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PubMed1983

Biochemical evidence of selective nerve cell changes in the normal ageing human and rat brain.

Atrophy with ageing of human whole brain, entire temporal lobe, and caudate nucleus was assessed in autopsy specimens, by biochemical techniques. Only the caudate nucleus showed changes. Markers for several neurotransmitter systems were also examined for changes with age. In neocortex and temporal lobe of human brain, small decreases were detected in markers of cholinergic nerve terminals, whereas a large decrease (79%) occurred in the caudate nucleus. Findings were similar in striatum from 3--33-month-old rats. No change occurred in binding of [3H]quinuclidinyl benzilate by human samples. Markers of serotonergic terminals were also unchanged in human and rat brain. By contrast, binding of [3H]lysergic acid diethylamide and [3H]serotonin was decreased (32-81%) in human neocortex and temporal lobe, but not in caudate nucleus. A 43% loss of a marker of gamma-aminobutyrate terminals occurred in human neocortex, while [3H]muscimol binding increased (179%). No changes were detected in markers of catecholamine synapses in temporal lobe or rat striatum. Hence, with human ageing there appears to be a loss of markers of gamma-aminobutyrate neurones intrinsic to neocortex and acetylcholine cells intrinsic to the caudate nucleus, as well as a change in postsynaptic serotonin receptors in neocortex. These losses are accompanied by relative preservation of markers of ascending projections from basal forebrain and brain stem.

Aged↗
PubMed1985

Indoleamine-sensitive adenylate cyclase in rabbit retina: characterization and distribution.

Previous histological, electrophysiological, and biochemical reports have addressed the hypothesis that serotonin functions as a neurotransmitter in mammalian retinas. We have tested the effect on the levels of cyclic AMP of the application of exogenous serotonin, 5-methoxytryptamine, melatonin, and 5-methoxydimethyl-tryptamine to isolated, incubated rabbit retinas. All indoleamines tested significantly elevated intracellular levels of cyclic AMP in both light- and dark-adapted, incubated, intact retinas, provided a phosphodiesterase inhibitor was present. In homogenates of rabbit retina, all indoleamines tested also markedly increased adenylate cyclase activity over basal levels. Maximal activity was observed with 50 microM indoleamine; addition of GTP augmented this increase. The increase in enzyme activity persisted in the presence of known antagonists of dopamine and serotonin 5-HT2-receptors, but was blocked by the mixed 5-HT1, 5-HT2-antagonist lysergic acid diethylamide. The retinal locations of this response have also been identified using layer microdissection techniques on freeze-dried samples obtained from rabbit eyecups suprafused with indoleamine plus phosphodiesterase inhibitor. Cyclic AMP levels were measured in discrete retinal layers of both light- and dark-adapted suprafused eyecups, and increased levels were observed primarily in the inner and outer plexiform layers, which contain the synapses of the retinal neurons.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Photoaffinity labeling of the 5-hydroxytryptamine 1A receptor in rat hippocampus.

1-[2-(4-Azidophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (p-azido-PAPP) inhibits [3H]5-hydroxytryptamine [( 3H]5-HT) binding to 5-HT1A and 5-HT1B sites in rat brain with equilibrium dissociation constants (KD) of 0.9 nM and 230 nM, respectively. [3H]p-Azido-PAPP was synthesized and its reversible and irreversible binding properties to the hippocampal 5-HT1A site characterized. [3H]p-Azido-PAPP labeled a single class of sites in rat hippocampal membranes with a KD of 1 nM and a maximal binding density of 370 fmol/mg protein. The pharmacological profile of [3H]p-azido-PAPP binding was consistent with the radioligand's selective interaction with the 5-HT1A receptor. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of membranes preincubated with [3H]p-azido-PAPP and irradiated showed a major band of incorporation of radioactivity at approximately 55,000 daltons. This incorporation could be blocked when membranes were incubated with 1 microM of several agents that have high affinity for 5-HT1A sites [5-HT, 8-hydroxy-2-(di-n-propylamino)tetraline, TVX Q 7821, spiperone, buspirone, d-lysergic acid diethylamide, metergoline]. The results indicate that on photolysis [3H]p-azido-PAPP irreversibly labels a polypeptide that is, or is a subunit of, the 5-HT1A receptor in rat hippocampus.

Affinity Labels↗
PubMed1986

Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex.

Drug interactions with 5-HT1 (5-hydroxytryptamine type 1) binding site subtypes were analyzed in rat frontal cortex. 8-Hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) displays high affinity (Ki 3.3 +/- 1 nM) for 29 +/- 3% of total [3H]5-HT binding in rat frontal cortex and low affinity (Ki 9,300 +/- 1,000) for 71 +/- 4% of the remaining 5-HT1 sites. Therefore, non-5-HT1A binding in rat frontal cortex was defined as specific [3H]5-HT binding observed in the presence of 100 nM 8-OH-DPAT. 5-Methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl) 1 H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), mianserin, and methysergide produce shallow competition curves of [3H]5-HT binding from non-5-HT1A sites. Addition of 10(-3) M GTP does not increase the apparent Hill slopes of these competition curves. Computer-assisted iterative curve fitting suggests that these drugs can discriminate two distinct subpopulations of non-5-HT1A binding sites, each representing approximately 35% of the total [3H]5-HT binding in the rat frontal cortex. All three 5-HT1 binding site subtypes display nanomolar affinity for 5-HT and 5-methoxytryptamine. A homogeneous population of 5-HT1A sites can be directly labeled using [3H]8-OH-DPAT. These sites display nanomolar affinity for 8-OH-DPAT, WB 4101, RU 24969, 2-(4-[4-(2-pyrimidinyl)-1-piperazinyl] butyl)-1,2-benzisothiazol-3-(2H)one-1, 1-dioxidehydrochloride (TVX Q 7821), 5-methoxydimethyltryptamine, and d-lysergic acid diethylamide. The potencies of RU 24969, TFMPP, and quipazine for [3H]5-HT binding are increased by addition of 100 nM 8-OH-DPAT and 3,000 nM mianserin to the [3H]5-HT binding assay. Moreover, the drugs have apparent Hill slopes near 1 under these conditions. This subpopulation of total [3H]5-HT binding is designated 5-HT1B. By contrast, methysergide and mianserin become more potent inhibitors of residual [3H]5-HT binding to non-5-HT1A sites in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969. The drug competition curves under these conditions have apparent Hill slopes of near unity and these sites are designated 5-HT1C. Drug competition studies using a series of 24 agents reveals that each 5-HT1 subtype site has a unique pharmacological profile. These results suggest that radioligand studies can be used to differentiate three distinct subpopulations of 5-HT1 binding sites labeled by [3H]5-HT in rat frontal cortex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

[3H]1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine: a selective radioligand for 5-HT1A receptors in rat brain.

1-[2-(4-Aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (PAPP) inhibits [3H]5-hydroxytryptamine (5-HT, serotonin) binding to 5-HT1A and 5-HT1B sites in rat brain with apparent equilibrium dissociation constants (KD) of 2.9 and 328 nM, respectively. [3H]PAPP was synthesized, its binding to central serotonin receptors was examined, and its potential usefulness as a 5-HT1A receptor radioligand was evaluated. With either 10 microM 5-HT or 1 microM 8-hydroxy-2-(di-n-propylamino)tetralin to define nonspecific binding, [3H]PAPP bound to a single class of sites in rat cortical membranes with a KD of 1.6 nM and a maximal binding density (Bmax) of 162 fmol/mg of protein. d-Lysergic acid diethylamide and 5-HT, two nonselective inhibitors of [3H]5-HT binding, displaced 1 nM [3H]PAPP with a potency that matched their affinity for 5-HT1 receptors. Spiperone and 8-hydroxy-2-(di-n-propylamino)tetralin, two compounds that discriminate [3H]5-HT binding to 5-HT1A and 5-HT1B sites, inhibited [3H]PAPP binding in accordance with their much higher affinities for the 5-HT1A receptor subtype. Furthermore, the ability of N-(m-trifluoromethylphenyl)piperazine and ketanserin to inhibit [3H]PAPP binding reflected their low affinities for the 5-HT1A receptor. Several nonserotonergic compounds were also found to be relatively poor displacers of [3H]PAPP binding. The regional distribution of serotonin-sensitive [3H]PAPP sites correlated with the densities of 5-HT1A receptors in the cortex, hippocampus, corpus striatum, and cerebellum of the rat. These results indicate that [3H]PAPP binds selectively and with high affinity to 5-HT1A receptor sites in rat brain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1981

An electropharmacological analyses of the effects of some drugs on neuromuscular transmission in the vas deferens of the guinea-pig.

1 The effects of several drugs upon the excitatory junction potential (e.j.p.) in the guinea-pig vas deferens have been investigated. 2 Amiodarone, a noradrenergic neurone blocker which also blocks both alpha and beta-adrenoreceptors, did not reduce the e.j.p. 3 The alpha-adrenoreceptor antagonists, azapetine, piperoxan and prazosin, only enhanced the e.j.p. irrespective of their relative potencies at alpha 1 and alpha 2-adrenoreceptors. 4 Sotalol, a beta-adrenoreceptor antagonist, was without effect upon the e.j.p. 5 Clonidine and lysergic acid diethylamide, alpha-adrenoreceptor agonists, produced a dose dependent inhibition of the e.j.p. without apparently affecting the frequency or size of spontaneous junction potentials. 6 The effects of clonidine were antagonized by piperoxan in a competitive reversible manner. 7 It is argued that these results confirm the presence of alpha-adrenoreceptors prejunctionally upon the sympathetic excitatory innervation of the vas deferens but that although an endogenous alpha-adrenoreceptor agonist is released by nerve stimulation either the transmitter that is responsible for the e.j.p. is not noradrenaline or that the postjunctional receptors responsible for the generation of the e.j.p. are not adrenoreceptors.

Adrenergic alpha-Agonists↗
PubMed1959

The pharmacology of a molluscan smooth muscle.

The effects of a number of pharmacologically active substances on contraction and on membrane polarization of the anterior byssal retractor muscle of Mytilus edulis, L., have been studied. Tetramethylammonium bromide, trimethyl(4-oxopentyl)ammonium chloride and nicotine, like acetylcholine, produced depolarization and sustained contraction. Nicotine, on repeated application, lost acetylcholine-like activity and effectively blocked acetylcholine. In order of decreasing potency, methanthelinium, tubocurarine, benzoquinonium, tetraethylammonium, atropine, pentamethonium, and decamethonium blocked acetylcholine action. These agents did not show initial acetylcholine-like action and did not relax sustained contractions. Adrenaline, noradrenaline, tyramine, dibenamine, phentolamine, and lysergic acid diethylamide relaxed sustained contractions without reducing initial depolarization and tension development in response to acetylcholine or electrical stimuli. Adrenaline and noradrenaline often caused depolarization and contraction when first applied, and displayed relaxing action on subsequent application.

Acetylcholine↗
PubMed1960

Pharmacologically active peptides in the blood and urine of animals infected with Babesia rodhaini and other pathogenic organisms.

The blood and urine of mice and rats infected with Babesia rodhaini contain substances which stimulate the isolated guinea-pig ileum and rat duodenum. The amount of active material excreted increases as the infection increases. The active substances are stable to boiling with hydrochloric acid but not with alkali; they pass through a cellophane membrane and are soluble in hot ethanol. They are destroyed rapidly by papain and less rapidly by chymotrypsin, but are unaffected by trypsin or pepsin. Their action on smooth muscle is not affected by atropine, eserine, antihistamines, iproniazid, bretylium or by lysergic acid diethylamide. The active substances are probably peptides and there is evidence that the urine contains a mixture of peptides, some of which relax and some of which contract the rat duodenum. Similar active peptides appear in the urine of mice infected with Plasmodium berghei, Trypanosoma rhodesiense, Streptococcus pyogenes and Rift Valley fever virus.

Animals↗
PubMed1960

Apomorphine-induced pecking in pigeons.

Apomorphine produced persistent pecking in pigeons, the latent period, intensity and duration of which were related to the dose. The ED50 was estimated as 78.1+/-11.1 mug./kg. On chronic administration of apomorphine there was a significant decrease in latent period and weight which quickly returned to normal on stopping the drug. No conditioning and no tolerance were observed. The uncertain emetic effect of apomorphine in pigeons has been confirmed. Ten other centrally acting agents tested (caffeine, cocaine, 5-hydroxytryptamine, lysergic acid diethylamide, methamphetamine, morphine, nalorphine, pentylenetetrazol, strychnine, and yohimbine) failed to produce similar effects in pigeons.

Animals↗
PubMed1964

SOME ACTIONS OF CENTRALLY ACTIVE AND OTHER DRUGS ON THE TRANSMISSION OF SINGLE NERVE IMPULSES THROUGH THE ISOLATED SUPERIOR CERVICAL GANGLION PREPARATION OF THE RABBIT.

The effect of some centrally-active and other drugs on the transmission of single nerve impulses through the isolated superior cervical ganglion preparation of the rabbit has been studied by recording both preganglionic and postganglionic action potentials. Block of conduction in the axon could be distinguished from block of the synaptic mechanism. The drugs did not appear to exert any one characteristic form of blocking action. A continuous spectrum of drug action linked an agent such as meprobamate which acted predominantly on the synapse to benactyzine which acted mainly by blocking axonal conduction. The drugs have been divided into three groups. Group I: hexamethonium, meprobamate, paraldehyde, amylobarbitone, methylpentynol and azacyclonal; these acted relatively selectively at the ganglion. Group II: N714C (the cis-isomer of chlorprothixene), prochlorperazine, methylpentynol carbamate, pipradrol, promethazine, perphenazine and procaine; the action of these drugs on the ganglion could be accounted for entirely in terms of their axonal depressant action. Group III: chlorprothixene, promazine, N720 (dihydrochlorprothixene), chlorpromazine, hydroxyzine and benactyzine; these drugs also blocked axonal conduction but in addition they appeared to exert a "facilitating" action at the ganglionic synapse. The actions of adrenaline, adrenochrome, iproniazid, ergotoxine, mescaline and lysergic acid diethylamide on transmission were also studied. The implications of the modifications of ganglionic transmission produced by these drugs is discussed.

Action Potentials↗
PubMed1974

The response of the cat anococcygeus muscle to nerve or drug stimulation and a comparison with the rat anococcygeus.

1 The cat anococcygeus muscle is shown to possess a dual innervation similar to the rat anococcygeus, with a motor adrenergic innervation and an inhibitory innervation whose transmitter is unknown. The pharmacological properties of the cat muscle were investigated and compared with those of the rat muscle.2 The cat muscle contracts to noradrenaline, 5-hydroxytryptamine, tyramine, amphetamine, guanethidine, cocaine and lysergic acid diethylamide (LSD). The effects of noradrenaline and 5-hydroxytryptamine are blocked by phentolamine and methysergide respectively.3 The cat anococcygeus is relaxed by acetylcholine, carbachol, isoprenaline, ATP, prostaglandins E(1), E(2) and F(2alpha) and vasopressin, all of which contract the rat muscle. The effects of acetylcholine and carbachol are blocked by atropine and those of isoprenaline by propranolol.4 Field stimulation produces contraction of the cat anococcygeus, which is blocked by phentolamine and guanethidine but unaffected by hexamethonium, atropine or neostigmine.5 In the presence of guanethidine (10(-5)M), the tone of the muscle is raised and field stimulation produces relaxation of the muscle. These inhibitory responses are unaffected by phentolamine, hexamethonium, atropine or neostigmine.6 Neostigmine potentiates the effects of acetylcholine, but not of carbachol in relaxing the cat anococcygeus and in contracting the rat anococcygeus, but has no effect on either motor or inhibitory responses to field stimulation.7 Cold storage for up to eight days had little effect on either the motor response to noradrenaline or the motor or inhibitory response to field stimulation of the cat anococcygeus. Beyond eight days, the response to field stimulation diminishes more rapidly than the response to noradrenaline.

Amphetamine↗
PubMed1975

Timid singly-housed mice: their value in prediction of psychotropic activity of drugs.

1 About 45% of singly-housed male mice showed timidity (alert postures, running away, defensive postures) instead of aggression on interactions in pairs with group-housed male mice, though their partners did not show any aggression. The isolation-induced timidity was stable in repeated interactions. Timid mice also showed locomotion (walking across cage and rearing) and a small amount of sociable activity (sniffing, following partners and climbing over them). 2 Diazepam (5 mg/kg), chlordiazepoxide (20 mg/kg), chlorpromazine (7.5 mg/kg) and barbitone (60 mg/kg) given orally inhibited the isolation-induced timidity without reducing other motor activities in the timid mice. Imipramine lessened timidith only in a dose (80 mg/kg) which also decreased other components of behaviour in the timid isolates. (+)-Amphetamine and lysergic acid diethylamide (LSD) increased the timid response. 3 Comparison of the inhibition of timid activities with changes in other behaviour occurring at the same time seems a better measure of selective timidity-reducing effects of drugs than the rota-rod test. 4 Diazepam (5 mg/kg) increased sociable and locomotor activities. Barbitone (20 and 60 mg/kg) increased sociable activities; however, the higher dose also evoked some aggression in timid mice. 5 Behaviour of timid singly housed male mice seems to be a good measure for prediction of activity of drugs in relieving anxiety as well as for detection of aggression-evoking and sociability-increasing effects of drugs.

Aggression↗
PubMed1978

Pharmacological characterization of the presynaptic alpha-adrenoceptors regulating cholinergic activity in the guinea-pig ileum.

1 The presynaptic alpha-adrenoceptors located on the terminals of the cholinergic nerves of the guineapig myenteric plexus have been characterized according to their sensitivities to alpha-adrenoceptor agonists and antagonists.2 Electrical stimulation of the cholinergic nerves supplying the longitudinal muscle of the guinea-pig ileum caused a twitch response. Clonidine caused a concentration-dependent inhibition of the twitch response; the maximum inhibition obtained was 80 to 95% of the twitch response. Oxymetazoline and xylazine were qualitatively similar to clonidine but were about 5 times less potent. Phenylephrine and methoxamine also inhibited the twitch response but were at least 10,000 times less potent than clonidine.3 The twitch-inhibitory effects of clonidine, oxymetazoline and xylazine, but not those of phenylephrine or methoxamine, were reversed by piperoxan (0.3 to 1.0 mug/ml).4 Lysergic acid diethylamide (LSD) inhibited the twitch response, but also increased the basal tone of the ileum. Mepyramine prevented the increase in tone but did not affect the inhibitory action of LSD. Piperoxan or phentolamine only partially antagonized the inhibitory effect of LSD.5 Phentolamine, yohimbine, piperoxan and tolazoline were potent, competitive antagonists of the inhibitory effect of clonidine with pA(2) values of 8.51, 7.78, 7.64 and 6.57 respectively.6 Thymoxamine was a weak antagonist of clonidine; it also antagonized the twitch-inhibitory effect of morphine. Thus, its effect against clonidine is probably not mediated specifically at presynaptic alpha-adrenoceptors.7 Labetalol, itself, depressed the twitch response but did not antagonize the inhibitory effect of clonidine on the residual twitch.8 The results demonstrate that the presynaptic alpha-adrenoceptors in the guinea-pig ileum are of the same type as those located presynaptically in sympathetically innervated tissues. They are alpha(2)-adrenoceptors and are different from those located postsynaptically.

Acetylcholine↗
PubMed1979

Effects of drugs on behaviour of aggressive mice.

1 The occurrence of 11 aggressive and non-aggressive activities was observed in aggressive male mice treated with drugs in paired interactions with non-aggressive males given water. Effects of chlordiazepoxide, diazepam, barbitone, chlorpromazine, imipramine, (+)-amphetamine, lysergic acid diethylamide (LSD) all given orally and of intraperitoneal scopolamine were investigated.2 Scopolamine (0.25 and 0.75 mg/kg), (+)-amphetamine (0.25 and 1 mg/kg), chlorpromazine (2.5 mg/kg), diazepam (10 mg/kg) and chlordiazepoxide (50 mg/kg) reduced aggressive activities (attacks, aggressive unrest) without inhibiting walking across the cage or rearing in the aggressive mice. Thus, the inhibition of aggression induced by these drugs does not seem to be due to neuromuscular impairment and seems to this extent specific. On the other hand, imipramine lessened aggressive activities only at a dose (80 mg/kg) which also decreased walking across the cage and rearing. Barbitone or LSD did not change aggression at either dose tested (20 and 60 or 0.01 and 1 mg/kg, respectively). Aggressive activities were increased significantly only by chlordiazepoxide at a dose of 5 mg/kg.3 (+)-Amphetamine (0.25 mg/kg) and scopolamine (0.75 mg/kg) increased escapes and alert postures, respectively, in the aggressive mice.4 Diazepam and chlordiazepoxide decreased tail rattling at 1 and 5 mg/kg, respectively, doses 10 times lower than those inhibiting attacks. The other drugs tested inhibited tail rattling only at doses reducing attacks. Tail rattling appears to be a convenient measure for testing effects of drugs on behavioural conflict.5 Diazepam (5 and 10 mg/kg), chlordiazepoxide (20 and 50 mg/kg), barbitone (60 mg/kg) and scopolamine (0.25 and 0.75 mg/kg) increased sociable activities (sniffing, following partners and climbing over them) whereas (+)-amphetamine, chlorpromazine, imipramine and LSD did not. Effects of the drugs on sociable activities in aggressive mice seem to correlate with their action on punished responding and other types of suppressed behaviour.

Aggression↗
PubMed1979

Shape change of blood platelets--a model for cerebral 5-hydroxytryptamine receptors?

1. In blood platelets of rabbits isolated by a stractan gradient and incubated in a protein-poor medium, tryptamine, 5-hydroxytryptamine (5-HT) and derivatives, quipazine and mescaline caused a shape change. This shape change was inhibited by low concentrations of methysergide. 2. The most potent antagonists of the 5-HT-induced shape change included ergoline derivatives and neuroleptic drugs, which showed high stereoselectivity. 3. (+)-Lysergic acid diethylamide ((+)-LSD), psilocine and some N',N'-dimethylated tryptamines acted as mixed agonist-antagonists. 4. The compounds found to be agonists or mixed agonist-antagonists on platelets have previously been shown to act also as 5-HT agonists in the central nervous system (CNS). 5. With regard to 5-HT antagonists, the 5-HT receptors of platelets reacted differently from those described earlier in brain areas with dense 5-hydroxytryptaminergic innervation, but showed similarities to 5-HT receptors investigated previously in spinal cord, cerebral cortex and possibly reticular formation. 6. It is concluded that platelets may be considered with caution as models for some, but not for all, 5-HT receptors in the CNS.

Adenosine Diphosphate↗
PubMed1981

Cocaine cue in pigeons: time course studies and generalization to structurally related compounds (norcocaine, WIN 35,428 and 35,065-2) and (+)-amphetamine.

1 Pigeons trained to discriminate between the presence or absence of effects induced by cocaine hydrochloride (5.6 mg/kg) were tested for generalization with norcocaine and two phenyltropane analogues (WIN 35,428 and WIN 35,065-2). Separate dose-effect curves were obtained at different intervals after the injections so that possible changes both in potency and duration of action could be evaluated.2 Results showed that all of these drugs fully generalized to cocaine. The order of potency was WIN 35,428 > norcocaine > WIN 35,065-2 > cocaine when tested either at 15 or 60 min after injection. The cocaine-like effects were strongest for all drugs when tested 15 min after injection as compared to the tests at the 60 min interval. The decay of the cocaine-like stimulus effects occurred at about the same rate.3 Apomorphine (0.3, 0.56 and 1 mg/kg), morphine (3 and 5.6 mg/kg), Delta(9)-tetrahydrocannabinôl (0.3 and 0.56 mg/kg), and lysergic acid diethylamide (LSD-25, 0.056 and 0.1 mg/kg) did not induce more than 30% cocaine appropriate responses. (+)-Amphetamine produced 73% and 85% cocaine appropriate responses depending on the injection-test interval used, 15 and 30 min respectively.4 The amphetamine homologue, para-hydroxyamphetamine (3.8 mg/kg) did not generalize to cocaine. Tests with 30 mg/kg of procaine produced 40% cocaine appropriate responses. Cocaine is effective also when administered by gavage into the opening of the proventriculus.5 The use of the drug discrimination technique for studying structure activity relationships of drugs is discussed.

Animals↗
PubMed1992

GH4ZD10 cells expressing rat 5-HT1A receptors coupled to adenylyl cyclase are a model for the postsynaptic receptors in the rat hippocampus.

1. Vasoactive intestinal polypeptide (VIP) stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) production by cultured GH4ZD10 cells with an EC50 value of about 7 nM. The extracellularly recovered cyclic AMP predominated, and was reduced by co-incubation with 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) and 5-hydroxytryptamine (5-HT), whereas dopamine (0.1-30 microM) did not reduce VIP-stimulated cyclic AMP production. 2. The responses to 5-HT and 8-OH-DPAT were blocked by (-)-alprenolol and NAN 190. The antagonism by (-)-alprenolol was competitive in nature with a pA2 value of 7.0. 3. The responsiveness of the cells to 5-HT agonists was highly dependent upon the culturing conditions used. Thus, 8-OH-DPAT inhibition of VIP (30 nM)-stimulated cyclic AMP production decreased with increasing passage number of the cells. Reduction of the zinc concentration used to promote expression of the 5-HT1A receptor gene produced a greater sensitivity of the cells to 5-HT agonists. 4. Under such conditions, the following efficacies (5-HT = 100) were found: lisuride 106, (+)-lysergic-acid diethylamide 100, 5-methoxy-N,N-dimethyltryptamine 98, RU 24949 98, 5-carboxamidotryptamine 97, (+/-)-8-OH-DPAT 90, (+)-8-OH-DPAT 87, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine 86, flesinoxan 79/88, (-)-8-OH-DPAT 62, buspirone 43/50, ipsapirone 46. Spiroxatrine and spiperone had a low intrinsic activity, but reduced the response to 5-HT. These efficacies are similar to those reported in the literature for post-synaptically localized 5-HT1A receptors in the rat hippocampus. Thus, the GH4ZD10 cells serve as a useful in vitro model system for these receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Monoamines and schizophrenia.

The hypothesis that central biogenic amines may play a role in the pathophysiology of schizophrenia was originally based upon the fact that hallucinogenic and antipsychotic drugs have profound effects on central transmitter pathways where dopamine, noradrenaline and serotonin are involved. The structural similarities between hallucinogenic drugs such as amphetamine and mescaline, and catecholamines on the one hand and lysergic acid diethylamide (LSD) and indolamines such as serotonin on the other hand have by direct experimentation been shown to explain their important effects on the transmitter systems. The marked effect of several classes of chemically different antipsychotic drugs on central dopamine receptor function formed the basis for the dopamine hypothesis regarding the mechanisms of action of these drugs and also for the hypothesis that dopamine D2 receptor function played a significant role in the pathophysiology of schizophrenia. Direct experimental analysis of aminergic functions in the brain of schizophrenic patients, both during life and post mortem, has been and will for the foreseeable future continue to be a rational approach to the further elucidation of the validity of these hypotheses. Analysis of metabolite levels in the cerebrospinal fluid and plasma of schizophrenic patients has shown great variation in the results with reports of both elevated and reduced release of amines in the brains of schizophrenic patients. Analysis of the aminergic receptor structures in the postmortem human brain has relatively consistently revealed an increased density of D2 receptors in the major basal ganglia of schizophrenic patients. Whether these alterations represent a primary feature of brain structure in schizophrenia or a drug-induced effect still remains to be shown. Positron emission tomographic (PET) scan studies of D2 receptors in schizophrenia have demonstrated both increased densities and absence of change in the characteristics of D2 receptors in the patients as compared to matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipsychotic Agents↗