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K Gale

Publications and source records attributed to K Gale.

At least 91 records · Page 5Linked to original sources
PubMed1985

Mechanisms of seizure control mediated by gamma-aminobutyric acid: role of the substantia nigra.

The substantia nigra has been identified as a critical site at which gamma-aminobutyric acid (GABA) agonist drugs act to reduce susceptibility to a number of types of experimentally induced generalized seizures. Moreover, the ability of systemically administered GABA-elevating agents to protect against maximal electroshock seizures is directly correlated with an increase in GABA specifically in the nerve-terminal compartment of substantia nigra. The significance of these findings is discussed in terms of the role of specific nigral synapses for the control of seizure propagation. Evidence from lesion studies, as well as studies with opiates and substance P analogs, further supports the hypothesis that Inhibition of nigral efferents reduces susceptibility to generalized seizures. Inhibition of nigral outflow causes a decreased sensitivity to chemoconvulsants without precluding the animal's ability to exhibit any or all of the motor components of a seizure. We therefore propose that nigral outputs are capable of facilitating seizure propagation and can function as a gating mechanism for the generalization of convulsive activity.

Animals↗
PubMed1985

Infusion of opiates into substantia nigra protects against maximal electroshock seizures in rats.

Microinfusion of morphine sulfate (50 nmol), [d-Ala2]-Met-enkephalin (35 nmol) or dynorphin A 1-13 (1 nmol) bilaterally into the substantia nigra significantly attenuated seizures induced by maximal electroshock in rats. This action was accompanied by stereotyped behavioral hyperactivity. These anticonvulsant and behavioral effects were antagonized by systemic naloxone administration; neither effect was observed after intranigral microinjection of dynorphin A 1-17 amide (1 nmol). These results are consistent with a mu opiate receptor-mediated inhibition of substantia nigra efferent neurons, and with the proposal that bilateral inhibition of nigral efferents attenuates seizure propagation. However, intranigral morphine failed to alter the severity of i.v. bicuculline seizures, indicating that opiate-mediated inhibition in substantia nigra is distinct from that produced by gamma-aminobutyric acid.

Animals↗
PubMed1984

GABA agonist induced analgesia elicited from the lateral preoptic area in the rat.

Unilateral microinjections of the GABA agonists muscimol and baclofen into the lateral preoptic area (LPOA) of the rat brain resulted in a significant increase in the latency to respond to a hotplate stimulus on the side contralateral to the injection. Muscimol injected 1.5 mm dorsal to the LPOA site was significantly less effective in changing the hotplate reaction time. The LPOA therefore represents a site from which GABA receptor-mediated analgesia can be elicited.

Analgesia↗
PubMed1984

Proconvulsant effect of morphine on seizures induced by pentylenetetrazol in the rat.

The chemoconvulsant pentylenetetrazol (PTZ) was administered by a variety of routes to rats pretreated with morphine (10-50 mg/kg s.c.). In a naloxone-reversible, dose-dependent manner, morphine decreased the threshold for seizures induced by the slow intravenous infusion of PTZ. In addition, morphine increased the severity of seizures induced by the intravenous, intraperitoneal, and subcutaneous routes of administration of PTZ. Morphine also caused an increased incidence of multiple seizures following subcutaneous administration of PTZ. These results demonstrate that morphine has a proconvulsant effect on PTZ-induced seizures in the rat.

Animals↗
PubMed1984

Quantitative histochemical measurement of GABA-transaminase: method for evaluation of intracerebral lesions produced by excitotoxic agents.

GABA-transaminase (GABA-T) activity of fresh frozen coronal sections through rat striatum was evaluated 4-6 weeks after intrastriatal application of kainic or ibotenic acid. 16 micrograms sections were processed for GABA-T histochemistry and were evaluated quantitatively by computerized densitometry using image analysis. Alternate sections (200 micrograms) were assayed for GABA-T activity in vitro. Gross examination of sections stained for GABA-T revealed obvious lack of staining in the vicinity of lesions produced by either kainate (0.5-1.0 micrograms) or ibotenate (10-20 micrograms); the extent of each lesion was clearly delineated by the stain. Quantitative analysis of stained sections revealed that the lesioned tissue contained 80-90% less GABA-T activity than control tissue. This loss of GABA-T was in agreement with values obtained in adjacent sections assayed in vitro. Similar studies in substantia nigra clearly and quantitatively demonstrated damage induced by ibotenate or kainate in this nucleus as well as in tissue in the overlying reticular formation. Moreover, two compartments of GABA-T were discriminated in substantia nigra: one associated with neural perikarya, which was sensitive to kainic and ibotenic acids (80% of total GABA-T), and a second associated with afferent terminals arising from forebrain projections (20%). Thus, after destruction of neurons with kainic or ibotenic acid, GABA-T activity is largely eliminated. Under these conditions, it appears that glia contribute relatively little to the GABA-T activity measured either histochemically or by direct chemical assay in homogenates.

4-Aminobutyrate Transaminase↗
PubMed1984

Circling behavior elicited from the pedunculopontine nucleus: evidence for the involvement of hindbrain GABAergic projections.

Unilateral microinjection of GABA agonists into the pedunculopontine nucleus (PPN) of the rat resulted in contraversive postural asymmetry and circling behavior; GABA antagonists caused ipsiversive asymmetry and circling when applied to the PPN. A hemitransection was placed immediately caudal to substantia nigra (SN) and rostral to PPN in order to interrupt all connections between the PPN and ipsilateral forebrain nuclei. After hemitransection, microinjection of GABAergic drugs into the PPN on the hemitransected side produced postural asymmetry and circling identical to that observed in intact rats. The hemitransection resulted in a loss of glutamic acid decarboxylase activity in PPN (25%) not substantially greater than that observed in animals with unilateral destruction of SN, indicating that a major proportion of GABA terminals in PPN are derived from hindbrain sources. It appears that forebrain (that is, nigrotegmental) GABAergic projections are not essential for the GABA-mediated asymmetry elicited from PPN.

Animals↗
PubMed1984

Evidence that nigral substance P controls the activity of the nigrotectal GABAergic pathway.

The unilateral intranigral application of either of two substance P (SP) analogs with antagonist properties ( [DPro2,D-Phe7,D-Trp9]-SP and [D-Pro2,D-Trp7,9]-SP) induced a significant (37%) decrease in GABA turnover in the target region of the nigrotectal projections, namely the deep layers of the superior colliculus in the homolateral hemisphere, and was without any effect in the superficial layers. This action was not prevented by coinjection of the GABA antagonist bicuculline-methiodide. There was no effect of these SP analogs on GABA turnover in the deep layers of superior colliculus when they were microinjected in the ipsilateral median forebrain bundle or in the contralateral substantia nigra. These results are consistent with the proposal that nigral SP exerts a tonic excitatory action on efferent GABAergic projections from pars reticulata of substantia nigra.

Animals↗
PubMed1984

Binding of [3H]gamma-vinyl-GABA to GABA-transaminase in brain homogenates.

[3H]Gamma-vinyl-GABA, an irreversible inhibitor of GABA-transaminase, was used to label the enzyme in homogenates of rat brain. The binding procedure utilized was found to be specific for GABA-transaminase and linear with tissue obtained from several regions of rat brain up to concentrations of 8 micrograms protein/microliter. The specific binding was directly proportional to the activity of the enzyme measured in vitro and was completely inhibited by the GABA-transaminase inhibitors aminooxyacetic acid (100 microM) and 3-mercaptopropionic acid (1.0mM). The binding procedure was used to estimate the amount of active enzyme present in a homogenate of striatal tissue.

3-Mercaptopropionic Acid↗
PubMed1984

Intranigral application of substance P antagonists prevents the haloperidol-induced activation of striatal tyrosine hydroxylase.

The effect of intranigral injections of stable substance P analogs with antagonist properties, namely [D-Pro2, D-Trp7,9]-substance P and [D-Pro2, D-Phe7, D-Trp9]-substance P, on the activity of the nigrostriatal dopaminergic pathway was studied. Dopaminergic neural activity was evaluated by measuring changes in striatal tyrosine hydroxylase activity in response to systemic treatment with haloperidol. When injected into the substantia nigra of normal rats, neither of the two substance P analogs influenced the Vmax of striatal tyrosine hydroxylase or the affinity of the enzyme for its pteridine cofactor. However, when applied into the substantia nigra 10 min before systemic haloperidol, 20 micrograms of either substance P analog was able to prevent the haloperidol-induced activation of striatal tyrosine hydroxylase. The effect was not altered by concurrent microinjection of the GABA-antagonist bicuculline. These results suggests that nigral substance P plays an important role in the activation of nigrostriatal dopamine neurons produced by haloperidol. Thus, both substance P and GABA may reciprocally and independently regulate the activity of nigrostriatal dopamine neurons in response to changes in dopamine receptor activity.

Animals↗
PubMed1983

Morphine potentiates seizures induced by GABA antagonists and attenuates seizures induced by electroshock in the rat.

In a naloxone-reversible, dose-dependent manner, morphine (10-50 mg/kg i.p.) protected against seizures induced by maximal electroshock and increased the incidence and severity of seizures induced by bicuculline, in rats. Morphine also potentiated seizures induced by isoniazid and by picrotoxin. Thus, opiate activity influences the expression of seizures in contrasting ways depending upon the mode of seizure induction. Since morphine consistently potentiated seizures induced by interference with GABA transmission, it appears that GABAergic systems may be of particular significance for the elucidation of the varied effects of morphine on seizure susceptibility.

Animals↗
PubMed1983

Evidence that the nigrotegmental GABAergic projection mediates stereotypy induced by apomorphine and intranigral muscimol.

The substantia nigra plays a pivotal role in the relay of output from the striatum. One neural pathway from substantia nigra projects GABAergic fibers to the caudal mesencephalic tegmentum, terminating in the vicinity of the pedunculopontine nucleus (PPN). To evaluate the functional importance of this projection in the mediation of stereotyped behaviors of striatal and nigral origin, we microinjected low doses of the GABA agonist, muscimol, bilaterally into the vicinity of the PPN. This muscimol treatment resulted in a total blockade of all stereotyped behaviors normally elicited by systemic apomorphine or by intranigral muscimol. Blockade was not observed in animals microinjected with muscimol into the dorsal reticular formation, 1 mm above the level of the PPN. Our results indicate that the nigrotegmental projection may play a crucial role in the expression of stereotyped and dyskinetic behaviors of basal ganglia origin.

Animals↗
PubMed1983

Lesions of substantia nigra protect against experimentally induced seizures.

Bilateral lesions of substantia nigra (SN) were evaluated for anticonvulsant effects in rats. Electrolytic and kainic acid lesions of SN reduced bicuculline-elicited seizure activity; lesions in the ventral midbrain tegmentum adjacent to SN were without an anticonvulsant effect. Lesions of SN also reduced the incidence and duration of tonic hindlimb extension in the maximal electroshock seizure test. Bilateral SN lesions appeared to decrease seizure susceptibility to a given stimulus intensity rather than altering the motor pattern of the seizures. Our results support the view that SN efferents constitute a critical gating mechanism in the propagation of seizure activity.

Animals↗
PubMed1983

Effect of dopamine agonists on gamma-aminobutyric acid (GABA) turnover in the superior colliculus: evidence that nigrotectal GABA projections are under the influence of dopaminergic transmission.

The effect of dopamine (DA)-mimetic drugs on the turnover rate of gamma-aminobutyric acid (GABA) in the superficial and deep layers of superior colliculus (SC) was studied. As an index of GABA turnover, the rate of accumulation of GABA was measured after irreversible inhibition of GABA-transaminase by gamma-vinyl-GABA, microinjected directly into SC. The rate of GABA accumulation in the deep layers of SC decreased by 30 to 45% after systemic administration of apomorphine, amphetamine and cocaine. This effect of DA agonists was prevented by pretreatment with haloperidol. A similar decrease in the rate of GABA accumulation in the deep layers of SC was observed after microinjection of the GABA agonist, muscimol (0.4 nmol) directly into the substantia nigra. Nigral microinjection of the GABA antagonist bicuculline (1.0 nmol), which per se did not affect GABA accumulation in SC, antagonized the effect of apomorphine on GABA accumulation in the deep layers of SC. The results indicate that the nigrotectal GABAergic pathway which terminates in the deep layers of SC is subject to regulation by DA transmission. Furthermore, the effect of DA agonists on tectal GABA turnover is mediated via GABA release in SN. In the superficial layers of SC a small but significant decrease in GABA turnover was observed after apomorphine. In contrast to the effects observed in the deep layers of SC, this effect was not dependent on GABAergic transmission in substantia nigra, but was dependent upon the integrity of visual pathways.

Animals↗
PubMed1982

Substantia nigra: site of anticonvulsant activity mediated by gamma-aminobutyric acid.

Localization of the anatomic substrate for anticonvulsant activity mediated by gamma-aminobutyric acid (GABA) was examined using intracerebral injections of GABA agonists. Blockade of tonic hindlimb extension in the maximal electroshock test and blockade of tonic and clonic seizures produced by pentylenetetrazole and bicuculline were obtained by elevating GABA in the ventral midbrain tegmentum. Elevation of GABA in forebrain and hindbrain areas had no effect on convulsant activity. Blockade of tonic and clonic seizures was also obtained after microinjections of the direct GABA receptor agonist, muscimol, into the midbrain. The substantia nigra was identified as the critical midbrain site for GABA-mediated anticonvulsant activity. Local injection of GABA agonists into the midbrain provided seizure protection without a widespread augmentation of GABA-mediated activity throughout the brain and without impairing either alertness or motor function. Synapses in the substantia nigra appear to represent an important control mechanism for inhibiting the propagation of generalized convulsions.

Animals↗
PubMed1982

Evidence for GABA receptors on serotonergic afferent terminals in the substantia nigra and on nigral efferent projections to the caudal mesencephalon.

Changes in [3H]GABA binding in rat substantia nigra (SN) were examined after (1) hemitransections at various levels posterior to SN and (2) 5, 7-dihydroxytryptamine (5, 7-DHT) induced lesions of the dorsal or median raphe or SN. Hemitransections 2 mm caudal to SN resulted in a 52% decrease in specific high affinity [3H] GABA binding in SN when measured 2-3 weeks postoperatively. No significant change in nigral GABA binding was found in rats with hemitransections placed at a postcollicular level(through the rostral pons). 5, 7-DHT placements in median raphe, or directly into SN, caused a 27% decrease in specific [3H] GABA binding in SN. 5, 7-DHT lesions of the dorsal raphe did not significantly affect the binding of [3H]GABA in SN. These data suggest that a significant protion of GABA receptors in SN may be located presynaptically on axon terminals of serotonergic projections from the median raphe to SN. Other pathways between the SN and the caudal mesencephalon also appear to contain GABA receptors; these are likely to be efferent nigral projections to the mesencephalic reticular formation.

Afferent Pathways↗