Activity-dependent metaplasticity of inhibitory and excitatory synaptic transmission in the lamprey spinal cord locomotor network.
Paired intracellular recordings have been used to examine the activity-dependent plasticity and neuromodulator-induced metaplasticity of synaptic inputs from identified inhibitory and excitatory interneurons in the lamprey spinal cord. Trains of spikes at 5-20 Hz were used to mimic the frequency of spiking that occurs in network interneurons during NMDA or brainstem-evoked locomotor activity. Inputs from inhibitory and excitatory interneurons exhibited similar activity-dependent changes, with synaptic depression developing during the spike train. The level of depression reached was greater with lower stimulation frequencies. Significant activity-dependent depression of inputs from excitatory interneurons and inhibitory crossed caudal interneurons, which are central elements in the patterning of network activity, usually developed between the fifth and tenth spikes in the train. Because these interneurons typically fire bursts of up to five spikes during locomotor activity, this activity-dependent plasticity will presumably not contribute to the patterning of network activity. However, in the presence of the neuromodulators substance P and 5-HT, significant activity-dependent metaplasticity of these inputs developed over the first five spikes in the train. Substance P induced significant activity-dependent depression of inhibitory but potentiation of excitatory interneuron inputs, whereas 5-HT induced significant activity-dependent potentiation of both inhibitory and excitatory interneuron inputs. Because these metaplastic effects are consistent with the substance P and 5-HT-induced modulation of the network output, activity-dependent metaplasticity could be a potential mechanism underlying the coordination and modulation of rhythmic network activity. (+info)
The role of serotonin in craving: from basic research to human studies.
Increasing evidence suggests that craving may play a central role in the mechanisms of addiction. The experience of craving is largely characterized by obsessional thoughts about drugs, triggering compulsive drug-seeking and drug-taking behaviour. In the present article the possible involvement of brain 5-hydroxytryptamine (5-HT) in the mechanisms of craving and relapse is discussed by integrating the results of basic research with those obtained in human studies. Based on studies suggesting that the brain serotonergic system plays a central role in the regulation of impulse-control mechanisms, it is proposed that 5-HT deficiency may contribute to the loss of control over drug-taking, which is a crucial factor for the maintenance of addictive behaviour. (+info)
Altered serotonin innervation patterns in the forebrain of monkeys treated with (+/-)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery.
The recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is a potent and selective brain serotonin (5-HT) neurotoxin in animals and, possibly, in humans. The purpose of the present study was to determine whether brain 5-HT deficits persist in squirrel monkeys beyond the 18-month period studied previously and to identify factors that influence recovery of injured 5-HT axons. Seven years after treatment, abnormal brain 5-HT innervation patterns were still evident in MDMA-treated monkeys, although 5-HT deficits in some regions were less severe than those observed at 18 months. No loss of 5-HT nerve cell bodies in the rostral raphe nuclei was found, indicating that abnormal innervation patterns in MDMA-treated monkeys are not the result of loss of a particular 5-HT nerve cell group. Factors that influence recovery of 5-HT axons after MDMA injury are (1) the distance of the affected axon terminal field from the rostral raphe nuclei, (2) the degree of initial 5-HT axonal injury, and possibly (3) the proximity of damaged 5-HT axons to myelinated fiber tracts. Additional studies are needed to better understand these and other factors that influence the response of primate 5-HT neurons to MDMA injury and to determine whether the present findings generalize to humans who use MDMA for recreational purposes. (+info)
Differential pharmacology between the guinea-pig and the gorilla 5-HT1D receptor as probed with isochromans (5-HT1D-selective ligands).
1. Both the 5-HT1D and 5-HT1B receptors are implicated in migraine pathophysiology. Recently isochromans have been discovered to bind primate 5-HT1D receptors with much higher affinity than 5-HT1B receptors. In the guinea-pig, a primary animal model for anti-migraine drug testing, however, isochromans bound the 5-HT1D receptor with lower affinity than the gorilla receptor. 2. This species-specific pharmacology was investigated, using site-directed mutagenesis on cloned guinea-pig receptors heterologously expressed in human embryonic kidney 293 cells. Mutations of threonine 100 and arginine 102 at the extracellular side of transmembrane II of the guinea-pig 5-HT1D receptor to the corresponding primate residues, isoleucine and histidine, respectively, enhanced its affinity for isochromans to that of the gorilla receptor, with little effects on its affinities for serotonin, sumatriptan and metergoline. Free energy change from the R102H mutation was about twice as much as that from the T100I mutation. 3. For G protein-coupling, serotonin marginally enhanced GTPgamma35S binding in membranes expressing the guinea-pig 5-HT1D receptor and its mutants, but robustly in membranes expressing the gorilla receptor. Sumatriptan enhanced GTPgamma35S binding in the latter nearly as much as serotonin, and several isochromans by 30-60% of serotonin. 4. We discovered key differences in the function and binding properties of guinea-pig and gorilla 5-HT1D receptors, and identified contributions of I100 and H102 of primate 5-HT1D receptors to isochroman binding. Among common experimental animals, only the rabbit shares I100 and H102 with primates, and could be useful for studying isochroman actions in vivo. (+info)
Pharmacological studies of the acute and chronic effects of (+)-3, 4-methylenedioxymethamphetamine on locomotor activity: role of 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B/1D) receptors.
The 5-hydroxytryptamine(1B/1D) (5-HT(1B/1D)) antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127935) and 5-HT(1A) antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY 100635) were used to assess whether hyperactivity induced by 3 mg/kg (+)-3, 4-methylenedioxymethamphetamine [(+)-MDMA] is mediated by 5-HT(1B/1D) and/or 5-HT(1A) receptors. Activity in the periphery and center of an open field as well as rearing activity were measured in photobeam monitors. (+)-MDMA-induced peripheral and central activities were blocked by GR 127935 (0.3, 0.625, 1.25, and 2.5 mg/kg); central hyperactivity was blocked by 0.1, 0.3, and 0.625 mg/kg GR 127935. WAY 100635 (0.5-2 mg/kg) had little effect on (+)-MDMA-induced activity except for an enhancement of central activity at one dose (0.5 mg/kg). Central activity induced by (+)-MDMA increased from day 1 to day 5 of treatment with (+)-MDMA (3 mg/kg), whereas peripheral, central, and rearing activity significantly increased in (+)-MDMA-treated rats pretreated daily with GR 127935 (2.5 mg/kg). Withdrawal from (+)-MDMA, but not GR 127935 + (+)-MDMA, pretreatment was associated with heightened hyperactivity induced by the 5-HT(1B/1A) agonist RU 24969 (2 mg/kg i. p.); treatments were not associated with alterations in 5-HT and 5-hydroxyindoleacetic acid content or turnover in frontal cortex. These data support a role for 5-HT(1B/1D) in mediating the acute hyperactivity evoked by (+)-MDMA. The development of sensitization to (+)-MDMA was associated with supersensitivity to a 5-HT(1B/1A) agonist, suggesting that these receptors may contribute to sensitization. However, sensitization to (+)-MDMA developed even under conditions of 5-HT(1B/1D) receptor blockade, which is somewhat counter to this speculation. Perhaps, under circumstances of continued 5-HT(1B/1D) blockade, other mechanisms (e.g., dopamine) predominate in the progressive enhancement of behavior with repeated (+)-MDMA treatment. (+info)
Blockage of mouse muscle nicotinic receptors by serotonergic compounds.
Xenopus laevis oocytes were used to analyse the effects of serotonin (5-hydroxytryptamine, 5-HT) and serotonergic agents on ionic currents elicited by the activation of mammalian muscle nicotinic acetylcholine receptors (AChRs). 5-HT as well as other serotonergic agents, such as ketanserin, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), methysergide, spiperone, or fluoxetine alone (up to 1 mM), did not elicit membrane currents in Xenopus oocytes expressing AChRs, but they reversibly reduced the current elicited by acetylcholine (ACh-current). Serotonin was applied before, together with or after ACh application, and its effects were examined on desensitizing and non-desensitizing ACh-currents. 5-HT reduced the amplitude and accelerated the desensitization of the desensitizing currents. In contrast, non-desensitizing currents were reduced in amplitude but their time course was not significantly affected. With the same concentration of 5-HT the inhibition was stronger on desensitizing than on non-desensitizing ACh-currents. For example, 100 microM 5-HT reduced the peak of a desensitizing ACh-current to 0. 48 +/- 0.06 (peak current ratio) and after 40 s the current was reduced to a ratio of 0.25 +/- 0.04, whereas a non-desensitizing ACh-current was reduced to a ratio of 0.66 +/- 0.01. All the serotonergic agents tested inhibited the ACh-currents rapidly and reversibly, suggesting that they are acting directly on the AChRs. The half-inhibitory concentration, IC50, of 5-HT acting on non-desensitizing currents elicited by 250 nM ACh was 247 +/- 26 microM and the Hill coefficient was 0.88, suggesting a single site for the interaction of 5-HT with the receptor. It appears that 5-HT inhibits AChRs non-competitively because neither the half-effective concentration of ACh, EC50, for ACh-current nor the Hill coefficient were affected by 5-HT. Furthermore, the extent of inhibition of 5-HT on AChRs did not depend on the nicotinic agonist (suberyldicholine, ACh or nicotine). The inhibition of AChRs by serotonergic agents was voltage-dependent. The electrical distance of the binding site for 5-HT was 0.75, whereas for the other serotonergic agents tested it was 0.22, suggesting that ketanserin, 8-OH-DPAT, methysergide, spiperone and fluoxetine act within the ion channel, but at a site more external than that for 5-HT. These substances inhibited the ACh-current more potently than 5-HT. We conclude that 5-HT and serotonergic agents inhibit, in a non-competitive manner, the ACh-current in muscle AChRs by blocking the open receptor-channel complex. Moreover, 5-HT appears to promote the desensitized state of the receptor when the current is elicited by high ACh concentrations. (+info)
Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and alpha-linolenic acid deficient diet in formula-fed piglets.
This study examined the effects of diets deficient (D) in linoleic [18:2(n-6)] and linolenic acid [18:3(n-3)] at 0.8 and 0.05% energy, respectively, or adequate (C) in 18:2(n-6) and 18:3(n-3) at 8.3 and 0.8% energy, respectively, without (-) or with (+) 0.2% energy arachidonic [20:4(n-6)] and 0.16% energy docosahexaenoic [22:6(n-3)] acid in piglets fed from birth to 18 d. Frontal cortex dopaminergic and serotoninergic neurotransmitters and phospholipid fatty acids were measured. Piglets fed the D- diet had significantly lower frontal cortex dopamine, 3,4-dihydroxyphenylacetic (DOPAC), homovanillic acid (HVA), serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations than did piglets fed the C- diets. Frontal cortex dopamine, norepinephrine, DOPAC, HVA, serotonin and 5-HIAA were higher in piglets fed the D+ compared to those fed the D- diet (P < 0.05) and not different between piglets fed the D+ and those fed the C- diets or the C- and C+ diets. Piglets fed the D- diet had lower frontal cortex phosphatidylcholine (PC) and phosphatidylinositol (PI) 20:4(n-6) and PC and phosphatidylethanolamine (PE) 22:6(n-3) than did piglets fed the C- diet (P < 0.05). Piglets fed the D+ diet had higher frontal cortex PC and PI 20:4(n-6) and PC, PE, PS and PI 22:6(n-3) than did piglets fed the D- diet. These studies show that dietary essential fatty acid deficiency fed for 18 d from birth affects frontal cortex neurotransmitters in rapidly growing piglets and that these changes are specifically due to 20:4(n-6) and/or 22:6(n-3). (+info)
p-Chloroamphetamine (PCA) suppresses ingestive behavior in male rats.
Ingestive behavior was activated in male rats by intraoral intake and intake from a bottle of 1-M solution of sucrose. Intraperitoneal injection of p-chloroamphetamine (PCA), releasing central 5-hydroxytryptamine (5-HT) from serotonergic nerve terminals, inhibited ingestion of the sucrose solution. Significant inhibition of sucrose intake by PCA was observed at 1.25 and 2.5 mg/kg dose in a bottle intake test, and at 5.0 mg/kg dose in an intraoral intake test. These findings suggested that 1.25 and 5.0 mg/kg of PCA suppressed appetitive ingestive behavior and consummatory ingestive behavior in male rats, respectively. (+info)