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PubMed1980

The role of GABA and serotonin in the mediation of raphe-evoked spinal cord dorsal root potentials.

The possible involvement of bulbospinal serotonergic systems in the mediation of analgesia has created a need for a better understanding of the influence this system has on neuronal mechanisms in the spinal cord. Therefore, these studies were designed to examine the effects of caudal raphe stimulation on primary afferent depolarization and to determine the role of serotonin (5-HT) and GABA in the mediation of these stimulation-produced effects. Stimulation of the raphe evoked two electrotonically conducted dorsal root potentials (DRP-1 and DRP-2) and two compound action potentials (VRP-1 and VRP-2) which were recorded from the dorsal and ventral roots, respectively. Length constant measurements indicated that DRP-1 was generated in group II and DRP-2 in group I primary afferent fibers. Histological determination of stimulation sites revealed that short-latency potentials (DRP-1 and VRP-1) were evoked from many sites within the caudal brain stem, while the long-latency potentials (DRP-2 and VRP-2) were evoked primarily from sites within the caudal raphe nuclei. The role of serotonin in mediating these evoked potentials was assessed by administering various antagonists of serotonin (cinanserin, methysergide and D-lysergic acid diethylamide). These agents consistently attenuated the long-latency potentials (DRP-2 and VRP-2) but increased the magnitude of DRP-1. The possibility of a GABAergic neuron in the descending systems projecting to primary afferent terminals was studied. Depletion of GABA by semicarbazide blocked DRP-1, but had only a modest effect of DRP-2. However, the putative GABA antagonist, bicuculline, inhibited both DRP-1, and DRP-2. These results suggest that a GABA interneuron is not involved in the bulbospinal serotonergic depolarization of primary afferent terminals. This system appears to constitute a presynaptic filter of afferent input, with the capacity to inhibit different fiber groups.

Afferent Pathways↗
PubMed1985

beta-Adrenoceptor blocking agents recognize a subpopulation of serotonin receptors in brain.

The interaction of beta-adrenoceptor blocking agents with serotonin receptors in rat brain was analyzed by quantitative light microscopic autoradiography using (-) [125I]cyanopindolol (ICYP) as a ligand. In some brain areas such as the globus pallidus and dorsal subiculum, binding of ICYP was blocked with high affinity by some serotoninergic ligands, RU-24969 and serotonin, but not by lysergic acid diethylamide and 8-hydroxy-2-(N,N-di-n-propylamino)tetralin. Some beta-blockers also showed high affinity for these sites. These results supply direct evidence for the labeling of a subclass of serotonin receptors, the 5-HT-1B class, providing anatomical and pharmacological basis for some known serotonin-related effects of beta-adrenoceptor drugs.

Adrenergic beta-Antagonists↗
PubMed1982

Non-opioid psychotomimetic-like discriminative stimulus properties of N-allylnormetazocine (SKF 10,047) in the rat.

The purpose of this study was to characterize the discriminative stimulus property of dl-SKF 10,047 in the rat and to investigate if this property is the result of an interaction with opiate receptors or dopaminergic mechanisms. Male Sprague Dawley rats were trained in a two-lever food-reinforced procedure to discriminate between the effect of saline and of dl-SKF 10,047 (5 mg/kg). The trained rats dose dependently generalized the effect of dl-, d- and l-SKF 10,047, as well as cyclazocine, phencyclidine and ketamine but did not generalize the effect of either fentanyl, morphine, bremazocine, ethylketocyclazocine, pentazocine, nalorphine, naloxone, MR 2266, d-lysergic acid diethylamide, apomorphine or d-amphetamine. Neither naloxone, MR 2266, fentanyl, ethylketocyclazocine nor haloperidol antagonized the discriminative stimulus produced by dl-SKF 10,047. These data suggest that the discriminative stimulus property of dl-SKF 10,047 in the rat is not due to its interaction with either opiate receptors or dopaminergic mechanisms but may be related to its psychotomimetic effect in man.

Animals↗
PubMed1983

Influence of psychotomimetics and lisuride on synaptosomal dopamine release in the nucleus accumbens of rats.

In superfusion experiments with a crude synaptosomal fraction from the nucleus accumbens of rats, lysergic acid diethylamide, mescaline and N,N-dimethyltryptamine (representing different chemical classes of psychotomimetics) produced a concentration-related inhibition of K+-evoked [3H]dopamine release whereas spontaneous release remained unchanged. The nonpsychotomimetic ergoline lisuride tested at the same concentration range did not modulate spontaneous or K+-evoked [3H]dopamine release. The inhibitory effects of the psychotomimetics tested were antagonized by equal concentrations of haloperidol or methiothepine. It is postulated that the effects of psychotomimetics on DA release were triggered via simultaneous action at presynaptic dopamine and 5-hydroxytryptamine receptors which are located at dopamine nerve endings in the nucleus accumbens.

Animals↗
PubMed1987

Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT): implications for understanding the actions of novel anxiolytics.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) has effects both characteristic of a serotonin (5-hydroxytryptamine; 5-HT) agonist and antagonist. To investigate the mechanism(s) of action of 8-OHDPAT in vivo, rats were trained to discriminate 8-OHDPAT (0.4 mg/kg) from saline and given various neuroactive compounds during substitution test sessions. Of the 5-HT agonists tested, d-lysergic acid diethylamide, 5-methoxy-n,n-dimethyltryptamine, quipazine, Ru 24969 and 1-(m-trifluoromethylphenyl) piperazine did not mimic the training drug; the dopamine agonists apomorphine and SKF 38393 as well as the alpha 2-adrenoceptor agonist clonidine engendered predominantly saline-lever responding. However, the novel anxiolytics buspirone and ipsapirone as well as the ergot derivative lisuride substituted completely for 8-OHDPAT. In combination tests, 5-HT (ketanserin, metergoline, methysergide, pirenperone), dopamine (haloperidol) and norepinephrine antagonists (prazosin, propranolol) failed to attenuate the 8-OHDPAT cue. The similar stimulus properties of 8-OHDPAT and the novel anxiolytics (buspirone, ipsapirone) are mirrored by the common abilities of these agents to selectively inhibit 5-HT1A binding and release punished responding. Thus, the subpopulation of 5-HT1A receptors may mediate the behavioral effects of these compounds in animals and, in turn, the anxiolytic effects of buspirone and ipsapirone in humans. Although not primarily selective for 5-HT, lisuride may also mimic 8-OHDPAT by direct or indirect stimulation of 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Drug-induced penile erections in rats: indications of serotonin1B receptor mediation.

The induction of penile erections by a variety of compounds with a direct or indirect effect on serotonin (5HT) receptors was investigated in rats. L-5-Hydroxy-tryptophan (L-5HTP) induced penile erections when co-administered with nialamide and the peripheral decarboxylase inhibitor benserazide, indicating that the site of action for inducing penile erections is within the central nervous system. Penile erections were also induced by the 5HT uptake inhibitors zimelidine, fluoxetine, citalopram, Org 6997, by the 5HT-releasing agent fenfluramine and by the putative 5-HT1B receptor agonist 1-(3'-chlorophenyl)-piperazine (mCPP). The 5HT1A-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) did not induce penile erections. The less selective 5HT receptor agonists 5-methoxy-N,N-dimethyl-tryptamine (5MeODMT), 5-methoxytryptamine (5MeOT), dl-lysergic acid diethylamide (LSD) and Ru 24969 were also ineffective. Induction of penile erections by quipazine appeared only when this compound was co-administered with the 5HT2 receptor antagonist pirenperone. Receptor antagonists were tested against penile erections induced by Org 6997. The beta-adrenoceptor antagonists that also have 5HT1 antagonistic properties, (S)-pindolol and dl-propranolol, antagonized Org 6997-induced penile erections but butoxamine and metoprolol did not. Spiperone and pirenperone in doses selective for 5HT1A and 5HT2 receptors respectively were also inactive. Haloperidol, 0.46 mg/kg, partially attenuated penile erections induction. The data are discussed in the light of the hypothesis that penile erections induction by serotonin-mimetic compounds is mediated by 5HT1B receptors in the striatum.

5-Hydroxytryptophan↗
PubMed1988

A pharmacological analysis of the rat spinal cord serotonin (5-HT) autoreceptor.

The pharmacological characteristics of the presynaptic 5-HT receptor associated with the modulation of 5-HT release were investigated in a preparation of rat spinal cord synaptosomes (nerve terminals) superfused with a Tris-buffered Krebs solution containing fluoxetine (1 microM). The 5-HT receptor agonists serotonin (1-100 nM), lysergic acid diethylamide (10 nM-1 microM) and the 5-HT1B receptor agonists 1-(m-trifluoromethylphenyl)piperazine (100 nM-1 microM) and 1-(m-chlorophenyl) piperazine (100 nM-3 microM) concentration dependently decreased [3H]5-HT release, while 8-hydroxy-2-(di-n-propylamino)tetralin, a selective 5-HT1A receptor agonist, was inactive. The actions of the effective agonists were reversed by quipazine, an antagonist with high affinity for 5-HT1B binding sites, but not by spiperone, a 5-HT1A receptor antagonist. Furthermore, mesulergine, a 5-HT1C receptor antagonist was ineffective in reversing the action of 5-HT on [3H]5-HT release. These data indicate that the rat spinal cord nerve terminal autoreceptor has characteristics similar to the 5-HT1B binding site.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Studies of the biochemical basis for the discriminative properties of 8-hydroxy-2-(di-n-propylamino)tetralin.

The ability of a series of compounds to mimic the stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was compared to: (1) the affinity of these compounds for the 5-HT1A receptor; and (2) their efficacy to inhibit forskolin-stimulated adenylate cyclase activity. Although for nine compounds (flesinoxan, MDL 73005EF, gepirone, ipsapirone, buspirone, tandospirone, yohimbine, L 657,743 and rauwolscine) complete cross generalization was associated with high affinity for the 5-HT1A receptor, eltoprazine, d-lysergic acid diethylamide and BMY 7378 had pKD > 7.44, but did not show complete mimicry of 8-OH-DPAT. In addition, indorenate had a pKD of 7.88, yet the behavioral response was indistinguishable from the saline control. Because the above data indicated that affinity for the 5-HT1A receptor was necessary, but not sufficient for a receptor ligand to mimic 8-OH-DPAT, the in vitro efficacy of the various compounds at the 5-HT1A receptor was determined by measuring inhibition of forskolin-stimulated adenylate cyclase activity in hippocampal membranes. For a series of drugs (gepirone, ipsapirone, flesinoxan, buspirone, tandospirone, yohimbine, L 657,743 and rauwolscine) significant inhibition of forskolin-stimulated adenylate cyclase activity was observed, and these same drugs showed complete cross generalization. However, BMY 14802 and MDL 73005EF did not alter adenylate cyclase activity, yet completely mimicked the stimulus properties of 8-OH-DPAT. Eltoprazine had significant efficacy in inhibiting forskolin-stimulated adenylate cyclase activity, but only 30% of the responses following administration of this drug were on the 8-OH-DPAT-appropriate lever. Furthermore, although indorenate inhibited hippocampal adenylate cyclase activity, the behavioral response to this compound was indistinguishable from the saline control.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan.

The behavioral effects of 5-methoxy-6-methyl-2-aminoindan (MMAI) were examined using the drug discrimination procedure and direct observation for classification of the characteristic syndrome induced by MMAI. The stimulus effects of MMAI were studied in 5 different groups of rats trained to discriminate MMAI (1.71 mg/kg; 8 microM/kg), MDMA (3,4-methylenedioxymethamphetamine; 1.75 mg/kg; 7.6 microM/kg), (+)-MBDB ((+)-N-methylamino-(1,3-benzodioxo-5-yl)-2-butanamine; 1.75 mg/kg; 7.18 microM/kg), (+)-amphetamine (1 mg/kg; 5.4 microM/kg), or LSD ((+)-lysergic acid diethylamide tartrate; 0.08 mg/kg; 186 nM/kg) from saline. In substitution tests in rats trained to discriminate MMAI from saline, all the compounds which fully mimicked MMAI were serotonin (5-hydroxytryptamine, 5-HT) releasing agents. This substitution is symmetrical for MDMA and (+)-MBDB. Nevertheless, the dose-response curve of MMAI is parallel to those of (+)-fenfluramine (m-trifluoromethyl-N-ethylamphetamine) and p-chloroamphetamine. The results also show that MMAI lacks amphetamine-like and LSD-like discriminative stimulus effects, suggesting that MMAI is neither a psychostimulant nor a hallucinogen. Tests of the discriminability of MMAI after 5-HT depletion with the selective serotonin synthesis inhibitor, p-chlorophenylalanine (2 x 200 mg/kg i.p., pretreatment 72 h before test), showed only saline appropriate responding. Prolonged block (ca. 1 week) of the MMAI cue by p-chlorophenylalanine further supports the conclusion that endogenous 5-HT is essential for MMAI discrimination. Fluoxetine (10 mg/kg) or paroxetine (2.5 mg/kg), both selective 5-HT uptake inhibitors, reduced the discriminability of MMAI to 40% and 50%, respectively. None of the antagonists (ketanserin, methiothepin, pindolol, yohimbine, haloperidol) used in antagonism tests inhibited the stimulus properties of MMAI. These results and data from radioligand binding studies support the conclusion that direct activation or inhibition of known neurotransmitter receptors did not play a significant role in the discriminative cue of MMAI. The administration of 5, 10, or 20 mg/kg of MMAI to rats induced a behavioral syndrome consisting of hypolocomotion with accompanying catalepsy-like posture, turning, Straub tail, flat body posture, and suppressed sleeping time. In general, this is qualitatively similar to what is seen after administration of 5-HT precursors or 5-HT receptor agonists. In conclusion, the data from the drug discrimination study and the behavioral syndrome induced by MMAI suggest that MMAI is a potential selective releaser of serotonin.

3,4-Methylenedioxyamphetamine↗
PubMed1995

Characterization of a postjunctional 5-HT receptor mediating relaxation of guinea-pig isolated ileum.

The 5-HT receptor mediating postjunctional relaxation of precontracted guinea-pig ileum has been characterized using several agonists and antagonists. Substance P precontracted tissues were potently relaxed by 5-HT (5-hydroxytryptamine, serotonin), 5-CT (5-carboxamidotryptamine) and several other indoles. The rank order of potency, with pEC50 values in parentheses, was 5-CT (7.6) > 5-methoxytryptamine (5.7) > 5-HT (5.5) > alpha-methyl-5-HT (4.7) > 2-methyl-5-HT (< 4.0) = tryptamine (< 4.0) = N,N-dimethyl-tryptamine (< 4.0) = N,N-dimethyl-5-HT (< 4.0) = dipropyl-5-CT (< 4.0) = sumatriptan (< 4.0). 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin) acted as a potent (6.3), but partial, agonist with respect to 5-HT. The responses to 5-CT were antagonized by several compounds with the following rank order of affinity, with pKB values in parentheses: LSD (lysergic acid diethylamide; 8.1) = mesulergine (7.8) > methysergide (7.6) = spiperone (7.6) > clozapine (7.3) >> (-)-pindolol (< 6.0) > ketanserin (< 6.0) = ondansetron (< 6.0) = GR 113808 ([1-(2-methane-sulphonamido-ethyl)-piperidin-4-yl]-methyl-in dole-3- carboxylate maleate; < 6.0). The relaxant responses to 5-HT were also resistant to tetrodotoxin. These data are consistent with a functional 5-HT receptor, mediating relaxation of guinea-pig ileum, which exhibits an operational profile similar to that of the cloned guinea-pig 5-ht7 receptor. This study, therefore, provides evidence for a functional correlate of the 5-ht7 gene product.

5-Methoxytryptamine↗
PubMed1984

Contamination of serotonin-2 binding sites by an alpha-1 adrenergic component in assays with (3H)spiperone.

(3H)Spiperone binds to two sites in mouse cortical membranes. These binding sites are discriminated by methysergide and prazosin, but not by butaclamol, lysergic acid diethylamide, or ketanserin. One of these sites is serotonergic in nature and is the authentic S-2 binding site. The other component is adrenergic and corresponds to the alpha-1 adrenoreceptor. This alpha-1 component may be present in other S-2 binding assays using (3H)spiperone, or (3H)ketanserin. No (3H)spiperone binding to dopaminergic D-2 sites was found in mouse cortex. Methods of avoiding alpha-1 contamination of S-2 binding assays are suggested.

Animals↗
PubMed1985

Up-regulation of serotonergic binding sites labeled by [3H]WB4101 following fimbrial transection and 5,7-dihydroxytryptamine-induced lesions.

Lesions of the serotonergic afferents to the hippocampus, by fimbrial transection or by 5,7-dihydroxytryptamine treatment, produce an increase in the Bmax of [3H]WB4101 to its nanomolar affinity binding site, with no effect on its picomolar affinity binding site or on [3H]prazosin binding. The nanomolar site is serotonergic as the serotonergic agonists, serotonin and 8-hydroxydipropylaminotetraline (8-OH-DPAT) have nanomolar affinity for [3H]WB4101 binding when studied in the presence of a prazosin mask (30 nM) of the alpha-1 component of [3H]WB4101 binding. The serotonin receptor antagonists metergoline, lysergic acid diethylamide and lisuride also have high nanomolar affinities while ketanserin, yohimbine, prazosin and noradrenergic agonists have affinities in the micromolar range. Fimbrial transection or 5,7-dihydroxytryptamine injections produced 32% and 44% increases in the Bmax of [3H]WB4101 binding in the presence of a prazosin mask. Serotonin competition for [3H]WB4101 binding was identical in control and experimental tissue from each lesion experiment. Although specific binding of [3H]WB4101 was increased, there was no change in the affinities or the percentages of the two binding components for serotonin competition with [3H]WB4101. These data suggest that removal of the serotonergic input to the hippocampus produces an increase in the Bmax of serotonin receptor binding sites labeled by [3H]WB4101.

5,7-Dihydroxytryptamine↗
PubMed1984

Serotonin-S2 receptor binding sites and functional correlates.

Serotonin-S2 receptor binding sites have been labelled with several ligands such as [3H]spiperone, [3H]lysergic acid diethylamide (LSD), [3H]mianserin and [3H]ketanserin, the latter being the most selective ligand. The greatest concentration of the sites occurs in frontal cortical tissue, but they were also detected in striatum, nucleus accumbens and tuberculum olfactorium as well as on membranes of cat and human platelets. The serotonin-S2 sites, labelled with different ligands in different tissues, revealed similar binding properties for drugs, but careful definition of specific binding is necessary because of marked variation in the non-specific binding of drugs in different tissues. Serotonin-S2 sites were demonstrated to have a role in serotonin-induced behavioural excitation in rodents and they probably mediate perception of subjective feelings elicited by serotonin mimetics. In vivo studies revealed involvement of the serotonin-S2 sites in impairment of microcirculation by serotonin and in inflammation provoked by serotonin. On isolated tissues, serotonin-S2 sites mediate serotonin-induced vasoconstriction in peripheral blood vessels (e.g. superficial, coronary, splanchnic vessels) and cerebral blood vessels from various species including man. Serotonin-S2 sites also have a role in serotonin-induced contractions in tracheal smooth muscle and serotonin-induced bronchoconstriction in vivo, but the sites are unrelated to "M"- and "D"-serotonin receptor subtypes, which have been functionally characterized in gastrointestinal smooth muscle. Platelets proved to be an integral model for studying serotonin-S2 sites. Binding, measured on platelet membranes, was shown to be directly related to serotonin-induced platelet aggregation or changes in shape.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Dihydroergocristine-induced stimulation of the 5-HT autoreceptor in the hypothalamus of the rat.

In slices of the hypothalamus of the rat, prelabelled with [3H]5-hydroxytryptamine ([3H]5-HT), dihydroergocristine (DHEC) decreased in a concentration-dependent manner (0.01-1 microM) the release of [3H]transmitter elicited by stimulation. In the presence of phentolamine (1 microM), sulpiride (1 microM), atropine (1 microM) or methiothepin (0.1 microM), the effect of DHEC remained unchanged. However, methiothepin at 1 microM and citalopram at 1 microM antagonized the inhibition induced by DHEC. Methiothepin at 0.1 microM has been shown to be sufficient to shift to the right the concentration-effect curve of D-lysergic acid diethylamide (LSD) on the stimulation-evoked release of [3H]5-HT by a factor of 10. However, in the present experiments, 1 microM methiothepin was required to antagonize the effect of DHEC. Thus, the alpha adrenergic, dopaminergic and cholinergic activities of DHEC do not seem to be responsible for its effect on the release of 5-HT. The lower potency of methiothepin suggests, however, that stimulation of the 5-HT autoreceptor by DHEC may not fully explain the results.

Animals↗
PubMed1978

Effects of N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on shock elicited fighting in rats.

Rats were tested for shock elicited fighting under various doses of N,N-dimethyltryptamine (0.12, 0.25, 0.50, 1.0, 4.0, 8.0 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (0.06, 0.12, 0.5, 2.0 mg/kg). Both drugs produced an inhibition of fighting at higher doses but no significant effects at lower doses. The effects of these drugs on shock elicited fighting, as well as on other behaviors, thus differ from those of another indole hallucinogen, d-lysergic acid diethylamide, and are discussed in relation to their effects on single unit activity of the raphe-serotonin system and their interaction with other neurotransmitter systems.

Aggression↗
PubMed1981

Central 5-hydroxytryptamine and the effects of hallucinogens and phenobarbital on operant responding in rats.

The present study was designed to examine the role of 5-hydroxytryptamine (5-HT) neurons in the behavioral effects of d-lysergic acid diethylamide (LSD), an indolealkylamine hallucinogen, 2.5-dimethoxy-4-methylamphetamine (DOM) and mescaline, phenethylamine hallucinogens, and phenobarbital, a non-hallucinogen. Male rats, maintained at 70-80% of their free-feeding weights, were trained to press a lever for food pellet reinforcement on a fixed ratio-40 operant schedule. When trained, these rats responded at a constant, rapid rate (approximately 100 responses/min) during daily 40 min test sessions. Administration of hallucinogens caused an abrupt cessation of responding (a "pause"), for some portion of the session. The duration of this pause was dose-dependent for LSD (12.5-100 micrograms/kg), DOM (0.125-1.0 mg/kg) and mescaline (7.1-14.2 mg/kg). On the other hand, phenobarbital (12.5-50 mg/kg) did not cause pausing, but resulted in slowed, erratic intrasession response rates. When the same tests were repeated in rats that had previously received an intracerebroventricular injection of 5,7-dihydroxyptamine (5,7-DHT) the dose-response curves for the pausing induced by all three hallucinogens were shifted to the left, while the behavioral disruption produced by phenobarbital was unaltered. In these animals the 5-HT but not the norepinephrine concentrations was markedly reduced in all brain regions examined. These results suggest that 5-HT neurons are involved with the behavioral effects of hallucinogens but not of phenobarbital.

5,7-Dihydroxytryptamine↗
PubMed1981

The behavioral effects of hallucinogens in rats following 5,7-dihydroxytryptamine administration into the medial forebrain bundle.

The hypothesis that 5-hydroxytryptamine (5-HT) neurons and/or receptors are involved in the mechanism of action of hallucinogens is supported by the fact that intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) selectively destroys central 5-HT neurons in the brain and potentiates the behavioral effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. The locus in the brain where this potentiation might occur is not known. In the present experiment, the medial forebrain bundle (MFB) was studied because it is the primary tract containing fibers from the cell bodies in the raphe nuclei to forebrain structures receiving 5-HT input. Male rats received 5,7-DHT (6 micrograms/2 microliter) or vehicle injections bilaterally into the MFB; this procedure caused a significant reduction of 5-HT in the cortex, hippocampus and hypothalamus of lesioned rats, but not in the striatum. Regional dopamine and norepinephrine concentrations were not affected by this treatment. The behavioral effects of the hallucinogens were tested in a situation in which the animals pressed a bar under a fixed ratio-40 (FR-40) schedule of food reinforcement. The disruptive effects of LSD on responding were enhanced in the 5,7-DHT-treated animals, while the effects of DOM were diminished; there was no change in the response to mescaline. These data suggest that, while 5-HT neurons are involved in the behavioral effects of hallucinogens, the precise sites and/or mechanisms of action of LSD, DOM and mescaline may differ.

5,7-Dihydroxytryptamine↗
PubMed1986

Dissociations between the effects of hallucinogens on behavior and raphe unit activity in behaving cats.

The hypothesis that hallucinogenic drugs exert their behavioral effects by an action at pre- or postsynaptic serotonin receptors was evaluated by co-administering various drugs that possess either serotonin agonist or antagonist properties, while concurrently monitoring behavior and the electrophysiological activity of serotonin-containing dorsal and median raphe neurons in freely moving cats. Co-administration of the serotonin receptor blockers, metergoline or mianserin, with lysergic acid diethylamide (LSD) produced no change in the inhibitory effects of LSD on raphe neurons, but produced a dose-dependent blockade of the behavioral effects of LSD in the cat. The latter data suggest that perhaps LSD exerts its behavioral effects by an action at postsynaptic serotonin receptors. Co-administration of drugs that increase synaptic serotonin, L-5-hydroxytryptophan, tranylcypromine, fluoxetine or p-chloramphetamine with LSD greatly potentiated the inhibitory effect of LSD on raphe unit activity, but also produced dose-dependent decreases in these behavioral effects of LSD in the cat. Thus, both enhancing the activity at postsynaptic serotonin receptors and receptor antagonism blocked the behavioral effects of LSD. Co-administration of dopamine receptor blockers, haloperidol or chlorpromazine, produced no significant change in the response of raphe neurons to LSD, but these drugs also produced a dose-dependent blockade of the behavioral effects of LSD in the cat. Co-administration of the dopamine agonists, apomorphine or d-amphetamine, however, potentiated the behavioral effects of LSD, while producing a partial reversal of the inhibitory effects of LSD on raphe unit activity. The results are discussed in the context of using animal models to study the possible actions of hallucinogens in humans.

Animals↗