RESUMO
The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT-Cre/Oprm1fl/fl) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms. Male and female ChAT-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and Cre- (control) mice were tested for alcohol consumption in two drinking paradigms: limited access "Drinking in the Dark" and intermittent access. Quinine was added to the drinking bottles in the DID experiment to test aversion-resistant, "compulsive" drinking. Nicotine and sucrose drinking were also assessed so comparisons could be made with other rewarding substances. Cholinergic MOR deletion did not influence consumption or preference for ethanol (EtOH) in either drinking task. Differences were observed in aversion-resistance in males with Cre + mice tolerating lower concentrations of quinine than Cre-. In contrast to EtOH, preference for nicotine was reduced following cholinergic MOR deletion while sucrose consumption and preference was increased in Cre+ (vs. Cre-) females. Locomotor activity was also greater in females following the deletion. These results suggest that cholinergic MORs participate in preference for rewarding substances. Further, while they are not required for consumption of alcohol alone, cholinergic MORs may influence the tendency to drink despite negative consequences.
Assuntos
Consumo de Bebidas Alcoólicas , Camundongos Knockout , Quinina , Receptores Opioides mu , Recompensa , Animais , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Masculino , Feminino , Camundongos , Quinina/farmacologia , Quinina/administração & dosagem , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Nicotina/farmacologia , Etanol/farmacologia , Etanol/administração & dosagem , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Neurônios Colinérgicos/metabolismo , Autoadministração , Sacarose/administração & dosagem , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Interneurônios/metabolismoRESUMO
Patients with cerebral malaria with polymorphic Cytochrome P450 2C19 (CYP2C19) genotypes who receive concurrent treatment with quinine are at risk of inadequate or toxic therapeutic drug concentrations due to metabolic drug interactions. The study aimed to predict the potential dose regimens of quinine when coadministered with phenobarbital in adult patients with cerebral malaria and complications (e.g., lactic acidosis and acute renal failure) and concurrent with seizures and acute renal failure who carry wild-type and polymorphic CYP2C19. The whole-body physiologically based pharmacokinetic (PBPK) models for quinine, phenobarbital, and quinine-phenobarbital coadministration were constructed based on the previously published information using Simbiology®. Four published articles were used for model validation. A total of 100 virtual patients were simulated based on the 14-day and 3-day courses of treatment. using the drug-drug interaction approach. The predicted results were within 15% of the observed values. Standard phenobarbital dose, when administered with quinine, is suitable for all groups with single or continuous seizures regardless of CYP2C19 genotype, renal failure, and lactic acidosis. Dose adjustment based on area under the curve ratio provided inappropriate quinine concentrations. The recommended dose of quinine when coadministered with phenobarbital based on the PBPK model for all groups is a loading dose of 2000 mg intravenous (i.v.) infusion rate 250 mg/h followed by 1200 mg i.v. rate 150 mg/h. The developed PBPK models are credible for further simulations. Because the predicted quinine doses in all groups were similar regardless of the CYP2C19 genotype, genotyping may not be required.
Assuntos
Anticonvulsivantes/administração & dosagem , Antimaláricos/administração & dosagem , Malária Cerebral/tratamento farmacológico , Fenobarbital/administração & dosagem , Quinina/administração & dosagem , Convulsões/tratamento farmacológico , Acidose Láctica/epidemiologia , Acidose Láctica/patologia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/patologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Antimaláricos/uso terapêutico , Área Sob a Curva , Simulação por Computador , Citocromo P-450 CYP2C19/genética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Malária Cerebral/complicações , Malária Cerebral/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fenobarbital/uso terapêutico , Quinina/uso terapêutico , Convulsões/etiologia , Adulto JovemRESUMO
Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1 µmol/kg), QHCl (10 µmol/kg), or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min before administration and every 10 min after administration for a period of 2 h. Hunger was rated at the same time points on a visual analogue scale. ID bitter administration did not affect hunger sensations, motilin, or acyl-ghrelin release compared with its placebo infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50 and 70 min after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 min before food intake.NEW & NOTEWORTHY Bitter tastants are a potential new weight-loss treatment. This is a noninvasive, easy approach, which should be received with considerable enthusiasm by the public. However, literature about bitter administration lacks consistency in methods and findings. We summarize how the compound should be given based on: the site of administration, the best bitter compound to use, and at what timing in respect to the meal. This paper is therefore a fundamental step to continue research toward the further development of the "bitter pill."
Assuntos
Duodeno/efeitos dos fármacos , Fome/efeitos dos fármacos , Hormônios Peptídicos/sangue , Compostos de Amônio Quaternário/administração & dosagem , Quinina/administração & dosagem , Estômago/efeitos dos fármacos , Colecistocinina , Estudos Cross-Over , Feminino , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon , Humanos , Intubação Gastrointestinal , Motilina/sangue , Placebos , Método Simples-Cego , Paladar , Redução de Peso , Adulto JovemRESUMO
Sugar has been shown to be a powerful substitute for drugs in preclinical studies on addiction. However, the link between sugar intake and alcohol use disorder (AUD) is poorly understood. We assessed the influence of sucrose on ethanol drinking in both nondependent (ND) and dependent (D) Long-Evans rats during acute withdrawal using the postdependent state model. Ethanol (10%-40%) and sucrose (1%-4%) solutions were offered in an operant paradigm either independently or concurrently under ratio schedules of reinforcement. We showed that D rats displayed an enhanced motivation for both 10% ethanol solution (10E) and 4% sucrose solution (4S) as compared with ND rats, and a clear preference for 4S was observed in both groups. During acute withdrawal, D rats showed a strong motivation for 30% ethanol (30E), even when adulterated with quinine, but still preferred 4S despite the fact that a high level of negative reinforcement could be expected. However, when a premix solution (30E4S) was offered concurrently with 4S, the preference for 4S was lost in D animals, which consumed as much premix as 4S, whereas ND animals displayed preference for 4S. Altogether, those results suggest that reinforcing properties of sucrose surpass those of ethanol in D rats under acute withdrawal, which indicates that sugar is a powerful substitute for ethanol. Our results suggest that craving for sugar may be increased in AUD patients during withdrawal and raise the issue of dependence transfer from alcohol to sugar.
Assuntos
Alcoolismo/psicologia , Etanol/administração & dosagem , Sacarose/administração & dosagem , Consumo de Bebidas Alcoólicas , Animais , Condicionamento Operante , Masculino , Motivação , Quinina/administração & dosagem , Ratos , Ratos Long-Evans , Reforço Psicológico , AutoadministraçãoRESUMO
Stimulation of gastrointestinal taste receptors affects eating behaviour. Intraduodenal infusion of tastants leads to increased satiation and reduced food intake, whereas intraileal infusion of tastants does not affect eating behaviour. Currently, it is unknown whether oral- or intragastric administration of tastants induces a larger effect on eating behaviour. This study investigated the effects of oral- and/or intragastric administration of quinine on food intake, appetite sensations and heart rate variability (HRV). In a blinded randomised crossover trial, thirty-two healthy volunteers participated in four interventions with a 1-week washout: oral placebo and intragastric placebo (OPGP), oral quinine and intragastric placebo (OQGP), oral placebo and intragastric quinine (OPGQ) and oral quinine and intragastric quinine (OQGQ). On test days, 150 min after a standardised breakfast, subjects ingested a capsule containing quinine or placebo and were sham-fed a mixture of quinine or placebo orally. At 50 min after intervention, subjects received an ad libitum meal to measure food intake. Visual analogue scales for appetite sensations were collected, and HRV measurements were performed at regular intervals. Oral and/or intragastric delivery of the bitter tastant quinine did not affect food intake (OPGP: 3273·6 (sem 131·8) kJ, OQGP: 3072·7 (sem 132·2) kJ, OPGQ: 3289·0 (sem 132·6) kJ and OQGQ: 3204·1 (sem 133·1) kJ, P = 0·069). Desire to eat and hunger decreased after OQGP and OPGQ compared with OPGP (P < 0·001 and P < 0·05, respectively), whereas satiation, fullness and HRV did not differ between interventions. In conclusion, sole oral sham feeding with and sole intragastric delivery of quinine decreased desire to eat and hunger, without affecting food intake, satiation, fullness or HRV.
Assuntos
Apetite/efeitos dos fármacos , Agentes Aversivos/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Quinina/administração & dosagem , Sensação/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Idoso , Desjejum , Estudos Cross-Over , Duodeno , Comportamento Alimentar/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Fome/efeitos dos fármacos , Íleo , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Saciação/efeitos dos fármacos , Método Simples-Cego , Adulto JovemRESUMO
The ingestion of quinine, a bitter tastant, improves short-term (30 s) cycling performance, but it is unclear whether this effect can be integrated into the last effort of a longer race. The purpose of this study was to determine whether midtrial quinine ingestion improves 3,000-m cycling time-trial (TT) performance. Following three familiarization TTs, 12 well-trained male cyclists (mean ± SD: mass = 76.6 ± 9.2 kg, maximal aerobic power = 390 ± 50 W, maximal oxygen uptake = 4.7 ± 0.6 L/min) performed four experimental 3,000-m TTs on consecutive days. This double-blind, crossover design study had four randomized and counterbalanced conditions: (a) Quinine 1 (25-ml solution, 2 mM of quinine); (b) Quinine 2, replicate of Quinine 1; (c) a 25-ml sweet-tasting no-carbohydrate solution (Placebo); and (d) 25 ml of water (Control) consumed at the 1,850-m point of the TT. The participants completed a series of perceptual scales at the start and completion of all TTs, and the power output was monitored continuously throughout all trials. The power output for the last 1,000 m for all four conditions was similar: mean ± SD: Quinine 1 = 360 ± 63 W, Quinine 2 = 367 ± 63 W, Placebo = 364 ± 64 W, and Control = 367 ± 58 W. There were also no differences in the 3,000-m TT power output between conditions. The small perceptual differences between trials at specific 150-m splits were not explained by quinine intake. Ingesting 2 mM of quinine during the last stage of a 3,000-m TT did not improve cycling performance.
Assuntos
Ciclismo/fisiologia , Substâncias para Melhoria do Desempenho/administração & dosagem , Resistência Física/efeitos dos fármacos , Quinina/administração & dosagem , Administração Oral , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Percepção/fisiologia , Esforço Físico/fisiologia , SoluçõesRESUMO
A bitter substance induces specific orofacial and somatic behavioral reactions such as gapes in mice as well as monkeys and humans. These reactions have been proposed to represent affective disgust, and therefore, understanding the neuronal basis of the reactions would pave the way to understand affective disgust. It is crucial to identify and access the specific neuronal ensembles that are activated by bitter substances, such as quinine, the intake of which induces disgust reactions. However, the method to access the quinine-activated neurons has not been fully established yet. Here, we show evidence that a targeted recombination in active populations (TRAP) method, induces genetic recombination in the quinine-activated neurons in the central nucleus of the amygdala (CeA). CeA is one of the well-known emotional centers of the brain. We found that the intraoral quinine infusion, that resulted in disgust reactions, increased both cFos-positive cells and Arc-positive cells in the CeA. By using Arc-CreER;Ai3 TRAP mice, we induced genetic recombination in the quinine-activated neurons and labelled them with fluorescent protein. We confirmed that the quinine-TRAPed fluorescently-labelled cells preferentially coexpressed Arc after quinine infusion. Our results suggest that the TRAP method can be used to access specific functional neurons in the CeA.
Assuntos
Núcleo Central da Amígdala/metabolismo , Asco , Neurônios/metabolismo , Recombinação Genética/fisiologia , Percepção Gustatória/fisiologia , Paladar/fisiologia , Animais , Núcleo Central da Amígdala/química , Núcleo Central da Amígdala/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/química , Neurônios/efeitos dos fármacos , Quinina/administração & dosagem , Recombinação Genética/efeitos dos fármacos , Sacarina/administração & dosagem , Paladar/efeitos dos fármacos , Percepção Gustatória/efeitos dos fármacosRESUMO
RATIONALE: Animal models of compulsive drug use that continues despite negative consequences can be used to investigate the neural mechanisms of addiction. However, models of punished or aversion-resistant opioid self-administration are notably lacking. OBJECTIVES: We sought to develop an aversion-resistant, oral fentanyl self-administration paradigm. METHODS: In Experiment 1, C57BL/6J male and female, adult mice consumed fentanyl (10 µg/mL) in a two-bottle drinking in the dark task and escalating concentrations of quinine were added to the bottles. In Experiment 2, mice were trained to administer oral fentanyl (10 µg/mL) in an operant response task. Quinine was next added to the fentanyl solution in escalating concentrations. In Experiment 3, mice were trained to respond for oral fentanyl or fentanyl adulterated with 500 µM quinine on every session. In Experiment 4, mice were trained to respond for a 1% sucrose solution before introduction of quinine. RESULTS: Quinine reduced two-bottle choice consumption in males but not in females. Both sexes demonstrated the ability to detect the selected concentrations of quinine in fentanyl. In the operant chamber, mice responded robustly for oral fentanyl but introduction of quinine at any stage of training was insufficient to reduce responding. In contrast, quinine reduced responding for sucrose at concentrations above 250 µM. CONCLUSIONS: Mice will respond for and consume oral fentanyl in both a two-bottle choice and an operant response task. Quinine is detectable in fentanyl but mice will continue to respond for and consume fentanyl with quinine in both paradigms. These data support the use of these models in behavioral studies of compulsive-like opioid use.
Assuntos
Analgésicos Opioides/administração & dosagem , Comportamento Aditivo/psicologia , Comportamento de Escolha/efeitos dos fármacos , Fentanila/administração & dosagem , Quinina/administração & dosagem , Sacarose/administração & dosagem , Afeto/efeitos dos fármacos , Animais , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Autoadministração , Fatores Sexuais , Paladar/efeitos dos fármacosRESUMO
Cryptic Plasmodium niches outside the liver possibly represent a major source of hypnozoite-unrelated recrudescences in malaria. Maurizio Ascoli, an Italian physician and scientist, suggested that infection was maintained as a result of the persistence of endoerythrocytic parasites in the circulatory bed of some internal organs, mainly the spleen. This would explain a proportion of the recurrences in patients, regardless of the Plasmodium species. Ascoli proposed a method that included the co-administration of adrenaline, in order to induce splenic contraction, and quinine to clear expelled forms in major vessels. Driven by controversy regarding safety and effectiveness, along with the introduction of new drugs, the Ascoli method was abandoned and mostly forgotten by the malaria research community. To date, however, the existence of cryptic parasites outside the liver is gaining supportive data. This work is a historical retrospective of cryptic malaria infections and the Ascoli method, highlighting key knowledge gaps regarding these possible parasite reservoirs.
Assuntos
Antimaláricos/administração & dosagem , Infecções Assintomáticas , Epinefrina/administração & dosagem , Malária/prevenção & controle , Quinina/administração & dosagem , Baço/efeitos dos fármacos , Doença Crônica/prevenção & controle , História do Século XXRESUMO
OBJECTIVES: This retrospective analysis performed in Manhiça, Southern Mozambique, aimed to describe the frequency of post-malarial anemia (measured as a decrease of hematocrit ≥10%) and the need for blood transfusions in children with severe malaria treated with intravenous quinine or parenteral artesunate. METHODS: All children <15 years admitted with a parasitologically-confirmed diagnosis of malaria from 1st January 2003 to 31st December 2017, alive at hospital discharge, and with at least one measurement of hematocrit within 28 days after hospital discharge, detected by passive case detection, were included. RESULTS: The overall prevalence of post-malarial anemia observed in the study was 23.13%, with an estimated incidence rate of 288.84 episodes/1,000 children-month at risk in the follow-up period (28 days after discharge). There were no differences between treatment groups, although the study showed a higher association between blood transfusions and artesunate treatment. CONCLUSIONS: In this setting, children with severe malaria frequently present a meaningful decrease of hematocrit (>=10%) in the first weeks after their episode, sometimes requiring blood transfusions. Because of the high underlying prevalence of anemia in malaria-endemic settings, all children with severe malaria need to be actively followed up, irrespective of the treatment received.
Assuntos
Anemia/etiologia , Antimaláricos/administração & dosagem , Artesunato/administração & dosagem , Malária/complicações , Malária/tratamento farmacológico , Quinina/administração & dosagem , Administração Intravenosa , Adolescente , Anemia/epidemiologia , Antimaláricos/efeitos adversos , Artesunato/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Moçambique/epidemiologia , Quinina/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: Previous studies indicate that taste dysfunction occurs early in the development of Alzheimer's disease. It is debatable whether the deficit in taste is due primarily to peripheral sensory mechanisms or to central processing, or a combination of the two. OBJECTIVE: The aim of our current study is to combine behavior and histological data in APP/PS1 transgenic mice to determine whether APP/PS1 transgenic mice show deficits in unconditioned taste preference and avoidance behaviors and whether taste impairments are due to defects in the peripheral taste system and/or problems with central processing of taste information. METHODS: The APP/PS1 transgenic mutant mice were used as a model of Alzheimer's disease. We employed a brief-access gustometer test to assess immediate orosensory taste responses of APP/PS1 mice. We used immunohistochemistry to examine tongue, gustatory ganglion, and brain tissues to determine a cytological basis for behavioral deficits. RESULTS: There is a significant, selective reduction of bitter taste sensitivity in APP/PS1 mice. These mice also have a loss of TRPM5-expressing taste receptor cells in the circumvallate papillae of the tongue. While we observed no overt loss of neuron cell bodies within the primary gustatory sensory neurons, degeneration of the neurons' peripheral axons innervating the taste bud may play a role in the observed loss of TRPM5-expressing taste receptor cells. CONCLUSION: This data supports a potential role for peripheral taste dysfunction in AD through the selective loss of taste receptor cells. Further study is necessary to delineate the mechanisms and pathological significance of this deficit in AD.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Mutação/genética , Presenilina-1/genética , Distúrbios do Paladar/genética , Paladar/genética , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Quinina/administração & dosagem , Sacarose/administração & dosagem , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Paladar/efeitos dos fármacos , Distúrbios do Paladar/fisiopatologiaRESUMO
There is great interest in demonstrating acceptability of solid oral formulations in paediatric populations. This study investigated the acceptability of small, 7.5 mm, bitter-flavoured, coated tablets in healthy children and adults. A randomised, double-blind acceptability test was performed involving 101 children (4-12 years) and 52 adults (18-75 years). Acceptability was measured by participants as sensory assessment of taste, mouthfeel and hedonic perception, and by researcher observations of ability to swallow the tablet and negative facial expressions. Additionally, the taste-masking effect of film coatings was assessed based on the intensity of bitterness perception. At least one tablet was voluntarily swallowed by 35.7% of 4-6-year olds, 74% of 7-12-year olds and 98% of adults. The bitterness of the tablet did not affect participants' ability to swallow it. The sensory properties determined whether the tablet was acceptable. The following factors: low bitterness, high smoothness, high slipperiness and pleasant aftertaste had a positive impact on overall palatability in both populations. The paediatric scores during sensory evaluation of tablets differed from adults, showing lower acceptability. This study demonstrates the multifactorial nature of palatability of tablets and highlights that adults' palatability evaluation cannot be directly translated to a paediatric population.
Assuntos
Deglutição/efeitos dos fármacos , Quinina/administração & dosagem , Comprimidos , Paladar/efeitos dos fármacos , Tecnologia Farmacêutica/métodos , Administração Oral , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Percepção Gustatória , Adulto JovemRESUMO
Genetic variability in the ability to taste thiourea compounds has been studied for 80+ years. Over the last 3 decades, many studies have reported perceived intensity of concentrated propylthiouracil (PROP) associates with greater intensity from a broad range of stimuli, including nonbitter tastants, irritants, and retronasally delivered odorants. Thus, PROP phenotype has become a common measure of individual differences in orosensation. Much, but not all, of the phenotypic variation in PROP bitterness is explained by TAS2R38 polymorphisms. While differences in PROP bitterness are clearly due to genetic variation, mechanistically it is challenging to envision how this receptor (narrowly tuned to the N-C=S moiety) relates to overall orosensory response. Here, we report data for 200+ individuals who had been genotyped for TAS2R38 and phenotyped for PROP in a laboratory setting. Participants also reported the intensity of quinine, capsaicin, and sucrose on a general Labeled Magnitude Scale. Our data recapitulate earlier reports associating PROP bitterness with the intensity of the predominant qualities of sucrose, quinine, and capsaicin; however, we also find correlations between the intensities of sucrose, quinine, and capsaicin were much stronger with each other than with PROP. As expected, TAS2R38 diplotype did not associate with the intensity of sucrose, quinine, or capsaicin. The strength of PROP-capsaicin and PROP-sucrose relationships increased after grouping participants by TAS2R38 diplotype, with the greatest increases in association observed within homozygotes. Collectively, this suggests the suprathreshold intensity of PROP is a confounded phenotype that captures both genetic variation specific to N-C=S compounds and overall orosensation.
Assuntos
Agentes Aversivos/química , Capsaicina/química , Propiltiouracila/química , Quinina/química , Receptores Acoplados a Proteínas G/genética , Sacarose/química , Paladar/fisiologia , Adolescente , Adulto , Agentes Aversivos/farmacologia , Genótipo , Humanos , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Psicofísica , Quinina/administração & dosagem , Paladar/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Trauma related psychiatric disorders, such as posttraumatic stress disorder (PTSD), and alcohol use disorder (AUD) are highly comorbid illnesses that separately present an opposing, sex-specific pattern, with increased prevalence of PTSD in females and increased prevalence of AUD diagnoses in males. Likewise, PTSD is a risk factor in the development of AUD, with conflicting data on the impact of sex in the comorbid development of both disorders. Because the likelihood of experiencing more than one traumatic event is high, we aim to utilize chronic repeated predatory stress (CRPS) to query the extent to which sex interacts with CRPS to influence alcohol consumption, or cessation of consumption. METHODS: Male (n = 16) and female (n = 15) C57BL/6 J mice underwent CRPS or daily handling for two weeks during adolescence (P35-P49) and two weeks during adulthood (P65-P79). Following the conclusion of two rounds of repeated stress, behavior was assessed in the open field. Mice subsequently underwent a two-bottle choice intermittent ethanol access (IEA) assessment (P90-131) with the options of 20 % ethanol or water. After establishing drinking behavior, increasing concentrations of quinine were added to the ethanol to assess the drinking response to adulteration of the alcohol. RESULTS: CRPS increased fecal corticosterone concentrations and anxiety-like behaviors in the open field in both male and female mice as compared to control mice that had not been exposed to CRPS. Consistent with previous reports, we observed a sex difference in alcohol consumption such that females consumed more ethanol per gram of body mass than males. In addition, CRPS reduced alcohol aversion in male mice such that higher concentrations of quinine were necessary to reduce alcohol intake as compared to control mice. CRPS did not alter alcohol-related behaviors in female mice. CONCLUSION: Collectively, we demonstrate that repeated CRPS can induce anxiety-like behavior in both sexes but selectively influences the response to ethanol adulteration in males.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Etanol/administração & dosagem , Comportamento Predatório , Quinina/administração & dosagem , Estresse Psicológico/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Feminino , Masculino , Camundongos Endogâmicos C57BL , Caracteres SexuaisRESUMO
At the end of December 2019, they emerged a new coronavirus (SARS-CoV-2), triggering a pandemic of an acute respiratory syndrome (COVID-19) in humans. We report the relevant features of the first two confirmed cases of COVID-19 recorded from the 29th April 2020 in the Far North Region of Cameroon. We did a review of the files of these two patients who were admitted to the internal medicine ward of a medical Centre in Maroua Town, Far North Region. We present 2 cases of symptomatic COVID-19 patients, both males and health personnel, with an average age of 53 years, with no recent history of travel to a COVID-19 zone at risk and working in a then COVID-19 free region. They presented with extreme fatigue as their main symptom. Both were treated initially for severe malaria with quinine sulfate infusion with initial relief of symptoms. In the first confirmed case, at his re-hospitalization with an acute respiratory syndrome, a polymerase chain reaction (PCR) test in search of SARS-CoV-2 was requested with his results available 7 days into admission. For the second case, he had his results 48 hours on admission while he was prepared to be discharged. Both control PCR tests for COVID-19 came back negative 14 days after hospitalization. Health personnel remains a group at risk for the COVID-19 infection. The clinical manifestation at an early stage may be atypical mimicking endemic tropical infections. Also, the therapeutic potential of quinine salts in the relief of symptoms of COVID-19 is questionable and remains a subject to explore in our context.
Assuntos
Teste para COVID-19 , COVID-19/diagnóstico , Malária/diagnóstico , Antimaláricos/administração & dosagem , COVID-19/fisiopatologia , Camarões , Fadiga/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Quinina/administração & dosagemRESUMO
RATIONALE: Early-life environment influences reinforcer and drug motivation in adulthood; however, the impact on specific components of motivation, including hedonic value ("liking"), remains unknown. OBJECTIVES: The current study determined whether differential rearing alters liking and aversive responding to ethanol, sucrose, and quinine in an ethanol-naïve rat model. METHODS: Male and female rats were reared for 30 days starting at postnatal day 21 in either an enriched (EC), isolated (IC), or standard condition (SC). Thereafter, all rats had indwelling intraoral fistulae implanted and their taste reactivity to water, ethanol (5, 10, 20, 30, 40% v/v), sucrose (0.1, 0.25, 0.5 M), and quinine (0.1, 0.5 mM) was recorded and analyzed. RESULTS: EC rats had higher amounts of liking responses to ethanol, sucrose, and quinine and higher amounts of aversive responses to ethanol and quinine compared to IC rats. While EC and IC rats' responses were different from each other, they both tended to be similar to SCs, who fell in between the EC and IC groups. CONCLUSIONS: These results suggest that environmental enrichment may enhance sensitivity to a variety of tastants, thereby enhancing liking, while isolation may dull sensitivity, thereby dulling liking. Altogether, the evidence suggests that isolated rats have a shift in the allostatic set-point which may, in part, drive increased responding for a variety of rewards including ethanol and sucrose. Enriched rats have enhanced liking of both sucrose and ethanol suggesting that enrichment may offer a unique phenotype with divergent preferences for incentive motivation.
Assuntos
Meio Ambiente , Etanol/administração & dosagem , Abrigo para Animais , Quinina/administração & dosagem , Isolamento Social/psicologia , Sacarose/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Ratos , Ratos Long-Evans , Paladar/efeitos dos fármacos , Paladar/fisiologiaRESUMO
RATIONALE: Alcohol and nicotine addiction are prevalent conditions that co-occur. Despite the prevalence of co-use, factors that influence the suppression and enhancement of concurrent alcohol and nicotine intake are largely unknown. OBJECTIVES: Our goals were to assess how nicotine abstinence and availability influenced concurrent alcohol consumption and to determine the impact of quinine adulteration of alcohol on aversion-resistant alcohol consumption and concurrent nicotine consumption. METHODS: Male and female C57BL/6J mice voluntarily consumed unsweetened alcohol, nicotine, and water in a chronic 3-bottle choice procedure. In experiment 1, nicotine access was removed for 1 week and re-introduced the following week, while the alcohol and water bottles remained available at all times. In experiment 2, quinine (100-1000 µM) was added to the 20% alcohol bottle, while the nicotine and water bottles remained unaltered. RESULTS: In experiment 1, we found that alcohol consumption and preference were unaffected by the presence or absence of nicotine access in both male and female mice. In experiment 2a, we found that quinine temporarily suppressed alcohol intake and enhanced concurrent nicotine, but not water, preference in both male and female mice. In experiment 2b, chronic quinine suppression of alcohol intake increased nicotine consumption and preference in female mice without affecting water preference, whereas it increased water and nicotine preference in male mice. CONCLUSIONS: Quinine suppression of alcohol consumption enhanced the preference for concurrent nicotine preference in male and female mice, suggesting that mice compensate for the quinine adulteration of alcohol by increasing their nicotine preference.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Comportamento de Escolha/efeitos dos fármacos , Etanol/administração & dosagem , Nicotina/administração & dosagem , Uso de Tabaco/psicologia , Animais , Comportamento de Escolha/fisiologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinina/administração & dosagem , AutoadministraçãoRESUMO
The coformulated lopinavir/ritonavir significantly reduces quinine concentration in healthy volunteers due to potential drug-drug interactions (DDIs). However, DDI information in malaria and HIV coinfected patients are lacking. The objective of the study was to apply physiologically-based pharmacokinetic (PBPK) modeling to predict optimal dosage regimens of quinine when coadministered with lopinavir/ritonavir in malaria and HIV coinfected patients with different conditions. The developed model was validated against literature. Model verification was evaluated using the accepted method. The verified PBPK models successfully predicted unbound quinine disposition when coadministered with lopinavir/ritonavir in coinfected patients with different conditions. Suitable dose adjustments to counteract with the DDIs have identified in patients with various situations (i.e., a 7-day course at 1,800 mg t.i.d. in patients with malaria with HIV infection, 648 mg b.i.d. in chronic renal failure, 648 mg t.i.d. in hepatic insufficiency except for severe hepatic insufficiency (324 mg b.i.d.), and 648 mg t.i.d. in CYP3A4 polymorphism).
Assuntos
Lopinavir/farmacologia , Modelos Biológicos , Quinina/farmacocinética , Ritonavir/farmacologia , Adolescente , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Coinfecção , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/farmacologia , Humanos , Lopinavir/administração & dosagem , Malária/tratamento farmacológico , Pessoa de Meia-Idade , Quinina/administração & dosagem , Ritonavir/administração & dosagem , Adulto JovemRESUMO
The rate of gastric emptying and the release of gastrointestinal (GI) hormones are major determinants of postprandial blood-glucose concentrations and energy intake. Preclinical studies suggest that activation of GI bitter-taste receptors potently stimulates GI hormones, including glucagon-like peptide-1 (GLP-1), and thus may reduce postprandial glucose and energy intake. We evaluated the effects of intragastric quinine on the glycemic response to, and the gastric emptying of, a mixed-nutrient drink and the effects on subsequent energy intake in healthy men. The study consisted of 2 parts: part A included 15 lean men, and part B included 12 lean men (aged 26 ± 2 yr). In each part, participants received, on 3 separate occasions, in double-blind, randomized fashion, intragastric quinine (275 or 600 mg) or control, 30 min before a mixed-nutrient drink (part A) or before a buffet meal (part B). In part A, plasma glucose, insulin, glucagon, and GLP-1 concentrations were measured at baseline, after quinine alone, and for 2 h following the drink. Gastric emptying of the drink was also measured. In part B, energy intake at the buffet meal was quantified. Quinine in 600 mg (Q600) and 275 mg (Q275) doses alone stimulated insulin modestly (P < 0.05). After the drink, Q600 and Q275 reduced plasma glucose and stimulated insulin (P < 0.05), Q275 stimulated GLP-1 (P < 0.05), and Q600 tended to stimulate GLP-1 (P = 0.066) and glucagon (P = 0.073) compared with control. Quinine did not affect gastric emptying of the drink or energy intake. In conclusion, in healthy men, intragastric quinine reduces postprandial blood glucose and stimulates insulin and GLP-1 but does not slow gastric emptying or reduce energy intake under our experimental conditions.
Assuntos
Bebidas , Glicemia/efeitos dos fármacos , Alimentos Formulados , Esvaziamento Gástrico/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Quinina/administração & dosagem , Paladar/efeitos dos fármacos , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Método Duplo-Cego , Ingestão de Energia , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Voluntários Saudáveis , Humanos , Insulina/sangue , Masculino , Período Pós-Prandial , Fatores de Tempo , Adulto JovemRESUMO
Understanding why some people continue to drink alcohol despite negative consequences and others do not is a central problem in the study of alcohol use disorder (AUD). In this study, we used alcohol-preferring P rats (a strain bred to prefer to drink alcohol, a model for genetic risk for AUD) and Wistar rats (control) to examine drinking despite negative consequences in the form of an aversive bitter taste stimulus produced by quinine. Animals were trained to consume 10% ethanol in a simple Pavlovian conditioning task that paired alcohol access with an auditory stimulus. When the alcohol was adulterated with quinine (0.1 g/L), P rats continued to consume alcohol + quinine at the same rate as unadulterated alcohol, despite a demonstrated aversion to quinine-adulterated alcohol when given a choice between adulterated and unadulterated alcohol in the home cage. Conversely, Wistar rats decreased consumption of quinine-adulterated alcohol in the task, but continued to try the alcohol + quinine solution at similar rates to unadulterated alcohol. These results indicate that following about 8 weeks of alcohol consumption, P rats exhibit aversion-resistant drinking. This model could be used in future work to explore how the biological basis of alcohol consumption and genetic risk for excessive drinking lead to drinking that is resistant to devaluation.