endogenous opioid neurotransmission activating mu-opioid receptors is involved in stress and emotion regulatory processes and has been further implicated in MDD. OBJECTIVE: To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in volunteers with MDD and its relationship with clinical response to antidepressant treatment. DESIGN: Measures of mu-opioid receptor availability in vivo (binding potential [BP]) were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer carbon 11-labeled carfentanil during a neutral state. Changes in BP during a sustained sadness challenge were obtained by comparing it with the neutral state, reflecting changes in endogenous opioid neurotransmission during the experience of that emotion. SETTING: Clinics and neuroimaging facilities at a university medical center. PARTICIPANTS: Fourteen healthy female volunteers and 14 individually matched patient volunteers diagnosed with MDD were recruited via advertisement and through outpatient clinics. INTERVENTIONS: Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion. Following imaging procedures, patients underwent a 10-week course of treatment with 20 to 40 mg of fluoxetine hydrochloride. MAIN OUTCOME MEASURES: Changes in mu-opioid receptor BP during neutral and sustained sadness states, negative and positive affect ratings, plasma cortisol and corticotropin levels, and clinical response to antidepressant administration. RESULTS: The sustained sadness condition was associated with a statistically significant decrease in mu-opioid receptor BP in the left inferior temporal cortex of patients with MDD and correlated with negative affect ratings experienced during the condition. Conversely, a significant increase in mu-opioid receptor BP was observed in healthy control subjects in the rostral region of the anterior cingulate. In this region, a significant decrease in mu-opioid receptor BP during sadness was observed in patients with MDD who did not respond to antidepressant treatment. Comparisons between patients with MDD and controls showed significantly lower neutral-state mu-opioid receptor BP in patients with MDD in the posterior thalamus, correlating with corticotropin and cortisol plasma levels. Larger reductions in mu-opioid system BP during sadness were obtained in patients with MDD in the anterior insular cortex, anterior and posterior thalamus, ventral basal ganglia, amygdala, and periamygdalar cortex. The same challenge elicited larger increases in the BP measure in the control group in the anterior cingulate, ventral basal ganglia, hypothalamus, amygdala, and periamygdalar cortex. CONCLUSIONS: The results demonstrate differences between women with MDD and control women in mu-opioid receptor availability during a neutral state, as well as opposite responses of this neurotransmitter system during the experimental induction of a sustained sadness state. These data demonstrate that endogenous opioid neurotransmission on mu-opioid receptors, a system implicated in stress responses and emotional regulation, is altered in patients diagnosed with MDD.

Adrenocorticotropic Hormone↗

PubMed2002

Electrophysiologic evidence for an intersegmental reflex pathway between lumbar paraspinal tissues.

STUDY DESIGN: Electrophysiologic recordings were obtained from a lumbar paraspinal nerve or muscle in the anesthetized cat while electrically stimulating a paraspinal nerve or facet capsule in an adjacent lumbar segment. A variety of approaches were used to demonstrate the reflex nature of both the nerve and the muscle response. OBJECTIVE: The primary purpose of this study was to seek electrophysiologic evidence for the presence of intersegmental reflexes between adjacent lumbar vertebral segments. A second purpose of this study was to confirm a previous procedure used to evoke paraspinal reflexes. This previous work had shown that electrical stimulation of the L1-L2 facet joint capsule elicits electromyographic activity from multifidus muscle one to two vertebral segments caudal to the stimulated facet in a porcine preparation. SUMMARY OF BACKGROUND DATA: Biomechanical approaches have stressed the need for spinal stability to avoid conditions that could give rise to low back dysfunction. It seems reasonable to believe that reflex interactions between vertebral segments contribute to the sensorimotor integration of lumbar paraspinal tissues. It also seems reasonable to believe that alterations or abnormal elicitation of these reflexes could contribute to biomechanical changes associated with low back pain and paraspinal muscle spasm. METHODS: Experiments were performed on 23 alpha-chloralose anesthetized adult cats. In eight cats the L3, L4, and L5 medial branch from each dorsal ramus was exposed and placed on a bipolar hook electrode. In six cats the L4 medial branch was stimulated and a compound action potential was recorded from the L3 medial branch. In three of the six cats the L5 medial branch was stimulated and a compound action potential was recorded from the L3 medial branch. In one cat the L4 medial branch was stimulated and a compound action potential was recorded from the L5 medial branch. In one cat the L3 medial branch was stimulated and a compound action potential was recorded from the L5 medial branch. At the end of each protocol the medial branch was cut just proximal to the stimulating electrode to confirm that the compound action potential was reflexive in nature and not initiated by volume conduction. In 15 cats three approaches were used to confirm that multifidus electromyographic activity evoked by electrical stimulation of a lumbar facet capsule was reflexive in nature: 1) by anesthetizing the site of the sensory endings, i.e., the facet capsule, 2) by injecting lidocaine intrathecally to block neural conduction centrally, i.e., within the spinal canal, or 3) by cutting the afferent pathway, i.e., the medial branch of the dorsal ramus. RESULTS: Electrical stimulation of the medial branch of the dorsal ramus innervating the medial-most lumbar paraspinal tissues evoked a compound action potential in the medial branch innervating the medial-most paraspinal tissues one and two segments away. Stimulating voltages between 2 and 70 V were necessary to evoke the compound action potential. Each compound action potential was reflexive in nature because cutting the lumbar medial branch proximal to its contact with the stimulating electrode abolished each compound action potential. The conduction velocity of the reflex ranged from 3.5 to 6.1 m/sec. Electrical stimulation of a lumbar facet capsule evoked lumbar multifidus muscle electromyographic activity. However, injecting lidocaine intrathecally or transecting the medial branch of the dorsal ramus had no effect on electromyographic activity. Injecting lidocaine into the facet or into the multifidus muscle around the facet joint (near the stimulating electrode) significantly decreased the magnitude of the multifidus electromyography. CONCLUSION: These results indicate that afferent impulses conveyed by the medial branch of the dorsal ramus reflexly altered efferent activity to an adjacent lumbar segment. This intersegmental paraspinal reflex may span at least one or two vertebral segments. The data suggest that electrical stimulation of the facet joint capsule may not have reflexly elicited multifidus activity because neither chemical interruption (intrathecal lidocaine) nor physical interruption (nerve transection) of the presumed reflex pathway diminished or abolished the electromyographic response. Volume conduction of the stimulating currents likely elicited multifidus activity during electrical stimulation of the facet capsule. When using electrical stimulation of neural paraspinal tissues to evoke reflex muscle activity, appropriate control experiments must be performed to clearly demonstrate the reflexive nature of the response.

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