The characteristics and pharmacology of olfactory cortical LTP induced by theta-burst high frequency stimulation and 1S,3R-ACPD.

Long-term potentiation (LTP) of monosynaptic excitations in the olfactory cortex slice by theta burst high frequency stimulation (theta-HFS) and application of the metabotropic glutamate receptor-selective agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) has been studied. Theta-HFS optimally induced LTP when given 4 times at intervals of 20-30 min. The degree of LTP was significantly potentiated by the inclusion of picrotoxin in the perfusion medium but induction was prevented by D-2-amino-5-phosphonopentanoate (25 microM), L-2-amino-3-phosphonopropionate (125 microM), 5-(isoquinolinyl-sulphonyl)-2-methylpiperazine (50 microM), sangivamycin (25 microM) and thapsigargin (1 microM). Of the drugs tested, only D-2-amino-5-phosphonopentanoate failed to depotentiate established LTP. Application of 1S,3R-ACPD (100 microM) repeated 4 times at intervals of 20-30 min also optimally induced an LTP which was significantly less in unstimulated preparations and showed the same pattern of sensitivity to the drugs tested as LTP induced by theta-HFS. It is concluded that the induction of LTP by theta-HFS and 1S,3R-ACPD requires activation of both N-methyl-D-aspartate and metabotropic glutamate receptors and that a protein kinase is essential for the induction and maintenance of LTP. The likely mechanisms of induction and maintenance of olfactory cortical and hippocampal LTP are contrasted.

Actions of agonists of metabotropic glutamate receptors on synaptic transmission and transmitter release in the olfactory cortex.

1. The effects of agonists of on the evoked N-wave complex in slices of mouse have been studied: most experiments were carried out using slices perfused with Mg(2+)-free solution to which 10 microM of either 6,7-dinitroquinoxaline-2,3-dione or 6-cyano-7-nitroquinoxaline-2,3-dione was applied. 2. Following agonist washout, a slowly developing, long lasting potentiation of the complex occurred which was confined to the mediated component of the potential. The relative agonist potencies were 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 5-250 microM) = quisqualate (5-50 microM) > 1RS,3RS-cis-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 25-1000 microM) > L-glutamate (0.25-2.5 mM); NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and L-aspartate were inactive. 3. Potentiation of the NMDA receptor-mediated component by 1S,3R-ACPD (0.1 mM) was non-competitively antagonised by S-(+)- but not R-(-)-2-amino-3-phosphonopropionate (AP3, 0.125 mM), equally by D-(-) and L-(+)-2-amino-4-phosphonobutyrate (0.25 mM) and also by the protein kinase C inhibitors sphingosine, (25 microM), sangivamycin (25 microM) and 5-(isoquinolinylsulphonyl)-3-methylpiperazine (50 microM). 4. In a series of input-output experiments, 1S,3R-ACPD (0.1 mM) reversibly reduced the latency to peak of the NMDA receptor-mediated component at submaximal stimulus intensities, an effect blocked by S-(+)-AP3 (0.125 mM). On agonist washout, there was an increase in the area of the receptor-mediated component over all stimulus intensities, an effect blocked by the inhibitors of protein kinase C and by S-(+)-AP3 (0.125mM). 4-beta-Phorbol-12,13-diacetate (2.5 muM) also potentiated the component, an action inhibited by protein kinase C inhibitors but not by S-(+)-AP3. IS,3R-ACPD (0.1mM) had no significant effect on postsynaptic responses evoked by NMDA, AMPA and kainate, but significantly reversed a partial antagonism of NMDA responses produced by 7-chlorokynurenate (2.5 muM). The K+evoked release of glycine was selectively and significantly increased in the presence 0.1mM 1S,3R-ACPD(antagonized by 0.125 mM S-(+)-AP#) whereas following agonist washout, release of glycine fell to control levels but there was a significant increase in release of aspartate(antagonized by 25 muM sangivamycin and 0.125 muM S-(+)-AP3). It is concluded that mediate (i) a reduction in the latency of the mediated component of potentials by a mechanism that is independent of protein kinase C but which may depend on increased glycine release release and (ii) a long lasting increase in the total area of the potential by increasing transmitter (possibly aspartate) release by a mechanism that is protein kinase C-dependent.

Acute leukemia with t(1;3)(p36;q21), evolution to t(1;3)(p36;q21), t(14;17)(q32;q21), and loss of red cell A and Le(b) antigens.

At transformation of refractory anemia with ring sideroblasts to acute nonlymphocytic leukemia (ANLL) the bone marrow cells of a 75-year-old woman showed three different karyotypes, i.e., 46,XX,46,XX,t(1;3)(p36;q21) and 46,XX,t(1;3)(p36;q21),t(14;17)(q32;q21). She received no antileukemic therapy, and 1 year later, all her bone marrow cells were t(1;3)(p36;q21),t(14;17)(q32;q21). In association with the onset and first 11 months of ANLL, the platelet count increased 10-fold to a peak of 750 x 10(9)/L, providing further evidence that the t(1;3)(p36;q21) translocation causes stimulation of thrombopoiesis. Six months after transformation, her red cells showed reduced expression of A and Leb antigens. Serum alpha-n-3-acetylgalactosaminyl transferase (blood group A transferase) and red cell adenylate kinase were both reduced. The genes for both these substances are at 9q34, which suggests an abnormality here, although cytogenetically chromosome 9 appeared normal. This is the first case with t(1;3)(p36;q21) to show concurrent loss of red cell antigens and the first report detailing the course of untreated ANLL with t(1;3)(p36;q21).

Pharmacological evidence that NMDA receptors contribute to mono- and di-synaptic potentials in slices of mouse olfactory cortex.

Experiments have been carried out using slices of olfactory cortex of the mouse perfused in solution containing Mg2+ (1 mM) and in which the lateral olfactory tract was stimulated at a frequency of 1 pulse/5 sec to avoid polysynaptic activity. Application of the N-methyl-D-aspartate antagonist D-(-)-2-amino-5-phosphonopentanoic acid (APP, 25 microM) suppressed a low amplitude component of the potential, the latency to onset of which corresponded with that of the monosynaptically evoked N-wave in 14 of the 17 slices tested and duration of which exceeded that of the N-wave. A residual potential, recorded in slices to which the quisqualate-/kainate-selective antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) had been applied at a concentration of 10microM, was identical to the potential suppressed by APP. The residual potential in the presence of DNQX was blocked by APP, 7-chlorokynurenate (25 microM) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK801, 0.125-2 microM). It was potentiated in area by exogenous D-serine (1 mM) and in slices preincubated and perfused with Mg(2+)-free solution. It is concluded that, in addition to receptors of the quisqualate/kainate categories, N-methyl-D-aspartate receptors also contribute to both mono- and di-synaptic excitations in the olfactory cortex.

Both agonists and antagonists of the strychnine-insensitive glycine site of N-methyl-D-aspartate receptors modulate polysynaptic excitations in slices of mouse olfactory cortex.

In this study, it is reported that bath application of D-serine and, to a lesser extent glycine, potentiated polysynaptic but not monosynaptic excitations evoked in slices of mouse olfactory cortex perfused with solution containing Mg2+ (1 mmol/l), picrotoxin and strychnine (both 25 mumol/l). Effects were largely confined to the longer latency components of the field potentials and occurred at amino acid concentrations of between 0.01 and 1 mmol/l. The effects of D-serine and glycine were antagonized by 7-chlorokynurenate and indole-2-carboxylate, antagonists of the glycine regulatory site of the N-methyl-Daspartate (NMDA) receptor complex. D-Serine (glycine not tested) also potentiated, and 7-chlorokynurenate partially inhibited the longer latency components of the polysynaptic field potentials evoked in slices perfused in the absence of picrotoxin and strychnine. However, neither D-serine nor glycine potentiated responses evoked by the bath application of NMDA. It is concluded that under the present experimental conditions, the glycine regulatory sites of those NMDA receptor involved in the mediation of polysynaptic excitations in the mouse olfactory cortex are not saturated with endogenous glycine.

Pharmacological evidence that protein kinase C modulates monosynaptic excitations in the olfactory cortex.

The possible occurrence and role of protein kinase C at the lateral olfactory tract (LOT)-pyramidal cell synapse of the rat olfactory cortex slice has been investigated by determining the effects of both activators (4-beta-phorbol-12,13,diacetate [PDAc] and 1,2-dioctanoyl-sn-glycerol) and inhibitors (5-isoquinolinylsulphonyl)-2-methylpiperazine [H-7], sangivamycin and polymyxin B) of the enzyme on the surface field potential known as the N-wave. PDAc (0.3 to 20 mumol/l) and 1,2-dioctanoyl-sn-glycerol (25 to 250 mumol/l) increased the area and amplitude of the potential. In control slices in which a population spike was recorded, PDAc also triggered the appearance of multiple spikes. In a series of input-output experiments, PDAc (2.5 or 5 mumol/l) increased the area and amplitude of the N-wave relative to that of the action potential but did not significantly affect pyramidal cell excitability. The effects of PDAc on the N-wave were antagonised by all three protein kinase C inhibitors but not by the calmodulin antagonist calmidazolium and were greater in slices perfused with solution containing 10 rather than 1 mmol/l Mg2+ or 1.25 rather than 5 mmol/l Ca2+. The effect of PDAc on the amplitude but not area of the N-wave was blocked by the potassium channel blocker tetraethylammonium (10 mmol/l) but not by 4-aminopyridine (0.25 mmol/l). In a series of conditioning experiments, PDAc (1 to 5 mumol/l) reduced the amplitude of the N-wave evoked by a second stimulus compared to that evoked by the first conditioning pulse.(ABSTRACT TRUNCATED AT 250 WORDS)

A study of the possible mechanisms underlying the convulsant actions of a linear expanded xanthine.

The actions of a mixture of the 4- and 9-chloro derivatives of the linear expanded xanthine 5,7-diethyl-2-chloroimidazo[4,5-g]quinazoline-6,8 (5H,7H)-dione (chloro-DCQD) on the isolated olfactory cortex slice of the rat have been investigated. Chloro-DCQD evoked a slowly-developing depolarization which intensified over a drug application period of at least 4 min. A pharmacological investigation of the response showed that it was not mediated by blockade of potassium channels or activation of voltage-gated sodium channels, by a stimulant action at receptors to gamma-aminobutyric acid (GABA), excitatory amino acids or acetylcholine, or by antagonism of adenosine receptors. Chloro-DCQD (2.5 mM) potentiated responses evoked by N-methyl-D-aspartate (NMDA), L-aspartate and L-glutamate, probably by overcoming the magnesium ion block of the ion channel of the NMDA receptor complex. Chloro-DCQD (2.5 or 5 mM) also increased pyramidal cell excitability and abolished GABA-mediated postsynaptic inhibition but did not affect the excitability of, or neurotransmitter release from, the terminals of the lateral olfactory tract. Chloro-DCQD competitively antagonized the inhibitory actions of adenosine on the olfactory cortex. These effects are consistent with the reported convulsant actions of chloro-DCQD.

Antagonism of monosynaptic excitations in the mouse olfactory cortex slice by 6,7-dinitroquinoxaline-2,3-dione.

The effects of 6,7-dinitroquinoxaline-2,3-dione (DNQX) have been tested in slices of olfactory cortex of the mouse against responses evoked by N-methyl-D-aspartate, kainate and quisqualate and on the surface field potentials evoked on electrical stimulation of the lateral olfactory tract. At a concentration of 5 microM, DNQX competitively antagonized responses evoked by kainate and quisqualate, with only a small reduction in the responses to N-methyl-D-aspartate. In contrast, DL-(+-)-2-amino-5-phosphonopentanoic acid (APP, 50 microM) selectively antagonized depolarizations to N-methyl-D-aspartate. The amplitude of the field potential known as the N-wave was reduced by DNQX in a concentration-dependent reversible manner (IC50 = 2.92 +/- 0.33 microM; mean +/- SE mean, n = 4). DL-(+-)-2-Amino-5-phosphonopentanoic acid (50 microM) did not significantly affect this action of DNQX. It is concluded that DNQX inhibits monosynaptic excitations in the olfactory cortex by selectively blocking kainate and/or quisqualate receptors, although it is unclear whether the receptors are located at pre- and/or postsynaptic sites.

Effects of the anaesthetic 2,6-diisopropylphenol on synaptic transmission in the rat olfactory cortex slice.

1. The effects of the general anaesthetic 2,6-diisopropylphenol (DIP) on synaptic transmission and the actions of amino acid transmitter candidates have been investigated in rat olfactory cortex slices. 2. On electrical stimulation of the lateral olfactory tract (LOT), DIP (20 to 200 microM) increased the area of those surface field potentials which reflect gamma-aminobutyric acid (GABA)-mediated transmission in a concentration-dependent manner in 6 out of 12 slices. In a series of conditioning experiments, DIP (50 microM) also potentiated GABA-mediated pre- and post-synaptic inhibition. 3. Perfusion of slices with DIP (50 microM) potentiated the reduction in the excitability of the terminals of the LOT produced by exogenous GABA in a picrotoxin-sensitive manner. 4. DIP (50 microM) markedly potentiated the surface depolarizations evoked by GABA, muscimol and 3-aminopropanesulphonic acid. The effect on the response to 3-aminopropanesulphonic acid was observed over a concentration range of DIP of 6.25 to 50 microM and was not blocked by the benzodiazepine receptor antagonist Ro 15-1788. 5. In slices in which GABA-mediated transmission was abolished by picrotoxin (25 microM), DIP (50 microM) had no significant effect on monosynaptically-evoked excitatory transmission but depressed the areas of those field potentials which reflect di-/polysynaptic excitations in a concentration-dependent manner (from between 1.6 and 6.25 to 50 microM). 6. In a series of conditioning experiments DIP (50 microM) abolished the increase in the excitability of the pyramidal cells evoked on stimulation of deep association fibres. 7. DIP (50 microM) had no significant effect on surface depolarizations evoked by N-methyl-D-aspartate, quisqualate and kainate or by the transmitter candidates L-glutamate and L-aspartate. 8. It is concluded that, at clinically relevant concentrations, DIP potentiates GABA-mediated transmission probably by an interaction with the GABA receptor complex and inhibits di-/polysynaptic excitations, possibly by inhibiting the release of excitatory transmitters.

The pharmacology of excitatory transmission in the rat olfactory cortex slice.

The pharmacology of excitatory transmission in slices of olfactory cortex of the rat, perfused with solution containing picrotoxin, has been studied by assessing the effects of cis-2,3-piperidine dicarboxylate, a nonselective antagonist of excitatory amino acid receptors, 2-amino-5-phosphonopentanoate, a selective antagonist of N-methyl-D-aspartate (NMDA) receptors and 2-amino-4-phosphonobutyrate (APB) and baclofen, which act at APB and GABAB sites, respectively, on evoked surface field potentials. Monosynaptic excitatory transmission was monitored by measuring the amplitude of the N'a'-wave, evoked on stimulation of the lateral olfactory tract, whilst di-/polysynaptic excitatory transmission was evaluated by calculating the areas of the potentials evoked on direct stimulation of the superficial and deep-lying association fibre systems. On the basis of the effects of the drugs in this and earlier studies, it is concluded that: (i) transmission at the lateral olfactory tract-pyramidal cell synapse is mediated by kainate/quisqualate but not NMDA receptors and is regulated by inhibitory APB receptors, located on the tract terminals; (ii) NMDA receptors are involved in mediating excitatory transmission at the synapses of superficial association fibres with the proximal apical dendrites of pyramidal cells with inhibitory APB receptors playing a regulatory role; (iii) transmission at synapses of association fibres with basal dendrites of pyramidal cells, is mediated in part by NMDA receptors with (presynaptic?) GABAB receptors exerting a strong inhibitory influence. These proposed roles of NMDA receptors have been confirmed in experiments in which the effects of magnesium ions on field potentials evoked in slices perfused in magnesium-free solution were monitored.

Possible presynaptic actions of 2-amino-4-phosphonobutyrate in rat olfactory cortex.

1 The effect of 2-amino-4-phosphonobutyrate (APB) on facilitation at the lateral olfactory tract (LOT)-superficial pyramidal cell synapse of the olfactory cortex has been studied by recording the relative changes in amplitude of the N-waves evoked on stimulation of the LOT by pairs of stimuli. 2 Although APB (0.01 to 5 mM) reduced the amplitude of the conditioning response there was an overall increase in facilitation over conditioning intervals of up to 1700 ms which was concentration-dependent and inversely related to the concentration of extracellular calcium (1.25 to 5 mM). 3 The L-(+)-isomer of APB was more potent than the D-(-)-form in increasing synaptic facilitation. 4 The potassium channel blockers 4-aminopyridine (0.25 mM), 3,4-diaminopyridine (0.1 mM), tetraethylammonium (10 mM) and catechol (1 mM) all reduced facilitation but failed to antagonize the increase in facilitation produced by APB (1 mM). In contrast, all 4 drugs antagonized APB-induced reductions in the amplitude of the conditioning response. 5 APB (1 mM) significantly reduced the K+-evoked release of endogenous aspartate and glutamate but not of gamma-aminobutyric acid from slices of olfactory cortex. 6 It is suggested that APB reduces the amplitude of the conditioning response and increases synaptic facilitation by reducing transmitter release from the LOT terminals. The mechanism is unlikely to involve activation of terminal potassium currents.

Effects of barbiturates on responses evoked by excitatory amino acids in slices of rat olfactory cortex.

A study has been made of the effects of ranges of concentrations of phenobarbitone, pentobarbitone and thiopentone on responses evoked by gamma-aminobutyric acid (GABA), L-glutamate, L-aspartate, N-methyl-D-aspartate, kainate and quisqualate in slices of olfactory cortex of the rat. All three barbiturates affected GABA-evoked depolarizations similarly in that responses were potentiated by small doses but markedly inhibited at greater concentrations. Responses to L-aspartate and L-glutamate were little affected except at the largest dose of phenobarbitone tested (10 mM). The responses evoked by the selective agonists of excitatory amino acid receptors were inhibited by the barbiturates, the relative sensitivities being quisqualate greater than or equal to N-methyl-D-aspartate greater than or equal to kainate with phenobarbitone, quisqualate greater than or equal to kainate greater than N-methyl-D-aspartate with pentobarbitone and quisqualate greater than kainate = N-methyl-D-aspartate with thiopentone. The possible significance of these findings is discussed.

Sites and mechanisms of action of catechol (1,2-dihydroxybenzene) in the rat olfactory cortex slice.

Synaptic transmission in the isolated olfactory cortex slice from the rat was monitored by recording the surface field potentials evoked on lateral olfactory tract (LOT) stimulation. Catechol (approximately 0.05 to 2 mM) caused a concentration-dependent, partially reversible increase in the amplitudes of all field potentials. In a series of conditioning experiments, catechol (1 mM) potentiated postsynaptic inhibition by a mechanism which was at least partially picrotoxin-insensitive. When the relationship between the stimulus input and evoked output was investigated in picrotoxin-treated slices, for a given tract action potential amplitude, catechol (0.25 and 0.5 mM) increased the amplitude of the field potential known as the N-wave; in contrast, for a given N-wave amplitude, the latency of the population spike was increased. Catechol (1 mM) increased the K+-evoked release of endogenous aspartate by a tetrodotoxin-insensitive mechanism whereas the release of glutamate and gamma-aminobutyric acid (GABA) was unaffected. Catechol (1 mM) had no effect on submaximal depolarizations evoked by L-aspartate, L-glutamate or GABA. It is concluded that catechol potentiates excitatory transmission at the LOT-superficial pyramidal cell synapse, possibly by increasing evoked transmitter release. Other synaptic actions of catechol may be consequent upon this increased excitatory input but the results do not exclude the possibility of separate and distinct actions on polysynaptic transmission.

A quantitative estimate of the contribution made by various receptor categories to the depolarizations evoked by some excitatory amino acids in the olfactory cortex.

A study has been undertaken to assess the percentage contributions made by N-methyl-D-aspartate (NMDA), kainate and quisqualate receptors to the composite depolarizations evoked by L-cysteate, L-cysteinesulphinate, L-homocysteate and S-sulpho-L-cysteine in the rat olfactory cortex slice. The percentage contribution made by NMDA receptors, which was quantified by measuring the reduction in agonist responses in the presence of the highly selective NMDA receptor antagonist 2-amino-5-phosphonopentanoate (0.1 mM), was: L-homocysteate, 73%; S-sulpho-L-cysteine, 65%; L-cysteate, 42% and L-cysteinesulphinate, 30%. Responses mediated by NMDA, kainate and quisqualate receptors were abolished by a 'desensitization' procedure involving repeated application of a mixture containing high concentrations of the selective agonists followed by perfusion of the non-selective receptor antagonist cis-2,3-piperidine dicarboxylate (5 mM). Following this procedure, responses to L-homocysteate and S-sulpho-L-cysteine were almost abolished and simple calculation gave the contribution of kainate plus quisqualate receptors to the agonist responses as: L-cysteinesulphinate, 46%; L-cysteate, 34%; S-sulpho-L-cysteine, 28% and L-homocysteate, 23%. However, approximately 24% of the composite depolarizations evoked by L-cysteate and L-cysteinesulphinate was mediated by a mechanism not involving NMDA, kainate or quisqualate receptors, neither did it reflect possible electrogenic uptake of the amino acids nor an interaction with 2-amino-4-phosphonobutyrate receptors. It is suggested that this fraction of the depolarizations evoked by L-cysteate and L-cysteinesulphinate might be due to a non-receptor-mediated release of K+ or, perhaps, to activation of an as yet unidentified receptor category.

"Desensitization" of excitatory amino acid responses in the rat olfactory cortex.

Repeated application of the excitatory amino acid transmitter candidates, L-aspartate and L-glutamate and of N-methyl-D-aspartate, kainate and quisqualate to slices of olfactory cortex evoked progressively smaller depolarizations. These "desensitizations" were concentration-dependent, essentially irreversible and non-selective, although responses to gamma-aminobutyric acid (GABA) and to potassium ions were not significantly depressed. The specific N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid, partially blocked the reduction in responses to amino acids which accompanied "desensitization" by N-methyl-D-aspartate, suggesting that activation of receptors is an obligatory step in provoking the phenomenon. "Desensitization" of responses was not prevented by the lectin concanavalin A but was potentiated by ouabain, an inhibitor of the sodium-potassium pump. It is proposed that the phenomenon does not reflect a true desensitization of receptors but is possibly the result of accumulation of intracellular sodium because of overloading the sodium pump. Under circumstances where responses to N-methyl-D-aspartate, quisqualate and kainate were "desensitized" by approx. 96%, depolarizations evoked by L-aspartate and L-glutamate were reduced by only 55%: these residual responses were not antagonized by the excitatory amino acid receptor blockers, (+/-)cis-2,3-piperidine dicarboxylate and 2-amino-4-phosphonobutyrate or by dihydrokainate, an inhibitor of the uptake of glutamate and aspartate. One possibility is that the residual responses reflect an interaction between L-aspartate and L-glutamate and an as yet unknown category of receptors.

Binding characteristics of the selective alpha 2-adrenoceptor antagonist [3H]idazoxan to rat olfactory cortex membranes.

[3H]Idazoxan binding to membranes prepared from rat olfactory cortex obeyed saturation kinetics and was to a single population of sites. Although the density of sites was dependent on the incubation medium, binding was of high affinity (KD approximately 5.5 nM) with a Hill coefficient close to unity. Competition studies with a range of adrenoceptor agonists and antagonists confirmed that [3H]idazoxan binding was to alpha 2-adrenoceptors. Neither chemical lesions with the neurotoxin kainic acid nor chronic unilateral bulbectomy significantly altered any of the [3H]idazoxan binding parameters. These findings suggest that alpha 2-adrenoceptors are not located on the lateral olfactory tract terminals or pyramidal cells of the olfactory cortex.

Adenosine A1 receptors mediate the inhibitory effects of exogenous adenosine in the rat olfactory cortex slice.

A study has been undertaken to identify the category of receptors mediating the inhibitory effects of adenosine on evoked activity in slices of olfactory cortex in the rat. The approach has been to measure the relative potencies of adenosine and a range of structural analogues [2-chloroadenosine, 2' deoxyadenosine, cyclohexyladenosine, (-)-5'N-ethyl-carboxamide adenosine and N6(L-2-phenylisopropyl)adenosine] required to: inhibit excitatory transmission at the lateral olfactory tract-pyramidal cell synapse; inhibit the specific binding of [3H]cyclohexyladenosine to membrane preparations and evoke formation of cyclic AMP. In contrast to the relative concentrations of the analogues necessary to increase levels of cyclic AMP, those required to inhibit synaptic transmission were characteristic of a selectivity for adenosine A1 receptors. The presence of adenosine A1 receptors has been demonstrated directly by characterizing the binding of [3H]cyclohexyladenosine to membranes prepared from slices of olfactory cortex. It is concluded that inhibition of transmission at the lateral olfactory tract-pyramical cell synapse by adenosine is mediated by receptors of the A1 category.

Excitatory and inhibitory effects of dopamine on synaptic transmission in the rat olfactory cortex slice.

A study has been undertaken of the effects of dopamine on excitatory transmission at the lateral olfactory tract (LOT)-superficial pyramidal cell synapse of the rat olfactory cortex slice by measuring the effects of bath-applied dopamine on the amplitudes and latencies of the surface field potentials evoked on submaximal LOT stimulation in a total of 32 preparations. In 7 (22%) slices, dopamine had no detectable effects on transmission. In the remaining preparations, dopamine (1-250 microM) depressed transmission in a concentration-dependent manner. This action was unaffected by nadolol (10 microM), phentolamine (10 microM) and picrotoxin (25 microM) but was antagonized by chlorpromazine (10 microM) and trifluoperazine (0.2 and 0.5 microM) and mimicked by bromocriptine (0.01-5 microM) and apomorphine (0.25-25 microM). Investigation of the effects of dopamine on stimulus input-evoked potential output relationships indicated that the inhibitory effect of dopamine on transmission was mediated by a reduction in pyramidal cell excitability. In 6 slices (24% of those sensitive to dopamine) low dopamine concentrations (0.1-1 microM) facilitated transmission at the LOT-superficial pyramidal cell synapse. This excitatory effect was antagonized by nadolol and phentolamine (10 microM) and also by 100 microM 2-amino-5-phosphonovalerate (an antagonist of excitatory amino acid receptors of the N-methyl-D-aspartate type) but was unaffected by chlorpromazine (10 microM) and trifluoperazine (0.2 and 0.5 microM). By a comparison with the effects of noradrenaline on transmission, it is concluded that the excitatory effects of dopamine are mediated either indirectly by the release of noradrenaline or by a direct interaction of dopamine with adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Receptor types mediating the excitatory actions of exogenous L-aspartate and L-glutamate in rat olfactory cortex.

Changes in potential between the pial and cut surfaces of rat olfactory cortex slices evoked by N-methyl-D-aspartate (NMDA), quisqualate, kainate, L-glutamate and L-aspartate and also by gamma-aminobutyric acid (GABA) have been monitored using extracellular electrodes. All agonists produced a pial-negative potential response when superfused onto the pial surface, GABA, L-aspartate and L-glutamate being less potent than the others. Repeated applications of NMDA, but not of the other agonists, led to a progressive reduction in response to approximately 30% of the initial depolarization. The responses to NMDA (100 microM) were selectively abolished by (+/-)2-amino-5-phosphonopentanoic acid (APP; 100 microM) while depolarizations evoked by L-glutamate and L-aspartate (both at 10 mM) were only antagonized by 21 +/- 2 (n = 12) and 36 +/- 3 (n = 12) percent respectively (means +/- S.E.M.). gamma-D-Glutamylglycine (gamma-DGG; 1 mM) and (+/-)cis-2,3-piperidine dicarboxylate (cis-PDA; 2 and 5 mM), in addition to antagonizing responses to NMDA, also partially blocked quisqualate- and kainate-evoked depolarizations. When a mixture of APP (100 microM), gamma-DGG (1 mM) and cis-PDA (5 mM) was applied to preparations, although NMDA receptors were completely blocked and responses to both quisqualate and kainate antagonized by approximately 80%, L-glutamate and L-aspartate evoked depolarizations were only reduced by 51 +/- 7 (n = 4) and 49 +/- 4 (n = 4) percent respectively (means +/- S.E.M.). The results are discussed in terms of the contributions made by NMDA, quisqualate and kainate receptors to the composite responses evoked by L-aspartate and L-glutamate.

An unlikely role for cyclic AMP in the mediation of the excitatory and inhibitory effects of noradrenaline on transmission in the olfactory cortex.

Simultaneous measurements have been made of the actions of noradrenaline and other agonists, alone and in the presence of appropriate antagonists, on synaptic transmission and cyclic AMP levels in the rat olfactory cortex. The possible role of cyclic AMP as an obligatory mediator of the excitatory and inhibitory actions of noradrenaline is discussed.