Substance P stimulates inhibitory synaptic transmission in the guinea pig basolateral amygdala in vitro

To determine the physiological role of tachykinin NK1 receptors in the basolateral nucleus of the amygdala (BLN) we have studied the electrophysiological effects of substance P (SP) in the absence and presence of selective tachykinin receptor antagonists in guinea pig brain slices. Recordings were made from two populations of neurones; spiny pyramidal and stellate neurones, both thought to be projection neurones. Activation of NK1 receptors with SP increased the frequency of spontaneous inhibitory postsynaptic potentials in the majority of cells. This effect was blocked by bicuculline or tetrodotoxin, but not ionotropic glutamate receptor antagonists. The enhanced synaptic activity induced by SP was antagonised by the NK1 receptor antagonist L-760,735 but not by the less active enantiomer L-781,773 or the NK3 receptor antagonist L-769,927. Thus in the basolateral nucleus of the guinea pig amygdala, NK1 receptor activation preferentially stimulates inhibitory synaptic activity. Consistent with this observation, immunohistochemistry revealed NK1 receptor immunoreactivity to be largely restricted to a subset of GABA interneurones. These studies support a physiological role for SP in the regulation of pathways involved in the control of emotional behaviour.     

Presynaptic gamma-aminobutyric acid receptors in the rat anococcygeus muscle and their antagonism by 5-aminovaleric acid

1 The effect of the angiotensin converting enzyme inhibitor, MK 421 (N-((S)-1-(ethoxycarbonyl)-3-phenylpropyl)L-Ala-L-Pro), on the blood pressure of two-kidney Goldblatt hypertensive rats has been investigated in relation to he initial plasma renin activity (PRA) and the initial blood pressure of the individual animals. 2 Blood pressure was monitored by an indirect tail-cuff method at 1, 3, 6 and 24 h after dosing. MK 421 produced a fall in blood pressure in the majority of animals, but the extent of this reduction varied considerably between individuals. 3 The change in blood pressure showed a significant correlation with both the initial PRA and the initial blood pressures of the animals. However, only a modest correlation was found between the initial PRA and the degree of hypertension. 4 MK 421 (10 mg/kg, orally) produced a mean blood pressure change which was statistically significant (P less than 0.001) at all times tested. 5 It is concluded that the degree of antihypertensive activity of MK 421 is related to the degree of activity of the renin-angiotensin system which, in this model at least, is reflected by the PRA.     

Presynaptic modulation of synaptic transmission in Helix pomatia: the effects of serotonin and dopamine antagonists

Some presynaptic cells in Helix pomatia possess serotonin and dopamine receptors, which are involved in the modulation of synaptic transfer. The serotonin antagonists tryptamine, 7-methyltryptamine, morphine, atropine, and methysergide decreased transmitter mobilization. 5-Methoxy-gramine, which is a selective inhibitor of hyperpolarizing serotonin responses, had no effect. The dopamine antagonists curare, chlorpromazine and haloperidol decreased transmitter mobilization, while ergometrine, flupenthixol, promethazine and 6-OH dopamine induced a small increase. The mechanisms are discussed and the properties of the presynaptic receptors are compared to the postsynaptic receptors. The usefulness of cell F76 in Helix brain as a model system for vertebrate brain function is discussed.     

Dopaminergic modulation of oscillatory network inhibition in the rat basolateral amygdala depends on initial activity state

The amygdala receives dopaminergic innervation, and dopamine (DA) enhances various activities in cognitive and emotional behaviors. Periodic bursts of spontaneous inhibitory postsynaptic currents (IPSCs) with a low (<1 Hz) inter-event frequency have been observed in projection neurons of the basolateral nucleus of the amygdala (BL). Blockade of ionotropic glutamate receptors or GABA_A receptors abolishes these oscillatory IPSC bursts in the BL, suggesting that the activity has a network origin. Here, we investigated dopaminergic modulation of the oscillatory network inhibition in rat brain slices. We evaluated the effects of DA receptor agonists and antagonists on the network inhibition; the resultant changes were quantified by integrated power spectral density (0.1-3.0 Hz). DA enhanced the power when its initial activity was low, but reduced it when the activity was initially robust. These changes in the power were accompanied by changes in burst IPSC amplitude. D1-like receptor agonist SKF 38393, or DA together with the D2-like receptor antagonist sulpiride, reproduced DA’s facilitatory actions. D2-like receptor agonist quinpirole did not change the periodic IPSC burst activity of the high baseline power, though D₄ receptor agonist PD 168077, or DA together with the D1-like receptor antagonist SCH 23390, reduced its activity. These results suggest that: 1) dopaminergic modulation of the oscillatory network inhibition depends on its initial activity; and 2) facilitatory and suppressing effects of DA in the BL are mediated by D1-like receptors and D₄ receptors, respectively.     

Presynaptic modulation by endocannabinoids

Modulation of neurotransmitter release by G-protein-coupled receptors (GPCRs) is a prominent presynaptic mechanism for regulation of synaptic transmission. Activation of GPCRs located at the presynaptic terminal can decrease the probability of neurotransmitter release. This presynaptic depression involves activation of Gi/o-type G-proteins that mediate different inhibitory mechanisms, including inhibition of voltage-gated calcium channels, activation of potassium channels, and direct inhibition of the vesicle fusion process. A variety of neurotransmitters and modulatory agents can activate GPCRs that produce presynaptic depression. Among these are lipid metabolites that serve as agonists for GPCRs. The discovery of endocannabinoids and their cognate receptors, including the CB1 receptor, has stimulated intense investigation into the neurophysiological roles of these lipid metabolites. It is now clear that presynaptic depression is the major physiological role for the CB1 receptor. Endocannabinoids activate this receptor mainly via a retrograde signaling process in which these compounds are synthesized in and released from postsynaptic neuronal elements, and travel back to the presynaptic terminal to act on the CB1 receptor. This retrograde endocannabinoid modulation has been implicated in short-term synaptic depression, including suppression of excitatory or inhibitory transmission induced by postsynaptic depolarization and transient synaptic depression induced by activation of postsynaptic GPCRs during agonist treatment or synaptic activation. Endocannabinoids and the CB1 receptor also play a key role in one form of long-term synaptic depression (LTD) that involves a longlasting decrease in neurotransmitter release.     

An unusual effect of gamma-aminobutyric acid on synaptic transmission of frog tectal neurones in vitro.

Bath-applied gamma-aminobutyric acid (GABA) enhanced, in a dose-dependent fashion, the amplitude of optic nerve-evoked monosynaptic excitatory responses of the frog optic tectum superfused in vitro at 7 degrees C. Muscimol was more potent than GABA in eliciting similar effects. GABA-induced responses were antagonized by picrotoxin and were insensitive to bicuculline or strychnine. Raising the bath temperature to 20 degrees C reduced the potency of GABA on these preparations. No significant effect of GABA on the compound action potential of the whole optic nerve was found. These data indicate that GABA can amplify visual inputs to the tectum through bicuculline-insensitive mechanisms.     

Presynaptic inhibition of synaptic transmission in the rat hippocampus by activation of muscarinic receptors: involvement of presynaptic calcium influx

1. Modulation of presynaptic voltage-dependent calcium channels (VDCCs) by muscarinic receptors at the CA3–CA1 synapse of rat hippocampal slices was investigated by using the calcium indicator fura-2. Stimulation-evoked presynaptic calcium transients ([Ca_pre]_t) and field excitatory postsynaptic potentials (fe.p.s.ps) were simultaneously recorded. The relationship between presynaptic calcium influx and synaptic transmission was studied.
2. Activation of muscarinic receptors inhibited [Ca_pre]_t, thereby reducing synaptic transmission. Carbachol (CCh, 10 μM) inhibited [Ca_pre]_t by 35% and reduced fe.p.s.p. by 85%. The inhibition was completely antagonized by 1 μM atropine. An approximate 4^th power relationship was found between presynaptic calcium influx and postsynaptic responses.
3. Application of the N-type VDCC-blocking peptide toxin ω-conotoxin GVIA (ω-CTx GVIA, 1 μM) inhibited [Ca_pre]_t and fe.p.s.ps by 21% and 49%, respectively, while the P/Q-type VDCC blocker ω-agatoxin IVA (ω-Aga IVA, 1 μM) reduced [Ca_pre]_t and fe.p.s.ps by 35% and 85%, respectively.
4. Muscarinic receptor activation differentially inhibited distinct presynaptic VDCCs. ω-CTx GVIA-sensitive calcium channels were inhibited by muscarinic receptors, while ω-Aga IVA-sensitive channels were not. The percentage inhibition of ω-CTx GVIA-sensitive [Ca_pre]_t was about 63%.
5. Muscarinic receptors inhibited presynaptic VDCCs in a way similar to adenosine (Ad) receptors. The percentage inhibition of ω-CTx GVIA-sensitive [Ca_pre]_t by Ad (100 μM) was about 59%. There was no significant inhibition of ω-Aga IVA-sensitive channels by Ad. The inhibitions of [Ca_pre]_t by CCh and Ad were mutually occlusive.
6. These results indicate that inhibition of synaptic transmission by muscarinic receptors is mainly the consequence of a reduction of the [Ca_pre]_t due to inhibition of presynaptic VDCCs.

     

AMN082, an allosteric mGluR7 agonist that inhibits afferent glutamatergic transmission in rat basolateral amygdala

Glutamatergic neurotransmission has been implicated in the pathophysiology of psychiatric disorders, such as anxiety and depression. The possible contribution of group III metabotropic glutamate receptors has been poorly investigated, due to the lack of selective pharmacological tools. However, a selective agonist of mGLUR(7), AMN082 has been identified recently, and shown to act through an allosteric mechanism in recombinant cells expressing the receptor. Thus, using AMN082, we examined the role of mGLUR(7) in modulating synaptic transmission in the rat basolateral amygdala (BLA), a brain region known to be important for the genesis of anxious states. We found that bath application of AMN082 (1-10muM) produced a concentration-dependent inhibition of synaptic transmission evoked at 2Hz, but had no effect on transmission evoked at 0.05Hz. However, at this lower frequency, AMN082 (10muM) significantly increased the synaptic inhibition produced by a group III mGLUR agonist, L-AP4 (100muM). This effect was blocked by pre-application of CPPG (500muM), a group III mGLUR-preferring antagonist, consistent with the involvement of mGLUR(7). Thus, we have shown that AMN082 can modulate high frequency synaptic transmission in the BLA, in vitro, and appears to act on the receptor via an allosteric mechanism. These results suggest that mGLUR(7) has a unique role in regulating neuronal activity in the BLA and may be a target for novel drugs for the treatment of anxiety.     

NO/cGMP-dependent modulation of synaptic transmission

Nitric oxide (NO) is a multifunctional messenger in the CNS that can signal both in antero- and retrograde directions across synapses. Many effects of NO are mediated through its canonical receptor, the soluble guanylyl cyclase, and the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). An increase of cGMP can also arise independently of NO via activation of membrane-bound particulate guanylyl cyclases by natriuretic peptides. The classical targets of cGMP are cGMP-dependent protein kinases (cGKs), cyclic nucleotide hydrolysing phosphodiesterases, and cyclic nucleotide-gated (CNG) cation channels. The NO/cGMP/cGK signalling cascade has been linked to the modulation of transmitter release and synaptic plasticity by numerous pharmacological and genetic studies. This review focuses on the role of NO as a retrograde messenger in long-term potentiation of transmitter release in the hippocampus. Presynaptic mechanisms of NO/cGMP/cGK signalling will be discussed with recently identified potential downstream components such as CaMKII, the vasodilator-stimulated phosphoprotein, and regulators of G protein signalling. NO has further been suggested to increase transmitter release through presynaptic clustering of a-synuclein. Alternative modes of NO/cGMP signalling resulting in inhibition of transmitter release and long-term depression of synaptic activity will also be addressed, as well as anterograde NO signalling in the cerebellum. Finally, emerging evidence for cGMP signalling through CNG channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels will be discussed.     

Anisatin modulation of the gamma-aminobutyric acid receptor-channel in rat dorsal root ganglion neurons.

1. Anisatin, a toxic, insecticidally active component of Sikimi plant, is known to act on the GABA system. In order to elucidate the mechanism of anisatin interaction with the GABA system, whole-cell and single-channel patch clamp experiments were performed with rat dorsal root ganglion neurons in primary culture. 2. Repeated co-applications of GABA and anisatin suppressed GABA-induced whole-cell currents with an EC50 of 1.10 microM. No recovery of currents was observed after washout with anisatin-free solution. 3. However, pre-application of anisatin through the bath had no effect on GABA-induced currents. The decay phase of currents was accelerated by anisatin. These results indicate that anisatin suppression of GABA-induced currents requires opening of the channels and is use-dependent. 4. Anisatin suppression of GABA-induced currents was not voltage dependent. 5. Picrotoxinin attenuated anisatin suppression of GABA-induced currents. [3H]-EBOB binding to rat brain membranes was competitively inhibited by anisatin. These data indicated that anisatin bound to the picrotoxinin site. 6. At the single-channel level, anisatin did not alter the open time but prolonged the closed time. The burst duration was reduced and channel openings per burst were decreased indicating that anisatin decreased the probability of openings.     

Abnormal synaptic plasticity in basolateral amygdala may account for hyperactivity and attention-deficit in male rat exposed perinatally to low-dose bisphenol-A

If the pregnant and lactating female rats are exposed to environmental levels of bisphenol-A (BPA), their male offspring will display hyperactivity and attention-deficit. In patients with attention-deficit/hyperactivity disorder (ADHD), the size of the amygdala is reported to be reduced. This study examined functional alterations in the basolateral amygdala (BLA) of the postnatal 28-day-old male offspring exposed perinatally to BPA (BPA-rats). We specifically focused on the synaptic properties of GABAergic/dopaminergic systems in the BLA. A single electrical stimulation of the capsule fibers evoked multispike responses with an enhanced primary population spikes (1st-PS) in the BPA-rats. A single train of high-frequency stimulation of the fibers induced NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in BPA-rats, but not in control rats. Also, paired-pulse inhibition (PPI, GABA-dependent) in control rats was reversed to paired-pulse facilitation (PPF) in BPA-rats. Perfusion of slices obtained from BPA-rats with the GABA_A receptor (GABA_AR) agonist muscimol blocked the multispike responses and LTP, and recovered PPI. By contrast, the dopamine D1 receptor antagonist SCH23390 abolished LTP and attenuated the increased amplitude of 1st-PS in BPA-rats. Conversely, blockade of GABA_AR by bicuculline could produce the multispike responses and PPF in BLA in control rats. Furthermore, in BLA the infusion of SCH23390, muscimol or the NMDAR blocker MK801 ameliorated the hyperactivity and improved the deficits in attention. These findings suggest that the perinatal exposure to BPA causes GABAergic disinhibition and dopaminergic enhancement, leading to an abnormal cortical-BLA synaptic transmission and plasticity, which may be responsible for the hyperactivity and attention-deficit in BPA-rats.This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’.     

Muscarinic modulation of synaptic transmission via endocannabinoid signalling in the rat midbrain periaqueductal gray

The midbrain periaqueductal gray (PAG) is involved in organizing behavioral responses to threat, stress, and pain. These PAG functions are modulated by cholinergic agents. In the present study, we examined the cholinergic modulation of synaptic transmission in the PAG using whole-cell voltage-clamp recordings from rat midbrain slices. We found that the cholinergic agonist carbachol reduced the amplitude of evoked inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) in all PAG neurons, and this was abolished by the muscarinic receptor antagonist atropine. Carbachol increased the paired pulse ratio of evoked IPSCs and EPSCs, and it reduced the rate, but not the amplitude of spontaneous miniature IPSCs. The carbachol inhibition of evoked IPSCs was mimicked by the acetylcholinesterase inhibitor physostigmine and was reduced by the M1 and M1/M3 muscarinic receptor antagonists pirenzepine and 4-diphenylacetoxy-N-methylpiperidine, but not by the M2 and M4 antagonists gallamine and PD-102807 (3,6a,11,14-tetrahydro-9-methoxy-2-methyl-(12H)-isoquino [1,2-b]pyrrolo[3,2-f][1,3]benzoxazine-1-carboxylic acid, ethyl ester). The carbachol inhibition of evoked IPSCs was reduced by the cannabinoid CB(1) receptor antagonist AM251 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide) and the diacylglycerol (DAG) lipase inhibitor tetrahydrolipstatin, and it was abolished in the presence of both AM251 and gallamine. The carbachol inhibition of evoked EPSCs was also reduced in the combined presence of gallamine and AM251. These results indicate that M1 induced inhibition of GABAergic transmission within the PAG is mediated via endocannabinoids, which are produced via the phospholipase C/DAG lipase pathway and activate presynaptic cannabinoid CB(1) receptors. Thus, presynaptic muscarinic modulation of PAG function is mediated indirectly by M1 receptor-induced endocannabinoid signaling and directly by M2 receptors.     

Interneurons in the basolateral amygdala

The amygdala is a temporal lobe structure that is the center of emotion processing in the mammalian brain. Recent interest in the amygdala arises from its role in processing fear and the relationship of fear to human anxiety. The amygdaloid complex is divided into a number of subnuclei that have extensive intra and extra nuclear connections. In this review we discuss recent findings on the physiology and plasticity of inputs to interneurons in the basolateral amygdala, the primary input station. These interneurons are a heterogeneous group of cells that can be separated on immunohistochemical and electrophysiological grounds. Glutamatergic inputs to these interneurons form diverse types of excitatory synapses. This diversity is manifest in both the subunit composition of the underlying NMDA receptors as well as their ability to show plasticity. We discuss these differences and their relationship to fear learning.This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’.     

Negative modulation of the gamma-aminobutyric acid response by extracellular zinc.

We have studied the effects of divalent cations on the gamma-aminobutyric acid (GABA) response of voltage-clamped spinal cord neurons, using the whole-cell recording configuration. Zn, Cd, Ni, and Mn (but not Ba, Ca, or Mg) inhibit GABA-induced whole-cell currents when applied extracellularly. Although Zn is an effective inhibitor when applied extracellularly, it is ineffective when applied intracellularly. Inhibition by these cations is mediated by a common saturable recognition site that is distinct from the recognition sites for GABA, benzodiazepines, barbiturates, picrotoxin, or steroids. The maximal inhibition, or efficacy of inhibition, of GABA-induced currents is greater for Zn than for Cd, Ni, or Mn. The order of potency is Cd greater than Zn much greater than Ni much greater than Mn. Inhibition by Zn is partially surmountable by GABA, consistent with a decrease in both the maximum response and the affinity for GABA. The dose-response curve for inhibition of the GABA response by Zn is shifted to the right at a high GABA concentration but is unaffected by the presence of chlordiazepoxide, pentobarbital, or 5 beta-pregnan-3 alpha-ol-20-one. The results are consistent with a model in which a Zn-sensitive modulatory site exerts negative allosteric control over GABA receptor function.     

Lamotrigine reduces spontaneous and evoked GABAA receptor-mediated synaptic transmission in the basolateral amygdala: implications for its effects in seizure and affective disorders

Lamotrigine (LTG) is an antiepileptic drug that is also effective in the treatment of certain psychiatric disorders. Its anticonvulsant action has been attributed to its ability to block voltage-gated Na(+) channels and reduce glutamate release. LTG also affects GABA-mediated synaptic transmission, but there are conflicting reports as to whether inhibitory transmission is enhanced or suppressed by LTG. We examined the effects of LTG on GABA(A) receptor-mediated synaptic transmission in slices from rat amygdala, a brain area that is particularly important in epileptogenesis and affective disorders. In intracellular recordings, LTG (100 microM) reduced GABA(A) receptor-mediated IPSPs evoked by electrical stimulation in neurons of the basolateral nucleus. In whole-cell recordings, LTG (10, 50 and 100 microM) decreased the frequency and amplitude of spontaneous IPSCs, as well as the amplitude of evoked IPSCs, but had no effect on the kinetics of these currents. LTG also had no effects on the frequency, amplitude or kinetics of miniature IPSCs recorded in the presence of TTX. These results suggest that in the basolateral amygdala, LTG suppresses GABA(A) receptor-mediated synaptic transmission by a direct and/or indirect effect on presynaptic Ca(++) influx. The modulation of inhibitory synaptic transmission may be an important mechanism underlying the psychotropic effects of LTG.     

Muscarinic cholinergic modulation of synaptic transmission and plasticity in rat hippocampus following chronic lead exposure

The cholinergic system is believed to be associated with learning and memory functions. Lead (Pb²⁺) is a well-known neurotoxic metal that causes irreversible damage to the central nervous system (CNS). To investigate whether Pb²⁺ interferes with cholinergic modulation, we examined the effects of carbachol (CCh), a muscarinic cholinergic agonist, on synaptic transmission and plasticity in the CA1 area of the hippocampus of developmentally Pb²⁺-exposed rats. The results showed that: (1) In both control and Pb²⁺-exposed rats, 0.1 μM CCh significantly enhanced tetanus-induced long-term potentiation (LTP), while 5 μM CCh induced a reversible depression of field excitatory postsynaptic potentials (fEPSPs). However, both the enhancement of LTP and depression of fEPSPs were significantly smaller in Pb²⁺-exposed rats than in controls, suggesting that the extent of the effect of CCh on the cholinergic system was depressed by Pb²⁺. (2) In Pb²⁺-exposed rats, the enhancement of LTP induced by 0.1 μM CCh was attenuated by pirenzepine, a M₁AChR antagonist, but was not affected by methoctramine tetrahydrochloride (M-105), a M_2/4AChR antagonist. The depression of fEPSPs induced by 5 μM CCh was reduced by either pirenzepine or M-105. (3) Furthermore, paired-pulse facilitation (PPF) was not affected by 0.1 μM CCh in control and Pb²⁺-exposed rats but was increased by 5 μM CCh in either group; the increase in PPF was less pronounced in Pb²⁺-treated when compared to control rats. These results suggested that cholinergic modulation could be impaired by Pb²⁺, and this kind of impairment might occur via different mAChR subtypes. Our study delineated the effects of Pb²⁺ on muscarinic modulation, and this might be one of the underlying mechanisms by which Pb²⁺ impairs learning and memory.     

Thromboxane A2 agonist modulation of excitatory synaptic transmission in the rat hippocampal slice.

1. The effects of the selective thromboxane A2 (TXA2) receptor agonist I-BOP on neuronal excitability and synaptic transmission were studied in the CAl neurones of rat hippocampal slices by an intracellular recording technique. 2. Superfusion of I-BOP (0.5 microM) resulted in a biphasic change of the excitatory postsynaptic potential (e.p.s.p.), which was blocked by pretreatment with SQ 29548, a specific antagonist of TXA2 receptors. The inhibitory phase of I-BOP on the e.p.s.p. was accompanied by a decrease in neuronal membrane input resistance. 3. The sensitivity of postsynaptic neurones to glutamate receptor agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA), was unchanged by I-BOP (0.5 microM) pretreatment. 4. Bath application of Ba2+ (0.5 mM) prevented both the I-BOP-induced reduction of the neuronal membrane input resistance and the blockade of e.p.s.p. induced by I-BOP. 5. Intracellular dialysis of the hippocampal CA1 neurones with GDP (10 mM) significantly attenuated the I-BOP inhibition of e.p.s.p. and membrane input resistance. Incubation of the slices with either pertussis toxin (PTX, 5 micrograms ml-1 for 12 h) or cholera toxin (CTX, 5 micrograms ml-1 for 12 h) did not affect the biphasic action of I-BOP on the e.p.s.p. or the reduction of membrane input resistance induced by I-BOP. 6. Pretreatment of the slices with the protein kinase C (PKC) inhibitor, NPC-15437 (20 microM), abolished the biphasic modulation by I-BOP (0.5 microM) of the e.p.s.p. Intracellular application of a specific PKC inhibitor, PKCI 19-36 (20 microM), completely inhibited the I-BOP reduction of e.p.s.p. The specific cyclic AMP-dependent protein kinase (PKA) inhibitor, Rp-cyclic adenosine 3',5'-monophosphate (Rp-cyclic AMPS, 25 microM), had no effect on the I-BOP action. 7. In this study we have demonstrated, for the first time, the existence of functional TXA2 receptors in the hippocampus which mediate the effects of a TXA2 agonist on neuronal excitability and synaptic transmission. Activation of the presynaptic TXA2 receptors may stimulate the release of glutamate. Conversely, activation of postsynaptic TXA2 receptors leads to inhibition of synaptic transmission resulting from a decrease in the membrane input resistance of the neurones. The pre- and postsynaptic actions of the TXA2 agonist are both mediated by PTX- and CTX-insensitive G-protein-coupled activation of PKC pathways.