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Psychophysiologic effects of early lead exposure.

In several separate experiments neonatal rats were intubated daily with 9, 27 or 81 mg lead acetate/kg of body weight throughout their 3-week postnatal period of development. Based on average body weights, the total daily lead intake was 0.156, 0.454 or 1.384 mg lead per animal, respectively (in addition to normal lead intake from the environment). Subtle and specific behavioral changes, involving an inability to attenuate inappropriate behavior in a two-way shuttle or a habit-reversal operant task, occurred in offspring following exposure to a minimum of 0.454 mg lead per day. The specificity of this central dysfunction was such that motor activity was normal, stress responsiveness remained unaffected and simple learning ability was comparable to that of controls. The only indication of a central neurochemical modification accompanying this behavioral defect was a tendency for telencephalic acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities to be depressed, suggesting a possible involvement of the cholinergic system. Steady-state levels of brain monoamines were unaltered. The experimental weanlings displayed an inhibition of blood delta-amino levulinic acid dehydratase (ALAD) activity, a parallel reduction in regional brain ALAD activity, a moderate reduction in hematocrit and hemoglobin and an increase in kidney weight. This latter effect occurred even at the lowest level of lead intake, 0.156 mg lead per day.

Age Factors↗

Auditory brainstem responses in pervasive developmental disorders.

Several studies have reported prolonged neural transmission times on auditory brainstem responses (ABRs) measured in autistic children, a finding which implicates CNS dysfunction at the level of the brainstem in autistic conditions. This study measured ABRs in 25 children and adults with pervasive developmental disorders (PDDs), including autism, and 25 age- and sex-matched normal controls. Subjects were carefully evaluated audiometrically and neurologically and artifact was controlled to produce highly reliable measures. Prolonged transmission times were seen in only one PDD subject and in one normal control, while shortened transmission times were seen in four PDD subjects. The majority of PDD subjects showed normal ABRs. Previous reports of a significant incidence of prolonged transmission times among autistic and autisticlike subjects, thus, were not replicated. Possible reasons for this discrepancy are discussed.

Adolescent↗

Alpha7-nicotinic acetylcholine receptor subunit is not required for parasympathetic control of the heart in the mouse.

Nicotinic acetylcholine receptors (nAChR) are assembled from a pool of nine alpha-subunits and three beta-subunits into functional pentamers in peripheral autonomic neurons. The contribution of different subunits to native, physiologically important nAChR for synaptic transmission in autonomic ganglia is unclear. Here, we examined the importance of the alpha7-subunit for parasympathetic innervation of the heart. Normal (C57BL/6J), alpha7-deficient (Chrna7), and wild-type littermate mice were implanted with telemetry devices, and, under conscious, unsedated conditions, ECG recordings were obtained at baseline and after atropine, propranolol, and hexamethonium bromide administration. Spectral analysis of heart rate variability [power spectral analysis (PSA)] was performed for the evaluation of resting autonomic tone to the heart. At the completion of conscious studies, animals were anesthetized and underwent electrical stimulation of the vagus nerve (VS) while R-R intervals were recorded. Heart rate at baseline and after atropine, propranolol, or hexamethonium was similar in all three groups of animals. PSA curves were similar between normal, wild-type, and Chrna7 mice. VS showed no difference between control and Chrna7 mice throughout the range of stimulation (5-20 Hz). Mice deficient in the alpha7-nAChR subunit do not display differences in resting autonomic tone to the heart at baseline or under conditions of single and combined autonomic blockade. VS showed no difference in heart rate responses between normal and alpha7-deficient mice. These data support previous findings in vitro and highlight the important differences in function between nicotinic receptor subtypes because alpha3-deficient mice display major autonomic dysfunction. We conclude that the alpha7-subunit does not contribute critically to resting parasympathetic control of the heart.

Animals↗

Ventricular wall motion and NE release in post-ischemic reperfused myocardium.

To clarify the relationship between post-ischemic myocardial dysfunction and local cardiac sympathetic nerve function, we measured regional myocardial length and norepinephrine (NE) release during sympathetic nerve stimulation in 32 mongrel dogs. Coronary occlusion was produced by balloon occluder for 15 min and reperfused for 60 min. Dogs were divided into 3 groups as follows; Group 1 (n = 14): Sympathetic nerve stimulation, Group 2 (n = 9): Pre-treatment with yohimbine hydrochloride (0.2 mg/kg) and sympathetic nerve stimulation, Group 3 (n = 9): Exogenous NE administration. Sympathetic nerve stimulation or NE infusion were performed before occlusion and after reperfusion. In group 1, the extent of the increase in systolic shortening during sympathetic nerve stimulation (delta - shortening) lowered at 5 min after reperfusion and augmented progressively. But, delta-shortening at an early reperfusion period did not reduce in group 2 and 3. NE release from the ischemic myocardium decreased in group 1 and did not recover for 60 min. When the cardiac sympathetic nerve was denervated with 90% phenol solution, NE release further decreased in group 1. On the other hand, NE release did not decrease in group 2. These results indicate that the response to sympathetic nerve stimulation decreased in post-ischemic reperfused myocardium and this was due to diminished NE release. It was considered that sympathetic nerve conduction was not completely impaired in post-ischemic myocardium and pre-synaptic alpha-2 receptor mediated negative feedback mechanism would play an important role in these diminished NE release.

Animals↗

Pathogenesis of HIV-1 associated neurodegeneration.

A significant number of people infected with the human immunodeficiency virus (HIV) develop neurologic complications. The AIDS dementia complex is frequently accompanied by HIV encephalitis, which is characterized at the neuropathologic level by loss of neuronal subpopulations in the neocortex, limbic system, and basal ganglia in association with synaptic and dendritic damage, astrogliosis, and formation of microglial nodules and multinucleated giant cells. Recent studies have shown that the extent of neurodegeneration in this condition correlates directly with the amount of HIV-1 antigen in the brain. HIV-1 infection of the brain could result in neurodegeneration via neurotoxic effects of viral products (e.g., gp 120, Nef, Tat) and/or via alterations in the expression of host factors. The latter may include increased production of potentially detrimental factors such as cytokines, excitotoxic amino acids, free oxygen radicals, and bioactive lipid mediators as well as interference with the production or action of neurotrophic/protective factors. Derangements of the neuronal calcium homeostasis, lipid peroxidation, and induction of programmed cell death (apoptosis) may all play a role as final common pathogenetic pathways in HIV-1-induced neurodegeneration. Recent studies in transgenic mice (over)expressing HIV- or host-derived proteins in their central nervous system indicate that distinct neuronal populations may differ in their susceptibility to specific pathogenic factors. For example, glutamate-receptor-bearing pyramidal neurons were particularly susceptible to neurodegeneration promoted by HIV-1 products, whereas interneurons were more sensitive to the neurotoxic effects mediated by cytokines. For the design of effective treatments for the HIV-1-associated cognitive/motor complex, it will be important to determine whether the neurologic deficits in this entity result from global neuronal dysfunction or relate more specifically to the impairment of distinct neuronal subpopulations. It will also be critical to examine diverse in vitro and in vivo models to help decide which of the many pathogenetic processes that may be at work in this complex disease constitute the most promising therapeutic targets.

AIDS Dementia Complex↗

Effect of isolation rearing on pre- and post-synaptic serotonergic function in the rat dorsal hippocampus.

Several behavioural, neurochemical, and structural alterations found in isolation-reared rats are similar to those in human schizophrenia. This study investigated changes in cholinergic and serotonergic function in the hippocampus following isolation rearing. Rats were reared in social isolation from weaning for 6 weeks before study and compared to group-reared rats. An in vitro electrophysiological study investigated the effect of isolation rearing on postsynaptic 5-HT(1A) function on CA1 hippocampal neurones activated with the muscarinic agonist carbachol and found no change in the sensitivity of these postsynaptic receptors between the groups. However, a change in presynaptic function was identified, as there was a significant reduction in the time taken for neuronal firing to recover to 50% of the original rate following 5-HT (10 microM) application, in isolation compared to group-reared rats. These data suggest a possible change in reuptake following isolation. Uptake studies using (3)[H]5-HT, however, found no change in the inhibition of uptake produced by either fluoxetine or paroxetine in isolation compared to group-reared rats. The selective 5-HT(1B) antagonist CP-294253 (1 microM), increased endogenous 5-HT release from hippocampal slices in vitro and this effect was greater (P < 0.001) in group compared to isolation-reared rats. These results indicate that the change in presynaptic 5-HT neuronal function was due to impaired autoreceptor responsiveness. Carbachol (1 microM) increased the firing rate of all neurones recorded but only a proportion of these showed a concentration-related increase. Isolation rearing increased the sensitivity of neurones, showing a concentration-related increase in firing in response to carbachol, but had no effect on the other neurones. In summary, the present study showed that isolation rearing alters presynaptic 5-HT(1B) but not postsynaptic 5-HT(1A) receptor activity in the hippocampus. Isolation rearing in the rat results in hippocampal dysfunction, including reduced serotonergic and enhanced muscarinic activity of some neurones. These effects may in part underlie the behavioural consequences of isolation relevant to human developmental disorders.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Elementary neuronal dysfunctions in schizophrenia.

This paper describes an elementary deficit in sensory processing in people with schizophrenia. If paired sounds are presented to normal subjects, the response to the first sound, as measured by the P50 wave of the auditory-evoked potential, is much greater than the response to the second sound. The diminished response to the second sound is an example of a sensory gating mechanism that enables people to regulate their vigilance so that they can either detect all sounds in the environment or ignore most of them, in favor of narrowing the focus of their concentration. In schizophrenia, this mechanism is usually deficient; patients are in a state of hypervigilance and have diminished abilities to focus their attention. The deficiency appears to be genetically determined and to involve the brainstem control of sensory input to the hippocampus. Such sensory gating deficits may underlie more complex psychotic symptoms, such as hallucinations and delusions. Further studies of their neurobiology could lead to increased understanding of the pathophysiology of schizophrenia.

Arousal↗

Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor epsilon 4 subunit.

NMDA receptors, an ionotropic subtype of glutamate receptors (GluRs), play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. They are composed of the GluRzeta subunit (NR1) combined with any one of four GluRepsilon subunits (GluRepsilon1-GluRepsilon4; NR2A-NR2D). Although the GluRzeta subunit exists in the majority of the CNS throughout all stages of development, the GluRepsilon subunits are expressed in distinct temporal and spatial patterns. In the present study, we investigated neuronal functions in mice lacking the embryonic GluRepsilon4 subunit. GluRepsilon4 mutant mice exhibited reductions of [(3)H]MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] binding and (45)Ca(2+) uptake through the NMDA receptors. The expression of GluRzeta subunit protein, but not GluRepsilon1 and GluRepsilon2 subunit proteins, was reduced in the frontal cortex and striatum of the mutant mice. A postmortem examination in GluRepsilon4 mutant mice revealed that tissue contents of norepinephrine, dopamine, serotonin, and their metabolites were reduced in the hippocampus and that dopamine, as well as serotonin, metabolism was upregulated in the frontal cortex, striatum, hippocampus, and thalamus. To clarify the phenotypical influences of the alteration in neuronal functions, performances in various behavioral tests were examined. GluRepsilon4 mutant mice showed reduced spontaneous locomotor activity in a novel environment and less sensitivity to stress induced by the elevated plus-maze, light-dark box, and forced swimming tests. These findings suggest that GluRepsilon4 mutant mice have dysfunctional NMDA receptors and altered emotional behavior probably caused by changes in monoaminergic neuronal activities in adulthood.

Animals↗

From restoration of neuroplasticity to the treatment of depression: clinical experience.

The adult brain has more plasticity than previously believed. Neurogenesis, growth and branching of dendrites, and remodeling of synaptic contacts in different regions of the brain occur continuously. Numerous studies have reported a decrease in neuroplasticity in depressed patients and/or in animals subjected to stress and to different models of depression. This has led to the proposal of a new approach to the pathophysiology of depression: depression could be the result of the decrease in neuroplasticity in brain structures involved in the control of mood. This new approach to the pathophysiology of depression can lead to better understanding of, or the proposal of more solid hypotheses about, some issues such as the impact of genetics and environmental factors on the occurrence of depressive episodes, the increased risk of depression in patients with somatic diseases in which there are alterations of neuroplasticity, or the increased risk of depressive relapse in depressed patients in partial remission in whom we suspect that neuroplasticity is only partially restored. These observations have also led to the proposal of new hypotheses concerning the mode of action of antidepressant drugs. In this regard, tianeptine is of particular interest. Tianeptine's pharmacological and clinical properties have been extensively studied. Tianeptine has specific neurotrophic properties, and its antidepressant properties have been well demonstrated. Tianeptine provides early relief of anxious symptoms without sedation in depressed patients. The acceptability and safety profiles of tianeptine are appreciated by both physicians and patients; for instance, tianeptine does not induce sexual dysfunction, nausea, or weight gain. It is of interest to focus on what we already know about tianeptine's pharmacological and clinical properties, and to create mechanistic hypotheses about the similarities and differences observed in clinical practice between tianeptine and other antidepressants.

Anti-Anxiety Agents↗

Effects of DM-9384 in a model of amnesia based on animals with GABAergic neuronal dysfunctions.

The effects of N-(2,6-dimethyl-phenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (DM-9384), a cyclic derivative of GABA, were investigated and compared with those of aniracetam in an animal model of amnesia, using a passive avoidance task with animals that have GABAergic neuronal dysfunctions. Pre- and post-training administration of DM-9384 and aniracetam ameliorated bicuculline-induced amnesia, as indicated by parameters such as % retention and step-down latency. DM-9384 ameliorated picrotoxin-induced amnesia when administered pre-training, but not when administered post-training. Aniracetam failed to improve the picrotoxin-induced amnesia. DM-9384 displaced [3H]muscimol binding to GABAA receptors (-log IC50 = 8.07 M; Hill value = 0.23 +/- 0.04), but failed to displace about 20% of the specific muscimol binding, whereas aniracetam showed only a weak effect (-log IC50 = 3.63 M; Hill value = 0.37 +/- 0.06). From these results, it appears that DM-9384 ameliorated the GABA antagonist-induced amnesia by interacting with some GABAA receptors directly and/or indirectly.

Amnesia↗

I. Serotonin (5-HT) within dopamine reward circuits signals open-field behavior. II. Basis for 5-HT--DA interaction in cocaine dysfunctional behavior.

Light microscopic immunocytochemical studies, using a sensitive silver intensification procedure, show that dopamine (DA) and serotonin (5-HT) axons terminate on neurons in the nucleus accumbens (NAcc) (A10) terminals and also in dorsal striatum (DSTr) (A9) terminals. The data demonstrate a prominent endogenous anatomic interaction at these distal presynaptic sites between the neurotransmitters 5-HT and DA; the pattern of the 5-HT-DA interaction differs between A10 and A9 terminals. Moreover, in distinction to the variance shown anatomically between 5-HT--DA interactions at distal A9 and A10 sites, the 5-HT--DA interactions at the level of DA somatodendrites, the proximal site, are similar, i.e. 5-HT terminals in the midbrain tegmentum are profuse and have a massive overlap with DA neurons in both ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). We suggest with reference to the DA neurons of A10 and A9 pathways, inclusive of somatodendrites (sites of proximal presynaptic interactions in the midbrain) and axons (sites of distal presynaptic interactions), that 5-HT--DA interactions in A10 terminals are more likely to exceed those in the DStr arrangement. Furthermore, our neuroanatomic data show that axonally released DA at A10 terminals may originate from proximal 5-HT somatodendrites, i.e. dorsal raphe (DR) or the proximal DA somatodendrites, VTA. In vivo microvoltammetric studies were done with highly sensitive temporal and spatial resolution; the studies demonstrate basal (endogenous) real time 5-HT release at distal A10 and distal A9 terminal fields and real time 5-HT release at proximal A10 VTA somatodendrites. In vivo microvoltammetric studies were performed concurrently and on line with studies of DA release, also at distal A10 and distal A9 terminal fields and at proximal A10 somatodendrites. Serotonin release was detected in a separate voltammetric peak from the DA voltammetric peak. The electrochemical signal for 5-HT release was detected within 10-12 s and that for DA release within 12-15 s, after each biogenic amine diffused through the synaptic environment onto the microelectrode surface. The electrochemical signal for 5-HT and a separate electrochemical signal for DA are detected on the same voltammogram within 22-27 s; each electrochemical signal represents current changes in picoamperes, within seconds of detection time. The amplitude of each electrochemical signal reflects the changes in diffusion of each biogenic amine to the microelectrode surface. Each neurotransmitter has a distinct potential at which oxidation occurs; this results in a recording which has a distinct peak for a specific neurotransmitter. The concentration of each neurotransmitter within the synaptic environment is directly related to the electrochemical signal detected via the Cottrell equation. Voltammograms were recorded every 5 min. At the time that basal 5-HT release and basal DA release were recorded within same animal control, open-field behavioral studies were performed, also concurrently, by infrared photocell beams. The frequency of each behavioral parameter was monitored every 100 ms; the number of behavioral events, were summated every 5 min during the time course of study. Thus, the detection of neurotransmitters occurs in real time, while simultaneously monitoring the animal's behavior by infrared photocell beams. The results from the in vivo microvoltammetric and behavioral data from this study show that basal 5-HT release at distal A10 and A9 terminals dramatically increased with DA release. Moreover, each increase in basal 5-HT release, at both A10 and at A9 terminal fields occurred consistently and at the same time as each increase in open-field locomotion and stereotypy occurred naturally during the animal's exploration in a novel chamber. Thus, the terminology 'synchronous and simultaneous' describes aptly the correlation between 5-HT release at distal A10 and A9 terminal fields and open-field locomo

Animals↗

Changes in voluntary muscle strength, somatosensory transmission and skin temperature concomitant with pain relief during autotraction in patients with lumbar and sacral root lesions.

Earlier clinical observations of rapid changes of certain neurological dysfunctions after autotraction treatment of patients with lumbar and sacral root affections have been evaluated by objective registration methods. Isokinetic recordings of maximal voluntary strength showed that in 6 out of 8 patients, weakness of the foot dorsal flexor muscles could be more or less completely restored after one session of autotraction resulting in pain relief. In a group of patients with clinical signs of impaired sensibility, the low or abolished SEP responses to nerve stimulation on the affected side were restituted in 4 out of 5 cases during autotraction. The asymmetric leg skin temperatures in 10 patients with sciatic pain levelled off in the 6 cases obtaining pain relief by the traction. The results suggest a causal relationship between pain relief and restitution of certain neurological deficits.

Adult↗

Neuropharmacology of methylphenidate and a neural substrate for childhood hyperactivity.

What began as a simple chemical question about the clinical utility of MPH SL measurement has led our group across a broad expanse of research endeavors, from the problem of nonintercorrelated stimulant effects to a theory of hyperactivity as a dysregulatory disorder based on frontal-striatal dysfunction or dysmaturation. The transition has been from a traditional and fairly circumscribed question in psychopharmacology to a new interest in the neuropsychological approach to hyperactivity and its treatment. Biologic psychiatry and neuropsychology have developed as distinct disciplines well insulated from one another, but a degree of cross-fertilization is beginning to occur. Rather than thinking of childhood hyperactivity in terms of vague metapsychological concepts such as "attention" or "arousal," it will be perhaps more constructive to base a model for the disorder on the foundation of known elements of brain function. Perhaps the most interesting research areas to pursue will be neuropsychological and neurodiagnostic (for example, PET). The specific locus of disorders, such as the HKS and the specific mechanisms of drug action, may not be so elusive after all.

Antipsychotic Agents↗

beta-Secretase expression in normal and functionally deprived rat olfactory bulbs: inverse correlation with oxidative metabolic activity.

Cerebral hypometabolism, mitochondrial dysfunction, and beta-amyloid peptide (Abeta) accumulation are well-characterized manifestations of Alzheimer's disease (AD). beta-Secretase (BACE) is a prerequisite for amyloidogenesis, and it is up-regulated in sporadic AD. To explore a potential in vivo mechanism by which Abeta production is modulated by neuronal activity and/or oxidative metabolism, we compared BACE expression with cytochrome c oxidase (CO) or succinic dehydrogenase (SDH) activity in normal and functionally deprived adult rat olfactory bulb. In normal bulb, BACE was expressed predominantly in the glomerular layer, but labeling intensity within individual glomeruli varied substantially. A strong negative correlation existed between BACE labeling intensity and CO or SDH activity among individual glomeruli. Unilateral naris occlusion resulted in elevated glomerular BACE labeling in the deprived bulbs relative to the nondeprived counterparts, which was correlated with decreased CO activity in the same anatomic location. Enhanced BACE labeling was confirmed by measurements of elevated protein levels, enzymatic activity, and beta-site cleavage products of amyloid precursor protein in bulb extracts. Our findings reveal a negative regulation of BACE expression by physiological neuronal activity and an intrinsic inverse correlation between BACE expression and oxidative metabolism at the first synapse on the olfactory pathway. The results point to a biological role of BACE in synapse function and plasticity as well as a potential mechanism whereby reduced neuronal activity or metabolism could lead to amyloid overproduction in synaptic terminals.

Amyloid Precursor Protein Secretases↗

NE/DA interactions in prefrontal cortex and their possible roles as neuromodulators in schizophrenia.

The monoaminergic innervation of the rat prefrontal cortex arises from well-defined mesencephalic nuclei, with noradrenergic (NE) neurons located in the locus coeruleus, dopaminergic (DA) neurons located in the ventral tegmental area, and serotonergic (5-HT) neurons originating in the raphe nuclei. Specific destruction of the NE bundle was found to induce morphological (i.e., sprouting) as well as metabolic (i.e., changes in rate of DA utilization) modifications of mesocortical DA neurons, suggesting that these two catecholaminergic systems have functional interactions within the prefrontal cortex. This was substantiated by experiments showing that DA afferents modulate the sensitivity of cortical post-synaptic beta-adrenergic receptors and that, reciprocally, NE neurons control the sensitivity of cortical D1 receptors. Behavioural and pharmacological data have further indicated that the stimulation of cortical alpha-1 adrenergic receptors inhibits cortical DA transmission at D1 receptors. Secondly, we have attempted to analyze how such interactions between neuromodulatory systems may be related to the development of mental diseases such as schizophrenia. On the basis of studies in the literature describing the effects produced by the ingestion of hallucinogenic drugs or data collected regarding REM sleep, it is postulated that two modes of brain functioning exist: analogical and cognitive. Each mode is characterized by differences in the relative activities of NE, DA and 5-HT neurons. At birth, during REM sleep, and following the ingestion of hallucinogens, the mode of brain functioning is essentially analogical; in contrast, both analogic and cognitive modes are postulated to coexist in the awake state. Oscillations between these two modes are under the control of monoaminergic systems on which an increase in cortical DA release favours the cognitive processing mode, whereas intermittent activations of NE neurons would switch the brain into the analogical mode of processing. It is proposed that schizophrenic patients with "positive" symptoms suffer from an abnormal preponderance of the analogical mode while awake, whereas "negative" symptoms are due to the excessive presence of the cognitive mode. Although pure biological deficits cannot be excluded, these dysfunctions could be related to the absence of particular environmental variables early in the development of these patients. This condition is probably required to establish normal regulatory control of monoaminergic neuronal activity.

Dopamine↗

Noradrenergic blockade prevents attacks in a model of episodic dysfunction caused by a channelopathy.

Episodic neurological dysfunction often results from ion channel gene mutations. Despite knowledge of the mutations, the factors that precipitate attacks in channelopathies are not clear. In humans, mutations of the calcium channel gene CACNA1A are associated with attacks of neurological dysfunction in familial hemiplegic migraine and episodic ataxia type-2. In tottering mice, a mutation in the same gene causes attacks resembling paroxysmal dyskinesia. Stress, a trigger associated with human episodic disorders, reliably elicits attacks in tottering mice. Because noradrenergic neurotransmission is critical to the stress response and because noradrenergic hyperinnervation is observed in tottering mice, the role of norepinephrine in stress-induced attacks was investigated. Drugs that act at alpha-adrenergic receptors to block noradrenergic transmission prevented attacks. However, agents that facilitate noradrenergic neurotransmission failed to induce attacks. These results suggest that, while noradrenergic neurotransmission may be necessary for attacks, an increase in norepinephrine is not sufficient to induce attacks.

Adrenergic Agonists↗

Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P.

Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O(2))(11)] Substance P (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, somatostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GluR2) -positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase--immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)-- and beta-synuclein--LI, as well as by Timm staining, all of which revealed relatively normal patterns of excitatory terminal distribution. Control injections produced minor damage at the injection site, but no apparent specific loss of SPR-LI. One to 12 weeks after injection of SSP-saporin, extracellular electrophysiological field responses recorded in the CA1 pyramidal and dentate granule cell layers in response to afferent stimulation were blindly evaluated simultaneously in two sites 1-2 mm apart along the longitudinal hippocampal axis. SSP-saporin-treated rats exhibited relatively normal responses in some sites, whereas disinhibition and hyperexcitability indistinguishable from the pathophysiology produced by experimental status epilepticus were simultaneously recorded at adjacent sites. Anatomic analysis of the recording sites in each animal revealed that epileptiform pathophysiology was consistently observed only within areas of SPR ablation, whereas relatively normal evoked responses were recorded from immediately adjacent and relatively unaffected regions. These data establish the efficacy of [Sar(9), Met(O(2))(11)] Substance P-saporin for producing a selective and spatially extensive ablation of hippocampal inhibitory interneurons in vivo and a highly focal disinhibition that was restricted to the site of interneuron loss. These results also demonstrate that the "epileptic" pathophysiology produced by experimental status epilepticus or head trauma can be replicated by focal interneuron loss per se, without involving principal cell loss and other interpretive confounds inherent in the use of global neurologic injury models.

Animals↗

Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development.

Neonatal (postnatal days 8-21) exposure of rats to the selective serotonin reuptake inhibitor (SSRI), citalopram, results in persistent changes in behavior including decreased sexual activity in adult animals. We hypothesized that this effect was a consequence of abnormal stimulation of 5-HT(1A) and/or 5-HT(1B) receptors as a result of increased synaptic availability of serotonin during a critical period of development. We examined whether neonatal exposure to a 5-HT(1A) (8OH-DPAT) or a 5-HT(1B) (CGS 12066B) receptor agonist can mimic the effect of neonatal exposure to citalopram on adult sexual behavior. Results showed that neonatal treatment with 5-HT(1B) receptor agonist robustly impaired sexual behavior similar to the effect of citalopram, whereas exposure to 5-HT(1A) receptor agonist only moderately influenced male sexual activity in adult animals. These data support the hypothesis that stimulation of serotonin autoreceptors during development contributes to the adult sexual deficit in rats neonatally exposed to citalopram.

8-Hydroxy-2-(di-n-propylamino)tetralin↗