Evaluation of an automated complement fixation test (Seramat) for the detection of chlamydial antibodies in sheep and goat sera.
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Animals↗
Biomedical subjects
P Ardenghi
Publications and source records attributed to P Ardenghi.
Simultaneous modulation of retrieval by dopaminergic D(1), beta-noradrenergic, serotonergic-1A and cholinergic muscarinic receptors in cortical structures of the rat.
Retrieval of inhibitory avoidance has been recently shown to require intact glutamate receptors, protein kinases A and C and mitogen-activated protein kinase in the CA1 region of the rat hippocampus and in the entorhinal, posterior parietal and anterior cingulate cortex. These enzymatic activities are known to be modulated by dopamine D(1), beta-noradrenergic, 5HT1A and cholinergic muscarinic receptors. Here we study the effect on retrieval of this task of well-known agonists and antagonists of these receptors infused in the same brain cortical regions and into the basolateral amygdala, in rats. The drugs used were SKF38393 (D(1) agonist), noradrenaline, 8-HO-DPAT (5HT1A agonist), oxotremorine (muscarinic agonist), SCH23390 (D(1) antagonist), timolol (beta antagonist), NAN-190 (5HT1A antagonist) and scopolamine (muscarinic antagonist). All were studied at two different dose levels. The localised infusion of SKF38393, noradrenaline, NAN-190 and oxotremorine into any of the cortical structures mentioned 10 min prior to a 24-h retention test session of one-trial step-down inhibitory avoidance enhanced retention test performance. SCH2330, timolol, 8-HO-DPAT and scopolamine hindered retention test performance. In the basolateral amygdala only an enhancing effect of noradrenaline and an inhibitory effect of timolol were seen. Three hours after the infusions, retention test performance returned to normal in all cases. None of the treatments affected locomotion or rearing in an open field or behaviour in the elevated plus maze. Therefore, their effects on retention testing can be attributed to an influence on retrieval. In conclusion, memory retrieval of this apparently simple task requires the participation of CA1, entorhinal, posterior parietal and anterior cingulate cortex, and is strongly modulated by, dopaminergic D(1), beta-noradrenergic, muscarinic cholinergic and 5HT1A receptors in the four areas. The first three types of receptor enhance, and the latter inhibits, retrieval. Only beta-adrenoceptors appears to be involved in the modulation of retrieval of this task by the amygdala. The results bear on the well-known influence of emotion and mood on retrieval, and indicate that this involves many areas of the brain simultaneously. In addition, the results point to similarities and differences between the modulatory mechanisms that affect retrieval and those involved in the consolidation of the same task.
Amygdala↗
Facilitation and inhibition of retrieval in two aversive tasks in rats by intrahippocampal infusion of agonists of specific glutamate metabotropic receptor subtypes.
RATIONALE: The generic antagonist of glutamate metabotropic receptors (mGlus), MCPG, blocks retrieval of inhibitory avoidance when infused into the CA1 area of rat hippocampus. It was considered important to study the effect of agonists of different types of mGlus on retrieval both of this task and of a related one, contextual fear. OBJECTIVES: To measure the effect of three mGlu agonists (3HPG, which is selective to mGlu1; LCCG, which binds to mGlu2 and mGlu3; and LAP-4, which binds to mGlu4 and mGlu6), infused bilaterally into CA1, on the retrieval of one-trial inhibitory avoidance and contextual fear in rats. METHODS: Rats bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus were trained in one-trial step-down inhibitory avoidance or in a contextual fear task and tested for retention 24 h later. The drugs 3HPG, LCCG and LAP-4 were infused into CA1 at different concentration levels 10 min before retention testing. In addition, we studied the effect of these drugs on locomotor and exploratory activity measured in an open field, and on pro- and anti-conflict behaviour in an elevated plus-maze. RESULTS: 3HPG hindered, and LCCG and LAP-4 enhanced, retrieval of the two tasks. In all cases the effects were dose-dependent. The drugs had no effects on open field or plus maze behaviour. CONCLUSIONS: Retrieval of one-trial inhibitory avoidance and of contextual fear is regulated by mGlus in the CA1area of the rat hippocampus. The results suggest that mGlu2s, mGlu3s, mGlu4s and mGlu6s are necessary for retrieval and that mGlu1s play an inhibitory role. The effects are not explainable by nonspecific influences on locomotor or exploratory activity or anxiety levels.
Amino Acids, Dicarboxylic↗
Training in the step-down inhibitory avoidance task time-dependently increases cAMP-dependent protein kinase activity in the entorhinal cortex.
The cAMP/cAMP-dependent protein kinase (PKA) signaling pathway has been implicated in synaptic plasticity changes and memory consolidation. Several cortical structures are involved in the consolidation of memory for inhibitory avoidance. The aim of the present work was to observe the effects of training in the inhibitory avoidance task on the levels of PKA activity in the entorhinal, parietal and posterior cingulate cortex (EC, PARIET and PC), and the medial precentral area (Fr2) of the rat, at different post-training times (0, 1.5, 3 and 6h). PKA activity, assayed using [gamma-32P]ATP and kemptide, a selective substrate, increased in the EC 3 h after training, but no changes were observed in PARIET, PC and Fr2. These results suggest that the late phase of memory consolidation of inhibitory avoidance requires a functional PKA signaling pathway in the EC in a way that a 'peak' of PKA activity is observed.
Animals↗
Effects of infusions of the tyrosine kinase inhibitor radicicol into the hippocampus on short- and long-term memory of the inhibitory avoidance task.
The aim of the present work was to test the role of protein tyrosine kinases (PTKs) on both the short-term memory (STM) and long-term memory (LTM) of the inhibitory avoidance task in rats using the inhibitor of tyrosine kinase, radicicol. Rats implanted with cannulae in the CA1 area of the dorsal hippocampus received a 0.5 microl infusion of radicicol (0.5, 1, 5, 10, 20 microg/ml) or vehicle (water) at different times after training and were tested for STM (1.5 or 3 h) and LTM (24 h). Additionally, one group received radicicol 10 min prior to the test for LTM. Radicicol depressed both STM and LTM when infused before and immediately after training and had no effect on either form of memory when infused 30 or 90 min after training. Radicicol also depressed the retrieval of LTM. Our results indicate that memory formation and retrieval in the hippocampus can involve PTK activity, but the present findings should be taken merely as a possible starting point for future investigations.
Animals↗
Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade.
It is widely accepted that the formation of long-term memory (LTM) requires neuronal gene expression, protein synthesis and the remodeling of synaptic contacts. From mollusk to mammals, the cAMP/PKA/CREB signaling pathway has been shown to play a pivotal role in the establishment of LTM. More recently, the MAPK cascade has been also involved in memory processing. Here, we provide evidence for the participation of hippocampal PKA/CREB and MAPK/Elk-1 pathways, via activation of NMDA receptors, in memory formation of a one-trial avoidance learning in rats. Learning of this task is associated with an activation of p44 and p42 MAPKs, CREB and Elk-1, along with an increase in the levels of the catalytic subunit of PKA and Fos protein in nuclear-enriched hippocampal fractions. These changes were blocked by the immediate posttraining intra-hippocampal infusion of APV, a selective blocker of glutamate NMDA receptors, which renders the animals amnesic for this task. Moreover, no changes were found in control-shocked animals. Thus, inhibitory avoidance training in the rat is associated with an increase in the protein product of an IEG, c-fos, which occurs concomitantly with the activation of nuclear MAPK, CREB and Elk-1. NMDA receptors appear to be a necessary upstream step for the activation of these intracellular cascades during learning.
2-Amino-5-phosphonovalerate↗
Short- and long-term memory are differentially affected by metabolic inhibitors given into hippocampus and entorhinal cortex.
Rats were implanted with cannulae in the CA1 area of the dorsal hippocampus or in the entorhinal cortex and trained in one-trial step-down inhibitory avoidance. Two retention tests were carried out in each animal, one at 1.5 h to measure short-term memory (STM) and another at 24 h to measure long-term memory (LTM). The purpose of the present study was to screen the effect on STM of various drugs previously shown to affect LTM of this task when given posttraining at the same doses that were used here. The drugs and doses were the guanylyl cyclase inhibitor LY83583 (LY, 2.5 microMg), the inhibitor of Tyr-protein kinase at low concentrations and of protein kinase G (PKG) at higher concentrations lavendustin A (LAV, 0.1 and 0.5 microMg), the PKG inhibitor KT5823 (2.0 microMg), the protein kinase C (PKC) inhibitor staurosporin (STAU, 2.5 microMg), the inhibitor of calcium/ calmodulin protein kinase II (CaMKII) KN62 (3.6 microMg), the protein kinase A (PKA) inhibitor KT5720 (0.5 microMg), and the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059 (PD, 0.05 microMg). PD was dissolved in saline; all the other drugs were dissolved in 20% dimethyl sulfoxide. In all cases the drugs affected LTM as had been described in previous papers. The drugs affected STM and LTM differentially depending on the brain structure into which they were infused. STM was inhibited by KT5720, LY, and PD given into CA1 and by STAU and KT5720 given into the entorhinal cortex. PD given into the entorhinal cortex enhanced STM. LTM was inhibited by STAU, KN62, KT5720, KT5823, and LAV (0.5 microMg) given into CA1 and by STAU, KT5720, and PD given into the entorhinal cortex. The results suggest that STM and LTM involve different physiological mechanisms but are to an extent linked. STM appears to require PKA, guanylyl cyclase, and MAPKK activity in CA1 and PKA and PKC activity in the entorhinal cortex; MAPKK seems to play an inhibitory role in STM in the entorhinal cortex. In contrast, LTM appears to require PKA and PKC activity in both structures, guanylyl cyclase, PKG, and CaMKII activity in CA1, and MAPKK activity in the entorhinal cortex.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Participation of hippocampal metabotropic glutamate receptors, protein kinase A and mitogen-activated protein kinases in memory retrieval.
The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. In contrast to memory formation, the information about the molecular mechanisms of memory retrieval is surprisingly scarce and fragmentary. Here we show that pretest inhibition of the specific upstream activator of mitogen-activated protein kinase kinase, or of protein kinase A in the hippocampus, blocked retrieval of long-term memory for an inhibitory avoidance task, a hippocampal-dependent learning task. An activator of protein kinase A enhanced retrieval. Mitogen-activated protein kinase activation increased in the hippocampus during retrieval, while protein kinase A activity remained unchanged. Pretest intrahippocampal blockade of metabotropic glutamate receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, but not N-methyl-D-aspartate receptors or calcium/calmodulin dependent-protein kinase II, impaired retrieval. Thus, recall of inhibitory avoidance activates mitogen-activated protein kinase, which is necessary, along with metabotropic glutamate receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, and protein kinase A, for long-term memory expression. Our results indicate that memory formation and retrieval may share some molecular mechanisms in the hippocampus.
Animals↗
Differential role of hippocampal cAMP-dependent protein kinase in short- and long-term memory.
One-trial step-down inhibitory (passive) avoidance training is followed by two peaks of cAMP-dependent protein kinase (PKA) activity in rat CA1: one immediately after training and the other 3 h later. The second peak relies on the first: Immediate posttraining infusion into CA1 of the inhibitor of the regulatory subunit of PKA, Rp-cAMPS, at a dose that reduces PKA activity during less than 90 min, cancelled both peaks. Long-term memory (LTM) of this task measured at 24 h depends on the two peaks: Rp-cAMPS given into CA1 0 or 175 min posttraining, but not between those times, blocked LTM. However, the effect of immediate posttraining Rp-cAMPS on LTM could not be reversed by the activator of the regulatory subunit of PKA, Sp-cAMPS, given at 180 min, which suggests that, for LTM, the first peak may be more important than the second. When given at 0, 22, 45, or 90, but not at 175 min from training, Rp-cAMPS blocked short-term memory (STM) measured at 90 or 180 min. This effect of immediate posttraining Rp-cAMPS infusion on STM but not that on LTM was readily reversed by Sp-cAMPS infused 22 min later. On its own, Sp-cAMPS had effects exactly opposite to those of the inhibitor. It enhanced LTM when given at 0 or 175 min from training, and it enhanced STM when given at 0, 22, 45, or 90 min from training. These findings show that STM and LTM formation require separate PKA-dependent processes in CA1. STM relies on the continued activity of the enzyme during the first 90 min. LTM relies on the two peaks of PKA activity that occur immediately and 180 min posttraining.
Animals↗
6-Methyl-3'-bromoflavone, a high-affinity ligand for the benzodiazepine binding site of the GABA(A) receptor with some antagonistic properties.
6-Methyl-3'-bromoflavone inhibited [(3)H]flunitrazepam binding to the benzodiazepine binding site of the GABA(A) receptor (BDZ-bs) with Ki values between 10 and 50 nM in different brain regions. The GABA ratio of 1.03 for [(3)H]flunitrazepam binding to cerebral cortex, 0.76 for cerebellum, 0.7 for hippocampus, 0.7 for striatum, and 0.8 for spinal cord indicated an antagonistic or weak inverse agonistic profile of 6-methyl-3'-bromoflavone on BDZ-bs. Unlike classical benzodiazepines, it had no anticonvulsant, anxiolytic, myorelaxant, sedative, amnestic or motor incoordination effects. However, it antagonized the muscle relaxant, the sedative effect, and the changes in locomotor activity induced by diazepam. Taken together, these findings suggest that 6-methyl-3'-bromoflavone has an antagonistic profile on the BDZ-bs.
Animals↗
Pharmacological characterization of 6-bromo-3'-nitroflavone, a synthetic flavonoid with high affinity for the benzodiazepine receptors.
6-Bromo-3'-nitroflavone is a synthetic flavone derivative that selectively recognizes benzodiazepine receptors and has potent anxiolytic-like effects. Here, we describe in detail its pharmacological characterization. When i.p. injected in mice, 6-bromo-3'-nitroflavone (0.01-0.3 mg/kg) had an anxiolytic-like effect in the elevated plus-maze test. This effect was blocked by the specific benzodiazepine receptor antagonist, flumazenil. In addition, it exhibited anxiolytic-like actions when given orally (1 mg/kg). 6-Bromo-3'-nitroflavone did not exhibit myorelaxant effects (up to 30 mg/kg, i.p.). Unlike diazepam, this flavonoid produced no anterograde amnesia in a one-trial inhibitory avoidance learning. On the other hand, 6-bromo-3'-nitroflavone possessed mild anticonvulsant activity (0.1 mg/kg, i.p.) and provoked sedative-depressant actions only at doses 100-1000 times higher than those producing anxiolytic-like effects. 6-Bromo-3'-nitroflavone (0.1-1 mM) produced a lower potentiation of gamma-amino-butyric acid (GABA)-stimulated 36Cl- influx (126-138%) in comparison to diazepam (0.1 mM: 166%) in cerebral cortical membrane vesicles. Taken together, these findings suggest that 6-bromo-3'-nitroflavone has anxiolytic-like action possibly behaving as a partial agonist of the benzodiazepine receptors.
Animals↗
Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats.
cAMP/cAMP-dependent protein kinase (PKA) signaling pathway has been recently proposed to participate in both the late phase of long term potentiation in the hippocampus and in the late, protein synthesis-dependent phase of memory formation. Here we report that a late memory consolidation phase of an inhibitory avoidance learning is regulated by an hippocampal cAMP signaling pathway that is activated, at least in part, by D1/D5 receptors. Bilateral infusion of SKF 38393 (7.5 microg/side), a D1/D5 receptor agonist, into the CA1 region of the dorsal hippocampus, enhanced retention of a step-down inhibitory avoidance when given 3 or 6 h, but not immediately (0 h) or 9 h, after training. In contrast, full retrograde amnesia was obtained when SCH 23390 (0.5 microg/side), a D1/D5 receptor antagonist, was infused into the hippocampus 3 or 6 h after training. Intrahippocampal infusion of 8Br-cAMP (1.25 microg/side), or forskolin (0.5 microg/side), an activator of adenylyl cyclase, enhanced memory when given 3 or 6 h after training. KT5720 (0.5 microg/side), a specific inhibitor of PKA, hindered memory consolidation when given immediately or 3 or 6 h posttraining. Rats submitted to the avoidance task showed learning-specific increases in hippocampal 3H-SCH 23390 binding and in the endogenous levels of cAMP 3 and 6 h after training. In addition, PKA activity and P-CREB (phosphorylated form of cAMP responsive element binding protein) immunoreactivity increased in the hippocampus immediately and 3 and 6 h after training. Together, these findings suggest that the late phase of memory consolidation of an inhibitory avoidance is modulated cAMP/PKA signaling pathways in the hippocampus.
Animals↗
Systemic administration of ACTH or vasopressin reverses the amnestic effect of posttraining beta-endorphin or electroconvulsive shock but not that of intrahippocampal infusion of protein kinase inhibitors.
Retrograde amnesia was induced in rats trained in step-down inhibitory avoidance by four different treatments: an ip injection of beta-endorphin (1.0 microgram kg), an electroconvulsive shock (ECS), an intrahippocampal infusion of the calcium/calmodulin protein kinase II inhibitor, KN62 (0.08 microgram/side), given 0 h after training, or an intrahippocampal infusion of the protein kinase A inhibitor, KT5720 (0.5 microgram/side), given 3 h after training. Pretest ip injections of ACTH (0.2 microgram/kg) or vasopressin (10.0 micrograms/kg), but not saline, reversed the amnesia caused by beta-endorphin and ECS but not that caused by the enzyme inhibitors. This suggests that the amnesia produced by intrahippocampal KN62 and KT5720 administration is stronger than that caused by ECS and beta-endorphin, possibly because the former interfere directly with specific steps of the core biochemical chain of events that underlies memory consolidation.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine receptor have no effect on memory tasks in rats.
The naturally occurring flavonoids, chrysin (5,7-dihydroxyflavone) and apigenin (5,7,4'-trihydroxyflavone), and the synthetic compound, 6,3'-dinitroflavone have been recently reported to selectively bind with high affinity to the central benzodiazepine receptor, and to exert powerful anxiolytic and other benzodiazepine-like effects in rats. Their chemical analog, quercetin, shares none of these effects. In the present article we find that, in contrast to diazepam, chrysin, apigenin, and 6,3'-dinitroflavone have no amnestic effect on acquisition or retention of three different learning tasks (inhibitory avoidance, shuttle avoidance, and habituation to an open field), even when given at doses higher than those previously reported to be anxiolytic. Apigenin had a slight enhancing effect on training session performance and, when given posttraining, on test session retention, of crossing responses in the open field and hindered retention of inhibitory avoidance, and showed no anxiolytic action in an elevated plus maze. Unlike diazepam, none of these drugs had any analgesic effect in the tail-flick test. The data suggest that chrysin, apigenin, and 6,3'-dinitroflavoine, three flavonoids derivatives possessing anxioselective effects acting on central benzodiazepine receptors, may deserve clinical trials as anxiolytic agents.
Animals↗
Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala.
Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or in the amygdala were trained in one-trial step-down inhibitory (passive) avoidance using a 0.4 mA footshock. At various times after training (0, 1.5, 3, 6 or 9 h for animals implanted in the hippocampus; 0 or 3 h for those implanted in the amygdala), they received infusions of 8-Br-cAMP (cyclic adenosine monophosphate) (1.25 micrograms/side), SKF38393 (7.5 micrograms/side), SCH23390 (0.5 microgram/side), norepinephrine ClH (0.3 microgram/side), timolol ClH (0.3 microgram/side), 8-HO-DPAT (2.5 micrograms/side), NAN-190 (2.5 micrograms/side), forskolin (0.5 microgram/side) or KT5720 (0.5 microgram/side). Rats were tested for retention 24 h after training. SKF38393 is an agonist and SCH23390 an antagonist at dopamine D1 receptors, timolol is a beta-adrenoceptor antagonist, 8-HO-DPAT is an agonist and NAN-190 an antagonist at 5HT1A receptors, forskolin enhances adenylyl cyclase, and KT5720 inhibits protein kinase A. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory and KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF 38393, noradrenaline and NAN-190 caused memory facilitation, and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia. At 9 h from training, all treatments were again ineffective. When given into the amygdala 0 or 3 h post-training all treatments were ineffective, except for noradrenaline at 0 h, which caused retrograde facilitation. The data agree with the suggestion that in the hippocampus, but not the amygdala, a cAMP/protein kinase A pathway is involved in memory consolidation at 3 and 6 h from training, and that this is regulated by D1, beta, and 5HT1A receptors. This correlates with a previous report of increased cAMP levels, protein kinase A activity and P-CREB levels at 3-6 h from training in rat hippocampus in this task. This may be taken to suggest that the hippocampus, but not the amygdala, is involved in the long-term storage of step-down inhibitory avoidance in the rat.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Late and prolonged post-training memory modulation in entorhinal and parietal cortex by drugs acting on the cAMP/protein kinase A signalling pathway.
Rats implanted bilaterally with cannulae in the entorhinal or posterior parietal cortex or in the amygdaloid nucleus were trained in one-trial step-down inhibitory (passive) avoidance using a 0.3 mA footshock. At 0, 3, 6 or 9 h after training, they received localized 0.5 microliter infusions into these areas of a vehicle, or of 8-Br-cAMP, forskolin (adenylyl cyclase activator), KT5720 (protein kinase A inhibitor), SKF38393 (dopamine D1 receptor agonist), SCH23390 (D1 antagonist), norepinephrine hydrochloride, timolol hydrochloride (beta blocker), 8-HO-DPAT (5-HT1A receptor agonist) or NAN-190 (5-HT1A antagonist) dissolved in 20% dimethylsulfoxide (DMSO) in saline (vehicle). Rats were tested for retention 24 h after training. 8-Br-cAMP, forskolin, SKF 38393 and norepinephrine caused memory facilitation and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia when given into the entorhinal cortex 0, 3 or 6 h but not 9 h after training. When given into the posterior parietal cortex 0, 3 or 6 but not 9 h after training, KT5720 was amnestic. When given into this structure 3 or 6 h but not 0 or 9 h after training 8-Br-cAMP, forskolin and norepinephrine caused memory facilitation and KT5720, SCH23390 and timolol caused retrograde amnesia. All treatments given into the amygdala 0, 3 or 6 h after training were ineffective except for norepinephrine given at 0 h, which caused facilitation. The data point to a role of cAMP/protein kinase A-dependent mechanisms in memory formation in the entorhinal and parietal cortex, but not the amygdala, from 0 to 6 h after training, and to a strong modulation of these mechanisms by dopaminergic D1, beta-noradrenergic and 5-HT1A receptors. The lack of effect of NAN-190 but not 8-HO-DPAT in both cortical regions suggests that 5-HT1A receptors do not play a physiological role but can be activated pharmacologically. The fact that SCH23390 was amnestic but SKF38393 had no effect when given into the parietal cortex suggests that D1 receptors may play a maintenance rather than a stimulant role in this area.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Agents that affect cAMP levels or protein kinase A activity modulate memory consolidation when injected into rat hippocampus but not amygdala.
Male Wistar rats were trained in one-trial step-down inhibitory avoidance using a 0.4-mA footshock. At various times after training (0, 1.5, 3, 6 and 9 h for the animals implanted into the CA1 region of the hippocampus; 0 and 3 h for those implanted into the amygdala), these animals received microinfusions of SKF38393 (7.5 micrograms/side), SCH23390 (0.5 microgram/side), norepinephrine (0.3 microgram/side), timolol (0.3 microgram/side), 8-OH-DPAT (2.5 micrograms/side), NAN-190 (2.5 micrograms/side), forskolin (0.5 microgram/side), KT5720 (0.5 microgram/side) or 8-Br-cAMP (1.25 micrograms/side). Rats were tested for retention 24 h after training. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory whereas KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF38393, norepinephrine and NAN-190 caused memory facilitation, while KT5720, SCH23390, timolol and 8-OH-DPAT caused retrograde amnesia. Again, at 9 h after training, all treatments were ineffective. When given into the amygdala, norepinephrine caused retrograde facilitation at 0 h after training. The other drugs infused into the amygdala did not cause any significant effect. These data suggest that in the hippocampus, but not in the amygdala, a cAMP/protein kinase A pathway is involved in memory consolidation at 3 and 6 h after training, which is regulated by D1, beta, and 5HT1A receptors. This correlates with data on increased post-training cAMP levels and a dual peak of protein kinase A activity and CREB-P levels (at 0 and 3-6 h) in rat hippocampus after training in this task. These results suggest that the hippocampus, but not the amygdala, is involved in long-term storage of step-down inhibitory avoidance in the rat.
8-Bromo Cyclic Adenosine Monophosphate↗
Anxioselective properties of 6,3'-dinitroflavone, a high-affinity benzodiazepine receptor ligand.
6,3'-Dintroflavone is a synthetic flavone derivative with high affinity for central benzodiazepine receptors that has anxiolytic effects. Here, we describe its biochemical and pharmacological characterization. 6,3'-Dinitroflavone inhibited differentially [3H]flunitrazepam binding to central benzodiazepine receptors in several brain regions, showing a lower Ki value in the cerebellum (central benzodiazepine receptor type I-enriched area), and a higher Ki value in the spinal cord and in the dentate gyrus (central benzodiazepine receptor type II-enriched area). When i.p. injected in mice, 6,3'-dinitroflavone had a potent anxiolytic effect in the elevated plus maze test. This effect was blocked by the specific central benzodiazepine receptor antagonist, Ro 15-1788. 6,3'-Dinitroflavone did not exhibit anticonvulsant or myorelaxant effects in mice or amnestic effects in rats. Moreover, it abolished the myorelaxant effect of diazepam. On the other hand, 6,3'-dinitroflavone possessed a mild sedative action only at doses 100-300-fold greater than the anxiolytic one. Based on these findings, we suggest that 6,3'-dinitroflavone has a benzodiazepine partial agonist profile, with low selectivity for central benzodiazepine receptor types I and II.
Animals↗