Synaptic vesicle protein 2A: basic facts and role in synaptic function

In recent years, there has been considerable interest in determining the function of synaptic vesicle protein 2A and its role as a target for antiepileptic drugs. Although it is known that synaptic vesicle protein 2A is involved in normal synaptic vesicle function, its participation in synaptic vesicle cycling and neurotransmitter release in normal and pathological conditions is unclear. However, the experimental evidence suggests that synaptic vesicle protein 2A could be a vesicular transporter, regulate synaptic exocytosis as a gel matrix, or modulate synaptotagmin‐1 activity. This review describes and discusses the participation of synaptic vesicle protein 2A in synaptic modulation in normal and pathological conditions.     

The evolutionarily conserved gene LNP-1 is required for synaptic vesicle trafficking and synaptic transmission

The control of vesicle-mediated transport in nerve cells is of great importance in the function, development and maintenance of synapse. In this paper, we characterize the new Caenorhabditis elegans gene, lnp-1 . The lnp-1 gene is broadly distributed in many neuronal structures and its localization is dependent of the UNC-104/kinesin protein. Deletion mutations in lnp-1 result in increased resistance to aldicarb, an acetylcholinesterase inhibitor, and in locomotor defects. However, sensitivity to levamisole, a nicotinic agonist which, unlike aldicarb, only affects postsynaptic function, was similar to that of wild-type animals, suggesting a presynaptic function for LNP-1 in neurotransmission. The mislocalization of presynaptic proteins, such as synaptobrevin-1 or RAB-3, in lnp-1 mutants further supports this hypothesis. In summary, our studies suggest that LNP-1 plays a role in synaptogenesis by regulating vesicular transport or localization.     

Adenosine A1 receptor-mediated inhibition of dopamine release from rat striatal slices is modulated by D1 dopamine receptors

Dopamine release is regulated by presynaptic dopamine receptors and interactions between adenosine and dopamine receptors have been well documented. In the present study, dopamine release from isolated striatal slices from Wistar rats was measured using fast cyclic voltammetry. Single-pulse stimulation (0.1 ms, 10 V) was applied every 5 min over a 2-h period. Superfusion with the adenosine (A)(1) receptor agonist N(6)-cyclopentyladenosine (CPA), but not the A(2) receptor agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl] phenyl]propanoic acid (CGS 21680), inhibited dopamine release in a concentration-dependent manner (IC(50) 3.80 x 10(-7) m; n = 10). The dose-response curve to CPA was shifted to the right (IC(50) 6.57 x 10(-6) m; n = 6, P < 0.05 vs. control) by the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Neither the D(1) agonist 6-chloro-APB nor the D(1) antagonist R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol (SCH 23390) altered dopamine release on their own. However, SCH 23390 (3 microm) significantly attenuated the response to CPA (IC(50) 1.44 x 10(-5) m; n = 6, P < 0.01 vs. control). Furthermore, the inhibitory effect of CPA was significantly increased in the presence of 6-chloro-APB (1 microm). In radioligand binding experiments, CPA interacted with high- and low-affinity states of [(3)H]DPCPX-lableled A(1) receptors. The high-affinity agonist binding to A(1) receptors was inhibited by the stable guanosine triphosphate analogue Gpp(NH)p. In contrast, neither the proportion nor the affinity of high-affinity A(1) receptors was altered by dopamine or SCH 23390. These results provide evidence that the inhibition of dopamine release by adenosine A(1) receptors is dependent, at least in part, on the simultaneous activation of D(1) dopamine receptors. While the mechanism underlying this interaction remains to be determined, it does not appear to involve an intramembrane interaction between A(1) and D(1) receptors.     

突触前膜Ca~(2 )通道作为结构元件参与突触囊泡的停靠与融合

新近提供的证据表明 ,在神经递质释放中具关键作用的突触前膜Ca2 通道 ,除为Ca2 进入胞内提供路径外 ,还通过位于其胞内环 (LⅡ ～LⅢ)中的一段称为synprint位点的肽段与突触蛋白syntaxin和SNAP 2 5等相互作用 ,参与突触囊泡停靠 /融合。本文综述了相关资料     

Modulation of slow postsynaptic potentials by dopamine, in rabbit sympathetic ganglion

(1) Temporary exposure of rabbit's superior cervical ganglion (SCG) to dopamine (DA), in the presence of an inhibitor of catechol-o-methyltransferase (COMT) is consistently followed by a potentiation of the slow (s)-EPSP and s-IPSP, lasting for some hours. The fast (f)-EPSP is not significantly increased, but it is better maintained than in control ganglia. (2) Exposure to the COMT-inhibitor U-0521 alone induces less but substantial potentiations of both s-PSPs. This effect is explained as due to protection of DA released intraganglionically at rest. (3) This evidence suggests that COMT may significantly limit the access of catecholamines to postsynaptic receptors, for at least certain types of neuron-to-neuron synaptic actions. (4) The potentiation of both s-PSPs, whether induced by DA in the presence of U-0521 or by U-0521 alone, is depressed by DA-1 antagonists that have been found to depress DA-stimulation of adenyl cyclase in rabbit SCG; these are spiroperidol, butaclamol and, to a lesser extent, bromocriptine. The specific 'DA-2' antagonists metoclopramide and sulpiride, and the alpha-adrenergic antagonist dihydroergotamine, did not depress potentiation. (5) Potentiation of s-EPSP is viewed as identical in nature to the previously discovered DA-modulatory enhancement of direct muscarinic depolarizing actions (by acetylcholine or its agonists). Potentiation of s-IPSP may be due to a similar DA-modulation of other muscarinic response(s) involved in mediating the s-IPSP. The consistency and comparative ease with which these DA-modulatory effects can be induced, under presently described experimental conditions, should facilitate future study of this mode of synaptic action.     

Modulation by dopamine of population responses and cell membrane properties of hippocampal CA1 neurons in vitro

Dopamine (DA) was applied to rat hippocampal slices maintained in vitro. Extracellular and intracellular recording techniques were used to study the effect of DA on population responses, membrane potentials, and membrane responses to hyperpolarizing current pulses in CA1 pyramidal cells. Temporary exposure of hippocampal slices to DA has a dual effect. The initial action of DA is to produce a suppression of the extra-cellularly recorded population responses. In individual neurons, this initial effect is seen as a membrane hyperpolarization accompanied by a decrease in the amplitude of responses to hyperpolarizing current pulses. The frequency of occurrence of spontaneous depolarizations and spikes is reduced. The early action of DA is followed by a profound potentiation of the population responses that can last for hours. This long-lasting potentiation of the population response, induced by DA, is depressed by spiroperidol, a DA antagonist. In individual neurons, the late effect of DA is a long-lasting membrane depolarization associated with an increase in the amplitude of responses to hyperpolarizing current pulses. During this late phase, spontaneous activity is increased, as are single cell responses to stimulation of afferents. The evidence presented here indicates that DA is able to induce a long-lasting modification of the excitability of CA1 hippocampal neurons. This modulation of excitability by DA may be similar in nature to previously described DA-modulatory actions in the peripheral nervous system.     

A mechanism for influencing the septo-hippocampal theta rhythm by dopamine through the basal ganglia

A mechanism for basal ganglia and dopamine influence on the induction and frequency of the septo-hippocampal theta rhythm is proposed. This mechanism is based on dopamine-dependent modulation of the efficacy of excitatory inputs to the striatum and subsequent disinhibition through the basal ganglia of thalamic nucleus reuniens, and cholinergic pontine nuclei. Such disinhibition increases excitation of the targets of these nuclei in the medial septum, hippocampal CA1 area and entorhinal cortex. Modeling has shown (Borisyuk, 2004; Whittington et al., 1995) that a neuronal network with interconnected inhibitory neurons (such as the network including the septum, hippocampal formation and basal ganglia) generates oscillations whose frequency positively correlates with the “strength” of excitation and negatively correlates with the “strength“ of inhibition. It follows from the proposed mechanism that an increase in dopamine concentration or artificial activation of the D1 and D2 receptors in the striatum should lead to an increase in theta rhythm frequency in all parts of the network. This consequence of the proposed model is in agreement with known experimental data. Published in Russian in Neirokhimiya, 2008, Vol. 25, No. 3, pp. 184–190. The text was submitted by the author in English.     

Synaptic signals mediated by protons and acid‐sensing ion channels

Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca²⁺ currents through multivesicular release in ribbon‐type synapses is a proven phenomenon. In recent years, protons have been recognized as neurotransmitters that participate in neuronal communication in synapses of several regions of the CNS such as amygdala, nucleus accumbens, and brainstem. Protons are released by nerve stimulation and activate postsynaptic acid‐sensing ion channels (ASICs). Several types of ASIC channels are expressed in the peripheral and central nervous system. The influx of Ca²⁺ through some subtypes of ASICs, as a result of synaptic transmission, agrees with the participation of ASICs in synaptic plasticity. Pharmacological and genetical inhibition of ASIC1a results in alterations in learning, memory, and phenomena like fear and cocaine‐seeking behavior. The recognition of endogenous molecules, such as arachidonic acid, cytokines, histamine, spermine, lactate, and neuropeptides, capable of inhibiting or potentiating ASICs suggests the existence of mechanisms of synaptic modulation that have not yet been fully identified and that could be tuned by new emerging pharmacological compounds with potential therapeutic benefits.     

Bromocriptine-induced locomotor stimulation in mice is modulated by dopamine D-1 receptors

Summary Mice were pretreated with reserpine plus-methyl-p-tyrosine (10 mg/ kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge (i.e., three hours after the reserpine plus-methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors.     

Amphetamine elevates nucleus accumbens dopamine via an action potential‐dependent mechanism that is modulated by endocannabinoids

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential‐independent, non‐exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential‐dependent mechanism. Indeed, fast‐scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward‐related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast‐scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH‐induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH‐induced dopamine elevations, identifying an action potential‐dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential‐independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement.     

Dopamine efflux in the rat nucleus accumbens evoked by dopamine receptor stimulation in the entorhinal cortex is modulated by oestradiol and progesterone

This study compared the effects of dopamine receptor stimulation in the entorhinal cortex on dopamine release in the nucleus accumbens, measured by in vivo microdialysis in conscious Sprague-Dawley rats, with and without oestradiol and progesterone priming. Nonselective dopamine receptor stimulation with apomorphine reduced dopamine release in the nucleus accumbens, an effect which was prevented by injection of cis-flupenthixol into the entorhinal cortex. Selective D₁ receptor stimulation with SKF38393 increased dopamine release, whereas selective D₂ receptor stimulation with quinpirole did not affect dopamine release. Combined administration of oestradiol and progesterone potentiated the response to apomorphine and prevented the response to SKF38393. The effects of single hormone administration on the response to apomorphine suggested that the modulation was primarily due to oestradiol enhancing effects of progesterone. Experiments with high [K⁺] suggested these hormonal effects were exerted predominantly in the entorhinal cortex. The present experiments have demonstrated that dopaminergic modulation of transmission in a cortico-striatal loop linking temporal and prefrontal cortex is regulated by oestradiol and progesterone. Dysfunction in this system in humans may give rise to affective and cognitive symptoms which may, if initiated by a postpartum fall in oestrogen and progesterone concentrations, constitute the core pathophysiology of puerperal psychosis. Synapse 25:37–43, 1997. © 1997 Wiley-Liss, Inc.     

Dopamine D2 agonist-induced behavioural depression is reversed by dopamine D1 agonists

Summary The dopamine (DA) D2 agonist bromocriptine produced dose-dependent locomotor depression in mice with intact stores of DA, as measured in automated activity cages. The DA D1 agonist CY208-243, reversed the bromocriptine-induced depression. Using direct observational analysis, another selective DA D2 agonist, quinpirole, induced dose-dependent depression and this was reversed by the D1 agonist SKF38393. The effect of SKF38393 could be blocked by prior pretreatment with SCH23390. It is concluded that DA D2 agonist-induced locomotor depression is mediated via a DA D2 autoreceptor-mediated inhibition of DA release onto postsynaptic DA receptors. This reduction in release probably deprives postsynaptic D1 and D2 receptors of endogenous DA. However, since bromocriptine (and probably quinpirole) in all likelihood occupies both pre- and postsynaptic D2 receptors immediately on injection, and since CY208-243 and SKF38393 (respectively) could reverse the depression, the depression seems to be due specifically to a deprivation of DA at postsynaptic D1 receptors.     

Locomotor inhibition by the D3 ligand R-(+)-7-OH-DPAT is independent of changes in dopamine release

Summary The dopamine D₃ preferring ligand R-(+)-7-OH-DPAT induced strong hypolocomotion in rats. Doses producing reduction of locomotion failed to affect dopamine release or synthesis rate. These data support the hypothesis that the dopamine D₃ receptor is a postsynaptic receptor with an inhibitory influence on rat locomotor activity.     

Tonic modulation of inhibition by dopamine D4 receptors in the rat hippocampus

Dopaminergic pathways have been recognized to play a critical role in cognition and emotion. Dopamine D2 and D4 receptors are the target for most common antipsychotics and their activation, particularly those in the medial temporal lobe structures, has been associated with their beneficial actions. The entorhinal cortex, which is the cortical area most consistently and severely affected in schizophrenia constitutes the main input to the hippocampus. Since the D4 receptor is highly concentrated in the hippocampus, and the effects of the selective activation of D4 receptors on the input/output function of the hippocampal formation are poorly understood, we sought to investigate the role of these receptors in the synaptic transmission and paired-pulse inhibition from the perforant path to area CA1 and the dentate gyrus. The D4 receptor antagonist, clozapine, translated paired-pulse inhibition into paired-pulse potentiation in both perforant path targets. By contrast, the D2/D3 antagonist quinpirole had no effect. The blockade of the D2/3 receptors with sulpiride, and of D1/5 receptors with SCH-23390, has no effect on paired-pulse inhibition, suggesting that these receptors are not involved in feedforward inhibition in these hippocampal areas. Interestingly, the perfusion of the D4 selective antagonist, L-745,870 (Patel et al., 1997: J Pharmacol Exp Ther 283:636-647) during the blockade of D2/3 and D1/5 receptors produces a reversible decrease in paired-pulse inhibition in CA1, but not in the DG. Our results show that endogenous DA tonically modulates feedforward inhibition in area CA1 and the dentate gyrus through the activation of D4 receptors located in the interneuronal population of these hippocampal regions. Since activation of the D4 receptor inhibits GABA release and GABAergic synaptic transmission, we suggest that the perforant path stimulates interneurons that have the D4 receptor and that, in turn, contact other interneurons that synapse onto pyramidal cells. (c) 2004 Wiley-Liss, Inc.     

Release of somatostatin from extra-hypothalamic rat brain slices: inhibition by dopamine and morphine

Calcium-dependent potassium-evoked release of somatostatin-like immuno-reactivity (SSLI) and preloaded [3H]noradrenaline ([3H]NA) could be demonstrated simultaneously from slices of rat cerebral cortex, globus pallidus and trigeminal nucleus. The release of [3H]NA from cortical slices differed from that of somatostatin (SS) in its K+-dependency, with the release of SS having a higher threshold. Both morphine (10 microM) and dopamine (50 microM) significantly inhibited the potassium-evoked release of SS from the cerebral cortex, without affecting its basal release. The effect of morphine was naloxone reversible.     

Effect of endogenous dopamine on endogenous dopamine on extrastriated [11C]FLB 457 binding measured by PET

Central dopaminergic systems are known to be implicated in the pathophysiology of schizophrenia and recent in vivo dopamine receptor imaging studies have focused on the measurement of extrastriatal dopamine receptor. However, there are only a limited number of ligands that can measure the low-density D2 receptor in extrastriatal regions and their sensitivity to endogenous dopamine in extrastriatal regions has not yet been fully examined. In this study, the effect of endogenous dopamine on the extrastriatal binding of [(11)C]FLB 457 was examined in the rhesus monkey after facilitation with 1 mg/kg of methamphetamine (MAP) and was compared with the effect on the striatal binding of [(11)C]raclopride. The indices of receptor binding were obtained by four methods using cerebellum as a reference region. The bindings of [(11)C]FLB 457 in the frontal cortex, temporal cortex, and thalamus were not significantly changed after MAP treatment, while the striatal binding of [(11)C]raclopride was decreased by more than 20%. These results suggest that [(11)C]FLB 457 is not sensitive to endogenous dopamine in the extrastriatal regions of rhesus monkeys, despite a sufficient dose of MAP to decrease the binding of [(11)C]raclopride in the striatum.     

GBR12909 stimulates hypothalamo-pituitary-adrenal activity by inhibition of uptake at hypothalamic dopamine neurons

We have previously demonstrated that the inhibition of neurotransmitter uptake at dopamine (DA) terminals stimulates the hypothalamo-pituitary-adrenal axis. In the present study we investigated the role of central DA neuronal systems in the regulation of this axis. Administration of the DA uptake inhibitor GBR12909 (3–30 μg) into the third ventricle dose-dependently elevated serum adrenocorticotropin hormone (ACTH) levels in rats. GBR12909 (10 μg) elevated serum ACTH levels following administration into the paraventricular nucleus of the hypothalamus but not into the lateral ventricle. The administration of 6-OHDA into the third ventricle significantly decreased DA content in the hypothalamus and striatum and significantly attenuated the ACTH response to GBR12909 (10 μg, third ventricle or 10 mg/kg, i.p.). Conversely, 6-OHDA lesions of the medial forebrain bundle, which depleted 99% of DA in the caudate but did not decrease DA content in the hypothalamus, and did not attenuate the ACTH response to i.p. GBR12909. Measurement of GBR12909-induced inhibition of [³H]DA uptake into synaptosomal preparations indicates the presence of GBR12909-sensitive DA transporters in the region of the hypothalamus surrounding the thrid ventricle. The present findings suggest that an endogenous DA neuronal system terminating in the hypothalamus mediates the effects of stimulants on hypothalamo-pituitary-adrenal function and might play a role in the ongoing regulation of hypothalamo-pituitary-adrenal activity.