Inhibition Of Neuronal Firing Research Articles

Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatum.

It has been shown that striatal adenosine A2A receptors can antagonistically interact with dopamine D2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these findings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D2 agonist quinpirole reduced neuronal activity. However, when the adenosine A2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal firing seen after quinpirole alone was significantly potentiated (P< 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A2A antagonists in the treatment of PD by enhancing D2 receptor function.

Sensory Response of the Locus Ceruleus: Neonatal and Adult Studies

This chapter summarizes two topics from recent experiments concerning sensory response of locus ceruleus (LC) neurons: sensory response of LC neurons in fetal and neonatal rats and a long-lasting, GABAergic inhibition of LC neurons following caloric vestibular stimulation in adult rats. Despite less spontaneous activity of fetal and neonatal LC neurons, sensory stimuli have been very effective in producing the excitation of LC neurons in these immature animals. It has been shown that negative- and positive-feedback mechanisms operate to regulate the electrical activity of LC neurons. Activation of α 1 adrenoceptors causes excitation of LC neurons (positive feedback), while that of α 2 adrenoceptors results in the suppression of the neurons (negative feedback). Based on these findings, the tonic activation of fetal and neonatal LC neurons by sensory stimuli may be explained by the feedback mechanisms that are dependent on the spontaneous activity of the neurons. The sensory-evoked responses of LC neurons are mainly e citatory, despite the difference in response pattern, tonic or transient. It has been found that an atypical sensory response of LC neurons in adult rats, LC neurons revealed a long- lasting inhibition of neuronal firing following caloric vestibular stimulation or electrical stimulation of the medial vestibular nucleus. It is also indicated that the long-lasting suppression of LC neuronal firing following caloric vestibular stimulation is mediated by GABA. These results suggest that the caloric stimulation-induced LC inhibition is mediated by the ventrolateral medulla (VLM) and may be independent of the VLM-mediated pressor effect. As the VLM is the source of the major excitatory input to the LC, it is possible that VLM neurons receiving vestibular input exert excitatory influence on GABAergic neurons connecting to the LC.

The mu opioid receptor: from molecular cloning to functional studies.

Opioids have been used and abused by humans for centuries. The mu opioid receptor represents the high affinity binding site for opioid narcotics with high abuse liability such as morphine, codeine and fentanyl. Heroin (diacetylmorphine), a semi-synthetic derivative of morphine, crosses the blood-brain barrier more readily than morphine due to its increased hydrophobicity. Once in the brain heroin is hydrolyzed to morphine, which acts at the mu opioid receptor and results in euphoria, thus conferring the reinforcing properties of heroin. Using molecular biology techniques, the mu opioid receptors from several species have been cloned. This article reviews recent progress in this area, with respect to the two major cellular functions of the mu opioid receptor: reduction of intracellular cAMP concentration by inhibiting adenylyl cyclase activity, and inhibition of neuronal firing by modulating membrane ion channels.

Distinctive features of rilmenidine possibly related to its selectivity for imidazoline receptors.

Rilmenidine is an oxazoline derivative with antihypertensive activity which was developed to enhance the dissociation between the hypotensive and adverse effect profile of centrally acting agents. Experimental studies have indicated that rilmenidine is selective for both alpha 2-adrenoceptors (v alpha 1) and newly discovered nonadrenergic imidazoline receptors in the brain and in the periphery. In experimental studies, rilmenidine differs from clonidine in that it is more selective for imidazoline receptors than for alpha 2-adrenoceptors; at equihypotensive doses, rilmenidine causes less bradycardia and reduction in cardiac output, less sedation, and little or no antinociceptive action compared to clonidine. The hypotensive effects of rilmenidine are antagonised by idazoxan and yohimbine, but idazoxan (imidazoline structure) is six times more potent than yohimbine (a selective alpha 2-antagonist). In isolated renal proximal tubule cells, where imidazoline binding has also been shown, rilmenidine inhibits reabsorption of sodium. Clinical studies comparing 1 mg rilmenidine with placebo demonstrated significant reductions in blood pressure (BP) (61% rilmenidine v 23% placebo normalized to 160/90 mm Hg). The reduction in BP was not associated with classical alpha 2 side effects such as dry mouth or daytime drowsiness. Compared with clonidine (0.15 to 0.3 mg), equihypotensive doses of rilmenidine (1 to 2 mg) induced two to three times less dry mouth, daytime drowsiness, and constipation; no orthostatic hypotension was reported. Methyldopa (0.5 to 1 mg) v rilmenidine (1 to 2 mg) indicated a comparable reduction of BP with significantly less weakness, drowsiness, orthostatic dizziness, and dry mouth on rilmenidine; there was no evidence of the "clonidine withdrawal syndrome" on drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Convergence and divergence of neurotransmitter action in human cerebral cortex.

The postsynaptic actions of acetylcholine, adenosine, gamma-aminobutyric acid, histamine, norepinephrine, and serotonin were analyzed in human cortical pyramidal cells maintained in vitro. The actions of these six putative neurotransmitters converged onto three distinct potassium currents. Application of acetylcholine, histamine, norepinephrine, or serotonin all increased spiking by reducing spike-frequency adaptation, in part by reducing the current that underlies the slow after hyperpolarization. In addition, application of muscarinic receptor agonists to all neurons or of serotonin to middle-layer cells substantially reduced or blocked the M-current (a K+ current that is voltage and time dependent). Inhibition of neuronal firing was elicited by adenosine, baclofen (a gamma-aminobutyric acid type B receptor agonist), or serotonin and appeared to be due to an increase in the same potassium current by all three agents. These data reveal that individual neuronal currents in the human cerebral cortex are under the control of several putative neurotransmitters and that each neurotransmitter may exhibit more than one postsynaptic action. The specific anatomical connections of these various neurotransmitter systems, as well as their heterogeneous distribution of postsynaptic receptors and responses, allows each to make a specific contribution to the modulation of cortical activity.

Behavioral and neurophysiological evidence for a facilatory interaction between co-existing transmitters: cholecystokinin and dopamine

Cholecystokinin (CCK) and dopamine (DA) co-exist in ventral tegmental neurons which project via the mesencephalic pathway to the nucleus accumbens of the rat. CCK and DA are located in separate neurons in the substantia nigra which projects via the nigrostriatal pathway to the caudate nucleus in the rat. The functional significance of this peptide-amine co-localization was investigated using behavioral and neurophysiological techniques. CCK injected directly into the nucleus accumbens potentiated apomorphine-induced stereotypy and dopamine-induced hyperlocomotion. CCK injected directly into the caudate nucleus had no effect on apomorphine-induced stereotypy or dopamine-induced hyperlocomotion CCK injected alone into either site did not induce stereotypy or hyperlocomotion. The dose-response curve to apomorphine induction of stereotypy was shifted to the left by CCK, indicating increased sensitivity to the dopaminergic agonist. Neurophysiological analysis of the firing rate of ventral tegmental neurons demonstrated that CCK produced a left-shift in the dose-response curve of apomorphine on inhibition of neuronal firing. These data suggest that CCK acts as a modulator of dopamine, increasing neuronal responses to dopaminergic agonists. The potentiation of dopamine by CCK may be specific to the mesolimbic neurons, where CCK and DA co-exist in the rat.

Spinal clonidine inhibits neural firing in locus coeruleus

Intrathecally-administered clonidine inhibited the spontaneous firing of single neurons in the pontine nucleus locus coeruleus of rats. Such inhibition of neuron firing was not observed when the non-lipophilic α 2 adrenoceptor agonist (oxymetazoline) was administered intrathecally. It is concluded that lipophilic drugs like clonidine, when administered intrathecally, can have profound supraspinal actions and thus caution should be exercised in interpreting the sites of action of such drugs.

Inhibition of neuronal firing by opiates: evidence against the involvement of cyclic nucleotides.

1. Extracellular recordings were made in vitro from single neurones of the myenteric plexus of the guinea-pig ileum. 2. Neuronal firing was inhibited by morphine and normorphine (10 nM to 1 micrometer). Cyclic adenosine 3',5'-monophosphate (cyclic AMP) (100 micrometer to 1 mM) also inhibited the firing of the majority of the neurones. Prostaglandin E2 usually caused a short-lasting excitation of myenteric neurones and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was usually without effect on firing rate. 3. The inhibition of neuronal firing by normorphine was unaffected by prior and/or concurrent administration of cyclic AMP, dibutyryl cyclic adenosine 3',5'-monophosphate, prostaglandin E2 or 3-isobutyl-1-methylxanthine. As these four treatments might be expected to elevate intracellular levels of cyclic AMP, the results lend no support to the notion that a reduction in intracellular cyclic AMP is essential to the inhibition of firing produced by morphine.

Morphine: Effects on serotonergic neurons and neurons in areas with a serotonergic input

The hypothesis that morphine acts on the serotonergic system to produce analgesia is based on the previous observations that (1) lesions and stimulation of midbrain raphe nuclei alter the threshold to nociceptive stimuli; (2) morphine alters the turnover of serotonin (5-hydroxytryptamine; 5-HT). Microiontophoretic experiments were carried out to determine if morphine affected the firing rate of cells in five areas of the serotonergic system consisting of 5-HT containing neurons in the midbrain raphe nuclei (dorsal raphe and median raphe) or neurons in three areas (amygdala, optic tectum and subiculum) which are thought to receive a 5-HT input from the raphe n nuclei. Morphine administered microiontophoretically slowed or inhibited the spontaneous neuronal firing in 34% of the cells studied in both the pre- and post-synaptic areas; systematically administered morphine gave similar results. However, the inhibition of neuronal firing by morphine in the five areas of the serotonergic system studied was not a specific narcotic effect because (1) it was not stereospecific; and (2) it was rarely blocked by naloxone. The inhibitory effect of morphine does not appear to be related to the analgesic effects of morphine because neuronal firing in the midbrain raphe nuclei and three possible postsynaptic areas was rarely altered by a nociceptive stimulus. It is concluded that (1) the analgesic effect of morphine is not related to an effect on neurons in the midbrain raphe nuclei and three areas which receive an identified 5-HT input; and (2) the effect of morphine on neurons in these five areas of the serotonergic system is not a specific narcotic effect.

Effects of lysergic acid diethylamide on the uptake and retention of brain 5-hydroxytryptamine in vivo and in vitro

The effects of D-lysergic acid diethylamide (LSD) and other drugs on brain 5-hydroxytryptamine (5-HT) in vivo and in vitro and on 3H-5-HT administered intraventricularly have been studied in male Sprague-Dawley rats. The results in vivo show that the retention of 3H-5-HT in the brain is increased by treatment (i.p.) with LSD and p-chlorophenylalanine (PCPA) and decreased by reserpine. This LSD effect in vivo can be reversed by intraventricular ouabain (given together with 3H-5-HT) in amounts which cause brief convulsions. In vitro, LSD added to the medium initially (0–10 min) decreased uptake of 3H-5-HT in brain slices but enhanced its retention at 60 min. These effects of LSD were not observed either after pargyline treatment (i.p.) or in the presence of pargyline in vitro. These results are consistent with the idea that LSD decreases 5-HT turnover through an inhibition of neuronal firing, which can be overcome by neuronal depolarization sufficient to cause convulsions. It is suggested that the decreased 5-HT turnover seen after LSD is somehow mediated by a mechanism which protects 5-HT from deamination by monoamine oxidase, and that an effect on 5-HT uptake may be a mechanism involved in the interaction of LSD with brain 5-HT.

Excitation and inhibition of neuronal firing in visual cortex by reticular stimulation.

The frequency of action potentials of about one-third of the neurons sampled in the striate cortex of awake rabbits was clearly modified by mild stimulation of the reticular core of the brain stem. Reticular stimulation often brought about enhancement of firing in units activated by light, while it usually had the contrary effect upon light-inhibited units.