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Query: UMLS:C0220723 (PCA)
 4,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The results of our recent investigations have suggested that tolerance and cross-tolerance development to motor-impairing and hypothermic effects of ethanol was slowed when brain serotonin (5-HT) was extensively depleted by treatment with p-chlorophenylalanine (p-CPA). These findings have been extended by the observation that p-PCA also slowed the development of tolerance to motor-impairing effects of barbital whether tolerance was tested repeatedly in the same animal or in separate subgroups being tested only once. Additional support was provided by the demonstration that intracerebral injection of 5,7-dihydroxytryptamine (-DHT), which is known to deplete 5-HT markedly, also slowed the development of tolerance to motor-impairing and hypothermic effects of ethanol. In addition, when brain 5-HT level was elevated by administration of L-tryptophan, the rate of tolerance development to ethanol, as measured by motor impairment and hypothermia, was accelerated. In contrast to 5,7-DHT, intracerebral injection of 5,6-DHT was surprisingly found to accelerate the development of tolerance to ethanol. Upon further investigation, however, it was determined that the 5,6-DHT treatment depleted brain 5-HT levels by only 20% and, in addition, resulted in the development of supersensitivity. These results further confirm and extend the generality of our observations that 5-HT may be involved in the development of tolerance and cross-tolerance to sedatives. The possibility of a non-specific vs. specific effect of the serotoninergic system (as well as other aminergic systems) in tolerance and neuroplasticity deserves further investigation. The possible significance of these findings and the role of 5-HT (and noradrenaline) in the mechanism of tolerance are discussed in terms of analogy to enzyme or receptor mechanism.
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PMID:Role of serotonin in tolerance to ethanol and barbiturates: evidence for a specific vs. non-specific concept of tolerance. 16 Aug 66

Two different forms of hypermotility produced by the amphetamine derivatives PCA and H 77/77, 5 mg/kg of each, was studied in rats treated s.c. with the new 5-HT uptake inhibitor paroxetine. The substance inhibited the effect of PCA but did not influence that of H 77/77. The 5-HT-uptake inhibitors paroxetine, imipramine, and chlorimipramine were also administered p.o. at various times before PCA. The three substances inhibited PCA-induced hypermotility. Paroxetine 0.5-2 mg/kg, was active at intervals of 1-4 h and 4 mg/kg was active at 18-h interval. Imipramine and chlorimipramine 25-30 mg/kg showed PCA inhibition at treatment intervals of 1-2h, but 80-100 mg/kg or more was required to inhibit PCA at intervals of 4 and 18 h. Previous results have shown that PCA-induced hypermotility is antagonized by substances inhibiting 5-HT synthesis and uptake, whereas H 77/77-induced hypermotility is inhibited by substances blocking NA synthesis, uptake, and receptors. The previous and present results indicate that paroxetine is a selective 5-HT-uptake inhibitor. After oral administration paroxetine presumably produces a more potent and long-lasting 5-HT-uptake inhibition than imipramine and chlorimipramine.
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PMID:Influence of the new 5-HT-uptake inhibitor paroxetine on hypermotility in rats produced by p-chloroamphetamine (PCA) and 4,alpha-dimethyl-7-tyramine (H 77/77). 41 48

Treatment with the 5-HT neurotoxins p-chloroamphetamine (PCA, 2 X 10 mg/kg) or 5,7-dihydroxytryptamine (5,7-DHT, 2 X 6 microgram intracerebrally) stimulated the display of all aspects of sexual behavior, including ejaculations, by castrated male rats in the absence of testosterone (T) treatment and increased the behavioral sensitivity to a low level of T stimulation. The reduction of the (3H) 5-HT uptake after PCA treatment was more pronounced in the cortex than in the hypothalamus. 5,7-DHT treatment reduced the (3H) 5-HT uptake in the septum, hippocampus, amygdala, hypothalamus and cortex but the behavioral effects produced by the 5,7-DHT treatment could not be correlated to the biochemical effects in any of these brain areas. Since the behavioral effect of PCA appears to be stronger than that of 5,7-DHT, the 5-HT neurotoxins may exert their effect on sexual behavior in forebrain structures rather than in the hypothalamus. PCA treatment had a very small effect on mounting behavior but 5,7-DHT treatment stimulated the display of mounts and intromission patterns by ovariectomized female rats given no hormone treatment. Neither PCA nor 5,7-DHT had any effect on lordosis behavior tested before and after treatment with estradiol benzoate alone or in combination with progesterone. The observations support the conclusion that 5-HT is involved in the control by T of sexual behavior in male rats, but argue against a role of 5-HT in the neural control of lordosis behavior.
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PMID:Effects of p-chloroamphetamine and 5,7-dihydroxytryptamine on the sexual behavior of gonadectomized male and female rats. 73 36

Ipsapirone (1.25-10 mg kg-1), a non-benzodiazepine anxiolytic drug with high affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, increased dose-dependently the number of punished licks in the drinking conflict test (Vogel test) in rats. The anticonflict effect of the drug administered at a dose of 5 mg kg-1 was not modified in animals with lesions of 5-HT neurones, produced by p-chloroamphetamine (PCA, 2 x 10 mg kg-1). The anticonflict effect of ipsapirone in PCA-pretreated rats was antagonized by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)]butylpiperazine hydrobromide; 0.5-1 mg kg-1), but not by the selective alpha 1-adrenoceptor blocker prazosin (0.5 mg kg-1). Neither NAN-190 nor prazosin affected the punished response in PCA-pretreated rats. The present results indicate that the anticonflict effect of ipsapirone depends on stimulation of postsynaptic 5-HT1A receptors.
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PMID:Stimulation of postsynaptic 5-HT1A receptors is responsible for the anticonflict effect of ipsapirone in rats. 136 May 35

Alterations in serotonergic function following repeated cocaine injections were examined using neuroendocrine responses to a serotonin (5-HT) releaser and 5-HT agonists. Forty-two hours following administration of cocaine (1-15 mg/kg i.p.) twice daily for 7 or 30 days, male Sprague-Dawley rats were injected with the 5-HT releaser p-chloroamphetamine (PCA; 8 mg/kg i.p.) and blood samples were collected 1 h later for radioimmunoassays of plasma prolactin, plasma renin activity (PRA) and plasma renin concentration (PRC). PCA significantly increased secretion of prolactin and renin. These responses were attenuated in rats pretreated with cocaine for 30 days. In rats receiving cocaine for 7 days, the attenuation of PCA-induced secretion of prolactin and renin was less consistently observed. To determine whether these alterations were due to pre- or postsynaptic effects, rats were injected with cocaine (15 mg/kg i.p.) twice daily for 7 days, and the neuroendocrine responses to the direct 5-HT agonists RU 24969 and m-CPP were examined, 42 h after the last cocaine injection. Pretreatment with cocaine potentiated RU 24969-induced stimulation of plasma prolactin concentration. However, cocaine did not alter the ability of m-CPP to increase plasma prolactin concentrations. The stimulation of renin secretion in response to both 5-HT agonists was not altered by cocaine pretreatment. The data suggest that repeated cocaine impairs the function of serotonergic nerve terminals that regulate these endocrine responses. Furthermore, the 5-HT receptors that mediate prolactin secretion may exhibit supersensitivity.
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PMID:Repeated injections of cocaine inhibit the serotonergic regulation of prolactin and renin secretion in rats. 150 17

The anticonflict activity of ipsapirone, a non-benzodiazepine anxiolytic drug, with high affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, was studied in the drinking conflict test in the rat. The drug, administered in doses 1.25-20 mg/kg increased the number of punished licks, with the maximum effect observed after doses of 5-20 mg/kg of ipsapirone. The anticonflict effect of ipsapirone (5 mg/kg) was dose-dependently antagonized by the 5-HT1A receptor, alpha 1-adrenoceptor and dopamine receptor antagonist, NAN-190 (0.25-1 mg/kg) and by the beta-adrenoceptor blocker, SDZ 21009, which also has a high affinity for 5-HT1A and 5-HT1B receptors (2-8 mg/kg). On the other hand, the non-selective 5-HT receptor antagonist, metergoline (2 and 4 mg/kg), the 5-HT2/5-HT1C receptor antagonist, ritanserin (0.25 and 0.5 mg/kg), the selective alpha 1-adrenoceptor blocker, prazosin (0.25-0.5 mg/kg) and the beta-blockers, betaxolol (8 mg/kg) and ICI 118 551 (8 mg/kg), which have no affinity for 5-HT receptors, did not affect the anticonflict action of ipsapirone. The effect of ipsapirone was also not modified in animals with lesions of 5-HT neurones, produced by p-chloroamphetamine (PCA--2 x 10 mg/kg). These results suggest that the anticonflict effect of ipsapirone in the Vogel test, results from its interaction with 5-HT1A receptors, which are probably located postsynaptically.
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PMID:Evidence for the involvement of 5-HT1A receptors in the anticonflict effect of ipsapirone in rats. 168 48

The antidepressant-like activity of gepirone, a drug with a high and selective affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, was studied in the forced swimming test in rats. The drug, administered intraperitoneally in single doses of 2.5-20 mg/kg, potently and dose-dependently shortened the immobility time. The anti-immobility effect of gepirone (10 mg/kg) was dose-dependently antagonized by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist, NAN-190 (0.25 and 0.5 mg/kg), the beta-adrenoceptor blocker with the affinity for 5-HT1A and 5-HT1B receptors, pindolol (2 and 4 mg/kg), the 5-HT1A, 5-HT2 and dopamine receptor blocker spiperone (0.01 and 0.03 mg/kg) and by the dopamine receptor antagonist, haloperidol (0.125 and 0.25 mg/kg). On the other hand, the non-selective 5-HT receptor antagonist, metergoline (2 and 4 mg/kg), the selective 5-HT2 receptor antagonist, ketanserin (1 and 2 mg/kg), the selective alpha 1-adrenoceptor blocker, prazosin (0.25 and 0.5 mg/kg) and the beta-blockers with no affinity for 5-HT receptors, betaxolol (4 and 8 mg/kg) and ICI 118,551 (4 and 8 mg/kg), did not affect the anti-immobility effect of gepirone. The effect of gepirone was not modified, either, in animals with a lesion of the 5-HT system, produced by p-chloroamphetamine (PCA, 2 x 10 mg/kg) or p-chlorophenylalanine (PCPA, 3 x 300 mg/kg). The results obtained suggest that the anti-immobility effect of gepirone is mediated by activation of 5-HT1A receptors, most probably located postsynaptically and that dopamine may be involved in this action.
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PMID:Involvement of 5-HT1A receptors in the antidepressant-like activity of gepirone in the forced swimming test in rats. 168 49

The substituted amphetamines 4-chloroamphetamine (PCA), 3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine (FEN) share the common neurochemical action of acutely releasing central serotonin (5-HT), and yet their behavioral effects are quite different. The present study evaluated the effects of these compounds on acoustic and tactile startle reflexes. PCA and MDMA were qualitatively similar in producing dose-related increases in acoustic and tactile startle reflexes that were slow in onset, but sustained throughout the 3.5-hr test session. Changes in motor activity did not account for the observed excitation of startle. In marked contrast to MDMA and PCA, FEN did not alter tactile startle and tended to depress acoustic startle. The excitatory effect of 20 mg/kg of MDMA was prevented by the 5-HT uptake blockers MDL 27,777A and fluoxetine. MDMA excitation was not affected by a dose of the dopamine antagonist haloperidol that attenuated the startle-enhancing effect of d-amphetamine. MDMA excitation was greatly attenuated by a general depletion of central 5-HT produced by prior intraventricular injection of the 5-HT neurotoxin 5,7-dihydroxytryptamine. PCA and MDMA excitations of startle were attenuated in rats specifically depleted of spinal 5-HT or in rats with radio frequency lesions of the dorsal raphe nucleus. Thus, PCA and MDMA have similar prolonged excitatory effects on startle reflexes that are mediated by ascending (dorsal raphe) and descending (spinal) pathways, whereas FEN differs in its lack of excitation of startle. Differences in the neurochemical properties of these compounds or their patterns of 5-HT release may underlie their different behavioral profiles.
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PMID:Effects of the serotonin releasers 3,4-methylenedioxymethamphetamine (MDMA), 4-chloroamphetamine (PCA) and fenfluramine on acoustic and tactile startle reflexes in rats. 173 Oct 54

The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of 3H-5-HT than of 3H-DA. The amphetamine derivatives (+/-)fenfluramine, (+/-)norfenfluramine, (+/-)MDE, (+/-)PCA, and d-methamphetamine are all potent releasers of 3H-5-HT and show varying degrees of activity as 3H-DA releasers. The hallucinogen DOM does not cause significant release of either 3H-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting 3H-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.
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PMID:3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine. 182 38

The cytotoxic effects of amphetamine derivatives were studied by immunocytochemistry to identify the cellular compartments affected by these drugs, to obtain morphologic evidence of neuronal degeneration, and to assess the potential for regeneration. The substituted amphetamines, MDA, MDMA, PCA, and fenfluramine, all release serotonin and cause acute depletion of 5-HT from most axon terminals in forebrain. (1) Unequivocal signs of axon degeneration were seen at 36-48 hour survivals: 5-HT axons exhibited increased caliber, huge, swollen varicosities, fragmentation, and dilated proximal axon stumps. (2) Fine 5-HT axon terminals were persistently lost after drug administration, while beaded axons and raphe cell bodies were spared. These two types of 5-HT axons, which arise from separate raphe nuclei and form distinct ascending projections, are differentially vulnerable to psychotropic drugs. (3) From 2-8 months after treatment, there was progressive serotonergic re-innervation of neocortex along a fronto-occipital gradient. Longitudinal 5-HT axons grew into layers I and VI from rostral to caudal, before sprouting into middle cortical layers; this bilaminar pattern of growth simulates perinatal development of 5-HT innervation. This study demonstrates differential vulnerability of 5-HT projections, evidence for axonal degeneration, and sprouting of 5-HT axons leading to re-innervation of forebrain. While the sprouting axons are anatomically similar to the type that was damaged, it is not known whether a normal pattern of innervation is re-established.
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PMID:Neurotoxicity of MDMA and related compounds: anatomic studies. 197 16


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