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1.
Article in English | MEDLINE | ID: mdl-31918305

ABSTRACT

A simple, sensitive HPLC-MS/MS method was developed and validated for the determination of lidocaine in skin and plasma of rats. The methods were established and validated assessing lower limit of quantitation (LLOQ), linearity, intra and inter-day precision and accuracy, selectivity, recovery and matrix effect. Chromatography was done on a Gemini column embedded with C18 stationary phase (50 mm × 2.0 mm, 5 µm particle size), using a gradient with mobile phases consisting of 0.1% HCOOH in bidistilled water and 0.1% HCOOH in acetonitrile. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring, using target ions m/z 235.10 for lidocaine and m/z 245.10 for lidocaine-d10, used as internal standard. RESULTS: The linearity of the method was in the ranges of lidocaine concentrations 10.0-200.0 ng/mL for skin homogenate (accuracy 94.1-105.5%; R2 ≥ 0.998) and 0.025-2 ng/mL for plasma (accuracy 96.2-104.8%; R2 ≥ 0.996). The intra- and inter-day precision and accuracy determined on three quality control samples (20, 75 and 170 ng/mL for skin and 0.075, 0.4 and 1.5 ng/mL for plasma) were ≤4.2% and 103.8-108.2% for skin and ≤12.4% and 95.5-101.4% for plasma. The LLOQ was 10 ng/mL in skin homogenate and 0.025 ng/mL in plasma. The applicability of the method was demonstrated by measuring lidocaine in skin and plasma after exposure to medicated patches containing 5% lidocaine.


Subject(s)
Chromatography, High Pressure Liquid/methods , Lidocaine/analysis , Tandem Mass Spectrometry/methods , Transdermal Patch , Animals , Drug Stability , Lidocaine/administration & dosage , Lidocaine/pharmacokinetics , Limit of Detection , Linear Models , Male , Rats , Reproducibility of Results , Skin/chemistry
2.
Oncogene ; 35(48): 6212-6222, 2016 12 01.
Article in English | MEDLINE | ID: mdl-27212031

ABSTRACT

Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the C-X-C motif chemokine receptor 4 (CXCR4) pathway were downregulated only in muscles atrophying because of cancer: stromal cell-derived factor 1 (SDF1), adenylate cyclase 7 (ADCY7), and p21 protein-activated kinase 1 (PAK1). Notably, we found that, in the Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 was inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1, suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms (α, ß, γ) also declined in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anticachexia properties restored their expression. Overexpressing genes of this pathway (that is, SDF1 or CXCR4) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1ß had greater total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed time- and dose-dependent reductions in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (that is, CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer.


Subject(s)
Cachexia/etiology , Cachexia/pathology , Chemokine CXCL12/metabolism , Muscular Atrophy , Neoplasms/complications , Neoplasms/metabolism , Receptors, CXCR4/metabolism , Signal Transduction , Animals , Benzylamines , Biomarkers , Cyclams , Cytokines/metabolism , Disease Models, Animal , Female , Gene Expression , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Heterocyclic Compounds/pharmacology , Humans , Indoles/pharmacology , Male , Mice , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Neoplasms/genetics , Pyrroles/pharmacology , Rats , Signal Transduction/drug effects , Sunitinib
3.
Physiol Behav ; 124: 92-9, 2014 Jan 30.
Article in English | MEDLINE | ID: mdl-24184492

ABSTRACT

The environment in which a laboratory animal is housed can significantly influence its behaviour and welfare, acting as a potential confounding factor for those studies in which it is utilised. This study investigated the impact of two Individually Ventilated Cage (IVC) housing systems on anxiety-related behaviour and welfare indicators in two common strains of laboratory mice. Subjects were juvenile female C57BL/6J and BALB/c mice (N=128) housed in groups of four in two different IVC systems for 7weeks. System One had air delivery at the cage 'cover' level at 75 ACH (Air Changes/Hour) and System Two had air delivery at the 'animal' level at 50 ACH. Mice were assessed twice a week (e.g. bodyweight) or at the end of the study (e.g. anxiety tests). Our results showed significant differences in anxiety-related behaviour between strains and housing systems. Mice in System Two, regardless of strain, defecated more in the Elevated Plus Maze (EPM), spent less time in the open arms of the EPM, and less time in the central zone of the Open Field (OF). Strain differences in anxiety-like behaviour were seen in the increased defecation by BALB/c mice in the OF and EPM and less time spent in the open arms of the EPM compared to C57BL/6J mice. These results suggest that different IVC housing systems can influence mouse behaviour in different ways, with mice of both strains studied exhibiting more anxiety-related behaviour when housed in System Two (air entry at the 'animal' level at 50 ACH), which could impact upon experimental data.


Subject(s)
Anxiety/psychology , Behavior, Animal , Housing, Animal , Ventilation/methods , Animals , Anxiety/metabolism , Body Weight , Corticosterone/analysis , Drinking , Eating , Feces/chemistry , Female , Maze Learning , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Species Specificity , Wounds and Injuries/psychology
4.
J Neurochem ; 103(3): 1111-20, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17666043

ABSTRACT

We used the microdialysis technique to compare basal extracellular serotonin (5-HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase-2 (TPH-2), the rate-limiting enzyme in brain 5-HT synthesis. DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele of TPH-2 had less dialysate 5-HT in the medial prefrontal cortex and dorsal hippocampus (DH) (20-40% reduction) than C57BL/6J and C57BL/6N mice carrying the 1473C allele. Extracellular 5-HT estimated by the zero-net flux method confirmed the result of conventional microdialysis. Citalopram, 1.25, 5 and 20 mg/kg, dose-dependently raised extracellular 5-HT in the medial prefrontal cortex of C57BL/6J mice, with maximum effect at 5 mg/kg, but had significantly less effect in DBA/2J and BALB/c mice and in the DH of DBA/2J mice. A tryptophan (TRP) load enhanced basal extracellular 5-HT in the medial prefrontal cortex of DBA/2J mice but did not affect citalopram's ability to raise cortical and hippocampal extracellular 5-HT. The impairment of 5-HT synthesis quite likely accounts for the reduction of basal 5-HT and the citalopram-induced rise in mice carrying the mutated enzyme. These findings might explain why DBA/2 and BALB/c mice do not respond to citalopram in the forced swimming test. Although TRP could be a useful strategy to improve the antidepressant effect of citalopram (Cervo et al. 2005), particularly in subjects with low 5-HT synthesis, the contribution of serotonergic and non-serotonergic mechanisms to TRP's effect remains to be elucidated.


Subject(s)
Citalopram/pharmacology , Hippocampus/metabolism , Neurons/metabolism , Prefrontal Cortex/metabolism , Serotonin/biosynthesis , Tryptophan Hydroxylase/metabolism , Animals , Dose-Response Relationship, Drug , Drug Resistance/genetics , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , Gene Expression Regulation, Enzymologic/genetics , Genotype , Isoenzymes/drug effects , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Microdialysis , Neurons/drug effects , Prefrontal Cortex/drug effects , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Species Specificity , Tryptophan/metabolism , Tryptophan/pharmacology , Tryptophan Hydroxylase/drug effects , Tryptophan Hydroxylase/genetics , Up-Regulation/drug effects , Up-Regulation/genetics
5.
Neuropsychopharmacology ; 28(6): 1150-9, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12700684

ABSTRACT

Previous studies employed a second-order schedule paradigm maintained by cocaine reinforcement to show that BP897, a dopamine D(3) partial agonist, selectively modulated drug-seeking behavior. We investigated its effect on drug-seeking behavior induced by presentation of stimuli associated with and predictive of cocaine availability after a period of extinction and in the absence of any further cocaine. Male rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous (i.v.) 0.25 mg/0.1 ml/infusion cocaine (S(D+)) or no-reward (S(D-)) saline solution. Each infusion of cocaine or saline was followed by a response-cue signaling 20-s time-out (TO). After meeting the self-administration training criterion rats were placed on extinction conditions during which i.v. solutions and S(D)s were withheld. Every other 3 days on which rats met the extinction criterion, reinstatement tests were conducted, presenting the S(D+) or S(D-) noncontingently together with a contingent presentation of cocaine- or saline-cues signaling 20-s TO. Regardless of the order of presentation or the nature of the stimuli (auditory or visual), cocaine-associated but not saline-associated stimuli reinstated responding on the previously active lever. Presentation of cocaine-associated stimuli induced lasting drug-seeking behavior for at least eight test sessions. BP897 (1.0 mg/kg i.p.) significantly attenuated this behavior. Since it has been reported that BP897 can interact with a panel of different receptors with high affinity, we evaluated the effects of 7-OH-DPAT, an agonist to D(3) receptors, raclopride, a preferential antagonist to D(2) receptors, and WAY 100,635, an antagonist at 5-HT(1A) receptors, on drug-seeking behavior. 7-OH-DPAT (0.1-3.0 mg/kg i.p.) had biphasic effects on reinstatement induced by the cocaine-associated cues, low dosages reducing and high dosages increasing the impact of cocaine-associated stimuli on rats' behavior. Raclopride (0.1, 0.3 mg/kg s.c.) completely prevented drug-seeking behavior induced by the reintroduction of cocaine-associated stimuli. WAY 100,635 (0.1-1.0 mg/kg s.c.) had no effect on this behavior. These results, while confirming that the partial agonist at the D(3) receptors, BP897, might be a useful medication, also suggest a role of D(2) receptors in cue-induced cocaine-seeking behavior.


Subject(s)
Behavior, Addictive/psychology , Cocaine/administration & dosage , Cues , Receptors, Dopamine D2/physiology , Animals , Extinction, Psychological/drug effects , Extinction, Psychological/physiology , Male , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3 , Self Administration/methods , Self Administration/psychology , Tetrahydronaphthalenes/pharmacology
6.
Behav Pharmacol ; 11(2): 153-60, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10877120

ABSTRACT

We studied the anxiolytic-like activity of alnespirone and buspirone, two 5-HT(1A) receptor agonists, in a modified Geller-Seifter conflict model, and examined the role of 5-HT(1A) receptors by studying whether WAY-100635, a selective antagonist at these receptors, blocked their effects. Administered s.c. 30 minutes before testing, 0.5 and 1mg/kg alnespirone significantly increased punished responding, whereas lower doses (0.125 and 0.25 mg/kg) had no effect. At 1mg/kg, alnespirone significantly reduced the rates of unpunished responding. One dose of buspirone (1mg/kg) significantly increased punished responding and reduced unpunished responding. Lower doses were ineffective. Administered s.c. 40 minutes before testing, WAY-100635 had no effect on any parameter but completely antagonized the effects of alnespirone (1mg/kg) and buspirone (1mg/kg) on punished responding. The ability of buspirone to reduce unpunished responding was not antagonized by WAY-100635, probably reflecting a sedative effect of buspirone due to dopamine D2 receptor blockade. The results suggest that alnespirone and buspirone have anxiolytic-like activity in a conflict procedure by stimulating 5-HT(1A) receptors, presumably at a presynaptic level. Like buspirone, alnespirone may have useful effects in the treatment of anxiety disorders.


Subject(s)
Anti-Anxiety Agents/pharmacology , Buspirone/pharmacology , Conflict, Psychological , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Spiro Compounds/pharmacology , Animals , Conditioning, Operant/drug effects , Male , Piperazines/pharmacology , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT1 , Reinforcement Schedule , Serotonin Antagonists/pharmacology
7.
Neuropharmacology ; 39(6): 1037-43, 2000 Apr 03.
Article in English | MEDLINE | ID: mdl-10727714

ABSTRACT

8-OH-DPAT [8-hydroxy-2-(di-N-propylamino)tetralin], a 5-HT(1A) receptor agonist, and S 15535 (4-benzodioxan-5-yl)1-(indan-2-yl)piperazine, a partial agonist at 5-HT(1A) receptors, were administered into the dorsal raphe nucleus and dorsal hippocampus and their behavioral effects were assessed in a modified Geller-Seifter conflict model. Injected into the dorsal raphe nucleus 8-OH-DPAT, 1 microg but not 0.04 or 0.2 microg 0.5 microl(-1), and S 15535, 2.5 microg but not 0.1 or 0.5 microg 0.5 microl(-1), significantly increased punished responding with no effect on rates of unpunished or time-out responding. WAY 100635, a selective 5-HT(1A) receptor antagonist, injected subcutaneously at 0. 3 mg kg(-1) 30 min before 1 microg 8-OH-DPAT or 2.5 microg S 15535 in the dorsal raphe, completely antagonized their effects on punished responding. At doses ranging from 1 to 10 microg microl(-1) injected into the CA1 region of the dorsal hippocampus neither 8-OH-DPAT nor S 15535 modified punished responding or the rates of time-out. At the highest doses, 8-OH-DPAT significantly reduced unpunished responding whereas S 15535 had the opposite effect. The results suggest that stimulation of 5-HT(1A) receptors in the dorsal raphe nucleus has anxiolytic-like effects whereas stimulation of postsynaptic receptors in the dorsal hippocampus has no anxiolytic or anxiogenic effects, at least judging from changes in rates of punished responding. These results are compatible with the hypothesis that 5-HT(1A) receptor agonists and partial agonists attenuate anxiety by reducing serotonergic transmission in brain areas innervated by the dorsal raphe nucleus.


Subject(s)
8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Anxiety/psychology , Conditioning, Operant/drug effects , Conflict, Psychological , Hippocampus , Piperazines/pharmacology , Raphe Nuclei , Receptors, Serotonin , Serotonin Receptor Agonists/pharmacology , Animals , Male , Punishment , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/drug effects , Receptors, Serotonin, 5-HT1 , Serotonin Antagonists/pharmacology , Stereotaxic Techniques
8.
FEBS Lett ; 463(3): 281-4, 1999 Dec 17.
Article in English | MEDLINE | ID: mdl-10606738

ABSTRACT

To verify whether the sleep-inducing properties of oleamide were related to its ability to perturb membrane homeoviscosity, affecting 5-HT(2A) receptors, we compared the effects of oleamide and oleic acid, the latter lacking both the sleep-inducing effect and the action on 5-HT(2A) receptors. In binding studies the two compounds did not directly interact with rat brain cortex 5-HT(2A) receptors, nor did they increase the affinity of a 5-HT(2A) agonist, either in vitro or ex vivo. They had similar fluidizing effects, in vitro at high concentrations (>/=10 microM), and ex vivo after a dose of 100 mg/kg, and they reduced locomotor activity with similar potency. There thus appears to be no causal relationship between the fluidizing effects of oleamide and its sleep-inducing properties.


Subject(s)
Hypnotics and Sedatives/pharmacology , Oleic Acids/pharmacology , Receptors, Serotonin/drug effects , Sleep/drug effects , Animals , Brain/drug effects , Brain/metabolism , Fluorescence Polarization , Male , Membrane Fluidity/drug effects , Oleic Acid/pharmacology , Rats , Receptor, Serotonin, 5-HT2A , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Synaptosomes/drug effects , Synaptosomes/metabolism
9.
J Med Chem ; 42(21): 4362-79, 1999 Oct 21.
Article in English | MEDLINE | ID: mdl-10543880

ABSTRACT

The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel pyrroloquinoxalines and heteroaromatic-related derivatives are described. The new pyrroloquinoxaline-related ligands were tested in rat cortex, a tissue expressing high density of 5-HT(3) receptors, and on NG108-15 cells and exhibited IC(50) values in the low nanomolar or subnanomolar range, as measured by the inhibition of [(3)H]zacopride binding. The SAR studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as "molecular yardsticks" to probe the spatial dimensions of the lipophilic pockets L1, L2, and L3 in the 5-HT(3) receptor cleft, while the 7-OH pyrroloquinoxaline analogue was designed to investigate hydrogen bonding with a putative receptor site H1 possibly interacting with the serotonin hydroxy group. The most active pyrroloquinoxaline derivatives showed subnanomolar affinity for the 5-HT(3) receptor. In functional studies ([(14)C]guanidinium accumulation test in NG108-15 hybrid cells, in vitro) most of the tested compounds showed clear-cut 5-HT(3) agonist properties, while some others were found to be partial agonists. Several heteroaromatic systems, bearing N-substituted piperazine moieties, have been explored with respect to 5-HT(3) affinity, and novel structural leads for the development of potent and selective central 5-HT(3) receptor agonists have been identified. Preliminary pharmacokinetic studies indicate that these compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio between 2 and 20, unless they bear a highly hydrophilic group on the piperazine ring. None of the tested compounds showed in vivo anxiolytic-like activity, but potential analgesic-like properties have been possibly disclosed for this new class of 5-HT(3) receptor agonists.


Subject(s)
Pyrroles/chemical synthesis , Quinoxalines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood-Brain Barrier , Brain/metabolism , Guanidine/metabolism , Guinea Pigs , Hybrid Cells , In Vitro Techniques , Ligands , Male , Pyrroles/chemistry , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacokinetics , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT3 , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship
10.
Naunyn Schmiedebergs Arch Pharmacol ; 360(3): 262-9, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10543427

ABSTRACT

The hydroalcoholic extract of Hypericum perforatum L. is an effective antidepressant, although its mechanism of action is still unknown. It inhibits the synaptosomal uptake of serotonin (5-HT), dopamine and noradrenaline, suggesting a biochemical mechanism similar to the synthetic standard antidepressants. In the present study, further investigating this hypothesis, we confirmed that a hydromethanolic extract of H. perforatum inhibited [3H]5-HT accumulation in rat brain cortical synaptosomes with an IC50 value of 7.9 microg/ml. The IC50 of pure hyperforin was 1.8 microg/ml, so the activity of the total extract is not related only to its hyperforin content (<5%). This inhibitory effect, however, is not due to a direct interaction with, and blockade of, the 5-HT transporters since the extract, like hyperforin, did not inhibit [3H]citalopram binding (IC50 > 100 microg/ml and 10 microg/ml, respectively). We also found that 3-10 microg/ml of the extract, or 0.3-1 microg/ml hyperforin, induced marked tritium release from superfused synaptosomes previously loaded with [3H]5-HT. The releasing effect of the extract resembles the releasing effect of a reserpine-like compound (Ro 04-1284), i.e. it was slightly delayed and was 5-HT carrier- and calcium-independent. These data suggest that the hydromethanolic extract of H. peforatum, similarly to Ro 04-1284, rapidly depletes storage vesicles, raising the cytoplasmic concentration of 5-HT, and this increase is presumably responsible for the apparent inhibition of [3H]5-HT uptake. Therefore, our in vitro data do not confirm that the hydromethanolic extract of H. perforatum acts as a classical 5-HT uptake inhibitor but indicate reserpine-like properties. However, the concentrations of the active component(s) effective in vitro as reserpine-like agent(s) (i.e. corresponding to > or =3 microg/ml of the hydromethanolic extract) do not seem to be achieved in the brain after pharmacologically effective doses of the extract, as indicated by the finding that there were no significant changes of rat brain 5-HT and 5-hydroxyindoleacetic acid levels after a schedule of treatment (3 x 300 mg/kgday, orally) active in an animal model predictive of antidepressant-like activity. These data also suggest that the antidepressant effect of H. perforatum extracts is unlikely to be associated with interaction with GABA, benzodiazepine and 5-HT1 receptors since, in receptor binding studies, we found IC50 values higher than 5 microg/ml. Therefore other, still unknown, mechanisms are possibly involved in H. perforatum antidepressant effects.


Subject(s)
Brain/drug effects , Carrier Proteins/antagonists & inhibitors , Cerebral Cortex/drug effects , Hypericum , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins , Plant Extracts/pharmacology , Plants, Medicinal , Animals , Binding, Competitive/drug effects , Brain/metabolism , Cerebral Cortex/metabolism , Citalopram/metabolism , Dopamine/metabolism , Dopamine/pharmacokinetics , Immobilization , Male , Membrane Fluidity/drug effects , Motor Activity/drug effects , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, GABA/drug effects , Receptors, GABA/metabolism , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1 , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins , Synaptosomes/drug effects , Synaptosomes/metabolism , Time Factors , Tritium
11.
Br J Pharmacol ; 125(7): 1617-23, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9884092

ABSTRACT

The brain/plasma partition of nefazodone, hydroxynefazodone (OHNFZ) and m-chlorophenyl-piperazine (mCPP) and their antagonism of p-chloroamphetamine (PCA)-induced 5-hydroxytryptamine (5-HT) depletion and quipazine-induced head twitches were compared in rodents. Nefazodone (30 mg kg(-1), i.p.) rapidly entered the brain but concentrations were exceeded by mCPP, the metabolic ratio being 47 and 10 in the mouse and rat respectively. OHNFZ was detectable in plasma but never in brain. Brain concentrations of OHNFZ in the mouse (30 mg kg(-1), i.p.) were less than 10% of those in plasma, confirming a poor blood-brain barrier penetration. Concentrations of its metabolite mCPP were similar to those after 5 mg kg(-1)(i.p.) mCPP. In the mouse, nefazodone (30 mg kg(-1)) antagonized the 5-HT depleting effect of PCA 2 h after dosing, when it had disappeared from brain but when mCPP concentrations were similar to those after 5 mg kg(-1) (i.p.) mCPP. However, mCPP antagonized PCA less than nefazodone. In the rat, nefazodone pretreatment (30 mg kg(-1), 15 min) prevented (97% of inhibition) quipazine-induced head twitches. The effect was weaker (65% of inhibition) but significant when only mCPP was detected in brain. Analysis of brain concentrations of the two compounds after their ED50 against quipazine indicated that both contributed to the effect, although nefazodone was more active than mCPP in terms of concentrations required to obtain a comparable reduction of twitches. These findings show that mCPP concentrates in the brain following injection of nefazodone and may play a role in preventing quipazine-induced behaviour and PCA-induced 5-HT depletion. In contrast OHNFZ poorly enters the brain and its in vivo activity is mostly due to its biotransformation to mCPP.


Subject(s)
Brain/metabolism , Prodrugs/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Serotonin/metabolism , Triazoles/pharmacokinetics , Animals , Blood-Brain Barrier , Cerebral Cortex/metabolism , Head Movements/drug effects , Male , Mice , Piperazines/blood , Prodrugs/metabolism , Quipazine/pharmacology , Rats , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Serotonin Agents/pharmacology , Serotonin Receptor Agonists/pharmacology , Selective Serotonin Reuptake Inhibitors/blood , Selective Serotonin Reuptake Inhibitors/metabolism , Triazoles/blood , Triazoles/metabolism , p-Chloroamphetamine/pharmacology
12.
Brain Res ; 775(1-2): 30-6, 1997 Nov 14.
Article in English | MEDLINE | ID: mdl-9439825

ABSTRACT

Using a balanced conditioned place preference (CPP) paradigm, we studied the role of protein kinases A (PKA) and C (PKC) on the acquisition, consolidation and expression of cocaine place conditioning. H7, a non-selective inhibitor of protein kinases, was administered intracerebroventricularly at 1 and 10 micrograms/10 microliters. The higher dose significantly reduced the time spent by rats in the cocaine compartment when given immediately after each conditioning session (consolidation), whereas it had no effect when administered before cocaine during the training phase (acquisition) or before testing for place preference in the absence of cocaine (expression). The same effect was found on administering immediately after each training session 3 micrograms/10 microliters chelerythrine, a selective PKC inhibitor, or 10 micrograms/10 microliters H89, a selective PKA inhibitor, suggesting that both kinases contribute to the consolidation of stimulus-reward association which determines rats' behavior in the cocaine CPP. Changes in the activity of PKA and PKC may thus be part of the cascade of events that contribute to enhancing synaptic responses in the consolidation phase of cocaine CPP and determine rats' behavior associated with the memory of the rewarding effect of cocaine during cocaine CPP expression. These findings may have implications for the study of cocaine 'craving' and relapse.


Subject(s)
Cocaine/pharmacology , Conditioning, Operant/drug effects , Cyclic AMP-Dependent Protein Kinases/metabolism , Narcotics/pharmacology , Protein Kinase C/metabolism , Sulfonamides , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Alkaloids , Animals , Benzophenanthridines , Cocaine/administration & dosage , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Injections, Intraventricular , Isoquinolines/pharmacology , Male , Motor Activity/drug effects , Narcotics/administration & dosage , Phenanthridines/pharmacology , Protein Kinase C/antagonists & inhibitors , Rats , Rats, Sprague-Dawley
13.
Pharmacol Biochem Behav ; 55(1): 33-7, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8870035

ABSTRACT

Three 5-HT3 receptor antagonists, MDL 72222, tropisetron, and ondansetron were studied for their ability to modify the conditioned place preference (CPP) induced by 10 mg/kg IP cocaine in rats. MDL 72222 (0.03-3 mg/kg SC) and tropisetron (0.01-0.1 mg/kg SC) administered, respectively, 30 min and 1 h before each conditioning session, did not affect the acquisition of cocaine CPP. Ondansetron (0.01-0.1 mg/kg SC) administered 30 min before each conditioning session or just before testing likewise had no effect. At 0.1 mg/kg SC ondansetron did not modify the increase of extracellular dopamine caused by 10 mg/kg cocaine in the nucleus accumbens. The results suggest that 5-HT3 receptor antagonists have no effect on the rewarding properties of cocaine or on the behaviour elicited by the stimuli previously associated with the drug's action.


Subject(s)
Cocaine/pharmacology , Conditioning, Operant/drug effects , Dopamine Uptake Inhibitors/pharmacology , Dopamine/metabolism , Nucleus Accumbens/metabolism , Serotonin Antagonists/pharmacology , Animals , Extracellular Space/drug effects , Extracellular Space/metabolism , Indoles/pharmacology , Male , Microdialysis , Nucleus Accumbens/anatomy & histology , Nucleus Accumbens/drug effects , Ondansetron/pharmacology , Rats , Rats, Sprague-Dawley , Tropanes/pharmacology , Tropisetron
14.
Brain Res ; 731(1-2): 31-8, 1996 Aug 26.
Article in English | MEDLINE | ID: mdl-8883851

ABSTRACT

A series of experiments were conducted to investigate the role of dopaminergic D1 and D2 and glutamatergic NMDA and AMPA/kainate receptors on the establishment and expression of cocaine-induced conditioned locomotion in rats. In the first experiment conditioned locomotion was demonstrated by testing the animals in an environment previously associated with 15 mg/kg i.p. cocaine. The D2-receptor antagonist (-)-sulpiride (50 and 100 mg/kg i.p.) administered before cocaine during the conditioning phase did not modify the establishment of conditioned locomotion whereas when administered before testing only at the higher dose it partially reduced rats' locomotion in the absence of cocaine (expression). At the higher dose (0.1 mg/kg i.p.) the D1-receptor antagonist SCH 23390 attenuated the expression of cocaine-induced conditioned locomotion whereas the lower dose (0.03 mg/kg i.p.) had no effect. Both doses of the NMDA receptor antagonist MK-801 (0.125 and 0.25 mg/kg i.p.) blocked the development of cocaine-induced conditioned locomotion but neither dose, when administered before testing, modified locomotion in the absence of cocaine. Both doses of the AMPA/kainate receptor antagonist DNQX administered intracerebroventricularly (1 and 3 micrograms/rat) blocked cocaine-induced conditioned locomotion when given before cocaine during conditioning but when given before testing only the higher dose attenuated the conditioned activity. The results confirm the importance of the interaction between glutamatergic and dopaminergic systems for the conditional factors maintaining drug seeking behaviour. The findings may have implications for the treatment of cocaine craving and relapse.


Subject(s)
Cocaine/pharmacology , Dopamine Antagonists/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Locomotion/drug effects , Analysis of Variance , Animals , Benzazepines/pharmacology , Conditioning, Psychological/drug effects , Dizocilpine Maleate/pharmacology , Dopamine D2 Receptor Antagonists , Male , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, AMPA/antagonists & inhibitors , Receptors, Kainic Acid/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Recurrence , Substance-Related Disorders , Sulpiride/pharmacology
15.
Pharmacol Biochem Behav ; 52(4): 671-6, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8587903

ABSTRACT

Drugs with different intrinsic activity at 5-HT1A receptors and antagonists at 5-HT2A/2C and 5-HT3 receptors were studied for their ability to increase the rates of punished operant responding in rats. Like chlordiazepoxide (5 and 10 mg/kg) and diazepam (1.25 and 2.5 mg/kg), 0.125 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, and 5 and 10 mg/kg ipsapirone, a partial agonist at these receptors, increased the rates of punished responding, whereas (S)-WAY 100135, a 5-HT1A receptor antagonist, had no effect at doses from 1 to 10 mg/kg. 8-OH-DPAT and ipsapirone, like benzodiazepines, significantly reduced unpunished responding. The 5-HT2A/2C receptor antagonists ritanserin (2 mg/kg), mianserin (8 mg/kg), and mesulergine (0.1 mg/kg) significantly increased the rates of punished responding, whereas 0.5-2 mg/kg ketanserin, that has higher affinity for 5-HT2A than 5-HT2C receptors, had no effect. Antagonists, at 5-HT3 receptors such as ondansetron (0.001-0.1 mg/kg) and tropisetron (0.001-0.1 mg/kg), had no effect on punished or unpunished responding. The results show that agents acting as full or partial agonists at 5-HT1A receptors and blockers of postsynaptic 5-HT2C receptors have anxiolytic-like effects in a model of punished operant responding, whereas antagonists at 5-HT1A and 5-HT3 receptors have no such effect.


Subject(s)
Behavior, Animal/drug effects , Conditioning, Operant/drug effects , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Animals , Chlordiazepoxide/pharmacology , Diazepam/pharmacology , Ketanserin/pharmacology , Male , Punishment , Rats , Rats, Sprague-Dawley
16.
Eur J Pharmacol ; 284(3): 249-55, 1995 Sep 25.
Article in English | MEDLINE | ID: mdl-8666006

ABSTRACT

The effect of ipsapirone, a partial agonist at 5-HT1A receptors, and of diazepam on punished operant responding was studied in rats injected intracerebroventricularly with 150 microg 5,7-dihydroxytryptamine to deplete brain serotonin or pretreated with (S)-WAY 100135 (N-tert-butyl) 3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenylpropanamide dihydrochloride), an antagonist at 5-HT1A receptors. 5,7-Dihydroxytryptamine markedly depleted brain serotonin and caused a sustained increase in punished responding with no effect on rates of unpunished responding in sham-operated rats but had no effect in animals which had received 5,7-dihydroxytryptamine. At 5 and 10 mg/kg ipsapirone reduced unpunished responding similarly in sham-operated and 5,7-dihydroxytryptamine-treated rats. Diazepam 2.5 mg/kg i.p.significantly increased punished responding and reduced rates of unpunished responding similarly in sham-operated and in 5,7-dihydroxytryptamine-treated animals. At 3 and 10 mg/kg (S)-WAY 100135 did not modify punished or unpunished responding but at 10 mg/kg it completely antagonized the effect of 5 mg/kg/s.c. ipsapirone on unpunished and punished responding. The results suggest that ipsapirone releases behaviour that is suppressed by punishment by stimulating presynaptic 5-HT1A receptors.


Subject(s)
Anti-Anxiety Agents/pharmacology , Punishment , Pyrimidines/pharmacology , Receptors, Serotonin/physiology , Serotonin Receptor Agonists/pharmacology , 5,7-Dihydroxytryptamine/pharmacology , Animals , Conditioning, Operant/drug effects , Diazepam/pharmacology , Dose-Response Relationship, Drug , Male , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley
17.
Brain Res ; 673(2): 242-50, 1995 Mar 06.
Article in English | MEDLINE | ID: mdl-7606438

ABSTRACT

A balanced conditioning place preference (CPP) paradigm was used to study the role of dopamine D1 and D2 and glutamatergic NMDA and AMPA/kainate receptors on the acquisition and expression of cocaine place conditioning. The D1 receptor antagonist SCH 23390 (0.1-0.2 mg/kg i.p.), administered before cocaine during the training phase, significantly blocked the establishment of place conditioning (acquisition) but had no effect when administered before testing for place preference in the absence of cocaine (expression). Similar results were obtained with the non-competitive NMDA receptor antagonist MK-801 (0.1-0.5 mg/kg i.p.). The D2 receptor antagonist (-)-sulpiride (50-100 mg/kg i.p.) had no effect on either acquisition or expression of cocaine CPP. The AMPA/kainate receptor antagonist DNQX, administered intracerebroventricularly (0.2-3 micrograms/10 microliters), blocked cocaine CPP when given before testing but not when given before cocaine during the training trials. The results suggest that dopaminergic D1 (but not D2) and glutamatergic NMDA receptors are involved in the primary rewarding properties of cocaine (as assessed by the establishment of CPP) whereas the AMPA/kainate receptors are important only for the behaviour elicited by the stimuli previously associated with the drug action (CPP expression). The implications for the treatment of cocaine craving and relapse are discussed.


Subject(s)
Conditioning, Operant/drug effects , Dopamine D2 Receptor Antagonists , Excitatory Amino Acid Antagonists/pharmacology , Receptors, Dopamine D1/antagonists & inhibitors , Animals , Behavior, Animal , Benzazepines/pharmacology , Cocaine/pharmacology , Dizocilpine Maleate/pharmacology , Dopamine/pharmacology , Male , N-Methylaspartate/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Sulpiride/pharmacology
18.
Eur J Pharmacol ; 263(1-2): 187-91, 1994 Sep 22.
Article in English | MEDLINE | ID: mdl-7821351

ABSTRACT

The role of 5-HT1A receptors in the antinociceptive action of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was investigated by using the shock titration test in rats. A subcutaneous injection of 300 micrograms/kg 8-OH-DPAT significantly raised the threshold for flinching, jumping and vocalization whereas 100 micrograms/kg only inhibited the flinch response. l-Propranolol and (+)-[N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl propanamide dihydrochloride], (+)-WAY100135, two antagonists at 5-HT1A receptors at 10 mg/kg s.c. antagonized the effect of 300 micrograms/kg 8-OH-DPAT on all measures. The effect of 300 micrograms/kg 8-OH-DPAT on the three measures was unmodified in rats which had received 150 micrograms 5,7-dihydroxytryptamine intracerebroventricularly 10 days before testing. The results suggest that 8-OH-DPAT inhibits nociceptive responses by stimulating postsynaptic 5-HT1A receptors.


Subject(s)
8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Analgesics/pharmacology , Receptors, Serotonin/physiology , 5,7-Dihydroxytryptamine/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin/antagonists & inhibitors , Adrenergic alpha-Antagonists/pharmacology , Animals , Behavior, Animal/drug effects , Dioxanes/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Idazoxan , Injections, Intraventricular , Injections, Subcutaneous , Male , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology
19.
J Neurochem ; 63(1): 195-200, 1994 Jul.
Article in English | MEDLINE | ID: mdl-8207428

ABSTRACT

Experiments were performed to confirm that noradrenergic terminals regulate extracellular concentrations of dopamine (DA) in the frontal cortex of rats. The effects of 20 mg/kg 1-[2-[bis(4-fluorphenyl)methoxy]-ethyl]-4-(3- phenylpropyl)piperazine (GBR 12909), a selective inhibitor of DA uptake, and 2.5 mg/kg desipramine (DMI) on the extracellular concentrations of DA in the frontal cortex and striatum were studied in rats given 6-hydroxydopamine (6 micrograms/microliters) bilaterally into the locus coeruleus to destroy noradrenergic terminals. GBR 12909 increased dialysate DA similarly in the striatum of vehicle and 6-hydroxydopamine-treated rats, whereas in the frontal cortex it raised DA concentrations only in lesioned animals. DMI raised extracellular DA concentrations in the frontal cortex but not in the striatum of controls. The effect of DMI on cortical DA was abolished by the 6-hydroxydopamine lesion. GBR 12909, at a subcutaneous dose of 20 mg/kg, further increased cortical dialysate DA in rats given DMI intraperitoneally at 20 mg/kg or through the probe at 10(-5) mol/L. The data support the hypothesis of an important regulation of the extracellular concentrations of DA in the frontal cortex by noradrenergic terminals.


Subject(s)
Cerebral Cortex/physiology , Dopamine/analysis , Extracellular Matrix/chemistry , Neurons/chemistry , Neurons/physiology , Norepinephrine/metabolism , Animals , Cerebral Cortex/metabolism , Corpus Striatum/chemistry , Corpus Striatum/metabolism , Desipramine/administration & dosage , Desipramine/pharmacology , Dopamine/metabolism , Extracellular Matrix/metabolism , Injections, Intraperitoneal , Male , Neurons/metabolism , Neurotransmitter Uptake Inhibitors/pharmacology , Oxidopamine/pharmacology , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley
20.
Eur J Pharmacol ; 253(1-2): 139-47, 1994 Feb 21.
Article in English | MEDLINE | ID: mdl-8013540

ABSTRACT

SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6- tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10(-7)-10(-6) M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and alpha 1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10(-6) and 10(-5) M. The effect of 10(-6) M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10(-6) M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (+/-)-sulpiride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Naphthalenes/pharmacology , Pyridines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/pharmacology , Adenylyl Cyclases/metabolism , Analysis of Variance , Animals , Binding Sites , Hippocampus/drug effects , Hippocampus/metabolism , Male , Naphthalenes/metabolism , Pyridines/metabolism , Rats , Receptors, Adrenergic, alpha/drug effects , Receptors, Adrenergic, alpha/metabolism , Receptors, Dopamine D2/drug effects , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/metabolism
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