Effects of (+/-)-huprine Y and (+/-)-huprine Z, two new anticholinesterasic drugs, on muscarinic receptors.

The cholinergic profile of (+/-)-huprine Y and (+/-)-huprine Z on muscarinic receptors has been determined. Displacement of [3H]-pirenzepine and [3H]-QNB plus pirenzepine was performed in rat hippocampus. Both compounds showed a higher degree of affinity to M1 muscarinic receptors (P < 0.01) than to M2 muscarinic receptors. To determine the M1 agonist or antagonist role of the two huprines, studies of inositol phosphates (IP) production were performed. Both huprines significantly stimulated IP accumulation in a concentration-dependent manner. The reversion of this effect by different antagonists showed that M1 muscarinic receptors were activated by (+/-)-huprine Y and (+/-)-huprine Z, but some other mechanisms, such as alpha1-adrenoceptors or nicotinic receptors, were involved.

Interaction of a new potent anticholinesterasic compound (+/-)huprine X with muscarinic receptors in rat brain.

The interaction of rac-12-amine-3-clor-6,7,10,11-tetrahydro-9-ethyl-7-11-methanecyclo-octane[b]quinoline ((+/-)huprine X) with M(1) and M(2) receptors has been studied in rat brain. Specific binding of [(3)H]pirenzepine or [(3)H]quinuclinidylbenzylate to hippocampus preparations was inhibited by (+/-)huprine X. This drug displayed a greater affinity for M(1) (K(i)=0.338+/-0.41 microM) than M(2) (K(i)=4.66+/-0.32 microM) receptors. In functional studies, (+/-)huprine X (1 microM) increased the release of [(3)H]dopamine in cortical synaptosomes, and this effect was partially reverted by atropine and mecamylamine, suggesting an agonistic effect on both M(1) and nicotinic receptors. The inhibitory effect of (+/-)huprine X (10 microM) on [(3)H]acetylcholine release and the subsequent reversion by atropine suggests that the drug also has an agonist effect on M(2) receptors. The present results demonstrate that this acetylcholinesterase inhibitor has an ample cholinergic profile, which suggests a potential source of interest of (+/-)huprine X in Alzheimer's disease therapy.

Synthesis, in vitro pharmacology, and molecular modeling of syn-huprines as acetylcholinesterase inhibitors.

Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (+/-)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect.

Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of new tacrine-like analogues.

The synthesis and preliminary results for acetylcholinesterase and butyrylcholinesterase inhibition activity of a series of pyrano[2,3-b]quinolines (2, 3) and benzonaphthyridines (5, 6) derivatives are described. These molecules are tacrine-like analogues which have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyrans and 6-amino-5-cyanopyridines]-3-carboxylates via Friedlander condensation with selected ketones. These compounds showed moderate acetylcholinesterase inhibition activity, the more potent (2e, 5b) being 6 times less active than tacrine. The butyrylcholinesterase activity of some of these molecules is also discussed.

Different alpha1-adrenoceptor-induced inositol phosphate formation in the two portions of rat vas deferens.

The two portions of rat vas deferens differed in the postjunctional sensitivity to noradrenaline. Alpha1-adrenoceptor-linked phosphoinositide breakdown was analysed in this tissue. The noradrenaline-induced [3H]inositol phosphate accumulation was similar in both ends although the pEC50 was higher in the epididymal (5.97+/-0.07) than in the prostatic (5.47+/-0.15, P<0.01) portion. [3H]Prazosin showed similar density of binding sites in both portions. Tissue pretreated with pertussis toxin did not change [3H]inositol phosphate accumulation. Finally, Western blot analysis indicated a smaller concentration of Gq/11 protein in the prostatic half (-29+/-5%, P<0.01). These results suggest that the different sensitivity to noradrenaline could be due to the higher availability of this sort of G protein in the epididymal portion.

New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease.

Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.

Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.

Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.

Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.

Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.

D2 dopamine receptors and modulation of spontaneous acetylcholine (ACh) release from rat striatal synaptosomes.

1. The effect of two D3/2 dopamine receptor agonists, LY-171555 (quinpirole) and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on spontaneous [3H]-acetylcholine ([3H]-ACh) release were investigated in rat striatal synaptosomes. 2. Quinpirole and 7-OH-DPAT inhibited in a concentration-dependent manner the basal efflux of [3H]-ACh with similar Emax (maximal inhibitory effect) values (29.95 +/- 2.91% and 33.19 +/- 1.21%, respectively). Significant differences were obtained between the pEC50 (-log of molar concentration) of quinpirole (7.87 +/- 0.12) and 7-OH-DPAT (7.21 +/- 0.17; P < 0.01). 3. Different concentrations (0.3-10 nM) of haloperidol (D2/3 dopamine receptor antagonist) shifted to the right the concentration-response curves elicited by quinpirole and 7-OH-DPAT, without modifications in the Emax. 4. Slopes of a Schild plot obtained with haloperidol in the presence of quinpirole and 7-OH-DPAT were not significantly different from unity (0.85 +/- 0.05 and 1.17 +/- 0.11, respectively) and consequently haloperidol interacted with a homogeneous receptor population. The pKB values of haloperidol obtained from Schild regression were 9.96 +/- 0.15 (in presence of quinpirole) and 9.90 +/- 0.09 (in presence of 7-OH-DPAT). 5. Specific binding of [3H]-YM-09151-2 to membranes of striatal synaptosomes and cells expressing D2 and D3 dopamine receptors was inhibited by haloperidol. Analysis of competition curves revealed the existence of a single population of receptors. There were no differences between the estimated pKi (-log of molar concentration) values for synaptosomes (8.96 +/- 0.02) and cells expressing D2 receptors (8.81 +/- 0.05), but the pKi value from cells expressing D3 dopamine receptors differed significantly (8.48 +/- 0.06; P < 0.01). 6. In conclusion, the data obtained in the present study indicate that quinpirole and 7-OH-DPAT, two D3/2 dopamine receptor agonists, inhibit the spontaneous [3H]-ACh efflux and this effect is competitively antagonized by haloperidol and probably mediated through dopamine D2 receptors.

Use of the operational model of agonism and [3H]prazosin binding to assess altered responsiveness of alpha1-adrenoceptors in the vas deferens of spontaneously hypertensive rat.

Changes in functional responsiveness to alpha1-adrenoceptor activation with noradrenaline and in [3H]prazosin binding in the epididymal portion of vas deferens from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were investigated. The operational model fitting and the nested hyperbolic method were used to analyze the effects of irreversible receptor alkylation by phenoxybenzamine (0.1 microM) on the alpha1-adrenoceptor mediated contractile responses to noradrenaline of vasa deferentia from SHR and WKY rats. Saturation isotherms for [3H]prazosin revealed a significant increase (P < 0.05) in the Bmax in SHR vas deferens (145 +/- 19 fmol/mg protein) compared with vas deferens from normotensive controls (75 +/- 12 fmol/mg protein) without changes in the K(D). No differences in the proportion of high and low affinity binding sites for WB-4101 and 5-methylurapidil were observed. The maximum contractile response, alpha, (P < 0.001) and the pEC50 (P < 0.05) values for noradrenaline were greater for SHR than for WKY rat tissues. The apparent affinity (pK(A)) determined by the nested hyperbolic method and by the operational model of agonism was found to be similar in the two strains. In agreement with relative pEC50, the efficacy (tau) value for SHR was greater than for WKY rats. However, the difference in the tau estimates did not reach statistical significance. In summary, in the epididymal portion of SHR vas deferens, the increased maximum contractile response to noradrenaline is due to an increase of Em. Taken together, the tau values and the results from binding experiments lead to the assumption that the transducer constant K(E) must be greater in SHR than in WKY rats, suggesting a deterioration in the transduction of the stimulus provided by the agonist in hypertensive animals.

Alpha 1-adrenoceptor vasoconstriction in the tail artery during ageing.

1. We have studied the alpha 1-adrenoceptor-mediated responses in intact tail artery rings from 3-4 and 20-22 months old Sprague-Dawley rats, focusing on possible endothelial alterations. The influence of nitric oxide released by the endothelium, the number of alpha 1-adrenoceptors and the functional receptor reserve were evaluated to determine their contribution to the contractile response mediated by this receptor. The state of the endothelial layer was assessed by confocal microscopy. 2. Noradrenaline (1 nM-100 microM) induced concentration-dependent vasoconstriction. The maximum contractions to noradrenaline (P < 0.05) and to 75 mM KCl (P < 0.01) were higher in young than in old animals. 3. The density (Bmax) of alpha 1-adrenoceptors and the dissociation constant (KD) obtained in [3H]-prazosin binding experiments were unchanged by age. 4. The apparent affinity (pKA) and the percentage of functional receptors (qx 100) remaining after phenoxybenzamine (0.03 microM) were similar in both age groups. 5. After partial alpha 1-adrenoceptor inactivation with phenoxybenzamine, NG-nitro-L-arginine methylester (30 microM) significantly potentiated the E/[A] curve to noradrenaline in young rats. However, only responses to 0.1 to 1 microM noradrenaline were significantly potentiated in old animals. In addition, 94% of the vessels from young, but only 52% from old rats were relaxed by 80-100% of the noradrenaline (0.03 microM) contraction, with 1 microM acetylcholine. 6. No modifications in the area (micron2) or in the number of endothelial nuclei (per mm2) were observed between age groups. An elongation of the nuclei of endothelial cells was observed in the old animals. 7. These data suggest that the noradrenaline-induced contraction is decreased in old rats probably due to differences in either the contractile machinary or postreceptor mechanisms. These alterations may be accompanied by an impairment of the release or production of NO from endothelial cells.

Endothelial modulation of alpha 1-adrenoceptor contractile responses in the tail artery of spontaneously hypertensive rats.

1. Vascular contraction induced by phenylephrine was studied in tail artery rings from spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) with particular focus on the role of endothelium. The influence of receptor reserve and the density of alpha 1-adrenoceptors on the possible differences observed were also analysed. 2. Phenylephrine (0.01-100 microM) induced concentration-dependent vasoconstrictions. The maximum response (alpha, P < 0.001) was greater but the pEC50 (P < 0.05) smaller in rings from SHR than from WKY rats irrespective of the presence or absence of endothelium. 3. Removal of endothelial cells resulted in a decrease of the maximum contraction with no modification in the pEC50 in arteries from both WKY and SHR. 4. The density of alpha 1-adrenoceptors (Bmax) and the dissociation constant (KD) were found to be the same for preparations from SHR and WKY rats in [3H]-prazosin binding experiments. 5. The apparent affinity (pKA) determined by the nested hyperbolic method and the operational model was similar in tail arteries from the two rat strains, irrespective of the presence or absence of endothelium. However, in endothelium-denuded rings, the pKA value was enhanced when compared with intact rings, in both SHR and WKY rats. 6. In rings from hypertensive rats, the operational parameter maximum possible effect (Em) was greater and the agonist efficacy (tau) was smaller than in rings from normotensive rats. When the endothelium was removed log tau and Em diminished in preparations from both rat strains. 7. In summary, the increased maximum responsiveness to phenylephrine in rings from SHR could be due to enhancement in Em. The log tau values indicate a deterioration in the transduction of the stimulus provided by the agonist in tail arteries from hypertensive animals. This study also suggests that the absence of endothelium modifies the alpha 1-adrenoceptor-mediated vasoconstriction probably by altering the transduction signalling mechanisms. The importance of analysing the degree of endothelium functionality when comparing results from different groups of rats is stated.

Sources of calcium and alpha 1-adrenoceptor-mediated contraction in rat tail artery.

1. The relative importance of intracellular and extracellular Ca2+ on alpha 1-adrenoceptor-mediated contraction by noradrenaline and St-587 has been studied and correlated with the binding characteristics in intact tail artery from Sprague-Dawley rats. 2. Noradrenaline and St-587 behaved as full agonists inducing a concentration-dependent vasoconstriction. 3. Nifedipine (1 microM and 10 microM) blocked by 50% (P < 0.001) and 75% (P < 0.001) respectively, the maximum contraction (Emax) induced by St-587. Nevertheless, to reach 40% inhibition of Emax on noradrenaline responses (P < 0.01), 10 microM nifedipine was necessary. 4. Both agonists induced a concentration-dependent accumulation of inositol phosphates. Noradrenaline behaved as a full agonist and St-587 as a partial agonist for this response. 5. [3H]-prazosin binding to intact tail artery rings was saturable and of high affinity (KD = 4.44 +/- 0.46 nM; Bmax = 36.35 +/- 4.22 fmol mg-1 tissue). 6. Competition curves for inhibition of specific [3H]-prazosin binding by WB-4101 suggest that the rat tail artery contains two alpha 1-adrenoceptor subtypes in an approximate ratio of 60:40. 7. After irreversible alkylation of alpha 1B-adrenoceptors with 100 microM chloroethylclonidine (CEC), nifedipine (1 microM) influenced to a greater extent the St-587- than the noradrenaline-induced contraction. 8. Our results indicate that the degree of participation of intracellular and extracellular Ca2+ sources, on the alpha 1-adrenoceptor-mediated contraction, depends on the agonist used. The two alpha 1-adrenoceptor subtypes observed in binding experiments seem to be unrelated to the Ca2+ sources used for contraction.

Early environmental stimulation produces long-lasting changes on beta-adrenoceptor transduction system.

Long-term behavioral and biochemical effects of exposure to differential early stimulation (postnatal handling and/or enriched environment) were studied in 18- to 20-month-old Sprague-Dawley rats. Postnatal handling treatment was given between 1 and 22 postnatal days. In the enriched environment procedure, the pups were maintained under enriched conditions from weaning until postnatal Day 100. At 18 months of age animals were tested for working memory in an object recognition test, based on the differential exploration of familiar and new objects. Animals reared in the enriched environment performed better in the working memory test than did control or postnatally handled rats. No interaction was observed between postnatal handling and environmental enrichment on cognitive parameters. At 20 months of age, the animals were sacrificed and cyclic AMP formation was determined under basal conditions and after activation of beta-adrenoceptors in cerebral cortex and hippocampus. Both postnatal handling and its combination with exposure to enriched environment significantly increased basal cyclic AMP accumulation in cerebral cortex, but not in the hippocampus. Environmental enrichment was able to induce a long-lasting modification in the responsiveness of the beta-adrenergic neurotransmitter system as reflected by a decreased cyclic AMP accumulation after beta-adrenoceptor activation by means of isoprenaline, in either anatomical structure. It is suggested that manipulations of the environment early in life leading to a reduction in age-related memory deficits produce subtle but long-lasting modifications of noradrenergic transmission.

Action on noradrenergic transmission of an anticholinesterase: 9-amino-1,2,3,4-tetrahydroacridine.

The mechanism by which 9-amino-1,2,3,4-tetrahydroacridine (THA) inhibits beta-adrenoceptor linked cyclic AMP formation and its possible relationship with the cholinergic system were studied. In addition, the effect of THA on alpha 1-adrenoceptor coupled transduction systems was also investigated. THA was not able to influence the concentration-response curve for forskolin indicating that it is not acting on the catalytic subunit of the adenylate cyclase complex. On the other hand a cholinergic component seems to participate in the action of THA on beta-adrenoceptor stimulated adenylate cyclase activity since the blockade of muscarinic receptors with atropine (10 microM) partially prevented the reduction in cyclic AMP formation attained by THA in the hippocampus, in isoprenaline-stimulated conditions. This effect is not reproducible by another potent anticholinesterase physostigmine. Moreover, THA at concentrations up to micromolar did not affect alpha 1-adrenoceptor stimulated cyclic AMP formation or phosphoinositide hydrolysis. In conclusion, the neuropharmacological profile of THA is not to be restricted to the cholinergic system and its effectiveness in improving age-associated cognitive deterioration may involve an action on the beta-adrenoceptor coupled signal transduction system. Moreover, the action of THA on the beta-adrenergic and cholinergic systems in the brain could be relevant to the amelioration of cognitive deterioration and could lead to the development of new therapeutic strategies.

Effects of age on alpha 1-adrenoceptor subtypes in the heart ventricular muscle of the rat.

The effects of ageing on alpha 1-adrenoceptor subtypes have been examined in heart ventricular muscle of young (2-3 months) and middle-aged (18 months) Sprague-Dawley rats. Radioligand binding studies with [3H]prazosin revealed an age-related loss of binding sites (Bmax 56.7 +/- 1.93 fmol (mg protein)-1 age 2 months vs 31.7 +/- 2.45 fmol (mg protein)-1 age 18 months) not followed by changes in the dissociation constant value (Kd 0.16 +/- 0.03 nM age 2 months and 0.10 +/- 0.03 nM age 18 months). Competition curves with WB 4101 showed two distinct sites with different affinities, the proportion of sites with high affinity being similar for both age groups (22.2 +/- 1.89% vs 17.8 +/- 1.96% for animals aged 2 and 18 months, respectively). Agonist displacement curves of [3H]prazosin indicate the existence of two different affinity sites for the agonist, that are maintained regardless of the ageing process (R(high) = 16.2 +/- 1.54% and R(low) = 83.8 +/- 1.89% in rats aged 2 months and R(high) = 16.3 +/- 3.23% and R(low) = 83.7 +/- 3.95% in rats aged 18 months). The fractional inactivation of alpha 1-adrenoceptors by chloroethylclonidine resulted in a loss of [3H]prazosin specific binding, and a percentage of 22.5 +/- 0.95 and 22.6 +/- 4.2 of remaining binding sites for the groups of 2 and 18 months of age, respectively. The percentage of chloroethylclonidine-insensitive [3H]prazosin binding sites was similar to those with high affinity for WB4101. The present study confirms a decline of alpha 1-adrenoceptors with increasing age and reveals that the equilibrium of the expression of the two existing subpopulations of the receptor is maintained during ageing.

Differential effects of physostigmine and 1,2,3,4-tetrahydro-9-aminoacridine on the beta-adrenoceptor transduction system.

The effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) and physostigmine on beta-adrenoceptor-linked cyclic AMP accumulation have been analyzed in vitro in rat cortex and hippocampus. A 10-min incubation with increasing concentrations of THA reduced isoprenaline (10 microM)-stimulated cyclic AMP accumulation in a concentration-dependent manner in cortical (IC50 = 1.31 +/- 0.13 microM) and hippocampal (IC50 = 0.02 +/- 0.003 microM) structures. Conversely, physostigmine did not modify cyclic AMP synthesis in any experimental condition. The action of THA was non-competitive since it induced a non-parallel shift to the right of the concentration-response curve for isoprenaline. The differential effects of THA and physostigmine on the beta-adrenoceptor transduction system may account for the difference in their ability to restore cognitive function.

Post-train administration of 9-amino-1,2,3,4-tetrahydroacridine enhances passive avoidance retention and decreases beta-adrenoceptor-linked cyclic AMP formation in middle-aged rats.

The possible involvement of beta-adrenoceptor system in the effectiveness of 9-amino-1,2,3,4-tetrahydroacridine (THA) to attenuate retention deficits exhibited by middle-aged rats in a one-trial passive avoidance task has been investigated. THA (2.5 mg.kg-1), injected i.p. after training, induced a significant increase in test step-through latency (STL) in middle-aged rats. Post-training injection of THA reduced basal and isoprenaline stimulated cyclic AMP accumulation in cortex and hippocampus of every group of rats. It is suggested that the effect of THA on memory processes may involve an action on beta-adrenoceptor-linked cyclic AMP accumulation.

Acute effects of tetrahydroaminoacridine on beta-adrenoceptor-linked cyclic AMP accumulation in brain of young and middle-aged rats.

The effects of acute treatment with 1,2,3,4-tetrahydro-9-aminoacridine (THA), a 4-aminopyridine derivative clinically effective in Alzheimer's disease, on beta-adrenoceptor-linked cyclic AMP accumulation have been investigated in cortical and hippocampal structures of young and middle-aged rats. In a first series of experiments, pretreatment with 2.5 mg/kg THA decreased basal cyclic AMP accumulation. When a phosphodiesterase inhibitor was added to the preparation, THA again decreased cyclic AMP levels in young rats, but failed to significantly modify cyclic AMP accumulation in middle-aged animals. Finally, in isoprenaline-stimulated conditions, acute treatment with tacrine was able to diminish cyclic AMP accumulation in every group of rats. It is suggested that the neurochemical action of THA in mammalian brain is more complex than earlier has been anticipated and may involve an action on beta-adrenoceptors.