Adenosine receptor activation blocks seizures induced by bicuculline methiodide in the rat prepiriform cortex.
Explore the source record for details and available documents.
2-Chloroadenosine↗
Biomedical subjects
K Gale
Publications and source records attributed to K Gale.
Differential effects of chronic treatment with chlorpromazine versus cocaine on behavioral responsiveness to nigral GABA receptor stimulation.
We examined whether any locus postsynaptic to the GABAergic striatonigral projection might be involved in the enhancement of behavioral response to dopaminergic stimulants induced by chronic treatment with either neuroleptic drugs or stimulants. Rats exposed chronically to either chlorpromazine or cocaine were tested for behavioral responses to bilateral intranigral microinfusions of muscimol (2.5 ng bilaterally). Chronic chlorpromazine-treated rats responded with more intense stereotypy to nigral muscimol than controls, but chronic cocaine-treated rats were less responsive than controls to intranigral muscimol. It therefore appears that changes in the responsiveness of neural outputs from, or distal to, substantia nigra may contribute to the enhanced behavioral effects of dopaminergic stimulants caused by chronic exposure to dopaminergic antagonists, but that the critical neural changes responsible for cocaine sensitization probably do not occur at, or distal to, the nigral outflow from the basal ganglia. At least at the nigral level, different neural mechanisms evidently mediate the increased stereotypy response to dopaminergic stimulation induced by chronic administration of either neuroleptic or stimulant drugs.
Animals↗
Oral movements induced by interference with nigral GABA neurotransmission: relationship to tardive dyskinesias.
Previous studies have shown that the emergence of spontaneous dyskinetic behaviors, such as vacuous chewing movements, following several months of neuroleptic treatment in the rat, is correlated with depletion of nigral GABA. To explore the specificity of this relationship, we acutely interfered with nigral GABA transmission pharmacologically, by microinfusing either the GABA receptor antagonist, bicuculline, or the GABA-depleting agent, isoniazid, bilaterally into substantia nigra. We found that both acute treatments induced vacuous chewing movements in rats. Moreover, the time to onset of action of each of these drugs corresponded to the onsets of their respective effects on GABA transmission. In addition, we found that the application of muscimol into the target field of the nigrotegmental projection, which has been shown to block gnawing elicited by nigral GABA receptor stimulation, completely abolished elicitation of vacuous chewing movements by intranigral isoniazid. In contrast, bilateral microinfusions of muscimol into the nigrocollicular target region, in the deep layers of superior colliculus, blocked elicitation of gnawing by intranigral muscimol, but completely spared elicitation of vacuous chewing movements by intranigral isoniazid. We conclude that qualitatively different dyskinetic syndromes can be produced by bidirectional perturbations of nigral GABA function and are differentially mediated by nigrotegmental and nigrotectal projections. These syndromes may represent animal models of distinct components of extrapyramidal side effects of chronic neuroleptic administration.
Animals↗
Time-dependent enhancement of lymphocyte activation by mitogens after exposure to isolation or water scheduling.
The effects of isolation and water scheduling on mitogen induced lymphocyte proliferation were investigated. Isolated rats were animals which had been raised in group-housed conditions and then transferred to individual cages with ad lib access to water for a 1 or 2 week period. Water scheduled rats were maintained in group housing (5 rats per cage) with ad lib access to food but with access to water for a single 30 minute session each day. Responses of these groups were compared to those of animals which had been continuously group-housed with ad lib access to food and water. No differences in lymphocyte responses to phytohemagglutinin (PHA) were found 1 week after exposure to isolation. However, after 2 weeks, splenic and blood T lymphocytes from isolated animals demonstrated an increased proliferative response to suboptimum and maximum concentrations of PHA. Splenic B lymphocyte responses to lipopolysaccharide (LPS) from isolated animals were also increased by 2- to 3-fold compared to group-housed controls. Two weeks of exposure of animals to daily water scheduling similarly increased the splenic lymphocyte proliferation. This increased responsiveness to PHA was not accompanied by a significant change in the sensitivity of the lymphocytes to PHA, in the total number of white blood cells, or the proportion of splenic T or T helper lymphocytes. Our results show that the increase in lymphocyte proliferation is time-dependent, requires greater than 1 week of exposure to isolation and is due to factors other than changes in sensitivity to mitogen or T lymphocyte number.
Animals↗
Effect of haloperidol on transplants of fetal substantia nigra: evidence for feedback regulation of dopamine turnover in the graft and its projections.
Explore the source record for details and available documents.
Animals↗
Progression and generalization of seizure discharge: anatomical and neurochemical substrates.
Seizure activity is generated and propagated by specific subcortical circuits. The substantia nigra (SN) and the area tempestas (AT) have been identified as two exemplary substrates for the control of experimental seizures. In animal models, GABAergic transmission has been shown to protect against seizures of different origins and methods of induction. Neuroactive peptides and excitatory amino acids may work with GABA in the SN to control the propagation of a wide variety of seizure types. In contrast, inhibition of AT pons selectively protects against seizures associated with limbic circuits. The AT is also a site from which bilaterally synchronous convulsions can be triggered in response to manipulations of cholinergic, GABAergic, and excitatory amino acid receptors. Definition of other pathways of seizure development and the effects of pharmacologic treatments on discrete brain regions await further research efforts.
Amino Acids↗
Substantia nigra-mediated anticonvulsant actions: role of nigral output pathways.
Bilateral ablation of the superior colliculus in rats abolished the anticonvulsant effect of muscimol, a gamma-aminobutyric acid (GABA) agonist, infused into the substantia nigra. Our data indicate that the ability of intranigral muscimol to protect against maximal electroshock convulsions requires the integrity of the nigrotectal pathway. We present evidence that the nigrotegmental, nigrothalamic, and nigrostriatal projections do not appear to contribute to the nigral-evoked attenuation of electroshock convulsions. Inasmuch as the nigrotectal pathway utilizes the inhibitory neurotransmitter GABA, we hypothesize that the anticonvulsant effect of nigral manipulations in the electroshock test is a result of the disinhibition of neurons in the superior colliculus, the firing of which must therefore be capable of suppressing or disrupting electroshock-induced convulsions.
Animals↗
Behavioral assessment of functional deficit in rats with contusive spinal cord injury.
We have previously reported a method for assessing functional deficits in rats after contusive spinal cord injury in which a Combined Behavioral Score (CBS) is calculated that is indicative of the overall percent deficit (Exp. Neurol., 88: 123-134, 1985). The test battery used includes several neurologic tests as well as the Motor Score in which use of the hindlimbs in locomotion is graded. In this report we present correction criteria in order to reduce potential interlaboratory variability in assessing functional deficit by the CBS. Groups of rats were subjected to contusive injury using a weight drop technique. The calculated CBS at 4 weeks was compared to that obtained if the Motor Score was over- or underestimated by 1 grade. The results indicated a considerable effect on the calculated CBS, especially when the Motor Score was underestimated in mildly injured animals. Behavioral test data were examined in terms of the distribution of the responses to the various other behavioral tests in relation to the Motor Score. The results were used to develop a set of correction criteria that minimized the effects on the CBS of subjective errors in the Motor Score.
Animals↗
Enhancement of rat lymphocyte proliferation after prolonged exposure to stress.
Rats exposed to 5 weeks of isolation, water scheduling (daily consumption restricted to 30 min), and their combination demonstrated significantly enhanced splenic lymphocyte proliferative responses to phytohemagglutinin (PHA) compared to those of group-housed animals (five per cage) maintained under standard vivarium conditions. The increased response found with the combination treatment was of the same magnitude as that found with each stressor alone. Blood lymphocyte responses were similarly increased after 5 weeks of isolation. When animals were exposed to the combination treatment for 12 weeks, both blood and splenic lymphocyte responses were found to be enhanced by greater than 2- and 3-fold, respectively. At the time of sacrifice no changes were found in total white blood cell numbers or plasma corticosterone levels with any of these treatments. These data suggest that prolonged exposure to a stressor results in an enhancement of immune cell activity.
Animals↗
Anticonvulsant effects of GABA elevation in the deep prepiriform cortex.
Microinjection of gamma-vinyl GABA (GVG), a GABA elevating agent, into a discrete region of the deep prepiriform cortex elevated local GABA levels nearly 4-fold and exerted an anticonvulsant action against seizures induced by intravenous injection of the GABA antagonist, bicuculline, but was ineffective against seizures induced by maximal electroshock. This, together with a previous finding that blockade of GABA transmission in the deep prepiriform cortex induces convulsions, suggests that this area may be crucial, if not primarily responsible, for the genesis of clonic seizures resulting from a deficit in GABA function.
Aminocaproates↗
Substance P antagonists in substantia nigra are anticonvulsant.
Bilateral intranigral microinfusion of antagonist analogs of substance P significantly attenuated convulsions induced by maximal electroshock or intravenous bicuculline in rats. Infusions of substance P antagonists placed adjacent to the substantia nigra in the vicinity of the lateral hypothalamus were without anticonvulsant action. Our data indicate an as yet undescribed role for substance P antagonists in the regulation of seizure susceptibility, and provide additional evidence that decreasing the activity of substantia nigra outputs is anticonvulsant.
Animals↗
Role of excitatory amino acid transmission in the genesis of seizures elicited from the deep prepiriform cortex.
Previous studies in our laboratory have shown that bilateral motor seizures can be elicited from a discrete site within the deep prepiriform cortex (DPC) after a single, unilateral microinjection of picomole amounts of bicuculline, carbachol or kainic acid. The present work shows that 2-amino-7-phosphonoheptanoic acid (2-APH), a specific antagonist of receptors activated by n-methyl-D-aspartic acid (NMDA), when microinjected into DPC reduces the incidence of clonic seizures elicited by bicuculline, carbachol or kainic acid microinjected into the same site. In addition, NMDA, aspartate and glutamate unilaterally microinjected into DPC produces bilateral motor seizures comparable to those elicited by bicuculline, carbachol or kainic acid. These data suggest that activation of excitatory amino acid receptors is both necessary and sufficient for evoking seizures from DPC.
Animals↗
Intranigral muscimol attenuates electrographic signs of seizure activity induced by intravenous bicuculline in rats.
Rats were implanted with infusion cannulas in the substantia nigra (SN), and intracranial electrodes for recording the electroencephalogram (EEG). These rats received intravenous injections of bicuculline, producing repetitive high voltage spike-and-wave complexes. Pretreatment with bilateral intranigral infusions of the GABA agonist muscimol reduced the duration of EEG epileptic activity by over 80%, as compared to the effect of pretreatment with intranigral saline in the same rats. This antiepileptic effect of intranigral muscimol may reflect a primary influence of SN outputs on brain excitability.
Animals↗
Anticonvulsant action of 2-amino-7-phosphonoheptanoic acid and muscimol in the deep prepiriform cortex.
Microinjection of 2-amino-phosphonoheptanoic acid (2APH, 1 nmol), and antagonist for n-methyl-d-aspartate-sensitive receptors, into the deep prepiriform cortex (DPC) of the rat, prevented seizures induced by the intravenous administration of bicuculline. The GABA agonist, muscimol (39 pmol), injected into DPC produced a similar anticonvulsant effect. The DPC may therefore represent an important site of action for the anticonvulsant effects of GABA agonists and excitatory amino acid antagonists. Moreover, our data support the hypothesis that seizures induced by a deficiency in GABA transmission result, at least in part, from a relative overactivity of excitatory amino acid transmission in the DPC.
2-Amino-5-phosphonovalerate↗
Muscimol microinfused into the nigrotegmental target area blocks selected components of behavior elicited by amphetamine or cocaine.
We examined whether behaviors elicited by systemic administration of the stimulants amphetamine and cocaine involve the relay of outflow from basal ganglia to the target region of the GABAergic nigrotegmental pathway (nigrotegmental target area: NTT), in the region of the pedunculopontine nucleus. Bilateral microinfusions of the GABAA agonist muscimol (25 ng in each side) were administered into the NTT in stimulant-treated rats. Amphetamine- and cocaine-induced stereotyped sniffing and repetitive head movements were totally abolished by muscimol infusions. In contrast, stimulant-induced locomotion and snout contact fixation were spared or enhanced. These observations, which extend those of Childs and Gale (1983b) with apomorphine-induced gnawing, further implicate the GABAergic nigrotegmental pathway in the mediation of basal ganglia-related motor dysfunction. On the other hand, cocaine- and amphetamine-induced locomotion and snout contact fixation do not appear to depend upon mediation through GABA-receptive neurons in the NTT. Thus, the NTT may be selective for the processing of outflow from the basal ganglia.
Amphetamine↗
Role of the substantia nigra in GABA-mediated anticonvulsant actions.
The relationship between cerebral GABA content and susceptibility to seizures is addressed from the point of view of specific brain loci at which GABA synapses may control convulsive activity. The substantia nigra (SN) has been identified as a critical site at which GABA-agonist drugs act to reduce susceptibility to a number of types of experimentally induced generalized seizures. Moreover, the ability of GABA-elevating agents to protect against seizures in the maximal electroshock model is directly correlated with increases in GABA specifically in the nerve-terminal compartment of SN. Studies with 2-deoxyglucose indicate that a marked increase in metabolic activity in SN is a common feature of several types of generalized seizures; it is possible that some of this increased activity is associated with GABAergic nerve terminals that become activated in an attempt to suppress seizure spread. Because GABA has been shown to inhibit nigral efferents, it is likely that GABA terminals inhibit nigral projections that are permissive or facilitative to seizure propagation. In support of this, bilateral destruction of SN attenuated clonic and tonic chemoconvulsant and electroshock seizures. Other treatments capable of reducing nigral output, namely opiate agonists (morphine and D-Ala-Met-enkephalin), and substance P antagonist analogs, were also found to have anticonvulsant effects when applied bilaterally into SN. Thus, the seizure-facilitating nigral efferents may be subject to inhibition by both GABA and opiates and may normally be driven by substance P. Of the various outputs from SN, the GABAergic projections to thalamus, reticular formation and/or superior colliculus are most likely responsible for influencing seizure propagation. Experimental evidence does not indicate a significant role of pars compacta nigrostriatal dopamine neurons for controlling the various types of seizures subject to nigral influence. We propose that the inhibition of the GABAergic outputs from SN pars reticulata can suppress the progression of seizure discharge through circuits involving the target areas of these outputs. Because chemical or electrical stimulation of SN does not initiate convulsions, it appears that seizure activity generated elsewhere in the brain may be amplified or sustained by activity in these nigral outputs.
Aminocaproates↗
Intracerebral site of convulsant action of bicuculline.
Bicuculline was injected intracerebrally in several forebrain sites of the rat. In a discrete area in the vicinity of prepiriform cortex, a single, unilateral injection of bicuculline (49 pmol) produced generalized clonic seizures documented behaviorally and electroencephalographically. This is the first identification of an anatomical site from which generalized seizures can be elicited by low doses of a chemoconvulsant.
Animals↗
Spinal cord contusion in the rat: behavioral analysis of functional neurologic impairment.
A graded spinal cord injury in rats was produced by dropping a 10-g weight from 2.5, 5.0, 10,0, or 17.5 cm onto the exposed dura at the T8 vertebral level. Groups of rats (N = 10) for each of these weight drop (WD) levels as well as unoperated and WD controls (0 cm) were subjected to behavioral analysis that included evaluation of simple and complex reflexes as well as spontaneous and evoked motor patterns. On the basis of this analysis, we developed a protocol for evaluating functional deficits that follow spinal cord injury in the rat. The resulting combined behavioral score, a measure of functional deficit, closely correlated with the magnitude of the mechanical injury. The protocol used for neurologic assessment was administered routinely by personnel who were easily and rapidly trained. It should therefore prove useful in detecting the effects of treatment on recovery of function in a rat model of spinal cord injury.
Animals↗