Gerald D. Frye

Electrically elicited seizures from the inferior colliculus: A potential site for the genesis of epilepsy?

Most electrically induced seizures involve forebrain structures, such as the amygdala or frontal cortex, but the following studies characterized a specific anatomic site in the inferior colliculus which generated seizure-like behavior after a single, low current electrical stimulation. When a bipolar electrode was implanted into the dorsomedial aspect of the inferior colliculus, low stimulation currents (120 to 200 microA, 30 Hz) produced wild running behavior which outlasted the stimulation by 4 to 10 s. This wild running behavior was directly correlated with local afterdischarge in the inferior colliculus, while no changes were found in the EEG activity in the cortex or hippocampus. Though the threshold current necessary to invoke the wild running seizures remained stable for long periods of time, the presentation of two stimulations a day for 2 weeks caused a progressive increase in the duration of poststimulus wild running. In the last days of the chronic stimulations, some forelimb tonus or myoclonic jerks followed the wild running seizures. These latter behaviors were correlated with local afterdischarges at the electrode tips in the inferior colliculus and spiking EEG activity in the frontal cortex. Pharmacologically, haloperidol, phenobarbital, carbamazepine, and ethosuximide proved ineffective in attenuating the seizures, whereas phenytoin, sodium valproate, and chlordiazepoxide attenuated the seizures. These findings are discussed in relation to the genesis of epilepsy in humans.

The biochemical basis of the behavioral disorder in the Lesch-Nyhan syndrome.

An inherited complete deficiency of hypoxanthine-guanine phosphoribosyltransferase in male children is associated with a severe neurological disorder characterized by chloroform and athetoid movements, hypertonicity, mental retardation, and self-injurious behavior. In the review that follows several possible mechanisms by which the enzyme defect may cause the CNS disorder are discussed. Current evidence suggests that the primary neural deficit in the Lesch-Nyhan syndrome is a deficiency of dopamine in the basal ganglia. It is argued that this neurochemical lesion results from a deficiency of purine nucleotides which impairs arborization of nigrostriatal neurons during perinatal development. Differences in the ontogenetic timing of the neurochemical lesion may be partly responsible for the different neurological symptoms displayed by persons afflicted with the Lesch-Nyhan and Parkinsons syndromes.

Acute tolerance to ethanol inhibition of NMDA-mediated EPSPs in the CA1 region of the rat hippocampus

The time course of ethanol-induced inhibition of NMDA-mediated synaptic activity was studied in brain slices using extracellular electrophysiological techniques in the CA1 region of the hippocampus. Bath application of 60 mM ethanol inhibited NMDA-mediated field excitatory postsynaptic potentials (EPSPs) by at least 45% in 7/11 of the slices tested, with the remaining 4 slices inhibited by 8.7-35%. Most slices inhibited by at least 45% showed a significant reduction in ethanol inhibition over a 15 min ethanol exposure period, suggesting the development of acute tolerance. In a second set of experiments, tolerance to ethanol-induced inhibition of NMDA-mediated EPSPs that developed over time during the first ethanol exposure persisted during a second ethanol exposure. In contrast to ethanol, inhibition of EPSPs by the NMDA antagonist DL-2-amino-5-phosphonopentanoic acid (APV) remained stable during a comparable application of the drug. These results suggest that acute tolerance can develop to ethanol inhibition of NMDA mediated synaptic activity in the hippocampus.

Effects of combined lead and cadmium exposure: changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites

Adult male rats were maintained on 1 of 4 ad-lib diets: Group Control-Diet received a normal laboratory diet that contained no added chemicals: Group Lead-Diet received a diet containing 500 ppm (parts per million) lead: Group Cadmium-Diet received a diet containing 100 ppm cadmium: and Group Lead-Cadmium-Diet received a diet containing both 500 ppm lead and 100 ppm cadmium. After 60 days of exposure to their respective diets, animals were placed on restricted diets (15 g/day) of the identical food received during the exposure period. Each animal was trained to lever press on a fixed-interval 1-min schedule for 21 sessions (1 session day). The results of schedule training showed that lead alone or cadmium alone was associated with increased lever pressing relative to control diet. However, when lead and cadmium were exposed jointly, performance was not significantly different from control performance. Similar attenuation of effects were observed for central neurotransmitter functions. Specifically disturbances in dopamine and serotonin turnover that were produced by lead alone were attenuated by the cotreatment of cadmium and lead. Possible accounts of the apparent antagonism between cadmium and lead are discussed.

Effects of Chronic Ethanol Consumption on Rat GABAA and Strychnine-sensitive Glycine Receptors Expressed by Lateral/Basolateral Amygdala Neurons

It is well known that the anxiolytic potential of ethanol is maintained during chronic exposure. We have confirmed this using a light-dark box paradigm following chronic ethanol ingestion via a liquid diet. However, cessation from chronic ethanol exposure is known to cause severe withdrawal anxiety. These opposing effects on anxiety likely result from neuro-adaptations of neurotransmitter systems within the brain regions regulating anxiety. Recent work highlights the importance of amygdala ligand-gated chloride channels in the expression of anxiety. We have therefore examined the effects of chronic ethanol exposure on GABA(A) and strychnine-sensitive glycine receptors expressed by acutely isolated adult rat lateral/basolateral amygdala neurons. Chronic ethanol exposure increased the functional expression of GABA(A) receptors in acutely isolated basolateral amygdala neurons without altering strychnine-sensitive glycine receptors. Neither the acute ethanol nor benzodiazepine sensitivity of either receptor system was affected. We explored the likelihood that subunit composition might influence each receptors response to chronic ethanol. Importantly, when expressed in a mammalian heterologous system, GABA(A) receptors composed of unique alpha subunits were differentially sensitive to acute ethanol. Likewise, the presence of the beta subunit appeared to influence the acute ethanol sensitivity of glycine receptors containing the alpha(2) subunit. Our results suggest that the facilitation of GABA(A) receptors during chronic ethanol exposure may help explain the maintenance of ethanols anti-anxiety effects during chronic ethanol exposure. Furthermore, the subunit composition of GABA(A) and strychnine-sensitive glycine receptors may ultimately influence the response of each system to chronic ethanol exposure.

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.

Effects of (±)3,4-methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats

Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidols effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.

Self-injurious behavior in rats produced by intranigral microinjection of GABA agonists ☆

Bilateral injection of the GABA agonist muscimol (10-300 ng) into the caudal substantia nigra (pars reticulata) of rats produced dose-dependent stereotyped gnawing and self-biting. Limiting the opportunity to gnaw on inanimate objects shifted the dose-response curve for muscimol-induced self-injurious behavior (SIB) to the left and increased the maximum incidence of SIB. Microinjection of muscimol (30 ng) into the rostral and caudal regions of the substantia nigra were equally effective in producing SIB, though the incidence of SIB decreased sharply when muscimol was injected 1 mm rostral or caudal to the substantia nigra. Bilateral intranigral injection of THIP (100-1000 ng) and (+/-)baclofen (100-1000 ng) induced a low incidence of SIB. However, neither IP administration of picrotoxin (5 mg/kg) or simultaneous microinjection of (+)bicuculline methiodide (BMI; 300 or 1000 ng) along with muscimol (30 ng) blocked muscimol-induced SIB. In fact, (+)BMI increased the occurrence of self-biting and reduced the latency to onset of SIB. The involvement of GABAergic mechanisms in muscimol-induced SIB is discussed.

Involvement of the midbrain reticular formation in self-injurious behavior, stereotyped behavior, and analgesia induced by intranigral microinjection of muscimol.

Bilateral microinjection of muscimol (60 ng), a gamma-aminobutyric acid (GABA) agonist, into the central region of the substantia nigra (pars reticulata) produced self-injurious behavior (SIB), stereotyped behavior and analgesic-like effects in rats. Bilateral electrolytic lesions of the midbrain reticular formation ventrolateral to the periaqueductal gray matter completely blocked the SIB but had little effect on stereotyped behavior produced by intranigral muscimol. Lesions of the midbrain reticular formation reduced the antinociceptive effect of intranigral muscimol on the tail-flick but not on the hot-plate test. Bilateral microinjection of muscimol (10-100 ng) into the midbrain reticular formation produced intense stereotyped behavior and had an analgesic-like effect on the hot-plate test but not on the tail-flick test. Stereotyped behavior appeared to interfere with the paw-lick response on the hot-plate test. These data suggest that the antinociceptive effect of intranigral muscimol on the tail-flick test is mediated by fibers that project to or pass through the midbrain reticular formation and that analgesia may play an important role in muscimol-induced SIB. The midbrain reticular formation does not appear to be involved in the stereotyped behavior produced by intranigral muscimol.

Sustained ethanol inhibition of native AMPA receptors on medial septum/diagonal band (MS/DB) neurons

The direct impact of ethanol on native, non‐NMDA glutamate receptors was examined in acutely isolated MS/DB neurons from rat. The impact of ethanol functional tolerance and physical dependence on non‐NMDA receptor function was also determined. Non‐NMDA receptors were defined pharmacologically as predominantly the AMPA subtype, because both AMPA‐ or kainate‐activated currents were blocked by GYKI 52466, a selective AMPA receptor antagonist. The relative magnitude of potentiation of AMPA‐activated currents by 10 or 100 μM cyclothiazide was consistent with recombinant AMPA flop‐subtype receptors. Finally, the selective kainate receptor agonist, SYM 8021, induced little current in MS/DB neurons. AMPA receptor currents when activated by kainate were sensitive to ethanol, showing inhibition of ∼5–50% when 10–300 mM ethanol and kainate were briefly co‐applied (3 s). Ethanol (100 mM) also inhibited both the initial transient peak and sustained currents activated by AMPA. Inhibition was sustained during continuous ethanol superfusions of 5 min, suggesting a lack of acute tolerance to ethanol‐induced AMPA receptor blockade. Rapid application of 3–3000 μM kainate activated concentration‐dependent currents in MS/DB neurons from Control and Ethanol Dependent animals that were not significantly different. Also, direct ethanol inhibition (300 mM) of kainate‐activated currents was not reduced by ethanol dependence, suggesting a lack of functional tolerance. These results suggest that native AMPA receptors on MS/DB neurons are inhibited by pharmacologically‐relevant concentrations of ethanol. However, these receptors, unlike NMDA receptors, do not undergo adaptation with sustained ethanol exposure sufficient to induce physical dependence.