J. Peris - Profile on Academia.edu (original) (raw)
Papers by J. Peris
Systemic oxytocin increases glutamate efflux in the nucleus accumbens core of cocaine-experienced male and female rats but only increases dopamine efflux in males
Behavioural Brain Research, 2022
Oxytocin attenuates cocaine-seeking when administered both systemically and directly into the nuc... more Oxytocin attenuates cocaine-seeking when administered both systemically and directly into the nucleus accumbens core. This effect is blocked by intra-accumbens antagonism of mGlu2/3 and, together with our finding that intra-accumbens oxytocin increases glutamate concentrations in this brain region, indicates that pre-synaptic regulation of glutamate release by oxytocin influences cocaine relapse. However, mGlu2/3 receptors also regulate dopamine release in the nucleus accumbens. Here we aimed to determine whether systemic oxytocin increases glutamate and dopamine concentrations in the nucleus accumbens core of cocaine-experienced and cocaine-naïve male and female rats. A subset of rats self-administered cocaine (0.5mg/kg/infusion) and then underwent extinction training for 2-3 weeks. Rats were implanted with microdialysis probes in the accumbens core and samples were collected for a baseline period, and following saline (1mL/kg), and oxytocin (1mg/kg, IP) injections. Locomotion was assessed during microdialysis. In cocaine-experienced rats, oxytocin increased glutamate concentrations in the accumbens core to the same extent in males and females but only increased dopamine concentrations in male rats. Oxytocin did not alter glutamate levels in cocaine-naïve rats. Oxytocin did not produce sedation. These results extend previous findings that systemic oxytocin increases nucleus accumbens dopamine in a sex-specific manner in cocaine-experienced rats. These data are the first to find that systemic oxytocin increases nucleus accumbens glutamate after cocaine experience, providing a mechanism of action by which oxytocin attenuates the reinstatement of cocaine seeking in both male and female rats.
![Research paper thumbnail of Biphasic modulation of evoked [3H]D‐aspartate release by D‐2 dopamine receptors in rat striatal slices](https://attachments.academia-assets.com/117546832/thumbnails/1.jpg)
](Synapse, 1988
It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fiber... more It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fibers via presynaptically located D‐2 DA receptors although the evidence presented in the literature has not been conclusive. In the present experiments, the effect of D‐2 receptor ligands on K+‐stimulated tritium release from rat striatal slices preloaded with the nonmetabolizable glutamate analog [3H]D‐aspartate ([3H]ASP) was measured. The D‐2 receptor antagonist S‐sulpiride increased stimulated [3H]ASP release by 75% (EC50 value = 240 nM) and the biologically less‐active isomer R‐sulpiride, although equally effective, was tenfold less potent. The D‐2 receptor agonists pergolide and (+)‐4‐propyl‐9‐hydroxynapthoxazine (+PHNO) inhibited [3H]ASP release at nM concentrations; however, this effect was small (20%). This low efficacy of the exogenous agonists was apparently due to competition by high concentrations of endogenous DA since the effect of pergolide was increased in rats whose striata...
Psychopharmacology, 1993
Combined cocaine and ethanol abuse has become increasingly popular, yet research on the behaviora... more Combined cocaine and ethanol abuse has become increasingly popular, yet research on the behavioral and neurochemical interactions of these two substances is limited. Four groups of male rats received either daily cocaine (10 mg/kg, IP) or saline injections with either water (groups C and S) or only 15% ethanol to drink (groups CE and E). Initially, locomotor activity was increased equally by ethanol or cocaine and to the greatest extent by both. After 2 weeks of drug treatment, group C exhibited behavioral sensitization to cocaine, group E exhibited ethanol tolerance and group CE exhibited greater cocaine sensitization with no indication of ethanol tolerance. In support of enhanced sensitization to cocaine, amphetamine-stimulated 3H-dopamine (DA) release in striatum and D 2 DA receptor binding in the nucleus accumbens (NAC) were increased in group CE compared to group C. In support of a loss of ethanol tolerance, increases in striatal D 2 DA and 35S-TBPS binding seen in group E (which exhibited ethanol tolerance) were absent in group CE (which did not exhibit tolerance). Thus, the synergistic effect of ethanol and cocaine on behavior may be due to complex interactions of these two drugs both on DA and GABA transmission in mesolimbic and nigrostriatal areas.
Heart rate response to shock delivered via different implanted electrodes
Physiology & Behavior, 1986
The heart rate reaction elicited by electric shock was studied in rats stimulated via implanted e... more The heart rate reaction elicited by electric shock was studied in rats stimulated via implanted electrodes that were placed entirely beneath the skin (subcutaneous electrodes) or were passed under and through the skin (cutaneous electrodes). Cutaneous shock elicited greater cardioaccelerations than subcutaneous shock except at very low intensities. This finding may help to explain differences in conditioned heart rate responses when these two types of electrodes are used to deliver shock stimuli.
Pharmacology Biochemistry and Behavior, 1989
Persistent augmented dopamine release after acute cocaine requires dopamine receptor activation. ... more Persistent augmented dopamine release after acute cocaine requires dopamine receptor activation. PHARMACOL BIOCHEM BEHAV 32(1) 71-76, 1989.-Pretreatment of rats with a single injection of cocaine produces a persistent augmentation of amphetamine-induced [3H]dopamine ([aH]DA) release measured using the in vitro striatal slice preparation. Cocaine has several actions in the nigrostriatal DA system: it blocks DA uptake and thereby indirectly stimulates DA receptors and it also acts as a local anesthetic. We investigated which of these actions is responsible for the augmented amphetamine-stimulated PH]DA release by determining whether pretreatment with drugs sharing one or more of these actions also augmented release. Release was increased in striatal slices one week after a single injection of either mazindol, a DA uptake blocker and indirect DA receptor agonist, or apomorphine, a direct-acting receptor agonist, whereas the local anesthetic lidocaine had no effect. The prerequisite of DA receptor stimulation was confirmed by pretreatment prior to the cocaine injection with either a nonselective, a D-1 selective or a D-2 selective DA receptor antagonist. Each of these blocked the long-lasting augmentation of release. From these experiments, we conclude that cocaine indirectly activates both D-I and D-2 DA receptors to produce the persistent augmentation of striatal amphetamine-stimulated pH]DA release.
Pharmacology Biochemistry and Behavior, 1989
Diazepam sensitizes mice to FG 7142 and reduces rauscimol-stimulated S6C1-flloc. PHARMACOL BIOCHE... more Diazepam sensitizes mice to FG 7142 and reduces rauscimol-stimulated S6C1-flloc. PHARMACOL BIOCHEM BEHAV 33(2) 465-468, 1989.-Chronic treatment with benzodiazepine receptor agonists increases sensitivity to the convulsant action of FG 7142, an inverse agonist. We investigated whether or not changes in the nurnbcr and function of GABA-gated chloride channels accompanies this increased sensitivity. Diazepam, 5 mg.kg-t, was administered to mice daily for five days, and mice were then tested with a single injection of FG 7142, 40 nag.kg-~, at several intervals thereafter. At 24 hours after the last diazepam dose, 10 of 15 mice had clonic seizures following FG 7142 and four of the remaining five had myoclonic jerks. At 48 hours, only one of six mice developed a clonic seizure, and none were observed in mice tested at 96 or 144 hours. Muscimol-sfimnlated chloride flux was reduced in cortical synaptosomes from diazepam-treated mice at 24 hours but not at 48 or 96 hours. However, the binding of [35S]TBPS, a ligand closely associated with the chloride channel, was unchanged at 24 hours. These results suggest that a transient diminution in GABA-gated chloride channel function, unaccompanied by a reduction in channel number, may underlie the sensitization to the convulsant action of FG 7142 observed after withdrawal from chronic diazepam treatment.
Pharmacology Biochemistry and Behavior, 1992
--The effects of cocaine exposure in utero on cocaine-induced behaviors and dopamine (DA) transmi... more --The effects of cocaine exposure in utero on cocaine-induced behaviors and dopamine (DA) transmission in the nigrostriatal and mesolimbic pathways were measured in adult rats. Pregnant rats received either saline or cocaine (1 or 3 mg/kg, IV) daily throughout gestation. When offspring were 3 months of age, locomotor and stereotypic behaviors were rated after an injection of either saline or cocaine (10 mg/ kg, IP). Cocaine in utero increased the response to cocaine in adult offspring and increased basal locomotion in female offspring. Cocaine in utero increased amphetamine-stimulated release in female offspring but decreased release in males. On the other hand, male rats that had received cocaine in utero exhibited greater basal tritium release. One injection of cocaine increased amphetamine-stimulated [3H]DA release from striatal slices of male rats but not female rats. Neither cocaine in utero nor in vivo affected D2 DA receptor binding in striatum nor nucleus accumbens. Thus, cocaine in utero behaviorally sensitized animals to subsequent cocaine exposure and increased [3H]DA release from nigrostriatal endings, but the relationship of these two variables depended upon gender.
![Research paper thumbnail of Modulation of γ-[3H]aminobutyric acid release from rat cortical slices by α2-adrenoceptors](https://attachments.academia-assets.com/117546829/thumbnails/1.jpg)
](Neuroscience Letters, 1987
Life Sciences, 1993
Marked regional differences in the mRNA levels for the different subunits of the (3ABA. receptor ... more Marked regional differences in the mRNA levels for the different subunits of the (3ABA. receptor may result in functional differences throughout the brain. The effects of d~fferent GABA, agonists and antagonists on GABA A receptor function was measured using ~CI" upta"ke in microsacs made from cerebellum (CB), superior colliculus (SC), substantia nigra (SN), inferior colliculus (IC) or cortex (CT) containing equal amounts of protein. GABA increased CI" uptake in all regions in a dosedependent and saturable manner but with markedly different efficacies across brain regions. Maximal GABA-stimulated uptake was 59+2 nmoles of CI" per mg protein in CT, 25+5 in SC, 24+4 in CB, 16+1 in IC and 6.7+1.4 in SN. Museimol increased CI" uptake with greater potency than GABA but with similar efficacies in CT, CB, SC and SN; the efficacy of muscimol in IC was increased to 27.4+5. Picrotoxin inhibited maximal GABA-stimulated CI" uptake in CB, SC and CT but did not decrease uptake in IC or SN. Bicuculline methiodide completely inhibited uptake in CB and CT, partially inhibited uptake in IC, and did not affect uptake in SC and SN. These data provide functional support for regional heterogeneity of the GABA k receptor/Cl" ionophore between nigrocollicular regions and CB and CT. The original structural model of the GABA A receptor/chloride ionophore (GR/CI) consisted of four protein subunits with a2/32 configuration (1,2) possessing four types of binding sites: GABA, benzodiazepine (BDZ), barbiturate and convulsant. In this model, occupation of the GABA, BDZ or barbiturate sites by agonists increases chloride (CI') transport while occupation of the convulsant site by substances like picrotoxin (PTX) and t-butylbicyclophosphorothionate (TBPS) inhibit channel function. The recently updated model is a complex hetero-oligomer composed of a total of 4-5 polypeptide subunits from at least thirteen different types including a 1.s,/31-3, "71-~ and (3-5). The regionally-selective expression of each subtype negates the possibility Haat ~ubunit composition is homogeneous throughout the brain (6,7). The a 1,/3~ and "/2 subtypes are ubiquitous in brain, while a6 occurs only in cerebellar (CB) granule cells, and'the/31 and d~ subtypes are found only in cortex (CT), striatum and CB granule cells. There are no a 4 or a 6 subunits in substantia nigra reticulata (SNR), superior colliculus (SC) or inferior colliculus (IC). Briefly, CT possesses all but the a s subtype, SNR has only the al,/3~, '71 and "72 subtypes, and deeper layers of SC and IC contain mostly the al,/32 and "77 subtypes (6,7). Radioligand binding to the different sites on the receptor complex supports regior~al differences in GR/CI. For example, there are an equal number of 3Hmuscimol, 3H-bicuculline (BIC) and 35S-TBPS binding sites in CT as expected (8). However, in SNR, IC and SC, there are a very high number of convulsant sites, somewhat fewer BIC sites and relatively low amounts of agonist sites (8-13). In summary, both in situ hybridization studies and radioligand binding assays suggest different isoforms of the GR/CI exist in nigrocollicular regions. The different a subtypes vary in determining receptor sensitivity to GABA (14-16) and certain agents acting via the BDZ site (17-20). The/3 subtypes determine GABA binding affinities and efficacies (21,22). The "7~ subunit is necessary for BDZ modulation of GABA responses (23). Less than five years ago, it w~s thought that at least one a subunit plus one/3 subunit was necessary
European Journal of Pharmacology, 1989
The repeated administration of N-methyl-fl-carboline-3-carboxamide (FG 7142) to mice leads to 'ch... more The repeated administration of N-methyl-fl-carboline-3-carboxamide (FG 7142) to mice leads to 'chemical kindling', i.e. the development of seizures in response to doses which were initially insufficient to produce convulsive activity. To determine if chemical kindling produced changes in the GABA A receptor/chloride channel complex, we measured the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the convulsant site of the complex by quantitative autoradiography. As a measure of chloride channel function, we studied muscimol-stimulated uptake of 36C1 by isolated brain synaptosomes. Kindling decreased the Bma x of [35S]TBPS binding in cortex but not in cerebellum or hippocampus. Kindling did not alter binding affinities in any of these brain regions. Some mice injected with FG 7142 did not kindle despite receiving the same treatment as kindled mice. These 'injected but not kindled' mice did not display decreased receptor binding in any of these brain areas. Muscimol-stimulated 36C1 uptake into cortical synaptosomes was also diminished by chemical kindling. These findings suggest that a decrease in functioning GABA-regulated chloride channels may be responsible for chemical kindling with FG 7142.
The AAPS Journal, 2006
In many cases the clinical outcome of therapy needs to be determined by the drug concentration in... more In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo technique that allows direct measurement of unbound tissue concentrations and permits monitoring of the biochemical and physiological effects of drugs throughout the body. Microdialysis was fi rst used in pharmacodynamic research to study neurotransmission, and this remains its most common application in the fi eld. In this review, we give an overview of the principles, techniques, and applications of microdialysis in pharmacodynamic studies of local physiological events, including measurement of endogenous substances such as acetylcholine, catecholamines, serotonin, amino acids, peptides, glucose, lactate, glycerol, and hormones. Microdialysis coupled with systemic drug administration also permits the more intensive examination of the pharmacotherapeutic effect of drugs on extracellular levels of endogenous substances in peripheral compartments and blood. Selected examples of the physiological effects and mechanisms of action of drugs are also discussed, as are the advantages and limitations of this method. It is concluded that microdialysis is a reliable technique for the measurement of local events, which makes it an attractive tool for local pharmacodynamic research.
Selective Changes in GABAergic Transmission in Substantia Nigra and Superior Colliculus Caused by Ethanol and Ethanol Withdrawal
Alcoholism: Clinical and Experimental Research, 1992
One of ethanol's actions after acute exposure is anticonvulsant activity whereas withdrawal f... more One of ethanol's actions after acute exposure is anticonvulsant activity whereas withdrawal from chronic ethanol exposure increases convulsant activity. An increase in neuronal transmission in the GABAergic pathways from striatum to the substantia nigra (SN) and a decrease in GABAergic transmission from SN to superior colliculus (SC) both appear to play a major role in inhibiting seizure propagation. If this is the case, then the changes in seizure sensitivity caused by ethanol may be expected to affect GABAergic transmission in opposite ways in SN and SC. We measured the effects of in vitro ethanol on pre‐ and postsynaptic indices of GABA transmission using SN and SC tissue from both ethanol‐naive rats and rats given ethanol in their drinking water for 24 days and then withdrawn for 24 hr, a treatment that decreases seizure latency. While ethanol inhibited 3H‐ GABA release from slices of SC at low concentrations (20‐100 mM), much higher concentrations were required to inhibit r...
Alcoholism: Clinical & Experimental Research, 2004
Ethanol increases taurine efflux in the nucleus accumbens or ventral striatum (VS), a dopaminergi... more Ethanol increases taurine efflux in the nucleus accumbens or ventral striatum (VS), a dopaminergic terminal region involved in positive reinforcement. However, this has been found only at ethanol doses above 1 g/kg intraperitoneally, which is higher than what most rats will self-administer. We used a sensitive on-line assay of microdialysate content to test whether lower doses of ethanol selectively increase taurine efflux in VS as opposed to other dopaminergic regions not involved in reinforcement (e.g., dorsal striatum; DS). Adult male rats with microdialysis probes in VS or DS were injected with ethanol (0, 0.5, 1, and 2 g/kg intraperitoneally), and the amino acid content of the dialysate was measured every 11 sec using capillary electrophoresis and laser-induced fluorescence detection. In VS, 0.5 g/kg ethanol significantly increased taurine levels by 20% for 10 min. A similar increase was seen after 1 g/kg ethanol, which lasted for about 20 min after injection. A two-phased taurine efflux was observed with the 2.0 g/kg dose, where taurine was increased by 2-fold after 5 min but it remained elevated by 30% for at least 60 min. In contrast, DS exhibited much smaller dose-related increases in taurine. Glycine, glutamate, serine, and ␥-aminobutyric acid were not systematically affected by lower doses of ethanol; however, 2 g/kg slowly decreased these amino acids in both brain regions during the hour after injection. These data implicate a possible role of taurine in the mechanism of action of ethanol in the VS. The high sensitivity and time resolution afforded by capillary electrophoresis and laser-induced fluorescence detection will be useful for detecting subtle changes of neuronally active amino acids levels due to low doses of ethanol.
Sensitization to Cocaine in the Nigrostriatal Dopamine System
PsycEXTRA Dataset
Pharmacology Biochemistry and Behavior, 1985
mice were fed lab chow containing phenobarbital for seven or eight days. Upon withdrawal of the p... more mice were fed lab chow containing phenobarbital for seven or eight days. Upon withdrawal of the phenobarbital diet, dependence was evidenced by appearance of hypothermia, handling-induced convulsions and lethal seizures. Functional tolerance was determined by injecting phenobarbital into mice treated with the phenobarbital diet or a pair-fed control diet and measuring the brain concentration of phenobarbital at the time of loss of righting reflex and the time of regaining righting reflex. Both measures demonstrated that chronic consumption of phenobarbital resulted in functional tolerance. When the diet was withdrawn for two days, tolerance was no longer present, indicating a rapid reversal of the adaptive changes. The veratridine-stimulated uptake of 24Na by isolated brain synaptosomes was used as a measure of membrane function. Sodium uptake was inhibited in vitro by pentobarbital and ethanol, and the inhibitory effects of these drugs were attenuated by chronic in vivo phenobarbital treatment. The fluidity of brain synaptic plasma membranes was estimated by the
Key factors influencing Local Agenda 21 planning approaches
Sustainable Development and Planning IV, 2009
Osteoarthritis and Cartilage, 2006
nary metabolic fingerprint has been identified that distighuishes healthy guinea pigs from ones t... more nary metabolic fingerprint has been identified that distighuishes healthy guinea pigs from ones that spontaneously developed osteorathritis. The meniscal transection guinea pig model of early osteoarthritis might prove to be a useful tool to search for early osteoarthritis biomarkers. Furthermore, this model is suitable to test newly developed therapies aimed at treating osteoarthritis in an early stage, for instance by stimulating anabolic processes rather than preventing joint destruction. The ineffectiveness of the compounds tested further underscores the urgent need for a new generation of drugs.
Journal of International Development, 2014
This article aims to explore the different accountability discourses of the various actors in the... more This article aims to explore the different accountability discourses of the various actors in the Spanish international aid system and to examine them in light of the various theoretical interpretations of development accountability. The conclusions reached suggest a technical and financial accountability model, largely isolated from international debates where political and social issues are at the core of the concept. Although this can be explained by a range of factors which are specific to the Spanish aid system, there are also interesting tendencies that are deepening a new understanding and practice of the idea.
European Journal of Internal Medicine, 2008
European Journal of Internal Medicine, 2008
We retrospectively reviewed all clinical records of patients with DILI admitted to our Unit from ... more We retrospectively reviewed all clinical records of patients with DILI admitted to our Unit from February 1996 to December 2006. A database was constructed, reporting data regarding age, sex, clinical features at onset, laboratory results, suspected drugs and follow-up. The diagnosis of DILI was based on the presence of at least three of the International Consensus Criteria (J Hepatol 1990). Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data, since histology was performed only in a minority of patients. All patients were negative for hepatitis A, B, C, EBV and CMV serology and non organ-specific autoantibody screening. Results: Forty six cases out of 6,134 patients received a discharge diagnose of DILI. There were 23 men and 23 women, mean age was 54.2 (range 11-88 yrs), 35 patient (74%) were older than 40 years. Five patients had an associated chronic liver disease (2 cirrhosis and 3 HCV-related chronic hepatitis). At clinical presentation all patients had abnormal liver function tests (LFTs), 22 patients were jaundiced and 3 patients was admitted for hepatic failure, manifest as hepatic encephalopathy. Liver damage was hepatocellular in 19 patients, cholestatic in 15 and mixed in 12. In 10 (22%) of cases, two or more drugs were involved. NSAIDs (n =17), psychotropic drugs (n =7) and antibiotics (n =10) were the most commonly involved drugs, followed by anti-platelet, anti-diabetic drugs and statins. NSAIDs were involved in three cases of acute liver failure and, among them, one was listed for liver transplantation but died while on the waiting list. All patients had regular follow-up visits every three months for at least one year after discharge. All patients, including those with pre-existing liver disease had a complete normalization of LFTs at the end of follow-up. Conclusions: Severe DILI requiring hospital admission is very rare and appears more common in patients over 40 years. NSAIDs, psychotropic drugs and antibiotics are the most common responsible drugs. Even in severe cases, recovery is almost the rule and only a few patients have an unfavourable course and eventually die
Systemic oxytocin increases glutamate efflux in the nucleus accumbens core of cocaine-experienced male and female rats but only increases dopamine efflux in males
Behavioural Brain Research, 2022
Oxytocin attenuates cocaine-seeking when administered both systemically and directly into the nuc... more Oxytocin attenuates cocaine-seeking when administered both systemically and directly into the nucleus accumbens core. This effect is blocked by intra-accumbens antagonism of mGlu2/3 and, together with our finding that intra-accumbens oxytocin increases glutamate concentrations in this brain region, indicates that pre-synaptic regulation of glutamate release by oxytocin influences cocaine relapse. However, mGlu2/3 receptors also regulate dopamine release in the nucleus accumbens. Here we aimed to determine whether systemic oxytocin increases glutamate and dopamine concentrations in the nucleus accumbens core of cocaine-experienced and cocaine-naïve male and female rats. A subset of rats self-administered cocaine (0.5mg/kg/infusion) and then underwent extinction training for 2-3 weeks. Rats were implanted with microdialysis probes in the accumbens core and samples were collected for a baseline period, and following saline (1mL/kg), and oxytocin (1mg/kg, IP) injections. Locomotion was assessed during microdialysis. In cocaine-experienced rats, oxytocin increased glutamate concentrations in the accumbens core to the same extent in males and females but only increased dopamine concentrations in male rats. Oxytocin did not alter glutamate levels in cocaine-naïve rats. Oxytocin did not produce sedation. These results extend previous findings that systemic oxytocin increases nucleus accumbens dopamine in a sex-specific manner in cocaine-experienced rats. These data are the first to find that systemic oxytocin increases nucleus accumbens glutamate after cocaine experience, providing a mechanism of action by which oxytocin attenuates the reinstatement of cocaine seeking in both male and female rats.
Synapse, 1988
It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fiber... more It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fibers via presynaptically located D‐2 DA receptors although the evidence presented in the literature has not been conclusive. In the present experiments, the effect of D‐2 receptor ligands on K+‐stimulated tritium release from rat striatal slices preloaded with the nonmetabolizable glutamate analog [3H]D‐aspartate ([3H]ASP) was measured. The D‐2 receptor antagonist S‐sulpiride increased stimulated [3H]ASP release by 75% (EC50 value = 240 nM) and the biologically less‐active isomer R‐sulpiride, although equally effective, was tenfold less potent. The D‐2 receptor agonists pergolide and (+)‐4‐propyl‐9‐hydroxynapthoxazine (+PHNO) inhibited [3H]ASP release at nM concentrations; however, this effect was small (20%). This low efficacy of the exogenous agonists was apparently due to competition by high concentrations of endogenous DA since the effect of pergolide was increased in rats whose striata...
Psychopharmacology, 1993
Combined cocaine and ethanol abuse has become increasingly popular, yet research on the behaviora... more Combined cocaine and ethanol abuse has become increasingly popular, yet research on the behavioral and neurochemical interactions of these two substances is limited. Four groups of male rats received either daily cocaine (10 mg/kg, IP) or saline injections with either water (groups C and S) or only 15% ethanol to drink (groups CE and E). Initially, locomotor activity was increased equally by ethanol or cocaine and to the greatest extent by both. After 2 weeks of drug treatment, group C exhibited behavioral sensitization to cocaine, group E exhibited ethanol tolerance and group CE exhibited greater cocaine sensitization with no indication of ethanol tolerance. In support of enhanced sensitization to cocaine, amphetamine-stimulated 3H-dopamine (DA) release in striatum and D 2 DA receptor binding in the nucleus accumbens (NAC) were increased in group CE compared to group C. In support of a loss of ethanol tolerance, increases in striatal D 2 DA and 35S-TBPS binding seen in group E (which exhibited ethanol tolerance) were absent in group CE (which did not exhibit tolerance). Thus, the synergistic effect of ethanol and cocaine on behavior may be due to complex interactions of these two drugs both on DA and GABA transmission in mesolimbic and nigrostriatal areas.
Heart rate response to shock delivered via different implanted electrodes
Physiology & Behavior, 1986
The heart rate reaction elicited by electric shock was studied in rats stimulated via implanted e... more The heart rate reaction elicited by electric shock was studied in rats stimulated via implanted electrodes that were placed entirely beneath the skin (subcutaneous electrodes) or were passed under and through the skin (cutaneous electrodes). Cutaneous shock elicited greater cardioaccelerations than subcutaneous shock except at very low intensities. This finding may help to explain differences in conditioned heart rate responses when these two types of electrodes are used to deliver shock stimuli.
Pharmacology Biochemistry and Behavior, 1989
Persistent augmented dopamine release after acute cocaine requires dopamine receptor activation. ... more Persistent augmented dopamine release after acute cocaine requires dopamine receptor activation. PHARMACOL BIOCHEM BEHAV 32(1) 71-76, 1989.-Pretreatment of rats with a single injection of cocaine produces a persistent augmentation of amphetamine-induced [3H]dopamine ([aH]DA) release measured using the in vitro striatal slice preparation. Cocaine has several actions in the nigrostriatal DA system: it blocks DA uptake and thereby indirectly stimulates DA receptors and it also acts as a local anesthetic. We investigated which of these actions is responsible for the augmented amphetamine-stimulated PH]DA release by determining whether pretreatment with drugs sharing one or more of these actions also augmented release. Release was increased in striatal slices one week after a single injection of either mazindol, a DA uptake blocker and indirect DA receptor agonist, or apomorphine, a direct-acting receptor agonist, whereas the local anesthetic lidocaine had no effect. The prerequisite of DA receptor stimulation was confirmed by pretreatment prior to the cocaine injection with either a nonselective, a D-1 selective or a D-2 selective DA receptor antagonist. Each of these blocked the long-lasting augmentation of release. From these experiments, we conclude that cocaine indirectly activates both D-I and D-2 DA receptors to produce the persistent augmentation of striatal amphetamine-stimulated pH]DA release.
Pharmacology Biochemistry and Behavior, 1989
Diazepam sensitizes mice to FG 7142 and reduces rauscimol-stimulated S6C1-flloc. PHARMACOL BIOCHE... more Diazepam sensitizes mice to FG 7142 and reduces rauscimol-stimulated S6C1-flloc. PHARMACOL BIOCHEM BEHAV 33(2) 465-468, 1989.-Chronic treatment with benzodiazepine receptor agonists increases sensitivity to the convulsant action of FG 7142, an inverse agonist. We investigated whether or not changes in the nurnbcr and function of GABA-gated chloride channels accompanies this increased sensitivity. Diazepam, 5 mg.kg-t, was administered to mice daily for five days, and mice were then tested with a single injection of FG 7142, 40 nag.kg-~, at several intervals thereafter. At 24 hours after the last diazepam dose, 10 of 15 mice had clonic seizures following FG 7142 and four of the remaining five had myoclonic jerks. At 48 hours, only one of six mice developed a clonic seizure, and none were observed in mice tested at 96 or 144 hours. Muscimol-sfimnlated chloride flux was reduced in cortical synaptosomes from diazepam-treated mice at 24 hours but not at 48 or 96 hours. However, the binding of [35S]TBPS, a ligand closely associated with the chloride channel, was unchanged at 24 hours. These results suggest that a transient diminution in GABA-gated chloride channel function, unaccompanied by a reduction in channel number, may underlie the sensitization to the convulsant action of FG 7142 observed after withdrawal from chronic diazepam treatment.
Pharmacology Biochemistry and Behavior, 1992
--The effects of cocaine exposure in utero on cocaine-induced behaviors and dopamine (DA) transmi... more --The effects of cocaine exposure in utero on cocaine-induced behaviors and dopamine (DA) transmission in the nigrostriatal and mesolimbic pathways were measured in adult rats. Pregnant rats received either saline or cocaine (1 or 3 mg/kg, IV) daily throughout gestation. When offspring were 3 months of age, locomotor and stereotypic behaviors were rated after an injection of either saline or cocaine (10 mg/ kg, IP). Cocaine in utero increased the response to cocaine in adult offspring and increased basal locomotion in female offspring. Cocaine in utero increased amphetamine-stimulated release in female offspring but decreased release in males. On the other hand, male rats that had received cocaine in utero exhibited greater basal tritium release. One injection of cocaine increased amphetamine-stimulated [3H]DA release from striatal slices of male rats but not female rats. Neither cocaine in utero nor in vivo affected D2 DA receptor binding in striatum nor nucleus accumbens. Thus, cocaine in utero behaviorally sensitized animals to subsequent cocaine exposure and increased [3H]DA release from nigrostriatal endings, but the relationship of these two variables depended upon gender.
Neuroscience Letters, 1987
Life Sciences, 1993
Marked regional differences in the mRNA levels for the different subunits of the (3ABA. receptor ... more Marked regional differences in the mRNA levels for the different subunits of the (3ABA. receptor may result in functional differences throughout the brain. The effects of d~fferent GABA, agonists and antagonists on GABA A receptor function was measured using ~CI" upta"ke in microsacs made from cerebellum (CB), superior colliculus (SC), substantia nigra (SN), inferior colliculus (IC) or cortex (CT) containing equal amounts of protein. GABA increased CI" uptake in all regions in a dosedependent and saturable manner but with markedly different efficacies across brain regions. Maximal GABA-stimulated uptake was 59+2 nmoles of CI" per mg protein in CT, 25+5 in SC, 24+4 in CB, 16+1 in IC and 6.7+1.4 in SN. Museimol increased CI" uptake with greater potency than GABA but with similar efficacies in CT, CB, SC and SN; the efficacy of muscimol in IC was increased to 27.4+5. Picrotoxin inhibited maximal GABA-stimulated CI" uptake in CB, SC and CT but did not decrease uptake in IC or SN. Bicuculline methiodide completely inhibited uptake in CB and CT, partially inhibited uptake in IC, and did not affect uptake in SC and SN. These data provide functional support for regional heterogeneity of the GABA k receptor/Cl" ionophore between nigrocollicular regions and CB and CT. The original structural model of the GABA A receptor/chloride ionophore (GR/CI) consisted of four protein subunits with a2/32 configuration (1,2) possessing four types of binding sites: GABA, benzodiazepine (BDZ), barbiturate and convulsant. In this model, occupation of the GABA, BDZ or barbiturate sites by agonists increases chloride (CI') transport while occupation of the convulsant site by substances like picrotoxin (PTX) and t-butylbicyclophosphorothionate (TBPS) inhibit channel function. The recently updated model is a complex hetero-oligomer composed of a total of 4-5 polypeptide subunits from at least thirteen different types including a 1.s,/31-3, "71-~ and (3-5). The regionally-selective expression of each subtype negates the possibility Haat ~ubunit composition is homogeneous throughout the brain (6,7). The a 1,/3~ and "/2 subtypes are ubiquitous in brain, while a6 occurs only in cerebellar (CB) granule cells, and'the/31 and d~ subtypes are found only in cortex (CT), striatum and CB granule cells. There are no a 4 or a 6 subunits in substantia nigra reticulata (SNR), superior colliculus (SC) or inferior colliculus (IC). Briefly, CT possesses all but the a s subtype, SNR has only the al,/3~, '71 and "72 subtypes, and deeper layers of SC and IC contain mostly the al,/32 and "77 subtypes (6,7). Radioligand binding to the different sites on the receptor complex supports regior~al differences in GR/CI. For example, there are an equal number of 3Hmuscimol, 3H-bicuculline (BIC) and 35S-TBPS binding sites in CT as expected (8). However, in SNR, IC and SC, there are a very high number of convulsant sites, somewhat fewer BIC sites and relatively low amounts of agonist sites (8-13). In summary, both in situ hybridization studies and radioligand binding assays suggest different isoforms of the GR/CI exist in nigrocollicular regions. The different a subtypes vary in determining receptor sensitivity to GABA (14-16) and certain agents acting via the BDZ site (17-20). The/3 subtypes determine GABA binding affinities and efficacies (21,22). The "7~ subunit is necessary for BDZ modulation of GABA responses (23). Less than five years ago, it w~s thought that at least one a subunit plus one/3 subunit was necessary
European Journal of Pharmacology, 1989
The repeated administration of N-methyl-fl-carboline-3-carboxamide (FG 7142) to mice leads to 'ch... more The repeated administration of N-methyl-fl-carboline-3-carboxamide (FG 7142) to mice leads to 'chemical kindling', i.e. the development of seizures in response to doses which were initially insufficient to produce convulsive activity. To determine if chemical kindling produced changes in the GABA A receptor/chloride channel complex, we measured the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the convulsant site of the complex by quantitative autoradiography. As a measure of chloride channel function, we studied muscimol-stimulated uptake of 36C1 by isolated brain synaptosomes. Kindling decreased the Bma x of [35S]TBPS binding in cortex but not in cerebellum or hippocampus. Kindling did not alter binding affinities in any of these brain regions. Some mice injected with FG 7142 did not kindle despite receiving the same treatment as kindled mice. These 'injected but not kindled' mice did not display decreased receptor binding in any of these brain areas. Muscimol-stimulated 36C1 uptake into cortical synaptosomes was also diminished by chemical kindling. These findings suggest that a decrease in functioning GABA-regulated chloride channels may be responsible for chemical kindling with FG 7142.
The AAPS Journal, 2006
In many cases the clinical outcome of therapy needs to be determined by the drug concentration in... more In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo technique that allows direct measurement of unbound tissue concentrations and permits monitoring of the biochemical and physiological effects of drugs throughout the body. Microdialysis was fi rst used in pharmacodynamic research to study neurotransmission, and this remains its most common application in the fi eld. In this review, we give an overview of the principles, techniques, and applications of microdialysis in pharmacodynamic studies of local physiological events, including measurement of endogenous substances such as acetylcholine, catecholamines, serotonin, amino acids, peptides, glucose, lactate, glycerol, and hormones. Microdialysis coupled with systemic drug administration also permits the more intensive examination of the pharmacotherapeutic effect of drugs on extracellular levels of endogenous substances in peripheral compartments and blood. Selected examples of the physiological effects and mechanisms of action of drugs are also discussed, as are the advantages and limitations of this method. It is concluded that microdialysis is a reliable technique for the measurement of local events, which makes it an attractive tool for local pharmacodynamic research.
Selective Changes in GABAergic Transmission in Substantia Nigra and Superior Colliculus Caused by Ethanol and Ethanol Withdrawal
Alcoholism: Clinical and Experimental Research, 1992
One of ethanol's actions after acute exposure is anticonvulsant activity whereas withdrawal f... more One of ethanol's actions after acute exposure is anticonvulsant activity whereas withdrawal from chronic ethanol exposure increases convulsant activity. An increase in neuronal transmission in the GABAergic pathways from striatum to the substantia nigra (SN) and a decrease in GABAergic transmission from SN to superior colliculus (SC) both appear to play a major role in inhibiting seizure propagation. If this is the case, then the changes in seizure sensitivity caused by ethanol may be expected to affect GABAergic transmission in opposite ways in SN and SC. We measured the effects of in vitro ethanol on pre‐ and postsynaptic indices of GABA transmission using SN and SC tissue from both ethanol‐naive rats and rats given ethanol in their drinking water for 24 days and then withdrawn for 24 hr, a treatment that decreases seizure latency. While ethanol inhibited 3H‐ GABA release from slices of SC at low concentrations (20‐100 mM), much higher concentrations were required to inhibit r...
Alcoholism: Clinical & Experimental Research, 2004
Ethanol increases taurine efflux in the nucleus accumbens or ventral striatum (VS), a dopaminergi... more Ethanol increases taurine efflux in the nucleus accumbens or ventral striatum (VS), a dopaminergic terminal region involved in positive reinforcement. However, this has been found only at ethanol doses above 1 g/kg intraperitoneally, which is higher than what most rats will self-administer. We used a sensitive on-line assay of microdialysate content to test whether lower doses of ethanol selectively increase taurine efflux in VS as opposed to other dopaminergic regions not involved in reinforcement (e.g., dorsal striatum; DS). Adult male rats with microdialysis probes in VS or DS were injected with ethanol (0, 0.5, 1, and 2 g/kg intraperitoneally), and the amino acid content of the dialysate was measured every 11 sec using capillary electrophoresis and laser-induced fluorescence detection. In VS, 0.5 g/kg ethanol significantly increased taurine levels by 20% for 10 min. A similar increase was seen after 1 g/kg ethanol, which lasted for about 20 min after injection. A two-phased taurine efflux was observed with the 2.0 g/kg dose, where taurine was increased by 2-fold after 5 min but it remained elevated by 30% for at least 60 min. In contrast, DS exhibited much smaller dose-related increases in taurine. Glycine, glutamate, serine, and ␥-aminobutyric acid were not systematically affected by lower doses of ethanol; however, 2 g/kg slowly decreased these amino acids in both brain regions during the hour after injection. These data implicate a possible role of taurine in the mechanism of action of ethanol in the VS. The high sensitivity and time resolution afforded by capillary electrophoresis and laser-induced fluorescence detection will be useful for detecting subtle changes of neuronally active amino acids levels due to low doses of ethanol.
Sensitization to Cocaine in the Nigrostriatal Dopamine System
PsycEXTRA Dataset
Pharmacology Biochemistry and Behavior, 1985
mice were fed lab chow containing phenobarbital for seven or eight days. Upon withdrawal of the p... more mice were fed lab chow containing phenobarbital for seven or eight days. Upon withdrawal of the phenobarbital diet, dependence was evidenced by appearance of hypothermia, handling-induced convulsions and lethal seizures. Functional tolerance was determined by injecting phenobarbital into mice treated with the phenobarbital diet or a pair-fed control diet and measuring the brain concentration of phenobarbital at the time of loss of righting reflex and the time of regaining righting reflex. Both measures demonstrated that chronic consumption of phenobarbital resulted in functional tolerance. When the diet was withdrawn for two days, tolerance was no longer present, indicating a rapid reversal of the adaptive changes. The veratridine-stimulated uptake of 24Na by isolated brain synaptosomes was used as a measure of membrane function. Sodium uptake was inhibited in vitro by pentobarbital and ethanol, and the inhibitory effects of these drugs were attenuated by chronic in vivo phenobarbital treatment. The fluidity of brain synaptic plasma membranes was estimated by the
Key factors influencing Local Agenda 21 planning approaches
Sustainable Development and Planning IV, 2009
Osteoarthritis and Cartilage, 2006
nary metabolic fingerprint has been identified that distighuishes healthy guinea pigs from ones t... more nary metabolic fingerprint has been identified that distighuishes healthy guinea pigs from ones that spontaneously developed osteorathritis. The meniscal transection guinea pig model of early osteoarthritis might prove to be a useful tool to search for early osteoarthritis biomarkers. Furthermore, this model is suitable to test newly developed therapies aimed at treating osteoarthritis in an early stage, for instance by stimulating anabolic processes rather than preventing joint destruction. The ineffectiveness of the compounds tested further underscores the urgent need for a new generation of drugs.
Journal of International Development, 2014
This article aims to explore the different accountability discourses of the various actors in the... more This article aims to explore the different accountability discourses of the various actors in the Spanish international aid system and to examine them in light of the various theoretical interpretations of development accountability. The conclusions reached suggest a technical and financial accountability model, largely isolated from international debates where political and social issues are at the core of the concept. Although this can be explained by a range of factors which are specific to the Spanish aid system, there are also interesting tendencies that are deepening a new understanding and practice of the idea.
European Journal of Internal Medicine, 2008
European Journal of Internal Medicine, 2008
We retrospectively reviewed all clinical records of patients with DILI admitted to our Unit from ... more We retrospectively reviewed all clinical records of patients with DILI admitted to our Unit from February 1996 to December 2006. A database was constructed, reporting data regarding age, sex, clinical features at onset, laboratory results, suspected drugs and follow-up. The diagnosis of DILI was based on the presence of at least three of the International Consensus Criteria (J Hepatol 1990). Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data, since histology was performed only in a minority of patients. All patients were negative for hepatitis A, B, C, EBV and CMV serology and non organ-specific autoantibody screening. Results: Forty six cases out of 6,134 patients received a discharge diagnose of DILI. There were 23 men and 23 women, mean age was 54.2 (range 11-88 yrs), 35 patient (74%) were older than 40 years. Five patients had an associated chronic liver disease (2 cirrhosis and 3 HCV-related chronic hepatitis). At clinical presentation all patients had abnormal liver function tests (LFTs), 22 patients were jaundiced and 3 patients was admitted for hepatic failure, manifest as hepatic encephalopathy. Liver damage was hepatocellular in 19 patients, cholestatic in 15 and mixed in 12. In 10 (22%) of cases, two or more drugs were involved. NSAIDs (n =17), psychotropic drugs (n =7) and antibiotics (n =10) were the most commonly involved drugs, followed by anti-platelet, anti-diabetic drugs and statins. NSAIDs were involved in three cases of acute liver failure and, among them, one was listed for liver transplantation but died while on the waiting list. All patients had regular follow-up visits every three months for at least one year after discharge. All patients, including those with pre-existing liver disease had a complete normalization of LFTs at the end of follow-up. Conclusions: Severe DILI requiring hospital admission is very rare and appears more common in patients over 40 years. NSAIDs, psychotropic drugs and antibiotics are the most common responsible drugs. Even in severe cases, recovery is almost the rule and only a few patients have an unfavourable course and eventually die