Serotonin neurotransmission in cocaine sensitization.
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Animals↗
Biomedical subjects
J M Paris
Publications and source records attributed to J M Paris.
Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding.
Repeated cocaine intoxication can result in the development of behavioral sensitization in animals and psychosis in humans, phenomena that have been associated with alterations in dopamine (DA) function. Using electrophysiologic and autoradiographic techniques, modifications of central serotonin (5-hydroxytryptamine; 5-HT) systems were investigated in rats treated with a regimen of cocaine administration that produced behavioral sensitization. The inhibitory response of single 5-HT neurons in the dorsal raphe (DR) to (-)-cocaine, the 5-HT uptake inhibitor fluoxetine or the 5-HT1A agonist 8-hydroxy-2-[di-N-propylamino]tetralin (8-OHDPAT) was significantly enhanced in cocaine-treated rats. Furthermore, several brain areas that contain either cell bodies (DR) or terminals for 5-HT (medial and sulcal prefrontal cortex, frontal cortex) showed cocaine-induced elevations in [3H]imipramine-labeled 5-HT uptake sites, while [3H]-8-OHDPAT-labeled 5-HT1A receptors were decreased only in the central medial amygdala. These results suggest that modifications of autoregulatory mechanisms secondary to alterations of 5-HT uptake processes may contribute to the development of cocaine sensitization.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Lack of serotonin neurotoxicity after intraraphe microinjection of (+)-3,4-methylenedioxymethamphetamine (MDMA).
Systemic administration of 3,4-methylenedioxymethamphetamine (MDMA) produces depletions of serotonin (5-HT) and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA), decreases 5-HT reuptake sites and diminishes tryptophan hydroxylase activity in various forebrain regions. MDMA has been shown to be neurotoxic to the fine fibers originating from dorsal raphe (DR) 5-HT neurons but not the beaded fibers from the median raphe (MR) nucleus. In the present experiment, MDMA was microinjected directly into the DR or MR to determine whether differential neurotoxicity developed in the DR versus MR fiber systems as measured by 5-HT levels and immunocytochemistry. Two weeks following stereotaxic injection with either vehicle or (+)MDMA (50 micrograms base in 2 microliters) into the DR or MR, rat brains were assayed for 5-HT and catecholamine content or 5-HT immunocytochemistry. HPLC analysis revealed no significant changes in monoamine or metabolite concentrations in the hippocampus and striatum of rats administered intra-DR or -MR (+)MDMA. Raphe sections stained for 5-HT also did not reveal any apparent neurotoxicity. A single cerebral injection of (+)MDMA does not produce neurotoxicity to 5-HT neuronal systems originating in the raphe, although neurotoxicity of multiple MDMA injections into these raphe nuclei cannot be ruled out.
3,4-Methylenedioxyamphetamine↗
Antimicrobial activity against Staphylococcus aureus of semisynthetic injectable streptogramins: RP 59500 and related compounds.
Pristinamycin displays unique antibacterial properties due to the synergy between its two components, pristinamycin I and pristinamycin II. Because this antibiotic is not water-soluble, its administration is restricted to the oral route, and its therapeutic potential is thereby limited. Novel water-soluble derivatives of the naturally-occurring antibiotic pristinamycin were obtained by modifications of its two major components. The modifications included regioselective and stereoselective substitution alpha to the carbonyl group in the 4-oxo-pipecolic acid residue of pristinamycin IA (PIA) and stereoselective conjugate addition to the double bond of the dehydroproline ring in pristinamycin IIA (PIIA). We report here the in-vitro and in-vivo activities of some representative water-soluble derivatives of pristinamycin IA and pristinamycin IIA against Staphylococcus aureus reference strains, sensitive or resistant to methicillin and/or macrolides.
Animals↗
Decrease of GABA-immunoreactive neurons in the amygdala after electrical kindling in the rat.
The present study was designed to investigate the effects of electrical kindling in vivo on GABA immunoreactivity (GABA-IR) of the lateral and basolateral amygdaloid nuclei 2-6 months post-stimulation. Male Sprague-Dawley rats were implanted with bipolar electrodes in the basolateral nucleus and stimulated once per day until 3-5 stage 5 seizures were observed. Coronal sections containing the amygdala were processed for GABA-IR using the contralateral side of the brain. Results indicate that, in comparison to controls, fully kindled animals showed a significant decrease in total number of GABA-IR amygdala neurons. Decreases in GABA-positive punctate structures surrounding unlabeled pyramidal cells were also observed, but not quantified. The present data suggest that epileptogenesis of the amygdala is associated with a significant reduction of GABA-IR in the lateral and basolateral areas throughout the contralateral amygdaloid nucleus.
3,3'-Diaminobenzidine↗
Cocaine-induced behavioral sensitization is not associated with loss of GABA-immunoreactive neurons in the amygdala.
We investigated whether cocaine-induced behavioral sensitization (15 mg/kg, twice daily for 7 days) is associated with changes in gamma-aminobutyric acid (GABA) neurons in the lateral-basolateral amygdala of male Sprague-Dawley rats. The number of GABA-immunoreactive neurons in the amygdala did not differ between cocaine- and saline-treated rats. Although some aspects of this behavioral phenomenon parallel the kindling model of epilepsy, limbic alterations in GABA neurons do not appear to be associated with behavioral sensitization to cocaine.
Amygdala↗
Serotonin 5-HT3 antagonists do not alter the discriminative stimulus properties of cocaine.
The central nervous system (CNS) of the rat is known to contain serotonin (5-HT) type -3 receptors (5-HT3). Behavioral evidence suggests that 5-HT3 receptors interact with mesolimbic dopamine (DA) systems and that 5-HT3 antagonists can interfere with the hyperlocomotive effects of amphetamine and cocaine and the rewarding and stimulus effects of morphine, nicotine and ethanol. Cocaine, which blocks the reuptake of DA, norepinephrine (NE), and 5-HT in the CNS, also may be an antagonist at 5-HT3 receptors. The purpose of the present study was to determine whether systemic administration of the 5-HT3 antagonists ICS 205930 or MDL 72222 could mimic or block the discriminative stimulus properties of cocaine. Once rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline, substitution tests with various doses of cocaine (0.313-10 mg/kg), ICS 205930 (2-24 mg/kg), and MDL 72222 (2-16 mg/kg) were conducted. Cocaine produced a dose-related increase in cocaine-appropriate responding while the 5-HT3 antagonists engendered primarily saline-lever responding. Neither ICS 205930 nor MDL 72222 were able to antagonize the stimulus effects of cocaine (5 mg/kg). Response rates were not significantly reduced when the 5-HT3 antagonists were given in combination with cocaine. The results indicate that although 5-HT3 antagonists can inhibit some of the unconditioned behavioral effects of psychomotor stimulants, the discriminative stimulus effects of cocaine remain intact.
Animals↗
Muscimol injections into the median raphe nucleus increase serum ACTH and corticosterone concentrations via a nonserotonergic mechanism.
Midbrain raphe serotonin (5-HT) neurons can influence the pituitary-adrenal axis. The midbrain raphe nuclei also contain a number of non-5-HT neurons, including gamma-aminobutyric acid (GABA) interneurons which can modulate 5-HT neuronal activity. We investigated the effects of intraraphe injections of the GABAA agonist, muscimol, on serum adrenocorticotropin hormone (ACTH) and corticosterone concentrations. Rats were infused with muscimol (0, 25, 50, and 100 ng in 0.5 microliters saline) into the median raphe nucleus (MR). The animals were killed 30 min later, and trunk blood was collected for measurement of serum concentrations of ACTH and corticosterone by radioimmunoassay. Muscimol dose dependently increased plasma concentrations of these two pituitary-adrenal hormones. In order to determine the role of MR 5-HT neurons in these effects, separate groups of implanted animals were infused with either the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) or ascorbic acid vehicle into the MR. Two weeks later, the animals were infused with muscimol (100 ng in 0.5 microliters) and sacrificed as above. Treatment with 5,7-DHT, which markedly reduced hippocampal concentrations of 5-HT (-83%) and 5-HIAA (-73%), did not block intra-MR muscimol-induced elevations in ACTH and corticosterone. Thus, 5-HT neurons within the MR apparently do not mediate the increased activity of the pituitary-adrenal axis produced by stimulation of MR GABAA receptors.
5,7-Dihydroxytryptamine↗
Intra-midbrain raphe injections of the neurokinin-3 agonist senktide inhibit food and water intake in the rat.
Microinjection and lesion studies have implicated the midbrain dorsal (DR) and median raphe (MR) nuclei in behavioral arousal. This behavioral state is manifested as locomotor hyperactivity, hyperphagia, hyperdipsia and increases in plasma corticosteroid release. Intra-midbrain raphe injections of the GABAA agonist muscimol elicit this behavioral activation. We have demonstrated that similar infusions of tachykinins produce locomotor hyperactivity through activation of neurokinin-3 (NK-3) receptors located on serotonin cell bodies. The purpose of the present study was to determine the effects of intra-MR and DR infusions of senktide, an NK-3 agonist, on food and water consumption in nondeprived rats. Male Sprague-Dawley rats were implanted with indwelling intra-MR or intra-DR cannula. Infusions of muscimol (25 ng/0.5 microliters) into the MR increased water intake, while MR and DR infusions increased food consumption. In contrast, intra-MR injections of senktide decreased water intake and intra-MR and DR injections decreased food intake. The results suggest that the behavioral states induced by muscimol and neurokinin infusions into the raphe are distinct and that raphe/neurokinin pathways are involved in consummatory mechanisms.
Animals↗
Behavioral sensitization to cocaine is not associated with changes in serotonin (5-HT) fiber immunoreactivity in rat forebrain.
We investigated whether cocaine-induced behavioral sensitization is associated with changes in serotonin (5-HT) immunoreactivity. Male Sprague-Dawley rats were injected with either cocaine (15 mg/kg, IP) or saline twice daily for seven days. Their behavior was observed and rated for locomotor activation and stereotypy. One day after the final injection, the brains were processed for 5-HT immunohistochemistry. The intensity of 5-HT immunoreactive staining of 5-HT axons and terminal varicosities was blindly rated in cocaine-sensitized rats and found not to differ from saline-treated rats. The results support the hypothesis that unlike some amphetamine derivatives, repeated cocaine administration which results in behavioral sensitization is not neurotoxic to 5-HT axons and terminals in the forebrain.
Animals↗
Neurokinin innervation of the rat median raphe nucleus does not originate in the brain stem.
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Animals↗
Neuronal sites mediating locomotor hyperactivity following central neurokinin agonist administration.
The stable substance P analog, DiMeC7, increases spontaneous locomotor activity after infusion into the lateral ventricles or median raphe nucleus (MRN). The elevated locomotion observed after intracerebroventricular (ICV) infusion of DiMeC7 was attenuated, but not blocked, by bilateral 6-hydroxydopamine (6OHDA) lesions of the ventral tegmental area (VTA). In contrast, bilateral 6OHDA lesions of the nucleus accumbens (NAS) blocked the motor activity induced by ICV administration of DiMeC7. Similar lesions did not affect the increases in motor behavior observed after MRN infusions of DiMeC7. However, the hyperactivity following MRN microinjections of DiMeC7 was attenuated by intraperitoneal administration of the dopamine (DA) antagonist, haloperidol. The results suggest that ICV infusions of DiMeC7 increase locomotor activity by acting directly on neurons in the NAS and in part by influencing, directly or indirectly, the activity of DA cells in the VTA. The increased motor activity seen after MRN administration of DiMeC7 appears to depend on DA neurons but not on projections to the NAS.
Animals↗
Lack of neurotoxicity after intra-raphe micro-injections of MDMA ("ecstasy").
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3,4-Methylenedioxyamphetamine↗
Intra-raphe neurokinin-induced hyperactivity: effects of 5,7-dihydroxytryptamine lesions.
Rats were implanted with cannulae in the median raphe nucleus (MR). 5,7-Dihydroxytryptamine (5,7-DHT) or vehicle was infused either directly through the MR cannula, or bilaterally into the medial forebrain bundle (MFB). The MR 5,7-DHT lesions completely blocked the hyperactivity elicited by injections into the MR of the neurokinin (NK) 3 agonists, DiMe-C7 and senktide, and the NK-2 agonist, neurokinin A. In contrast, the MFB 5,7-DHT lesions did not affect the locomotor hyperactivity produced by intra-MR administration of DiMe-C7 and senktide, but appeared to attenuate the effects of NKA. The data indicate that intra-raphe neurokinin-induced hyperactivity is mediated by 5-HT neurons, and that 5-HT projections to the forebrain may be involved in the behavioral activation induced by intra-raphe neurokinin A administration, but not that induced by intra-MR NK-3 agonists.
5,7-Dihydroxytryptamine↗
A dose-response analysis of intra-raphe tachykinin-induced hyperactivity.
The nonmammalian (eledoisin, kassinin and physalaemin) and mammalian tachykinins (substance P and neurokinin (NK) A), as well as the metabolically stable neurokinin analogs, DiMe-C7 [( pGlu5, MePhe8, Sar9]substance P (5-11)] and senktide, were infused into the median raphe nucleus of rats via chronically implanted cannulas, and their effects on locomotor activity analyzed. The NK-3 receptor agonists, senktide and DiMe-C7, as well as the endogenous NK-2 receptor ligand, NKA, produced dose-dependent increases in locomotor activity. Substance P, eledoisin, kassinin and physalaemin elevated activity but not dose-dependently. Regression analyses demonstrated that senktide and DiMe-C7 were the most potent and efficacious of the peptides tested. The slopes of the senktide and DiMe-C7 dose-response curves were parallel and differed significantly from the slope of the NKA dose-response curve. Infusions of the endogenous NK-3 ligand, NKB (3.0 pmol in 1.0 microliter), also elicited hyperactivity equivalent to that produced by an equimolar dose of senktide. These and previous findings suggest that activation of NK-2 and NK-3 receptors in the midbrain raphe leads to behavioral arousal through their influence on serotonin neurons.
Amino Acid Sequence↗
Hemodialysis materials.
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Biocompatible Materials↗
A comparison of acute stress paradigms: hormonal responses and hypothalamic serotonin.
The effects of stress on plasma renin activity (PRA), plasma prolactin and corticosterone levels, and hypothalamic 5-HT and 5-HIAA concentrations were investigated using a 3 and 12 min conditioned fear (CER) paradigm; 20 min immobilization; 20 min exposure to shallow or deep cold water; 2, 12 and 22 min of intermittent footshock with or without 20 min recovery; and, a 3 min CER with 0, 10, 30 and 60 min recovery. PRA was increased by all the stressors, except shallow cold water, reaching a maximum after 12 min and returning to control values within 10-20 min post-stress. Prolactin levels also were increased by all the stressors, except shallow and deep cold water. Prolactin levels were maximal after 12 min and returned to baseline within 20-60 min post-stress, depending on the stressor. Corticosterone levels were elevated by all the stressors, but not as rapidly as PRA or prolactin, reaching a maximum after about 20 min and returning to baseline concentrations within 30-60 min post-stress. None of the stressors produced significant changes in hypothalamic 5-HT and 5-HIAA concentrations.
Animals↗
Intra-median raphe infusions of muscimol and the substance P analogue DiMe-C7 produce hyperactivity: role of serotonin neurons.
Injections into the midbrain median raphe nucleus (MR) of the metabolically stable substance P analogue, DiMe-C7, produce dose-dependent increases in locomotor activity (LMA). Ibotenic acid (8.0 micrograms in 2.0 microliter vehicle) lesions of the MR block the hyperkinetic effects of optimal doses of both DiMe-C7 (1.0 microgram in 0.5 microliter vehicle) and the GABAA agonist, muscimol (100 ng in 0.5 microliter vehicle). This observation indicates that the increases in LMA produced by intra-MR DiMe-C7 and muscimol infusion are not due to diffusion to sites outside the MR. Intra-MR administration of the selective serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (6.0 micrograms in 1.5 microliter vehicle), following pretreatment with the norepinephrine and dopamine reuptake inhibitor, nomifensine maleate (15 mg/kg, i.p.), blocked the hyperactivity induced by intra-MR infusions of DiMe-C7 (1.0 microgram) but not that of muscimol (100 ng). These observations suggest that the LMA effects of intra-MR DiMe-C7 and muscimol administration are mediated by different neural mechanisms. The LMA effects of DiMe-C7 depend on intact 5-HT neurons in the MR, whereas the effects of muscimol depend on intact non-5-HT MR cells.
5,7-Dihydroxytryptamine↗