Tolerance to tyrosine hydroxylase activation in n. accumbens and c. striatum after repeated injections of "classical" and "atypical" antischizophrenic drugs.
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Animals↗
Biomedical subjects
K Gale
Publications and source records attributed to K Gale.
Evidence for a role of nigral gamma-aminobutyric acid and substance P in the haloperidol-induced activation of striatal tyrosine hydroxylase.
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Aminobutyrates↗
Presence of substance P and GABA in separate striatonigral neurons.
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Aminobutyrates↗
Dopamine-sensitive adenylate cyclase: location in substantia nigra.
A dopamine-sensitive adenylate cyclase with characteristics similar to those measured in the striatum is present in the rat substantia nigra. Destruction of dopamine cell bodies by intranigral 6-hydroxydopamine application failed to abolish the response of nigral adenylate cyclase to dopamine. In contrast, brain hemitransection between the striatum and substantia nigra, or a more circumscribed lesion of striatonigral pathways, abolished the dopamine stimulation of adenylate cyclase in the substantia nigra. These results suggest that dopamine receptors within the substantia nigra are not located on dopamine cell bodies but are associated with a pathway, containing gamma-aminobutyric acid or substance P, which projects from forebrain structures to the substantia nigra.
Adenylyl Cyclases↗
Participation of GABA receptors in the short-term activation of striatal tyrosine-3-monooxygenase elicited by neuroleptics.
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Aminobutyrates↗
Chemoconvulsant seizures: advantages of focally-evoked seizure models.
Studies of short and long-term changes in regional metabolism, blood flow, gene expression (including immediate early genes and genes for neurotrophic factors), sprouting and cell death following seizures are pivotal to an understanding of the neural networks responsible for the generation of seizures. At the same time, this information forms a basis for understanding the pathophysiology associated with chronic, recurrent seizures. Systemic chemoconvulsant seizure models, produced by systemically administered chemoconvulsant agents, although convenient, are plagued with difficulties which confound the interpretation of their effects on the nervous system. These difficulties include widespread direct cellular and physiological effects of the chemoconvulsant drugs, most of which are independent of seizures. In addition, numerous physiological changes occur as a secondary consequence of, or ancillary to, seizures, and it can be especially difficult to separate these effects from the direct effects of the propagated seizure discharge itself. Some of these difficulties can be overcome by the use of focally-evoked seizure models. Such models avoid the diffuse presence of drug throughout the CNS and thereby eliminate most of the direct cellular and physiologic actions of the drug apart from seizure-induction. Large regions of the brain distant from the focal site of drug application then can be examined for molecular, structural and physiologic changes uncomplicated by the presence of drug. Moreover, different focal sites of drug application can be compared to evaluate the specificity of the molecular changes to the neural network engaged in the seizure discharge. For example, limbic seizures, evoked by chemoconvulsant application into area tempestas, can be compared with brainstem convulsions evoked by chemoconvulsant application into inferior colliculus.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Electroencephalographic evidence for a dose-related biphasic effect of morphine on bicuculline-induced seizures in the rat.
The effects of systemic pretreatment with morphine sulfate (MS) on electroencephalographic (EEG) manifestations of seizures due to bicuculline (BIC) were studied in freely moving rats. Electrodes were placed on frontal and occipital cortices, into the hippocampus and into a region of the prepiriform cortex, area tempestas (AT). BIC (0.1-0.25 mg/kg i.v.) elicited dose-dependent changes in electrocortical activity, consisting of 3 stages: stage 1, slight increase in periods of desynchronization; stage 2, trains of 4-6 Hz spike-and-wave complexes and of 2-4 Hz slow waves; stage 3, 'grand mal' seizures. Isolated spikes and hypersynchronous high voltage spikes occurred in the hippocampus during stage 2 and stage 3, respectively. In the AT, EEG abnormalities were observed during stage 3 only. During the recovery period, cortical synchronization occurred associated with the presence of occasional synchronous spikes in both deep areas. After pretreatment with MS (2, 12, and 25 mg/kg), stage 3 EEG seizures occurred with doses of BIC (0.12 or 0.18 mg/kg i.v.) that in the absence of MS produced only stage 1 or 2. In contrast, after pretreatment with a low dose of MS(0.5 mg/kg) the seizures induced by a maximally effective dose of BIC (0.25 mg/kg) were markedly attenuated. Thus, the effect of MS on BIC-induced seizure activity appears to be biphasic, potentiating seizures at doses at or above 2 mg/kg and inhibiting seizures at lower doses.
Animals↗
A crucial epileptogenic site in the deep prepiriform cortex.
Antagonists of gamma-aminobutyric acid (GABA)- or glycine-mediated neurotransmission, muscarinic cholinergic agonists, and excitatory amino acids and their analogues are all considered to be potent chemoconvulsant agents. However, although systemic injections of these agents have been used to create experimental models of generalized epilepsy, there has been no identification of a specific locus at which any of these drugs act to initiate generalized seizures. We recently located a forebrain region from which seizures can be elicited by the GABA antagonist bicuculline, and now report that manipulations of excitatory amino acid transmission and cholinergic transmission can also elicit seizures from this site. Bilateral clonic seizures can be elicited after unilateral application of picomole amounts of bicuculline, kainic acid or carbachol and micromole amounts of glutamate. Local application of the GABA agonist muscimol prevents the appearance of seizures on subsequent microinjection of all convulsant agents examined, whereas local application of the muscarinic antagonist, atropine, only prevents seizures induced by carbachol. This region is therefore a site of action for the epileptogenic effects of neuroactive agents with diverse mechanisms of action; it may also represent a site at which GABA agonists could function therapeutically to control epileptogenesis.
Animals↗
Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats.
Fluoxetine was evaluated for anticonvulsant effects in a rat model of focally evoked complex partial seizures (CPS) secondarily generalized. Fluoxetine was administered intraperitoneally (i.p.) 1 h before seizures were induced by focal intracerebral application of the GABAA receptor antagonist, bicuculline methiodide (118 pmol) unilaterally into a discrete epileptogenic site in the deep prepiriform cortex ("area tempestas," AT) of rats. Significant dose-dependent protection from clonic motor seizures was obtained after 5-, 10-, and 20-mg/kg doses of fluoxetine, with 50% protection occurring after the 5-mg/kg dose. Suppression of electrographic seizure activity was concomitant with suppression of motor seizures. These observations support and extend previous findings of other investigators who showed that fluoxetine exerts anticonvulsant actions against maximal electroshock (MES) convulsions and audiogenic convulsions in genetically seizure-prone rodents.
Acoustic Stimulation↗
Role of brainstem structures in seizures initiated from the deep prepiriform cortex of rats.
Previous studies showed that brainstem seizures can still be evoked after transections that separate forebrain from brainstem. We sought to determine whether forebrain-evoked electrographic seizures require brainstem connections for initiation and generalization. Male Sprague-Dawley rats weighing 295-320 g implanted with epidural electrodes had brain transections placed at the pre-, mid-, or postcollicular level. In experiment 1, the transections were limited to severing the brainstem, sparing the telencephalon laterally; these are referred to as "core" transections. In experiment 2, the transections severed the brainstem and also cut through the lateral telencephalon. These "extended" transections were either (a) bilateral, (b) unilateral (i.e., a hemitransection confined to one hemisphere), or (c) partial (sparing pathways ventral to the pretectal nuclei). All transections were performed under ether anesthesia, and seizures were initiated 3 h later by focal infusion of bicuculline (BIC) into the area tempestas (AT) through a previously implanted guide cannula. In experiment 1, bilateral forebrain electrographic seizures occurred in the complete absence of connections between forebrain and brainstem, showing that the brainstem is not required for forebrain-evoked seizures. In experiment 2, forebrain seizures evoked by BIC in AT were suppressed by bilateral extended transections which interrupted connections between AT and the caudal lateral telencephalon. Under these circumstances, application of carbachol with BIC reinstated the forebrain seizure response. These results indicate that carbachol application served to compensate for loss of an excitatory influence on AT resulting from the severing of connections with the caudal telencephalon. The demonstration of direct projections from entorhinal cortex to AT using Fluoro-Gold tracing together with the finding that extended brain transections caudal to the telencephalon do not suppress focally evoked forebrain seizures provided further support for the notion that AT afferents from the caudal telencephalon regulate the sensitivity of AT to BIC. The present findings provide further evidence that seizure substrates in the forebrain and brainstem are separable and independent.
Afferent Pathways↗