RESUMEN
Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of use vary across individuals. Yet, when rats self-administer cocaine under short-access conditions, their behavior tends to be well-regulated, though individual differences can emerge with long- or intermittent-access. In contrast, significant individual differences emerge when rats self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30 % of rats exhibit high levels of drug-taking. This study assessed SUD-like phenotypes of male and female rats self-administering MDPV or cocaine by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to determine whether: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administer cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. Compared to cocaine, rats that self-administered MDPV exhibited a more severe phenotype, even under short-access conditions. Long- and intermittent-access to cocaine and MDPV temporarily altered drug-taking patterns but did not systematically change SUD-like phenotypes. Behavioral and quantitative autoradiography studies suggest phenotypic differences are not due to expression of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT2A, or 5-HT2C receptors. This study suggests individuals who use synthetic cathinones may be at greater risk for developing a SUD, and short-access MDPV self-administration may provide a useful method to study the transition to disordered substance use in humans.
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Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (n=8/diet) ate either a standard laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32-56 mg/kg, IP) injections. Morphine was administered acutely and chronically, which involved 19 days of twice daily injections (increasing in 1/4 log dose increments every 3 days: 3.2-56 mg/kg, IP) to induce dependence and assess tolerance. The adverse effects of morphine (i.e., tolerance, withdrawal, changes in body temperature) were assessed throughout the study. Morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Additional adverse effects of morphine were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss, in ways that could be relevant for patients. Significance Statement The present study in female rats suggests that eating a high fat/low carbohydrate (ketogenic) or a traditional high fat/high carbohydrate diet does not impact the pain-relieving or adverse effects of opioids (i.e., tolerance or withdrawal). However, eating a ketogenic diet may have beneficial effects on opioid withdrawal-related weight loss. Individuals diagnosed with obesity taking opioids for pain-related conditions might therefore consider adopting a ketogenic diet when opioid administration is discontinued to potentially mitigate withdrawal-related weight loss.
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Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long- and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT2A, or 5-HT2C receptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.
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The present study assessed the sex-dependent effects of insulin resistance on the reinforcing effects of nicotine. Female and male rats received a chronic high-fat diet (HFD) or regular diet (RD) for 8 weeks. A subset of rats then received vehicle or a dose of streptozotocin (STZ; 25 mg/kg) that induces insulin resistance. To assess insulin resistance, glucose levels were measured 15, 30, 60, 120, and 180 min after an insulin injection (0.75 U/kg). Nine days later, the rats were given extended access to intravenous self-administration (IVSA) of nicotine (0.015, 0.03, 0.06 mg/kg) in an operant box where they consumed their respective diet ad libitum and performed responses for water deliveries. Each nicotine dose was delivered for 4 days with 3 intermittent days of abstinence in their home cage. The day after the last IVSA session, physical signs were compared following administration of mecamylamine (3.0 mg/kg) to precipitate nicotine withdrawal. The results revealed that there were no changes in insulin resistance or nicotine intake in HFD alone rats regardless of sex. Insulin resistance was observed in HFD-fed rats that received STZ, and the magnitude of this effect was greater in males versus females. Our major finding was that nicotine intake was greater among HFD + STZ female rats as compared to males. Lastly, the physical signs of withdrawal were similar across all groups. Our results suggest that females diagnosed with disorders that disrupt insulin signaling, such as diabetes may be at risk of greater vulnerability to nicotine use due to enhanced reinforcing effects of this drug.
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Diabetes Mellitus Experimental/patología , Dieta Alta en Grasa , Resistencia a la Insulina/fisiología , Nicotina/farmacología , Animales , Glucemia , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Mecamilamina/farmacología , Ratas , Ratas Wistar , Refuerzo en Psicología , Factores Sexuales , Estreptozocina/farmacologíaRESUMEN
Highly palatable foods and substance of abuse have intersecting neurobiological, metabolic and behavioral effects relevant for understanding vulnerability to conditions related to food (e.g., obesity, binge eating disorder) and drug (e.g., substance use disorder) misuse. Here, we review data from animal models, clinical populations and epidemiological evidence in behavioral, genetic, pathophysiologic and therapeutic domains. Results suggest that consumption of highly palatable food and drugs of abuse both impact and conversely are regulated by metabolic hormones and metabolic status. Palatable foods high in fat and/or sugar can elicit adaptation in brain reward and withdrawal circuitry akin to substances of abuse. Intake of or withdrawal from palatable food can impact behavioral sensitivity to drugs of abuse and vice versa. A robust literature suggests common substrates and roles for negative reinforcement, negative affect, negative urgency, and impulse control deficits, with both highly palatable foods and substances of abuse. Candidate genetic risk loci shared by obesity and alcohol use disorders have been identified in molecules classically associated with both metabolic and motivational functions. Finally, certain drugs may have overlapping therapeutic potential to treat obesity, diabetes, binge-related eating disorders and substance use disorders. Taken together, data are consistent with the hypotheses that compulsive food and substance use share overlapping, interacting substrates at neurobiological and metabolic levels and that motivated behavior associated with feeding or substance use might constitute vulnerability factors for one another. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.
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Trastorno por Atracón/fisiopatología , Encéfalo/fisiopatología , Adicción a la Comida/fisiopatología , Obesidad/fisiopatología , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Trastorno por Atracón/genética , Trastorno por Atracón/metabolismo , Encéfalo/metabolismo , Adicción a la Comida/genética , Adicción a la Comida/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Obesidad/genética , Obesidad/metabolismo , Refuerzo en Psicología , Recompensa , Factores de Riesgo , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
The COVID-19 pandemic caused significant disruption during the spring of 2020. Many college students were told to leave campus at spring break and to complete the semester remotely. This study evaluates effects of this disruption on student well-being. Measures of psychological symptoms, perceived stress, and alcohol use during the pandemic were completed by 148 students in spring 2020 and 352 students in fall 2020 at a university in the southeastern U.S. Results from both cohorts were compared to 240 students who completed the same measures in the fall 2019 semester. Participants in spring 2020 reported more mood disorder symptoms, perceived stress, and alcohol use than did pre-pandemic participants and worry about COVID-19 was negatively associated with well-being. By fall 2020 symptoms had largely returned to pre-pandemic levels. In general, White students reported a greater effect of the pandemic on well-being than did African American students. Young adults appear to be less vulnerable to the most serious medical complications associated with COVID-19, but nonetheless experience psychological effects from the pandemic. Universities and practitioners who work with college students can help young adults manage their symptoms and avoid behaviors like risky alcohol use when confronted with stressors such as the COVID-19 pandemic.
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Consumo de Alcohol en la Universidad/psicología , COVID-19/psicología , COVID-19/transmisión , SARS-CoV-2 , Estrés Psicológico/complicaciones , Adolescente , Miedo , Femenino , Humanos , Masculino , Trastornos del Humor/psicología , Factores de Riesgo , Sudeste de Estados Unidos , Estrés Psicológico/psicología , Adulto JovenRESUMEN
Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat chow are more sensitive than rats eating standard chow to the behavioral effects (e.g., locomotion and yawning) of dopaminergic drugs (e.g., quinpirole and cocaine). Daily dietary supplementation with 20% (w/w) fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole-induced yawning and cocaine-induced locomotion; however, doctors recommend that patients take fish oil just two to three times a week. To test the hypothesis that intermittent (i.e., 2 days per week) dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole and cocaine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2 days per week) dietary fish oil supplementation were tested once weekly with quinpirole [0.0032-0.32 mg/kg, intraperitoneally (i.p.)] or cocaine (1.0-17.8 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and cocaine. Intermittent dietary supplementation of fish oil prevented high fat chow-induced enhanced sensitivity to dopaminergic drugs in male and female rats. Future experiments will focus on understanding the mechanism(s) by which fish oil produces these beneficial effects.
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Cocaína/farmacología , Dieta Alta en Grasa/efectos adversos , Aceites de Pescado/farmacología , Quinpirol/farmacología , Animales , Cocaína/administración & dosificación , Suplementos Dietéticos , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Aceites de Pescado/administración & dosificación , Locomoción/efectos de los fármacos , Masculino , Quinpirol/administración & dosificación , Ratas , Ratas Sprague-Dawley , Bostezo/efectos de los fármacosRESUMEN
Rats eating high fat chow are more sensitive to the behavioral effects of dopaminergic drugs, including methamphetamine and the dopamine D2/D3 receptor agonist quinpirole, than rats eating standard chow. However, limited work has explored possible sex differences regarding the impact of diet on drug sensitivity. It is also unknown whether eating high fat chow enhances sensitivity of rats to other dopamine (e.g., D1) receptor agonists. To explore these possibilities, male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat) were tested once per week for 6 weeks with dopamine D1 receptor agonist SKF 82958 (0.01-3.2 mg/kg) or methamphetamine (0.1-3.2 mg/kg) using cumulative dosing procedures. Eating high fat chow increased sensitivity of male and female rats to methamphetamine-induced locomotion; however, only female rats eating high fat chow were more sensitive to SKF 82958-induced locomotion. SKF 82958-induced eye blinking was also marginally, although not significantly, enhanced among female rats eating high fat chow, but not males. Further, although dopamine D2 receptor expression was significantly increased for SKF 82958-treated rats eating high fat chow regardless of sex, no differences were observed in dopamine D1 receptor expression. Taken together, the present study suggests that although eating high fat chow enhances sensitivity of both sexes to dopaminergic drugs, the mechanism driving this effect might be different for males versus females. These data further demonstrate the importance of studying both sexes simultaneously when investigating factors that influence drug sensitivity. SIGNIFICANCE STATEMENT: Although it is known that diet can impact sensitivity to some dopaminergic drugs, sex differences regarding this effect are not well characterized. This report demonstrates that eating a high fat diet enhances sensitivity to methamphetamine, regardless of sex; however, sensitivity to dopamine D1 receptor agonist SKF 82958 is increased only among females eating high fat chow, but not males. This suggests that the mechanism(s) driving diet-induced changes in drug sensitivity might be different between sexes.
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Benzazepinas/farmacología , Dieta Alta en Grasa/efectos adversos , Metanfetamina/farmacología , Receptores de Dopamina D1/agonistas , Animales , Parpadeo/efectos de los fármacos , Interacciones Farmacológicas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Ratas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismoRESUMEN
Omega-3 (N3) fatty acids are dietary nutrients that are essential for human health. Arguably, one of their most critical contributions to health is their involvement in the structure and function of the nervous system. N3 fatty acids accumulate in neuronal membranes through young adulthood, becoming particularly enriched in a brain region known to be the locus of cognitive control of behavior-the prefrontal cortex (PFC). The PFC undergoes a surge in development during adolescence, coinciding with a life stage when dietary quality and intake of N3 fatty acids tend to be suboptimal. Such low intake may impact neurodevelopment and normative development of cognitive functions suggested to be protective for the risk of subsequent substance and alcohol use disorders (UD). While multiple genetic and environmental factors contribute to risk for and resilience to substance and alcohol use disorders, mounting evidence suggests that dietary patterns early in life may also modulate cognitive and behavioral factors thought to elevate UD risk (e.g., impulsivity and reward sensitivity). This review aims to summarize the literature on dietary N3 fatty acids during childhood and adolescence and risk of executive/ cognitive or behavioral dysfunction, which may contribute to the risk of subsequent UD. We begin with a review of the effects of N3 fatty acids in the brain at the molecular to cellular levels-providing the biochemical mechanisms ostensibly supporting observed beneficial effects. We continue with a review of cognitive, behavioral and neurodevelopmental features thought to predict early substance and alcohol use in humans. This is followed by a review of the preclinical literature, largely demonstrating that dietary manipulation of N3 fatty acids contributes to behavioral changes that impact drug sensitivity. Finally, a review of the available evidence in human literature, suggesting an association between dietary N3 fatty and neurodevelopmental profiles associated with risk of adverse outcomes including UD. We conclude with a brief summary and call to action for additional research to extend the current understanding of the impact of dietary N3 fatty acids and the risk of drug and alcohol UD.
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Ácidos Grasos Omega-3 , Adolescente , Adulto , Encéfalo , Niño , Dieta , Ácidos Grasos , Humanos , Adulto JovenRESUMEN
Consuming a high fat diet can lead to many negative health consequences, such as obesity, insulin resistance, and enhanced sensitivity to drugs acting on dopamine systems. It has recently been demonstrated that dietary supplementation with fish oil, which is rich in omega-3 fatty acids, can prevent this high fat diet-induced enhanced sensitivity to dopaminergic drugs from developing. However, it is not known whether fish oil supplementation can reverse this effect once it has already developed. To test the hypothesis that dietary supplementation with fish oil will reverse high fat diet-induced enhanced sensitivity to quinpirole, a dopamine D2/D3 receptor agonist, male Sprague-Dawley rats were fed either standard chow (17% kcal from fat), high fat chow (60% kcal from fat), standard chow, or high fat chow supplemented with 20% (w/w) fish oil. Body weight, food consumption, and sensitivity to quinpirole-induced (0.0032-0.32 mg/kg) penile erections were examined throughout the course of the experiment. Eating high fat chow enhanced sensitivity of rats to quinpirole-induced penile erections (i.e. resulted in a leftward shift of the ascending limb of the dose-response curve). Dietary supplementation with fish oil successfully treated this effect, as dose-response curves were not different for rats eating standard chow and rats eating high fat chow with fish oil. These results suggest that in addition to preventing the negative health consequences of eating a high fat diet, fish oil can also reverse some of these consequences once they have developed.
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Conducta Animal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Aceites de Pescado/farmacología , Animales , Peso Corporal/efectos de los fármacos , Suplementos Dietéticos , Dopaminérgicos/metabolismo , Agonistas de Dopamina/farmacología , Resistencia a la Insulina/fisiología , Masculino , Obesidad/tratamiento farmacológico , Erección Peniana/efectos de los fármacos , Quinpirol/metabolismo , Quinpirol/farmacología , Ratas , Receptores de Dopamina D2 , Receptores de Dopamina D3RESUMEN
This study examined whether the strong reinforcing effects of nicotine and changes in insulin biomarkers observed in diabetic rats are modulated via insulin. A model of diabetes was employed involving administration of streptozotocin (STZ), which produces hypoinsulinemia in rats. The present study included vehicle- or STZ-treated rats that received sham surgery or insulin pellets. Two weeks later, the rats were given extended access to intravenous self-administration (IVSA) of saline or nicotine. Concomitant changes in food intake, water responses, and body weight were assessed during 12 days of IVSA. After the last session, plasma levels of insulin, leptin, amylin, and glucagon-like peptide-1 (GLP-1) were assessed using Luminex® technology. In a separate cohort, phosphorylated insulin receptor substrate-2 (pIRS-2) and insulin growth factor-1 receptor ß (IGF-1Rß) were assessed in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of vehicle- or STZ-treated rats that received sham surgery or an insulin pellet. STZ-treated rats displayed an increase in glucose levels, a decrease in body weight, and an increase in nicotine, food, and water intake relative to controls. STZ-treated rats also displayed a decrease in plasma insulin and leptin levels and an increase in amylin and GLP-1 levels relative to controls. Importantly, all of the STZ-induced changes in behavior and insulin biomarkers were prevented by insulin supplementation. STZ-treated rats also displayed a decrease in pIRS-2 and IGF-1Rß in the NAc (but not VTA), an effect that was also prevented by insulin. These data suggest that insulin systems in the NAc modulate the strong reinforcing effects of nicotine in male diabetic rats.
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Diabetes Mellitus Experimental/metabolismo , Péptido 1 Similar al Glucagón/sangre , Proteínas Sustrato del Receptor de Insulina/metabolismo , Insulina/sangre , Polipéptido Amiloide de los Islotes Pancreáticos/sangre , Leptina/sangre , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Núcleo Accumbens/metabolismo , Receptor IGF Tipo 1/metabolismo , Refuerzo en Psicología , Área Tegmental Ventral/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Biomarcadores/sangre , Peso Corporal/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Masculino , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Ratas , Ratas Wistar , Autoadministración , AguaRESUMEN
Eating a high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g., cocaine). Further, in male rats, eating high fat chow impairs expression of insulin signaling phosphorylated protein kinase B (pAkt), which is vital for maintaining dopamine homeostasis. Eating high fat chow enhances sensitivity of female rats to drugs that act indirectly on dopamine receptors (e.g., cocaine); however, less is known about sensitivity of females to drugs that act directly on dopamine receptors (e.g., quinpirole). Further, it is not known if pAkt expression is impaired in female rats eating high fat chow. Some quinpirole-induced behaviors (e.g., penile erections and yawning) are either absent or occur at very low frequency in adult female rats. It is not known if quinpirole sensitivity in adolescent rats is more comparable between sexes. The present report examined another unconditioned behavioral effect (i.e., rearing) induced by once-weekly cumulative doses of quinpirole (0.0032-0.32mg/kg) in male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), for several weeks throughout development, (spanning adolescence and early adulthood). Following behavioral assessments, pAkt expression was examined using western blot protein analysis. Eating high fat chow increased sensitivity of male rats to the quinpirole-induced yawning, as compared to male rats eating standard chow. However, other unconditioned behavioral effects of quinpirole (yawning and hypothermia) remained unchanged. Female rats yawned significantly less than male rats, and eating a high fat chow had no effect on any quinpirole-induced unconditioned behavioral effect in female rats. Eating high fat chow also reduced pAkt levels in male, but not female rats. Taken together, these data suggest that alternative behavioral and biochemical assays should be considered to measure sensitivity of female rats to the behavioral effects of dopamine receptor agonists, and further demonstrate the importance of studying drug sensitivity in both male and female subjects.
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Cuerpo Estriado/efectos de los fármacos , Dieta Alta en Grasa , Agonistas de Dopamina/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinpirol/farmacología , Transducción de Señal/efectos de los fármacos , Bostezo/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
Eating a diet high in fat can lead to negative health consequences, including obesity and insulin resistance. Omega-3 polyunsaturated fatty acids (such as those found in fish oil) prevent high fat diet-induced obesity and insulin resistance in rats. Eating a high fat diet also enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g. quinpirole, a dopamine D2/D3 receptor agonist). To test the hypothesis that dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to the behavioral effects of quinpirole (0.0032-0.32 mg/kg), male rats ate standard laboratory chow, high fat chow, standard chow with fish oil, or high fat chow with fish oil (20% w/w). After 5 weeks, rats eating high fat chow were more sensitive (e.g. leftward shift of the quinpirole dose-response curve) than rats eating standard chow to yawning induced by quinpirole. Dietary supplementation with fish oil prevented this effect. That is, quinpirole dose-response curves were not different between rats eating high fat chow supplemented with fish oil and standard chow fed controls. These data add to a growing literature showing the complex relationship between diet and dopamine systems, and the health benefits of fish oil.
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Aceites de Pescado/farmacología , Quinpirol/farmacología , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa , Grasas de la Dieta , Suplementos Dietéticos , Agonistas de Dopamina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Aceites de Pescado/uso terapéutico , Resistencia a la Insulina/fisiología , Masculino , Obesidad , Quinpirol/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Bostezo/efectos de los fármacosRESUMEN
Lorcaserin is approved by the Food and Drug Administration for treating obesity and is under consideration for treating substance use disorders; it has agonist properties at serotonin (5-HT)2C receptors and might also have agonist properties at other 5-HT receptor subtypes. This study used drug discrimination to investigate the mechanism(s) of action of lorcaserin. Male Sprague-Dawley rats discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed-ratio 5 schedule for food. Lorcaserin (0.178-1.0 mg/kg) dose-dependently increased lorcaserin-lever responding. The 5-HT2C receptor agonist mCPP and the 5-HT2A receptor agonist DOM each occasioned greater than 90% lorcaserin-lever responding in seven of eight rats. The 5-HT1A receptor agonist 8-OH-DPAT occasioned greater than 90% lorcaserin-lever responding in four of seven rats. The 5-HT2C receptor selective antagonist SB 242084 attenuated lorcaserin-lever responding in all eight rats and the 5-HT2A receptor selective antagonist MDL 100907 attenuated lorcaserin-lever responding in six of seven rats. These results suggest that, in addition to agonist properties at 5-HT2C receptors, lorcaserin also has agonist properties at 5-HT2A and 5-HT1A receptors. Because some drugs with 5-HT2A receptor agonist properties are abused, it is important to fully characterize the behavioral effects of lorcaserin while considering its potential for treating substance use disorders.
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Benzazepinas/farmacología , Discriminación en Psicología/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Condicionamiento Operante/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Antagonistas de la Serotonina/farmacologíaRESUMEN
BACKGROUND: Eating a diet high in fat can lead to obesity, chronic metabolic disease, and increased inflammation in both the central and peripheral nervous systems. Dietary supplements that are high in omega-3 polyunsaturated fatty acids can reduce or prevent these negative health consequences in rats. Eating high fat chow also increases the sensitivity of rats to behavioral effects of drugs acting on dopamine systems (e.g., cocaine), and this effect is greatest in adolescent females. METHODS: The present experiment tested the hypothesis that dietary supplementation with fish oil prevents high fat chow induced increases in sensitivity to cocaine in adolescent female rats. Female Sprague-Dawley rats (post-natal day 25-27) ate standard laboratory chow (5.7% fat), high fat chow (34.4% fat), or high fat chow supplemented with fish oil (20% w/w). Cocaine dose dependently (1-17.8mg/kg) increased locomotion and induced sensitization across 6 weeks of once-weekly testing in all rats; however, these effects were greatest in rats eating high fat chow. RESULTS: Dietary supplementation with fish oil prevented enhanced locomotion and sensitization in rats eating high fat chow. There were no differences in inflammatory markers in plasma or the hypothalamus among dietary conditions. CONCLUSIONS: These results demonstrate that dietary supplementation with fish oil can prevent high fat diet-induced sensitization to cocaine, but they fail to support the view that these effects are due to changes in proinflammatory cytokines. These data add to a growing literature on the relationship between diet and drug abuse and extend the potential health benefits of fish oil to stimulant drug abuse prevention.
Asunto(s)
Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Cocaína/farmacología , Dieta Alta en Grasa/efectos adversos , Aceites de Pescado/farmacología , Locomoción/efectos de los fármacos , Animales , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Hipotálamo/metabolismo , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin) is approved by the United States Food and Drug Administration for treating obesity, and its therapeutic effects are thought to result from agonist activity at serotonin (5-HT)2C receptors. Lorcaserin has affinity for other 5-HT receptor subtypes, although its activity at those subtypes is not fully described. The current study compared the behavioral effects of lorcaserin (0.0032-32.0 mg/kg) to the effects of other 5-HT receptor selective agonists in rats (n = 8). The 5-HT2C receptor selective agonist 1-(3-chlorophenyl)piperazine (mCPP, 0.032-1.0 mg/kg) and lorcaserin induced yawning which was attenuated by the 5-HT2C receptor selective antagonist 6-chloro-5-methyl-N-(6-[(2-methylpyridin-3-yl)oxy]pydidin-3-yl)indoline-1-carboxamide (1.0 mg/kg). The 5-HT2A receptor selective agonist 2,5-dimethoxy-4-methylamphetamine (0.1-3.2 mg/kg) induced head twitching, which was attenuated by the 5-HT2A receptor selective antagonist R-(+)-2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL 100907, 0.01 mg/kg), lorcaserin (3.2 mg/kg), and mCPP (3.2 mg/kg). In rats pretreated with MDL 100907 (1.0 mg/kg), lorcaserin also induced head twitching. At larger doses, lorcaserin produced forepaw treading, which was attenuated by the 5-HT1A receptor selective antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (0.178 mg/kg). While the behavioral effects of lorcaserin in rats are consistent with it having agonist activity at 5-HT2C receptors, these data suggest that at larger doses it also has agonist activity at 5-HT2A and possibly 5-HT1A receptors. Mounting evidence suggests that 5-HT2C receptor agonists might be effective for treating drug abuse. A more complete description of the activity of lorcaserin at 5-HT receptor subtypes will facilitate a better understanding of the mechanisms that mediate its therapeutic effects.
Asunto(s)
Fármacos Antiobesidad/farmacología , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Anfetaminas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Movimientos de la Cabeza/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Bostezo/efectos de los fármacosRESUMEN
Diet can impact sensitivity of rats to some of the behavioral effects of drugs acting on dopamine systems. The current study tested whether continuous access to sucrose is necessary to increase yawning induced by the dopamine receptor agonist quinpirole, or if intermittent access is sufficient. These studies also tested whether sensitivity to quinpirole-induced yawning increases in rats drinking the non-caloric sweetener saccharin. Dose-response curves (0.0032-0.32 mg/kg) for quinpirole-induced yawning were determined once weekly in rats with free access to standard chow and either continuous access to water, 10% sucrose solution, or 0.1% saccharin solution, or intermittent access to sucrose or saccharin (i.e., 2 days per week with access to water on other days). Cumulative doses of quinpirole increased then decreased yawning, resulting in an inverted U-shaped dose-response curve. Continuous or intermittent access to sucrose enhanced sensitivity to quinpirole-induced yawning. Continuous, but not intermittent, access to saccharin also enhanced sensitivity to quinpirole-induced yawning. In all groups, pretreatment with the selective D3 receptor antagonist PG01037 shifted the ascending limb of the quinpirole dose-response curve to the right, while pretreatment with the selective D2 receptor antagonist L-741,626 shifted the descending limb to the right. These results suggest that even intermittent consumption of diets containing highly palatable substances (e.g. sucrose) alters sensitivity to drugs acting on dopamine systems in a manner that could be important in vulnerability to abuse drugs.
Asunto(s)
Conducta Animal/efectos de los fármacos , Benzamidas/farmacología , Sacarosa en la Dieta/administración & dosificación , Ingestión de Líquidos , Edulcorantes no Nutritivos/administración & dosificación , Piridinas/farmacología , Quinpirol/farmacología , Sacarina/administración & dosificación , Bostezo/efectos de los fármacos , Administración Oral , Animales , Antagonistas de los Receptores de Dopamina D2/farmacología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Indoles/farmacología , Masculino , Piperidinas/farmacología , Ratas Sprague-Dawley , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D3/metabolismoRESUMEN
Eating high fat chow accelerates the development of sensitization to cocaine-induced locomotion in female rats. It is not known whether consumption of sucrose or saccharin also increases sensitivity to the behavioral effects of cocaine or whether continuous (or intermittent) access to these feeding conditions is necessary to change sensitivity. Adolescent female Sprague-Dawley rats were assigned to one of seven feeding conditions from postnatal day 25 through to postnatal day 60. The rats either ate high fat (60% kcal from fat) chow and drank water or ate standard (17% kcal from fat) chow and drank either water, a 10% sucrose solution, or a 0.1% saccharin solution. The rats either had continuous access to high fat chow, sucrose, or saccharin, or had intermittent access (i.e. 2 days/week) to these substances, with access to water and standard chow on other days. As compared with standard chow, continuous (but not intermittent) access to high fat chow enhanced the development of sensitization to cocaine-induced (1-17.8 mg/kg) locomotion; drinking sucrose or saccharin (continuous or intermittent access) did not alter the development of sensitization to cocaine-induced locomotion. The impact of feeding condition on the behavioral effects of cocaine varies between sexes and across dietary composition.
Asunto(s)
Cocaína/farmacología , Grasas de la Dieta/administración & dosificación , Sacarina/administración & dosificación , Sacarosa/administración & dosificación , Animales , Ingestión de Líquidos , Ingestión de Alimentos , Ingestión de Energía/efectos de los fármacos , Femenino , Locomoción/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Eating high fat chow increases the sensitivity of male rats to some behavioral effects of the direct-acting dopamine receptor agonist quinpirole; it is not known whether sensitivity to quinpirole is similarly enhanced in female rats eating high fat chow. Female Sprague-Dawley rats had free access to standard chow (5.7% fat) or either free or restricted access (i.e. body weight matched to rats eating standard chow) to high fat (34.3% fat) chow. Quinpirole (0.0032-0.32 mg/kg) produced hypothermia and a low frequency of yawning. Eating high fat chow produced insulin resistance without affecting quinpirole-induced yawning or hypothermia. Pretreatment with the dopamine D2 receptor antagonist L-741,626 failed to increase quinpirole-induced yawning, indicating that the low frequency of yawning was not due to enhanced D2 receptor sensitivity. Compared with younger (postnatal day 75), drug-naive female rats in a previous study, rats in the present study (postnatal day 275) were more sensitive to cocaine-elicited (1-17.8 mg/kg) locomotion and the development of sensitization across 5 weeks; however, eating high fat chow did not further enhance these effects. These results suggest that drug history and age might modulate the effects of diet on sensitivity to drugs acting on dopamine systems.
Asunto(s)
Dieta Alta en Grasa , Agonistas de Dopamina/farmacología , Quinpirol/farmacología , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Animales , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Cocaína/farmacología , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/administración & dosificación , Antagonistas de los Receptores de Dopamina D2/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos , Femenino , Hipotermia/fisiopatología , Indoles/farmacología , Resistencia a la Insulina/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Piperidinas/farmacología , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Bostezo/efectos de los fármacos , Bostezo/fisiologíaRESUMEN
Feeding conditions can impact sensitivity to drugs acting on dopamine receptors; less is known about the impact of feeding conditions on the effects of drugs acting on serotonin (5-HT) receptors. This study examined the effects of feeding conditions on sensitivity to the direct-acting 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.1-3.2 mg/kg) and the direct-acting dopamine D3/D2 receptor agonist quinpirole (0.0032-0.32 mg/kg). Male Sprague-Dawley rats had free access (11 weeks), followed by restricted access (6 weeks), to high fat (34.3%, n=8) or standard (5.7% fat; n=7) chow. Rats eating high fat chow became insulin resistant and gained more weight than rats eating standard chow. Free access to high fat chow did not alter sensitivity to DOM-induced head twitch but increased sensitivity to quinpirole-induced yawning. Restricting access to high fat or standard chow shifted the DOM-induced head twitch dose-response curve to the right and shifted the quinpirole-induced yawning dose-response curve downward in both groups of rats. Some drugs of abuse and many therapeutic drugs act on 5-HT and dopamine systems; these results show that feeding conditions impact sensitivity to drugs acting on these systems, thereby possibly affecting vulnerability to abuse, as well as the therapeutic effectiveness of drugs.