Mechanisms underlying the antidopaminergic effect of clonazepam and melatonin in striatum

Intrastriatal injection of the GABA_A antagonist, bicuculline, caused about a 75% decrease in the inhibitory effect of the central-type benzodiazepine (BZ) agonist, clonazepam or the indoleamine hormone, melatonin, on apomorphine-induced rotation in a 6-hydroxydopamine model of dopaminergic supersensitivity. Pretreatment with the peripheral-type BZ antagonist, PK 11195 (intrastriatally or intraperitoneally), also attenuated the antidopaminergic effect of these drugs but with much less potency than bicuculline. However, the combination of both bicuculline and PK 11195, injected directly into the striatum, completely blocked the antidopaminergic action of clonazepam or melatonin. These results indicate that the antidopaminergic action of clonazepam and melatonin in the striatum involves two distinct mechanisms: (1) a predominant GABAergic activation via the BZ/GABA_A receptor complex, and (2) a secondary mechanism linked to a PK 11195- sensitive BZ receptor pathway. Recent studies indicate that PK 11195 blocks BZ-induced inhibition of the adenylyl cyclase-cyclic AMP pathway in the striatum. Since cyclic AMP has been implicated in the rotational behaviour of 6-hydroxydopamine-lesioned animals, it is possible that the antidopaminergic action of clonazepam and melatonin also involves suppression of this second messenger. All rights reserved.     

Anticonvulsant effects of neurotropin

Department of Normal Physiology, N. I. Pirogov Odessa Medical Institute. Department of Normal Physiology, I. M. Sechenov First Moscow Medical Institute. Laboratory of General Pathology of the Nervous System, Research Institute of General Pathology and Pathophysiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 111, No. 1, pp. 49–52, January, 1991.     

Angiotensin II-induced depression of Purkinje cell firing and possible modulatory action on GABA responses

Effects of octapeptide angiotensin II (AII) were tested on cortical neurons of rat's cerebellum by means of microiontophoresis. It was observed that AII consistently depressed spontaneous firing of Purkinje cell, whereas other unidentified neurons were unaffected. When tested against responses of Purkinje cell to depressant putative neurotransmitters, namely, GABA, glycine, taurine, 5-hydroxytryptamine and noradrenaline, it was observed that AII specifically enhanced depressant action of GABA, while the responses to other substances were unaffected. Both AII-induced depression of cell firing and the AII-induced enhancement of GABA depression were antagonized by a specific GABA antagonist, bicuculline methochloride. We therefore suggest that AII exerts an inhibitory action on Purkinje cells through its modulatory action on bicuculline-sensitive GABA receptors.     

Inactivation by 6-hydroxydopamine of the cerebral factor(s) responsible for the inhibition of the autoxidation of norepinephrine in vitro

The effect of extracts from rat cerebral cortex was examined on the stability of norepinephrine-HC1 (NE) in 16 mM Na-phosphate buffer, pH 7.4, at 37 degrees C. The autoxidation products of NE were detected spectrophotometrically at 480 nm. Dialysed samples from a synaptosomal preparation and from the 100,000 g supernatant of a crude homogenate were tested. Aliquots from these preparations, in the range of 0.005-5.0 or 0.01-10.0 micrograms protein/ml, respectively, produced up to 80-85% inhibition of the autoxidation of 100 microM NE for a period of at least 3 h. Similar results were obtained with albumin and ovalbumin at 10- and 10(3)-times higher concentrations, respectively. After the preparations were exposed to 0.1-1.0 mg 6-hydroxydopamine-HC1/mg protein for 5 min at 25 degrees C followed by rapid dialysis, the maximal inhibitory effect was reduced to between 95% to less than 5% of control values. The percent inactivation by a given quantity of 6-hydroxydopamine (6-OHDA) was inversely related to the potency of the untreated sample. Additional observations are presented which suggest that the destruction of the antioxidant activity is caused by breakdown products of 6-OHDA reacting with nucleophilic sites of the preparation. Similar inactivating substances are expected to be formed from other autoxidizing catecholamines, although at a slower rate.     

Effect of GABA-ergic agents on the analgesic effect of morphine in rats

In order to detect possible interaction between GABA and opiates, the effects of GABA-ergic drugs on analgesia induced by morphine were studied. The vocalization response to electrical stimulation of the tail in rats was used as an index of the action of morphine. Thiosemicarbazide, an inhibitor of glutamate decarboxylase, and bicuculline, which blocks GABA-ergic receptors, drugs which, it is suggested, can be considered as a group of GABA-negative compounds, weaken and shorten the effect of morphine. Depakine, an inhibitor of -ketoglutarate-GABA-transaminase, like GABA itself, given in large doses (GABA-positive effects) strengthens morphine analgesia and prolongs its effect. The possible causes of these relations between GABA and opiates are discussed.Laboratory of Pharmacology of the Nervous System, Institute of Pharmacology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 7, pp. 35–37, July, 1979.     

Properties of ipsilateral retinogeniculate afferents in albino and hooded rats

By recording single unit activities from the dorsal lateral geniculate nucleus in albino and hooded rats, physiological properties of the ipsilateral retinogeniculate afferents were compared with those of the contralateral ones. The results show that the ipsilateral retinogeniculate pathway was characterized by intermediate conduction velocities, relatively high incidence of the tonic response and the visual field representation of central 30° from the vertical midline on both sides.     

Interactions between naloxone and GABA in the control of locomotor activity in the rat

Summary It was found that naloxone causes a small but significant reduction of motility. The GABA_B agonist baclofen and the GABA transaminase inhibitor-acetylenic GABA (GAG) also reduced locomotor activity. When a subeffective dose of baclofen was combined with naloxone 0.8 or 3.2 mg/kg, baclofen significantly inhibited motility beyond the inhibition caused by naloxone + saline. GAG, in a dose of 12.5 mg/kg, was also potentiated by naloxone, 3.2 mg/kg. The locomotion reducing effects of naloxone could be blocked by either picrotoxin or bicuculline. It is concluded that GABAergic mechanisms participate in the inhibition of locomotor activity provoked by naloxone. The possibility that this drug disinhibits GABAergic neurons is discussed.     

Effects of GABAergic drugs on the GABA turnover in the substantia nigra and the corpus striatum of the rat

Summary Changes in the endogenous GABA concentration and in GABA turnover following GABA receptor stimulation or blockade were studied in the substantia nigra and the corpus striatum of the rat. The GABA agonists, muscimol, baclofen and THIP decreased the accumulation of GABA following inhibition of GABA--ketoglutaric acid aminotransferase by-acetylenic GABA (GAG) in both structures investigated. Only the effect of muscimol in the substantia nigra was inhibited by the GABA antagonist, bicuculline. Muscimol, baclofen and progabide reduced the disappearance rate of GABA in the substantia nigra following inhibition of the glutamate decarboxylase by 4-deoxypyridoxine. The endogenous GABA concentration was decreased in the corpus striatum following muscimol, THIP or baclofen, probably due to a decreased synthesis of GABA. Smaller effects were seen on the endogenous GABA concentration in the substantia nigra, since both the synthesis and the utilization of GABA were decreased by muscimol and baclofen. Thus, the turnover of brain GABA might be regulated by changes in receptor activity.     

腹腔注射蝇蕈醇和荷包牡丹碱对异丙酚小鼠翻正反射的影响

目的：观察腔注射γ-氨基丁酸A（GABAA）受体激动剂蝇蕈醇和（或）其拮抗剂荷包牡丹碱对异丙酚致小鼠翻正反射消迭持续时间及ED50的影响。方法：①40只小鼠随机分为4组,每组10只,分别腹腔注射生理盐水10ml/kg、蝇蕈醇0．5mg/kg、荷包牡丹碱4mg/kg。蝇蕈醇0．5mg/kg 荷包牡丹碱4mg/kg,15min后静注20mg/kg异丙酚,记录小鼠翻正反射消失持续时间。②57只小鼠随机分为4组,如下腹腔注射药物后,测定异丙酚使小鼠翻正反射消失的ED50值。结果：腹腔注射0．5mg/kg蝇蕈醇明显延长异丙酚致小鼠翻正反射消失的时间（P＜0．05）;并降低ED50值（P＜0．05）;4mg/kg荷包牡丹碱对异丙酚致小鼠翻正反射消失的持续时间和ED50值皆无明显影响,但可部分拮抗蝇蕈醇对异丙酚麻醉的增强作用。结：GABAA受体可能不是异丙酚全麻作用的主要靶位。     

Postsynaptic inhibition of invertebrate neuromuscular transmission by avermectin B1a

The avermectins are a family of novel macrocyclic lactones which paralyze nematodes and insects. One highly potent member of this family, avermectin B1a, has been shown to block neuromuscular transmission in the lobster opener and stretcher muscles. Continuous superfusion of these muscles with the drug (6 microM) resulted in a rapid loss of intracellularly recorded inhibitory postsynaptic potentials. Amplitudes of excitatory potentials and membrane input resistance declined at a slower rate, with a similar time course (25-30 min). These effects were not reversed by prolonged washing. A 3-5 mV hyperpolarization was also observed, which was reversed to depolarization in low chloride lobster saline. Picrotoxin (20 microM) blocked the effects of avermectin B1a on excitatory postsynaptic potentials. Both gamma-aminobutyric acid (GABA) and avermectin B1a decreased the slope of current voltage curves in the stretcher muscle, reflecting an increase in membrane conductance. These changes were greatly reduced by application of bicuculline (50 microM) or picrotoxin (20 microM) Avermectin B1a had no effect on the "fast" axon excitatory electrical responses (glutaminergic) of the cockroach extensor tibiae muscle fibers which lack an inhibitory (GABAergic) input. It is concluded that at the lobster neuromuscular junction, avermectin B1a acts on the GABAergic synapse and lowers input resistance of the muscle membranes by causing an increase in chloride ion permeability.