Sham-stimulated Rats Research Articles

Lasting increase in serotonin 5-HT1A but not 5-HT4 receptor subtypes in the kindled rat dentate gyrus: dissociation from local presynaptic effects.

We examined the effect of kindling on serotonergic neurotransmission in the hippocampus by measuring serotonin (5-HT) release and uptake in hippocampal synaptosomes and 5-HT1A and 5-HT4 receptor subtypes during and at different times after electrical kindling of the dentate gyrus. Using quantitative receptor autoradiography, we found that binding of 8-[3H]hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) to 5-HT1A receptors was selectively increased by 20% on average (p < 0.05) in the dentate gyrus of the stimulated and contralateral hippocampus 2 days after stage 2 (stereotypes and occasional retraction of a forelimb) and by 100% on average (p < 0.05) 1 week after stage 5 (tonic-clonic seizures) compared with sham-stimulated rats. A 20% increase (p < 0.05) was observed 1 month after the last generalized seizure. No changes were found after a single afterdischarge. 5-HT4 receptors, which colocalize with 5-HT1A receptors on hippocampal neurons, were not modified in kindled tissue. [3H]5-HT uptake and its release as well as the 5-HT1B autoreceptor function did not differ from shams in hippocampal synaptosomes at stages 2 and 5. Systemic administration of 100 and 1,000 microg kg(-1) 8-OH-DPAT or 1,000 microg kg(-1) WAY-100,635, 30 min before each electrical stimulation, did not significantly alter kindling progression or the occurrence of stage 5 seizures in fully kindled rats. The changes in 5-HT1A receptor density in the dentate gyrus are part of the plastic modifications occurring during kindling and may contribute to modulating tissue hyperexcitability.

Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats.

The aim of the present study is to monitor the extracellular gamma-aminobutyric acid (GABA) levels in the lumbar dorsal horn of allodynic rats, which respond to spinal cord stimulation (SCS) with a normalization of the tactile withdrawal threshold. In addition, we monitored the GABA levels in nonresponding and sham-stimulated rats. Partial constriction injury of the sciatic nerve was performed, and a permanent electrode for SCS was inserted into the spinal canal. The response to SCS was assessed with von Frey hairs in awake animals. Later, microdialysis was performed in the dorsal horn of the spinal cord under halothane anesthesia. The concentration of GABA in the microdialysate was assessed by high-performance liquid chromatography. Extracellular GABA levels in rats with sciatic nerve lesions and allodynia (2.3 +/- 0.5 nmol/L) were significantly lower (P < 0.001) than in control rats with intact sciatic nerves (8.1 +/- 1.0 nmol/L), whereas only slightly decreased GABA levels (5.7 +/- 1.1 nmol/L) were detected in nonallodynic rats with sciatic nerve lesions. In the allodynic rats, which respond to SCS by a normalization of the tactile withdrawal threshold, significantly (P < 0.001) increased GABA levels (6.7 +/- 2.3 nmol/L) were detected after SCS. In contrast, neither the allodynic rats, which did not respond to SCS, nor the sham-stimulated allodynic rats displayed increased GABA levels in response to stimulation. Our results indicate that the development of allodynia, a common symptom in neuropathic pain states, may be linked to a decreased spinal release of GABA. We suggest that an SCS-induced release of GABA could be important for the suppression of allodynia observed in rats after SCS. Similar mechanisms could also be involved in the SCS-induced alleviation of pain in patients with peripheral neuropathy.

Long-term decrease in the hippocampal [ 3H]inositoltriphosphate binding following repeated electroshock in the rat

A quantitative autoradiographic study was made on the binding of the phosphatidylinositol system ligand [3H]inositol(1,4,5)-triphosphate (IP3) to forebrain sections from electroconvulsive shock (ECS)-treated rats. One group of rats was sacrificed 1 day and 1 month, respectively, after 12 ECSs administered three times weekly for 4 weeks. SHAM-stimulated rats served as controls. A single ECS did not change the [3H]IP3 binding in any of the brain regions examined. One day after the last of 12 ECSs, a decrease in [3H]IP3 binding (21%) was found within the CA1 region of the hippocampus and the piriform cortex (39%). In rats sacrificed 1 month after the last of 12 ECSs, the [3H]IP3 binding in piriform cortex had returned to control level. In the CA1 region of the hippocampus, the binding was still decreased (24%). It is possible that changes in the phosphatidylinositol system may play a part in the neurobiological events responsible for the therapeutic effect of electroconvulsive therapy.

Autoradiographic distribution of cerebral blood flow increases elicited by stimulation of the nucleus basalis magnocellularis in the unanesthetized rat

The nucleus basalis magnocellularis (NBM) of the rat, equivalent of Meynert's nucleus in the primate, is the origin of the main cholinergic innervation of the cerebral cortex. Stimulation of this area has been previously shown to induced marked, cholinergically mediated, blood flow increases in the frontal and parietal cortices. However, the complete distribution of the cerebrovascular effects of NBM stimulation within the whole brain has not been determined. In the present study, we used the [ 14C]iodoantipyrine autoradiographic method to measure local cerebral blood flow (CBF) in the unanesthetized rat, chronically implanted with a stimulation electrode. We performed unilateral electrical stimulation of the NBM in order to compare both the interhemispheric differences in blood flow and the differences with a group of sham-stimulated rats. Considerable blood flow increases were found in most neocortical areas, exceeding 400% in the frontal area, compared to the control group. Marked responses also appeared in discrete subcortical regions such as the zona incerta, some thalamic nuclei and structures of the extrapyramidal system. These responses were mostly ipsilateral to the stimulation. The significance and the distribution of these blood flow increases are related first, to anatomical and functional data on mainly the cholinergic projections from the NBM, but also non-cholinergic pathways connected with the NBM, second, to biochemical data on the basalocortical system, and third, to the limited ultrastructural data on the innervation of microvascular elements. This cerebrovascular study represents a step in the elucidation of the function of the basalocortical system and provides data which may be related to certain deficits of degenerative disorders such as Alzheimer's disease in which this system is consistently affected.

Electrical sensitization of the meso-limbic dopaminergic system in rats: a pathogenetic model for schizophrenia

To study whether it was possible to modify mesolimbic dopaminergic activity by intermittent electrical stimulations (IES), 44 rats were either electrically stimulated or sham-stimulated in the ventral tegmental area (VTA) once daily for 70 days. This was done through chronically implanted intracranial electrodes. The intensity of electrical stimulation was determined by the lowest current that elicited a definite motor response. Stimulated rats demonstrated a significantly potentiated behavioral response after 70 stimulations. Seven months after IES rats still demonstrated an increased sensitivity to electrical stimulations in the VTA. A new stimulation period only resulted in a modest additional fall in threshold values. There was a highly significant difference between the current needed to provoke a given response in sensitized rats and in sham-stimulated rats. The behavioral response to stimulation was suppressed both by the dopamine (DA) D 2 receptor antagonists haloperidol and raclopride and by the DA D 1 receptor antagonist SCH 23390. Furthermore, stimulated rats showed an enhanced response to stimulation with amphetamine and to a lesser extent with apomorphine. Between stimulation periods sensitized animals demonstrated a reduced social interaction. In conclusion intermittent electrical stimulations of the VTA resulted in a syndrome characterized by a hypersensitive response to electrical and pharmacological DA provocation combined with abnormal social interaction. This animal model has points of resemblance with recent interpretations of the DA hypothesis for schizophrenia.

Medial posterior hypothalamic input is involved in adrenocortical activation following forebrain limbic stimulation

Previous experiments have demonstrated that posterior hypothalamic deafferentation, which involved also the medial forebrain bundle, has prevented the rise in serum corticosterone following limbic stimuli. Consequently, the effects of a small medial posterior hypothalamic deafferentation, excluding the medial forebrain bundle, on corticosterone responses following electrical stimulation of the hippocampus, amygdala, septum and reticular formation in the rat were studied. Posterior hypothalamic deafferentation did not change basal corticosterone levels but significantly inhibited the adrenocortical responses following stimulation of the above structures when compared to intact or sham-stimulated rats. Posterior hypothalamic deafferentation did not affect median eminence corticotropin releasing factor-41 content. It is concluded that a medial posterior hypothalamic input is involved in adrenocortical activation following limbic stimulation.

Delta-9-tetrahydrocannabinol attenuates luteinizing hormone release induced by electrochemical stimulation of the medial preoptic area.

Despite diverse pharmacological actions, drugs commonly used for blocking ovulation in the rat have not been observed to exert differential effects on the LH response to preoptic stimulation, thus suggesting blocking action above the final hypothalamic GnRH pathway. To determine if ovulatory blockade by delta-9-tetrahydrocannabinol (THC) is consistent with that scheme, LH surges evoked by preoptic stimulation were contrasted with those elicited during blockade by atropine (ATR), a classic ovulation-blocking agent with which other drugs have been compared. THC (10 mg/kg) or ATR (350 mg/kg) treatment before the proestrous critical period uniformly blocked LH release and ovulation in sham-stimulated rats. Preoptic stimulation evoked LH surges after both drug treatments (p less than 0.001), peak levels increasing with the intensity of stimulation (p less than 0.05). However, both maximum LH concentration (p less than 0.05) and total integrated LH release (p less than 0.01) were lower in THC-blocked rats. Inspection of the oviducts revealed no difference in the incidence of ovulation or the number of ova discharged. The reduced LH response during THC blockade was not attributable to variation in the extent or locus of histologically determined stimulation sites. These results distinguish THC from ATR and, by extension, other blocking drugs that do not overtly affect the LH response to preoptic stimulation. Thus, ovulatory blockade by THC may involve a different mechanism, which likely includes inhibitory action within the preoptic-to-tuberal GnRH pathway.

A glutamate antagonist blocks perforant path stimulation-induced reduction of dynorphin peptide and prodynorphin mRNA levels in rat hippocampus

Stimulation of the perforant path elicites a behavioral response, wet dog shakes (WDS), and reduction in hippocampal dynorphin A(1–8) immunoreactivity (DYN-IR) and prodynorphin mRNA (DYN mRNA) in rats. This study examined whether glutamate, the proposed endogenous transmitter released by perforant fibers, mediated the above responses. A glutamate antagonist, γ- d-glutamylglycine (DGG, 25 μg/0.5 μl), or artificial cerebrospinal fluid (ACSF, 0.5 μl) was injected into the ventral hippocampus 10–20 min prior to acute or daily stimulation of the left perforant path in rats. In acuted stimulation experiments, 4 consecutive stimulation trials elicited a total of73 ± 4WDS at an average threshold intensity of0.46 ± 0.03mA in ACSF-treated rats. The hippocampal DYN-IR in these animals decreased by more than 40% in both dorsal and ventral hippocampus relative to sham-stimulated rats. DGG injections significantly elevated the threshold for WDS (0.78 ± 0.05mA, P < 0.01), reduced the number of WDS (45 ± 6, P < 0.01), and partially antagonized stimulation-induced reduction of DYN-IR in the ventral, but not dorsal, hippocampus. In daily stimulation experiments, rats received a single trial of stimulation once per day for 6 days. Daily DGG pretreatment almost completely abolished WDS at control threshold intensities, and significantly inhibited stimulation-induced decrease of DYN-IR in both dorsal and ventral hippocampus. In situ hybridization using a 35S-labeled oligodeoxyribonucleotide probe demonstrated a clear depletion of DYN mRNA signal in the dentate granule cell layer of ACSF-treated animals. This depletion was completely prevented in DGG-treated rats. These data suggests that glutamate as the endogenous transmitter at perforant synapses regulates the release and biosynthesis of dynorphine peptides in dentate granule cells.

Neuroimmunomodulation: potentiation of delayed hypersensitivity and antibody production by chronic electrical stimulation of the rat brain.

This study deals with the structural and functional correlates of the immunoneuroendocrine interconnections, and explores the effects of localized brain stimulation on immune response. Bilateral symmetrical electrodes were placed in the dorsomedial nucleus, ventromedial nucleus and posterior area of the hypothalamus, and in the sensorimotor cerebral cortex of the rat brain. Electrical stimulations were applied for 39 consecutive days, 10 days before and 29 days after single immunization. In sham-stimulated rats, electrodes were lowered into the hypothalamic areas and sensorimotor cortex without passing any current. Animals with electrodes were divided post mortem into groups according to the histological location of the electrode tips. Intact rats served as additional controls. All animals were immunized with bovine serum albumin in complete Freund's adjuvant and tested for immune reactions 7, 14, 21, and 28 days after immunization. The most significant finding was the potentiated delayed skin hypersensitivity and, to a lesser extent, antibody production to bovine serum albumin in rats with stimulated dorsomedial hypothalamus and sensorimotor cortex. On days 21 and 28, skin reactions increased in rats with stimulated posterior hypothalamus. These immune effects could not be obtained when the stimulation was applied to the hypothalamic ventromedial nucleus. Several pathways of the immunoneuroendocrine interplay are suggested.

Prolactin secretion preceding delayed pseudopregnancy in rats after electrical stimulation of the hypothalamus.

Delayed pseudopregnancy (PSP) was induced by electrical stimulation of the dorsomedial-ventromedial hypothalamus under two different experimental conditions. To induce long delay PSP, 4-day cycling rats were stimulated on the third day of pentobarbital blockade of ovulation. A similar stimulus on the afternoon of diestrus day 2 under pentobarbital resulted in short delay PSP. The parameters of electrical stimulation were as follows: biphasic 1-msec pulse pairs, 100 Hz, 200 μA peak to peak, 30/60 sec for 30 min. In animals stimulated on the third day of ovulation blockade, blood samples (<0.4 ml each; <3 samples/24 h-rat) were taken from a chronic intracardiac cannula to 0300, 0600, 0900,1200,1500,1800, or 2400 h for 3 days beginning on the morning after the stimulus. By contrast with sham-stimulated rats and stimulated rats continuing to cycle, those rats later manifesting PSP presented twice daily PRL surges similar to those of PSP at 0300–0600 and 1500–1800 h through the third day of the long delay interval. After similar stimulation on diestrus day 2 to induce the short delay PSP, trunk blood was collected after rapid decapitation at 2400 or at 0300, 0600, or 0900 h during the next morning. A modest but significant (P < 0.05) increase in PRL above control levels occurred at 0300 h. These findings are in contrast to our earlier study of short delay PSP induced by cervical stimulation in which there was no immediate rise in PRL during the delay interval. This difference may be related either to the difference in locale of the stimulus (hypothalamus vs. cervix) or, quantitatively, to the relatively prolonged stimulus used in the present experiments. Therefore, surging of PRL may or may not occur during the delay interval and is not essential for initiating the subsequent PSP.

ELECTRICAL STIMULATION OF THE HYPOTHALAMUS: SIMULTANEOUS EFFECTS ON THE PITUITARY-ADRENAL AND THYROID SYSTEMS OF THE RAT.

Electrical stimulation of various sites in the medial ventral hypothalami of adult female rats was done through chronically implanted electrodes in order to determine simultaneous effects on the pituitaryadrenal and thyroid systems. A series of stimulations (10 min daily, 4–9 days) delivered to preoptic, suprachiasmatic and anterior hypothalamic areas induced cytological activation of pars distalis basophils, markedly reduced pituitary thyrotrophin (TSH) stores, increased plasma TSH concentrations 4- to 5-fold, and resulted in histological stimulation of the thyroid gland. Comparable excitation of the posterior median eminence and arcuate nuclear regions of the tuberal hypothalamus produced effects of similar magnitude. The mere presence of electrodes in the hypothalamus without electrical stimulation had no significant effect on TSH secretion and histology of the thyroid, but caused adrenal hypertrophy and elevation of plasma corticosteroid levels in sham-stimulated rats. Excitation of the rostral or cau...