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Biomedical subjects

G D Frye

Publications and source records attributed to G D Frye.

At least 55 records · Page 3Linked to original sources
PubMed1984

Comparison of the CNS effects induced by TRH and bicuculline after microinjection into medial septum, substantia nigra and inferior colliculus: absence of support for a GABA antagonist action for TRH.

Antagonism of ethanol-induced depression of locomotion was observed after intracisternal injection of thyrotropin releasing hormone (TRH) and bicuculline methiodide (BICM), as well as after microinjection of these drugs into the medial septum. The present investigation compared the behavioral and physiological consequence of administering TRH and BICM into the medial septum, inferior colliculus and substantia nigra to quantitate the similarities between these compounds. BICM produced a major increase in locomotor activity when injected into the medial septum and stereotypies when injected into the substantia nigra, suggesting that GABA-containing neurons have widespread influences on motor function. The wild running and seizure activity observed after BICM injection into the inferior colliculus was also consistent with this latter view. The marked increase in rectal temperature observed when BICM was injected into the medial septum may also implicate GABAergic mechanisms in temperature control at this brain site. TRH produced no such behavioral or physiological changes when administered into these three sites. Thus, this work strongly suggests that TRH does not exert a widespread action as a GABA antagonist because TRH did not produce the same changes induced by BICM. The actions of BICM and TRH to antagonize ethanol-induced depression when microinjected into the medial septum suggests that this brain area may be a critical site for the depressant action of ethanol.

Animals↗
PubMed1984

Neonatal-6-hydroxydopamine treatment: model of susceptibility for self-mutilation in the Lesch-Nyhan syndrome.

Neonatal-6-OHDA treated rats given L-DOPA after a decarboxylase inhibitor showed a high incidence of self-mutilation behavior (SMB) and self-biting. These behaviors were not observed in adult-6-OHDA-treated rats or in controls. Since inhibition of dopamine-beta-hydroxylase did not prevent or inhibit the SMB exhibited in neonatal-6-OHDA-treated rats after L-DOPA, norepinephrine is not likely to be contributing to this response. The age dependent effects observed are consistent with the hypothesis that neonatal reduction of dopamine-containing fibers is responsible for the SMB susceptibility observed in Lesch-Nyhan disease, making the neonatal-6-OHDA-treated rat a model of this neurological syndrome.

Age Factors↗
PubMed1984

Behavioral differences between neonatal and adult 6-hydroxydopamine-treated rats to dopamine agonists: relevance to neurological symptoms in clinical syndromes with reduced brain dopamine.

Administration of L-dopa or apomorphine to neonatal and adult 6-hydroxydopamine (6-OHDA)-treated rats resulted in different behavioral responses depending on the age at which dopaminergic fibers were destroyed. When neonatal 6-OHDA-treated rats were tested as adults, they exhibited marked stereotypies, self-biting and self-mutilation behavior (SMB) when given these dopamine agonists. Self-biting as well as the incidence of SMB in neonatal 6-OHDA-treated rats showed dose-related changes between 10 and 100 mg/kg of L-dopa. This SMB and self-biting after L-dopa was observed as early as 22 to 24 days of age. Adult 6-OHDA-treated rats did not exhibit SMB or self-biting to L-dopa (100 mg/kg) or apomorphine (10 mg/kg), but did display paw treading and head nodding--behaviors not observed in neonatal 6-OHDA-treated rats. In addition, the locomotor response to apomorphine (1 mg/kg) was significantly greater in adult 6-OHDA-treated rats than in neonatal 6-OHDA-treated rats. Brain dopamine was reduced markedly in striatum, nucleus accumbens and olfactory tubercles in both 6-OHDA treatment groups with the reduction being slightly greater in rats treated with 6-OHDA neonatally. Serotonin content was elevated in striatum of rats treated neonatally with 6-OHDA, but not in adult 6-OHDA-treated rats. SMB and behaviors observed after L-dopa in rats treated neonatally with 6-OHDA were not apparent after L-dopa in rats with brain serotonin or norepinephrine reduced. Rats with brain dopaminergic fibers destroyed neonatally exhibited self-biting and SMB after L-dopa, suggesting that neonatal reduction of this amine is responsible for the SMB and self-biting in neonatal 6-OHDA-treated rats. 5-Hydroxytryptophan administration to neonatal 6-OHDA-treated rats did not induce SMB, indicating that release of serotonin by L-dopa is not responsible for this behavior. Because inhibition of dopamine-beta-hydroxylase did not alter the SMB response to L-dopa observed in neonatal 6-OHDA-treated rats, norepinephrine synthesized from L-dopa does not appear to contribute to the response. High doses of a decarboxylase inhibitor sufficient to inhibit conversion of dopa to dopamine in brain did not reduce the incidence of SMB. Administration of haloperidol (1 mg/kg) reduced the incidence of SMB, but did not antagonize the self-biting or the taffy pulling exhibited by L-dopa. In contrast, cisflupentixol completely blocked the SMB and self-biting induced by L-dopa.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1984

Ethanol-induced locomotor stimulation in rats after thyrotropin-releasing hormone.

Ethanol-induced sedation in Sprague-Dawley rats was antagonized by intracisternally administered thyrotropin releasing hormone (TRH) at a dose as low as 1 microgram. Furthermore, when a dose of 25 micrograms or greater of TRH was combined with ethanol doses above 2 g/kg, the locomotor activity was significantly greater than observed for TRH alone. A dose-related increase in activity was observed when varying doses of ethanol were administered with a constant dose of TRH (100 micrograms). This increase in locomotion induced by the TRH-ethanol combination could not be attributed to a change in TRH concentration, ethanol distribution or to a pituitary action of TRH. Inasmuch as tert-butanol in combination with TRH produced the same effects as ethanol, the hyperactivity does not appear to be associated with acetaldehyde formation. TRH acid and His-Pro-diketopiperazine, metabolites of TRH, did not produce hyperactivity when administered with ethanol, whereas MK-771, a TRH analog, produced a significant increase in locomotion in ethanol-treated rats greater than that for MK-771 alone. Three lines of evidence suggested that the hyperactivity induced by the TRH-ethanol combination could not be attributed to an influence of ethanol on the stimulant effects of TRH. First, pentobarbital- and chlordiazepoxide-induced depression of locomotion was antagonized by TRH (100 micrograms) but, unlike ethanol, locomotor stimulation greater than that for TRH was not observed. Second, behavioral observations did not reveal ethanol altering any effects of TRH that would compete with locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

The effects of neurotensin, beta-endorphin, and bombesin on ethanol-induced behaviors in mice.

The effects of the three peptides neurotensin, beta-endorphin, and bombesin on ethanol-induced behaviors were studied in mice. Intracisternal administration of these peptides to mice prolonged the duration of sleep induced by ethanol (5.2 g/kg). Neurotensin and beta-endorphin also enhanced ethanol-induced hypothermia. None of the peptides, when administered alone, produced sleep. However, all three compounds impaired the aerial righting reflex and induced sleep when followed by an IP dose of ethanol (3.5 g/kg), which alone did not induce sleep. These results, taken together with previous findings, suggest that neuropeptides may be involved in the complex mechanisms of action of ethanol on the CNS.

Animals↗
PubMed1983

Effects of postnatal trimethyltin or triethyltin treatment on CNS catecholamine, GABA, and acetylcholine systems in the rat.

The effects on brain neurochemistry of two neurotoxic tin compounds, trimethyltin (TMT) hydroxide and triethyltin (TET) sulfate, were examined. Long-Evans rats were treated with TMT hydroxide (1 mg/kg, i.p.) on alternate days from day 2 to 29 of life. These treatments caused a weight deficit of 10-20% by the time the animals were killed on day 55 by head-focused microwave irradiation. These TMT treatments are known to cause severe neuronal loss in the hippocampus and lesser damage in other brain regions. Accordingly, the concentration of gamma-aminobutyric acid (GABA) was decreased in the hippocampus; however, acetylcholine and choline concentrations were unaffected. These data suggest that TMT-induced effects on GABA systems are greater than that due simply to generalized neuronal loss. The TMT treatments also caused a significant decrease in dopamine concentrations in the striatum, but did not alter the concentrations of dihydroxyphenylacetic acid or homovanillic acid, the acidic metabolites of dopamine. Conversely, concentrations of dopamine and norepinephrine in the brain stem and norepinephrine in the cerebellum were not altered. Despite reports in the literature of TMT-induced neuronal damage in areas of the cortex, no effects on GABA, acetylcholine, or choline levels were found in the cortical areas examined, or in the hypothalamus. TET sulfate (0.3 mg/kg/day) was administered for 6 consecutive days of every week during days 2-29 of life. This dose is lower than that needed to cause intramyelin edema, yet it does result in long-term behavioral changes. Despite this, no changes in the concentration of any of the measured neurotransmitters or their metabolites were detected. In concert, these data demonstrate that neurochemical methods should not be used as neurological "screens," but rather to define specific mechanisms suggested by detailed behavior, pharmacological, and/or physiological studies.

Acetylcholine↗
PubMed1983

Differential sensitivity of ethanol withdrawal signs in the rat to gamma-aminobutyric acid (GABA)mimetics: blockade of audiogenic seizures but not forelimb tremors.

Intraperitoneal injection of ethanol (1-2 g/kg) and chlordiazepoxide (2-16 mg/kg) suppressed susceptibility to audiogenically induced, clonic-tonic seizures and antagonized forelimb tremor in rats undergoing ethanol withdrawal, 30 min after treatment. However, a smaller dose of ethanol (0.5 g/kg) actually increased clonic seizure frequency, suggesting that ethanol exerts a biphasic proconvulsant/anticonvulsant action. Direct activation of gamma-aminobutyric acid (GABA) receptors by intracisternal administration of GABA (100-1000 micrograms), muscimol (0.3-1.0 micrograms) or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) (0.3-3.0 micrograms) 5 to 10 min before testing also reduced susceptibility to audiogenic clonic-tonic seizures. In sharp contrast to these anticonvulsant actions, GABA, muscimol and THIP had no effect on withdrawal-induced forelimb tremors. Blockade of GABA uptake with 1-2,4-diaminobutyric acid (300 and 600 mg/kg i.p.) and inhibition of GABA transaminase with aminooxyacetic acid (12.5 and 25.0 mg/kg i.p.) both reduced susceptibility to seizures. However, anticonvulsant doses of these two drugs, unlike GABA, muscimol and THIP, also reduced forelimb tremor. Three other GABA transaminase inhibitors, gamma-vinyl GABA (450 and 900 mg/kg i.p.), gamma-acetylenic GABA (50-150 mg/kg i.p.) and ethanolamine-O-sulfate (250-750 mg/kg i.p.), were inactive against ethanol withdrawal audiogenic seizures and forelimb tremors. These results indicate that direct GABA receptor activation can selectively suppress one type of ethanol withdrawal response (i.e., audiogenic seizure susceptibility) while failing to influence another (forelimb tremors).

4-Aminobutyrate Transaminase↗
PubMed1983

Characterization of susceptibility to audiogenic seizures in ethanol-dependent rats after microinjection of gamma-aminobutyric acid (GABA) agonists into the inferior colliculus, substantia nigra or medial septum.

The relative anticonvulsant potential of the gamma-aminobutyric acid (GABA) agonist, muscimol, was compared after microinjection into either the inferior colliculus, substantia nigra or medial septum of ethanol-dependent rats. Bilateral microinjection of muscimol (10-30 ng) into the inferior colliculus 15 to 60 min before testing suppressed all sound-induced seizure components (wild running, clonus and tonus) in rats withdrawn from ethanol for 6.5 to 8.5 hr. However, forelimb tremors were not altered. Audiogenic seizures were suppressed for at least 3 hr after muscimol (30 ng). In the medial septum and substantia nigra, microinjection of muscimol (30-100 ng) only partially reduced the tonic component of audiogenic seizures and exerted no effect on the frequency of wild running or clonus. GABA (10 micrograms) and two other GABA agonists [4,5,6,7-tetrahydroisoxazolo[5, 40c]pyridin-3-ol (THIP), 300 ng and chlordiazepoxide, 10-30 micrograms], microinjected into the inferior colliculus, also reduced audiogenic seizure susceptibility. However, 1, 3-butanediol, which suppresses ethanol withdrawal seizures after peripheral administration in rats, was inactive. The relative proconvulsant potential of the GABA antagonist, bicuculline methiodide, also was compared after microinjection into either the inferior colliculus, substantia nigra or medial septum of ethanol naive rats. In each animal, audiogenic seizure-like wild running, clonus and tonus were evoked by microinjecting bicuculline methiodide into the inferior colliculus at the rate of 6.0 ng/6 min. However, these reactions did not occur when bicuculline methiodide was applied at a slower rate (1.8 ng/6 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1983

Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies.

Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.

Adenylyl Cyclases↗
PubMed1982

Evidence of a toxic effect of ethanol on bone in rats.

Tibiae from rats treated chronically for 12 days with enough ethanol to induce physical dependence were found to have an increased incidence of fracture during dissection and cleaning (7 of 12 or 58%) compared to control animals (1 of 12 or 8%). The site of the fractures, the proximal end of the tibia, showed an increased opacity to X-rays, and the dried bones were distinctly darker in appearance than similarly prepared control bones. The effects noted in our study suggest that the rat model could be useful for the study of the mechanisms by which alcohol affects bone growth, remodeling, and strength. These studies might shed new light on the pathogenesis of increased bone fragility in alcoholics.

Alcohol Drinking↗
PubMed1982

GABAergic modulation of ethanol-induced motor impairment.

Direct or indirect pharmacological manipulation of gamma-aminobutyric acid (GABA) receptor activity was examined in relation to the motor incoordinating actions of ethanol in the rat. Ethanol (1.13-3.0 g/kg i.p.) caused a dose-dependent increase in the height of aerial righting. This motor impairment was increased selectively by intracisternal injection of the GABA agonists muscimol (0.10 microgram), 4,5,6,7-tetrahydroisoxazole(5,4-c) pyridin(3-ol) (1.0 microgram) and GABA (1000 micrograms). The GABA antagonist, bicuculline (1.0 and 5.0 micrograms intracisternally), reduced impairment. Thus, direct manipulation of GABA receptor activity modulated motor incoordination caused by ethanol. In addition, indirect-acting GABA-mimetics, such as gamma-acetylenic GABA (100 mg/kg i.p.), aminooxyacetic acid (50 mg/kg i.p.), ethanolamine-O-sulfate (250 mg/kg i.p.) and L-2,4-diaminobutyric acid (600 mg/kg i.p.) all potentiated the increase in the height of aerial righting caused by ethanol treatment. Failure of ethanol to modify the binding of [3H]muscimol to cerebral cortical membranes in vitro suggested there was no direct competition for GABA binding sites or facilitation of the binding of GABA to these sites by ethanol. Also, no simple relationship was observed between the degree of motor impairment caused by either ethanol or gamma-acetylenic GABA and changes in GABA concentration in three brain areas. Although GABAergic neurons may be involved in the mechanism underlying ethanol-induced depression of motor coordination, the interaction does not involve a direct activation of GABA receptors by ethanol.

4-Aminobutyrate Transaminase↗
PubMed1981

Behavioral and biochemical studies of the scopolamine-induced reversal of neuroleptic activity.

Scopolamine reversed the reduction in avoidance responding caused by spiperone and antagonized the inhibitory effects of spiperone on the behavioral actions of d-amphetamine or apomorphine. Scopolamine-induced locomotor activity was greater in 6-hydroxydopamine (6-OHDA)-treated animals than in controls. This increase was prevented by administration of alpha-methyltyrosine, but not by inhibition of dopamine-beta-hydroxylase, indicating that this action of scopolamine was associated with presynaptic dopaminergic fibers. Therefore, the possibility that pre-synaptic dopaminergic function was the locus of the antagonism of spiperone by scopolamine was examined using drug interaction studies in 6-OHDA-treated rats. However, when 6-OHDA-treated rats were given alpha-methyltyrosine, scopolamine still reversed the spiperone blockade of apomorphine-induced locomotion. Although these data provided evidence for a post-synaptic action for this cholinergic blocking agent, scopolamine affected neither dopamine-stimulated adenylate cyclase activity nor 3H-spiperone binding in vitro. Furthermore, scopolamine did not alter the level of specific 3H-spiperone binding found in brain after in vivo administration. This suggests that the post-synaptic mechanism affected by scopolamine is different from the site affected by spiperone. Thus, it is concluded that scopolamine can affect both pre- or post-synaptic events associated with dopaminergic function and that both may contribute to the reversal of the actions of spiperone.

Adenylyl Cyclases↗
PubMed1981

An evaluation of the locomotor stimulating action of ethanol in rats and mice.

The locomotor activity of groups of three CD-1 female mice was increased by 1.0 and 2.0 g/kg ethanol, IP, was decreased during the first hour and increased during the second hour by 3.0 and 4.0 g/kg, and was decreased by 5.0 g/kg. The dose (2.0 g/kg) that caused the greatest increase in locomotor activity did not impair motor coordination, measured by the height of aerial righting in mice. Tests after oral administration of ethanol showed that the increase in locomotor activity of mice was not due to peritoneal irritation. The same dose (2.0 g/kg) did not increase the locomotor activity of C57BL/6J mice. Ethanol (0.1 to 3.0 g/kg) had no effect or decreased the locomotor activity of individual male Sprague-Dawley rats. These findings suggest that biological differences in strains and species of laboratory rodents contribute to the apparent variability of locomotor stimulation caused by ethanol. The presence or absence of an ethanol-induced increase in locomotor activity was not dependent on the sex or number of mice or rats tested. Intertrial-interval crossing by rats acquiring or performing an active avoidance task in a shuttle box was increased by ethanol. This action was dependent on the presentation of electric foot shock. Apomorphine (0.25 and 2.5 mg/kg) and fenmetozole (7.5 and 15.0 mg/kg) failed to inhibit the ethanol-induced increase in intertrial-interval crossing by rats, although these drugs have been shown previously to antagonize the ethanol-induced increase in the activity of mice ethanol treatment. The ethanol-induced increases in the spontaneous locomotor activity of CD-1 mice in photocell activity monitors and in intertrial-interval crosses in rats in a shuttle box task thus do not appear to share a common mechanism.

Animals↗
PubMed1981

Modification of the actions of ethanol by centrally active peptides.

Ethanol (2.0-5.0 g/kg, IP) caused a dose-related impairment of the aerial righting reflex of mice 60 min after injection. Ethanol (3.5 g/kg, IP) given simultaneously with neurotensin (30 micrograms, IC), bombesin (30 micrograms, IC) or beta-endorphin (20 micrograms, IC) caused a greater impairment of the reflex than ethanol alone. Simultaneous treatment with ethanol (4.0 g/kg, IP) and thyrotropin-releasing hormone (TRH, 3.0-30 micrograms, IC) caused less impairment of this measure than ethanol alone. None of the peptides altered the height of aerial righting when administered alone, or when administered with ethanol no peptide altered blood or brain ethanol content. Unexpectedly, TRH (20 and 40 mg/kg, IP) potentiated the action of ethanol by increasing punished licking in water-deprived rats, rather than antagonizing this acute action of ethanol. Like ethanol (1.0 and 2.0 g/kg, IP), beta-endorphin (100 micrograms, IC) suppressed ethanol-withdrawal tremor and audiogenic-seizure susceptibility in ethanol-dependent rats. beta-Endorphin (1 microgram) and bombesin (10 and 30 micrograms, IC) reduced only audiogenic-seizure susceptibility. TRH (10-100 micrograms, IC, or 1-40 mg/kg, IV) and neurotensin (10-100 micrograms, IC) had no effect on these ethanol-withdrawal signs. These findings suggest that centrally active peptides may play a role in certain acute and chronic actions of ethanol. Because TRH, neurotensin, bombesin and beta-endorphin do not alter all actions of ethanol in the same way, an interaction of ethanol with many functionally independent neuronal circuits is suggested.

Animals↗
PubMed1981

Differential effects of TRH, amphetamine, naloxone, and fenmetozole on ethanol actions: attenuation of the effects of punishment and impairment of aerial righting reflex.

The effects of four putative ethanol antagonists [thyrotropin releasing hormone (TRH), naloxone, d-amphetamine, and fenmetozole] on two distinct behavioral actions of ethanol were compared. TRH (20-40 mg/kg) reduced ethanol-induced impairment of the aerial righting reflex (ARR) but enhanced the ethanol-induced increase in punished drinking (anticonflict effect). Naloxone antagonized both actions of ethanol but only at high doses (20-60 mg/kg). Amphetamine (1-4 mg/kg) abolished the ethanol effect on punished drinking but did not alter its impairment of the ARR (1-8 mg/kg). Conversely, fenmetozole antagonized the ethanol impairment of the ARR (15-30 mg/kg) but not ethanol's anticonflict action. The inconsistent pattern of "antagonist" interactions of these drugs with the behavioral actions of ethanol suggests that ethanol alters several neurochemical systems to produce its behavioral effects.

Amphetamine↗
PubMed1981

Effects of TRH on central nervous system function.

Evidence has been reviewed which strongly suggests that TRH functions as a neurotransmitter or neuromodulator in the mammalian central nervous system. Both the peptide and its receptor sites are located in the brain. Furthermore, it has protein actions to modify the effects of many neuropharmacological agents and can itself cause alterations in functions mediated by the CNS. Data clearly indicate that many of these actions. of TRH are not dependent on the pituitary- thyroid axis. Various studies of neurotransmitter interactions with TRH have provided evidence that noradrenergic, serotonergic, GABAergic, and cholinergic systems may be influenced by TRH or mediate some of its actions. More than likely, other transmitters will be implicated as the complex actions of TRH are more thoroughly investigated and understood. One set of experiments suggested that TRH may be localized serotonergic fibers. Such findings provide strong support for the view that TRH has a role in the physiology of the CNS. In spite of the progress that has been made, there are several questions to be answered about mechanisms of synthesis, storage, release, and inactivation of TRH. Furthermore, physiological studies would be greatly facilitated if a specific antagonist of TRH actions were available. Controversy still exists about active forms of TRH in situ and the methods by which TRH can be measured in tissue. Future investigations which resolve these difficulties and questions should facilitate our understanding of the role of TRH in brain function and its complex interactions with other neural mechanisms.

Animals↗