RESUMO
Alcohol (ethanol) use is almost normative by late adolescence, in most western countries. It is important to identify factors that distinguish those who progress from alcohol initiation to sustained use of the drug, from those that keep a controlled pattern of drinking. The factors precipitating this transition may change across development. This study analyzed associations between behavioral endophenotypes and ethanol intake at three developmental periods. Exp. 1 measured ethanol drinking at postnatal day 18, via an intraoral infusion procedure, in male or female pre-weanling rats screened for anxiety response in the light-dark box test and for distance traveled in a novel open field. Exp. 2 measured, in juvenile/adolescent or young adult rats, the association between shelter seeking, exploratory/risk-taking behaviors, anxiety or hedonic responses, and ethanol intake. Ethanol intake in pre-weanlings was explained by distance traveled in a novel environment, whereas anxiety responses, measured in the multivariate concentric square field apparatus (MSCF), selectively predicted ethanol intake at adolescence, but not at adulthood. Those juvenile/adolescents with lower mean duration of visit to areas of the MSCF that evoke anxiogenic responses exhibited heightened ethanol intake. These findings suggest that the association between anxiety and ethanol intake may be specifically relevant during adolescence.
Assuntos
Consumo de Bebidas Alcoólicas , Etanol , Animais , Ansiedade , Feminino , Masculino , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
Early pre- or postnatal sensory experiences significantly influence flavor preference and food intake, and can induce liking for innately unpalatable flavors. Previous work found that newborn rats stimulated with an odor experienced shortly after birth exhibited heightened intake and seeking towards an artificial nipple containing quinine. This result suggests that odors made familiar trough early postnatal pre-exposure can shift the motivational value of unconditional stimuli. The objective of the current study was to assess the effect of an odor (lemon) experienced in-utero on the first intake responses towards an artificial nipple supplying quinine. The hypothesis, which was corroborated, was that stimulation with the olfactory stimulus experienced in-utero would increase the newborn's intake and grasp responses to the artificial nipple containing quinine. Exposure to the odor that had been pre-exposed in utero increased quinine intake and seeking (i.e., latency to grasp and total time in contact with the nipple, as well as number of and mean duration of nipple grasps) in 3-h-old pups. These results replicate those previously found with postnatal odor pre-exposure, and extend the phase for pre-exposure to the prenatal stage.
Assuntos
Ingestão de Alimentos , Comportamento Alimentar , Odorantes , Efeitos Tardios da Exposição Pré-Natal , Quinina/administração & dosagem , Animais , Animais Recém-Nascidos , Animais Lactentes , Feminino , Masculino , Gravidez , Ratos Sprague-Dawley , OlfatoRESUMO
Adolescents may be more sensitive to stress-induced alcohol drinking than adults, which would explain the higher prevalence of alcohol abuse and dependence in late adolescence than in adulthood. The present study analyzed the impact of restraint stress on the initiation of alcohol intake across 2 weeks of intermittent, two-bottle choice intake in male and female adolescent rats and adult female rats. Restraint stress significantly increased alcohol intake and preference in female adolescent rats but decreased alcohol intake and preference in male adolescent and female adult rats. The effects of restraint stress on alcohol intake were mitigated in adolescent females following administration of the κ opioid receptor antagonist norbinaltorphimine. Adolescent but not adult female rats that were subjected to restraint stress spent more time on the open arms of the elevated plus maze. Female adolescents exposed to stress also exhibited greater risk-taking behaviors in a concentric square field test compared with non-stressed controls. These results indicate age- and sex-related differences in the sensitivity to alcohol-stress interactions that may facilitate the initiation of alcohol use in female adolescents. The facilitatory effect of stress on alcohol intake was related to greater exploratory and risk-taking behaviors in young females after stress exposure.
Assuntos
Envelhecimento/fisiologia , Envelhecimento/psicologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Consumo de Bebidas Alcoólicas/psicologia , Caracteres Sexuais , Estresse Psicológico/fisiopatologia , Envelhecimento/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Modelos Animais de Doenças , Etanol/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos Wistar , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Restrição Física , Assunção de Riscos , Estresse Psicológico/tratamento farmacológicoRESUMO
Animal models of prenatal ethanol exposure (PEE) have indicated a facilitatory effect of PEE on adolescent ethanol intake, but few studies have assessed the effects of moderate PEE throughout adolescence. The mechanisms underlying this facilitatory effect remain largely unknown. In the present study, we analysed ethanol intake in male and female Wistar rats with or without PEE (2.0 g/kg, gestational days 17-20) from postnatal days 37 to 62. The results revealed greater ethanol consumption in PEE rats than in controls, which persisted throughout adolescence. By the end of testing, ethanol ingestion in PEE rats was nearly 6.0 g/kg. PEE was associated with insensitivity to ethanol-induced aversion. PEE and control rats were further analysed for levels of µ, δ and κ opioid receptor mRNA in the infralimbic cortex, nucleus accumbens shell, and ventral tegmental area. Similar levels of mRNA were observed across most areas and opioid receptors, but µ receptor mRNA in the ventral tegmental area was significantly increased by PEE. Unlike previous studies that assessed the effects of PEE on ethanol intake close to birth, or in only a few sessions during adolescence, the present study observed a facilitatory effect of PEE that lasted throughout adolescence. PEE was associated with insensitivity to the aversive effect of ethanol, and increased levels of µ opioid receptor transcripts. PEE is a prominent vulnerability factor that probably favors the engagement of adolescents in risky trajectories of ethanol use.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Aprendizagem da Esquiva/efeitos dos fármacos , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Fatores Etários , Animais , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Opioides delta/genética , Receptores Opioides kappa/genéticaRESUMO
The review focuses on operant self-administration of ethanol in immature, infant rats. Several methods for the analysis of ethanol intake in infants are available, yet only oral self-administration models the typical pattern of ethanol consumption found in humans. The study of ethanol intake in infants is important for our understanding of how early alcohol experiences facilitate subsequent engagement with alcohol. It seems that sensitivity to ethanol-induced operant reinforcement is found very early in life, a few hours after birth, and throughout the first three weeks of life. Most of the studies reviewed complied with most, albeit not all, of the criteria for operant behavior (e.g., greater responding than yoked controls and persistence of this difference after withholding the reinforcer). Operant self-administration of ethanol in infant rats seems to be, at least partially, mediated by endogenous opioid transmission and can be enhanced by prior exposure to ethanol. Furthermore, acquisition of ethanol-mediated operant learning seems to facilitate drug self-administration during adolescence. Relative to older subjects, infants exhibit lower sensitivity to ethanol's sedative, hypnotic and motor impairing effects. On the other hand, they exhibit increased sensitivity to the motor stimulant and rewarding effects of ethanol. We suggest that this pattern of response to ethanol may favor the rapid acquisition of operant self-administration in infant rats.
Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Etanol/administração & dosagem , Animais , Animais Recém-Nascidos , Ratos , AutoadministraçãoRESUMO
Animals exposed to chronic maternal separation (MS) exhibit enhanced ethanol self-administration and greater hormonal and behavioral responsiveness to stress in adulthood. Whether the effects of MS are immediately evident in infancy or whether they appear only later on development is still an unanswered question This study tested sensitivity to ethanol's behavioral stimulating effects in infant rats that experienced MS from postnatal Day 1-14. MS infants exhibited significantly greater reactivity to the motor stimulating effects of 1.25 g/kg ethanol than control animals, yet greater motor suppression after 2.5 g/kg ethanol. Baseline level of response to novelty was altered in MS infants, in a nor-binaltorphimine insensitive manner, that is, despite modified activity of the kappa-opioid system. These results indicate that the consequences of chronic maternal isolation emerge early in ontogeny, affecting ethanol sensitivity in infancy.
Assuntos
Etanol/administração & dosagem , Privação Materna , Atividade Motora/fisiologia , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Ratos , Ratos Wistar , AutoadministraçãoRESUMO
A question still to be answered is whether ethanol initiation has a greater effect on ethanol consumption if it occurs during adolescence than in adulthood. This study assessed the effect of ethanol initiation during adolescence or adulthood on voluntary ethanol consumption when animals were still within the same age range. Adolescent or adult rats were given 5, 2, or 0 ethanol exposures. The animals were tested for ethanol consumption through two-bottle choice tests, before undergoing a 1-week deprivation. A two-bottle assessment was conducted after the deprivation. Adolescents, but not adults, given two ethanol administrations during initiation exhibited significantly higher ethanol intake during the pre-deprivation period. These adolescents also exhibited a threefold increase in ethanol intake after 7 days of drug withdrawal, when compared with controls. These findings suggest that very brief experience with binge ethanol intoxication in adolescence, but not in adulthood, impacts later predisposition to drink.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Etanol/administração & dosagem , Fatores Etários , Animais , Masculino , Ratos , Ratos WistarRESUMO
Prenatal ethanol exposure significantly increases later predisposition for alcohol intake, but the mechanisms associated with this phenomenon remain hypothetical. This study analyzed (Experiment 1) ethanol intake in adolescent inbred WKAH/Hok Wistar rats prenatally exposed to ethanol (2.0g/kg) or vehicle, on gestational days 17-20. Subsequent Experiments (2, 3 and 4) tested several variables likely to underlie the effect of gestational ethanol on adolescent ethanol preference, including ethanol-induced locomotor activation (LMA), ethanol-induced emission of ultrasonic vocalizations (USVs) after exposure to a rough exteroceptive stimulus, and induction of the immediate early gene C-fos in brain areas associated with processing of reward stimuli and with the retrieval and extinction of associative learning. Prenatal ethanol induced a two-fold increase in ethanol intake. Adolescents exhibited significant ethanol-induced LMA, emitted more aversive than appetitive USVs, and postnatal ethanol administration significantly exacerbated the emission of USVs. These effects, however, were not affected by prenatal ethanol. Adolescents prenatally exposed to ethanol as fetuses exhibited reduced neural activity in infralimbic cortex (but not in prelimbic cortex or nucleus accumbens core or shell), an area that has been implicated in the extinction of drug-mediated associative memories. Ethanol metabolism was not affected by prenatal ethanol. Late gestational exposure to ethanol significantly heightened drinking in the adolescent offspring of an inbred rat strain. Ethanol-induced LMA and USVs were not associated with differential ethanol intake due to prenatal ethanol exposure. Prenatal ethanol, however, altered basal neural activity in the infralimbic prefrontal cortex. Future studies should analyze the functionality of medial prefrontal cortex after prenatal ethanol and its potential association with predisposition for heightened ethanol intake.
Assuntos
Envelhecimento/metabolismo , Consumo de Bebidas Alcoólicas/metabolismo , Etanol/administração & dosagem , Regulação da Expressão Gênica , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Consumo de Bebidas Alcoólicas/genética , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos WistarRESUMO
Adolescent rats exhibit ethanol-induced locomotor activity (LMA), which is considered an index of ethanol's motivational properties likely to predict ethanol self-administration, but few studies have reported or correlated ethanol-induced LMA with conditioned place preference (CPP) by ethanol at this age. The present study assessed age-related differences in ethanol's motor stimulating effects and analyzed the association between ethanol-induced LMA and conventional measures of ethanol-induced reinforcement. Experiment 1 compared ethanol-induced LMA in adolescent and adult rats. Subsequent experiments analyzed ethanol-induced CPP and conditioned taste aversion (CTA) in adolescent rats evaluated for ethanol-induced LMA. Adolescent rats exhibit a robust LMA after high-dose ethanol. Ethanol-induced LMA was fairly similar across adolescents and adults. As expected, adolescents were sensitive to ethanol's aversive reinforcement, but they also exhibited CPP. These measures of ethanol reinforcement, however, were not related to ethanol-induced LMA. Spontaneous LMA in an open field was, however, negatively associated with ethanol-induced CTA.
Assuntos
Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Etanol/farmacologia , Atividade Motora/efeitos dos fármacos , Reforço Psicológico , Fatores Etários , Animais , Etanol/administração & dosagem , Feminino , Masculino , Testes Neuropsicológicos , Ratos , Ratos Wistar , Paladar/efeitos dos fármacosRESUMO
We recently observed that naloxone, a non-specific opioid antagonist, attenuated operant responding to ethanol in infant rats. Through the use of an operant conditioning technique, we aimed to analyze the specific participation of mu, delta, and kappa opioid receptors on ethanol reinforcement during the second postnatal week. In Experiment 1, infant rats (PDs 14-17) were trained to obtain 5, 7.5, 10, or 15% ethanol, by operant nose-poking. Experiment 2 tested blood ethanol levels (BELs) attained by operant behavior. In Experiment 3, at PDs 16-18, rats received CTOP (mu antagonist: 0.1 or 1.0 mg/kg), naltrindole (delta antagonist: 1.0 or 5.0 mg/kg) or saline before training. In Experiment 4, rats received nor-binaltorphimine (kappa antagonist: 10.0 or 30.0 mg/kg, a single injection after completion of PD 15 operant training), spiradoline mesylate (kappa agonist: 1.0 or 5.0 mg/kg; at PDs 16-18) or saline (PDs 16-18), before the conditioning. Experiments 5 and 6 assessed possible side effects of opioid drugs in locomotor activity (LA) and conditioned taste aversion (CTA). Ethanol at 7.5 and 10% promoted the highest levels of operant responding. BELs were 12-15 mg/dl. In Experiment 3 naltrindole (dose-response effect) and CTOP (the lowest dose) were effective in decreasing operant responding. Nor-binaltorphimine at 10.0 mg/kg and spiradoline at 5.0 mg/kg also blocked ethanol responding. The effects of opioid drugs on ethanol reinforcement cannot be explained by effects on LA or CTA. Even though particular aspects of each opioid receptor require further testing, a fully functional opioid system seems to be necessary for ethanol reinforcement, during early ontogeny.
Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Etanol/administração & dosagem , Receptores Opioides/metabolismo , Reforço Psicológico , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Autoadministração , Paladar/efeitos dos fármacosRESUMO
Prenatal ethanol significantly heightens later alcohol consumption, but the mechanisms that underlie this phenomenon are poorly understood. Little is known about the basis of 'this effect of prenatal ethanol on the sensitivity to ethanol's reinforcing effects. One possibility is that prenatal ethanol exposure makes subjects more sensitive to the appetitive effects of ethanol or less sensitive to ethanol's aversive consequences. The present study assessed ethanol-induced second-order conditioned place preference (CPP) and aversion and ethanol-induced conditioned taste aversion (CTA) in infant rats prenatally exposed to ethanol (2.0 g/kg) or vehicle (water) or left untreated. The involvement of the κ opioid receptor system in ethanol-induced CTA was also explored. When place conditioning occurred during the ascending limb of the blood-ethanol curve (Experiment 1), the pups exposed to ethanol in utero exhibited greater CPP than untreated controls, with a shift to the right of the dose-response curve. Conditioning during a later phase of intoxication (30-45 min post-administration; Experiment 2) resulted in place aversion in control pups exposed to vehicle during late gestation but not in pups that were exposed to ethanol in utero. Ethanol induced a reliable and similar CTA (Experiment 3) in the pups treated with vehicle or ethanol during gestation, and CTA was insensitive to κ antagonism. These results suggest that brief exposure to a moderate ethanol dose during late gestation promotes ethanol-mediated reinforcement and alters the expression of conditioned aversion by ethanol. This shift in the motivational reactivity to ethanol may be an underlying basis of the effect of prenatal ethanol on later ethanol acceptance.
Assuntos
Condicionamento Clássico/efeitos dos fármacos , Etanol/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Reforço Psicológico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Feminino , Masculino , Motivação , Gravidez , Ratos , Ratos Wistar , Receptores Opioides kappa/antagonistas & inibidoresRESUMO
Effects of early ethanol exposure on later ethanol intake emphasize the importance of understanding the neurobiology of ethanol-induced reinforcement early in life. Infant rats exhibit ethanol-induced appetitive conditioning and ethanol-induced locomotor activation, which have been linked in theory and may have mechanisms in common. The appetitive effects of ethanol are significantly modulated by µ and δ opioid receptors, whereas µ but not δ receptors are involved in the motor stimulant effects of ethanol during early development. The involvement of the κ opioid receptor (KOR) system in the motivational effects of ethanol has been much less explored. The present study assessed, in preweanling (infant) rats, the modulatory role of the KOR system in several paradigms sensitive to ethanol-induced reinforcement. Kappa opioid activation and blockade were examined in second-order conditioned place preference with varied timing before conditioning and with varied ethanol doses. The role of KOR on ethanol-induced locomotion and ethanol-induced taste conditioning was also explored. The experiments were based on the assumption that ethanol concurrently induces appetitive and aversive effects and that the latter may be mediated by activation of kappa receptors. The main result was that blockade of kappa function facilitated the expression of appetitive ethanol reinforcement in terms of tactile and taste conditioning. The effects of kappa activation on ethanol conditioning seemed to be independent from ethanol's stimulant effects. Kappa opioid activation potentiated the motor depressing effects of ethanol but enhanced motor activity in control subjects. Overall, the results support the hypothesis that a reduced function of the KOR system in nondependent subjects should attenuate the aversive consequences of ethanol.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores Opioides kappa/fisiologia , Reforço Psicológico , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Guanidinas/farmacologia , Masculino , Morfinanos/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/efeitos dos fármacosRESUMO
A recent study found appetitive reinforcement in infant rats given 1.0 but not 2.0 g/kg ethanol and only when ethanol was delivered intragastrically (i.g., but not if intraperitoneally, i.p.; Nizhnikov, Pautassi, Truxell, & Spear [2009] Alcohol 43, 347-358). Corticosterone release could modulate ethanol's motivational effects. The goal of this study was to replicate the differential capability of i.g. vs. i.p. ethanol to induce conditioning and to find hormonal correlates underlying this phenomenon. Experiment 1 confirmed that 1.0 g/kg ethanol induced conditioned preference in infant rats when given i.g. but not i.p. In Experiment 2 corticosterone was assessed at 20, 40, 60, or 120 min after ethanol (0.0, 0.5, 1.0, and 2.0 g/kg, i.g. or i.p.). Route of administration failed to alter corticosterone release. The 2.0 g/kg, but not 0.5 or 1.0 g/kg, ethanol dose evoked heightened corticosterone release. The results confirm the differing motivational effects associated with i.g. and i.p. ethanol. These effects do not seem to be related to differential corticosterone responsiveness.
Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Condicionamento Psicológico/efeitos dos fármacos , Corticosterona/metabolismo , Etanol/administração & dosagem , Reforço Psicológico , Administração Oral , Animais , Animais Recém-Nascidos , Feminino , Injeções Intraperitoneais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Early environmental stress significantly affects the development of offspring. This stress has been modeled in rats through the maternal separation (MS) paradigm, which alters the functioning of the HPA axis and can enhance ethanol intake at adulthood. Infant rats are sensitive to ethanol's reinforcing effects, which modulate ethanol seeking and intake. Little is known about the impact of MS on sensitivity to ethanol's appetitive and aversive effects during infancy. The present study assessed ethanol-induced conditioned place preference established through second-order conditioning (SOC), spontaneous or ethanol-induced locomotor activity and ethanol intake in preweanling rats that experienced normal animal facility rearing (AFR) or daily episodes of maternal separation (MS) during postnatal days 1-13 (PDs 1-13). Low-ethanol dose (0.5 g/kg) induced appetitive conditioned place preference (via SOC) in control rats given conventional rearing but not in rats given maternal separation in early infancy, whereas 2.0 g/kg ethanol induced aversive conditioned place preference in the former but not the latter. The administration of a kappa antagonist at PD 1 or immediately before testing did not alter ethanol-induced reinforcement. High (i.e., 2.5 and 2.0 g/kg) but not low (i.e., 0.5 g/kg) ethanol dose induced reliable motor stimulation, which was independent of early maternal separation. Ethanol intake and blood alcohol levels during conditioning were unaffected by rearing conditions. Pups given early maternal separation had lower body weights than controls and showed an altered pattern of exploration when placed in an open field. These results indicate that, when assessed in infant rats, earlier maternal separation alters the balance between the appetitive and aversive motivational effects of ethanol but has no effect on the motor activating effects of the drug.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/psicologia , Privação Materna , Atividade Motora/efeitos dos fármacos , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Receptores Opioides kappa/antagonistas & inibidores , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/uso terapêutico , Consumo de Bebidas Alcoólicas/fisiopatologia , Alcoolismo/prevenção & controle , Alcoolismo/psicologia , Animais , Animais Recém-Nascidos , Comportamento Apetitivo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Masculino , Naltrexona/administração & dosagem , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Índice de Gravidade de DoençaRESUMO
There is a scarcity of research on ethanol affinity in alcohol-preferring (P) rats before weaning and it is unknown if neonate P rats exhibit ethanol intake preferences comparable to those observed in adult P rats. This study examined ethanol intake in P and alcohol-nonpreferring (NP) rats 3 hr after birth (Experiment 1, surrogate nipple test), at postnatal days (PD) 8, 12, and 18 (Experiment 2, consumption from the floor procedure) and at adolescence (Experiment 3, two-bottle choice test at PD32). The high-preference genotype was readily expressed 3 hr after birth. P neonates drank twice as much ethanol as their NP counterparts. This heightened ethanol preference transiently reversed at P8, reemerged as weaning approached (P18) and was fully expressed during adolescence. These results help to clarify the ontogeny of genetic predisposition for ethanol. Genetic predisposition for higher ethanol intake in P than in NP rats seems to be present immediately following birth.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Comportamento de Escolha , Etanol/administração & dosagem , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal , Feminino , Genótipo , Masculino , Ratos , Autoadministração , Especificidade da EspécieRESUMO
Ethanol's motivational consequences have been related to the actions of acetaldehyde, a metabolic product of ethanol oxidation. The present study assessed the role of acetaldehyde in the motivational effects of ethanol on preweanling rats. In Experiment 1 pups (postnatal days 13-14, PD 13-14) were given systemic administration of D-penicillamine (DP, a drug that sequesters acetaldehyde: 0, 25, 50 or 75 mg/kg) before pairings of 1.0 g/kg ethanol and a rough surface (sandpaper, conditioned stimulus, CS). At test, pups given sandpaper-ethanol pairings exhibited greater preference for the CS than unpaired controls, but this preference was not expressed by pups given DP. Pre-training administration of 25 or 50 mg/kg DP completely blocked the expression of ethanol-mediated appetitive conditioning. D-penicillamine did not alter blood ethanol levels. Subsequent experiments revealed that ethanol-induced activation was blocked by central (intra-cisterna magna injections, volume: 1 µl, dose: 0 or 75 µg) but not systemic treatment with DP (0, 25, 50 or 75 mg/kg; ip). These results indicate that: (a) preweanling rats are sensitive to the reinforcing effect of ethanol, and (b) that this effect is associated with the motor activating effect of the drug. These effects seem to be mediated by the first metabolite of ethanol, acetaldehyde.
Assuntos
Acetaldeído/metabolismo , Apetite/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Etanol/farmacologia , Animais , Etanol/sangue , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Age-related differences in ethanol sensitivity could put adolescents at risk for developing alcohol-related problems. Little information exists, however, about adolescent sensitivity to ethanol's appetitive effects and the neurobiological mechanisms underlying ethanol reinforcement during this developmental stage. The present study assessed the role of the opioid system in adolescent rats in an appetitive second-order schedule of ethanol reinforcement and ethanol-induced locomotor stimulation. On postnatal day 32 (PD32), animals were pretreated with the general opioid antagonist naloxone (0.0, 0.75, 1.50, or 2.5 mg/kg) and then given pairings of ethanol (0.0 or 2.0 g/kg, intragastrically) with intraoral pulses of water (conditioned stimulus 1 [CS1], first-order conditioning phase). CS1 delivery occurred 30-45 min after ethanol administration when the effect of ethanol was assumed to be appetitive. On PD33, adolescents were exposed to CS1 (second-order conditioning phase) while in a chamber featuring distinctive exteroceptive cues (CS2). Preference for CS2 was then tested. Adolescents given CS1-ethanol pairings exhibited greater preference for CS2 than controls, indicating ethanol-mediated reinforcement, but only when not pretreated with naloxone. Blood alcohol levels during conditioning were not altered by naloxone. Experiment 2 revealed that ethanol-induced locomotor activation soon after administration, and naloxone dose-dependently suppressed this stimulating effect. The present study indicates that adolescent rats are sensitive to ethanol's reinforcing and locomotor-stimulating effects. Both effects of ethanol appear to be mediated by endogenous opioid system activation.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Etanol/administração & dosagem , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Reforço Psicológico , Análise de Variância , Animais , Esquema de Medicação , Feminino , Masculino , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos WistarRESUMO
Adolescent initiation of ethanol consumption is associated with subsequent heightened probability of ethanol use disorders. The present study examined the relationship between motivational sensitivity to ethanol initiation in adolescent rats and later ethanol intake. Experiment 1 determined that ethanol induces locomotor activation shortly after administration but not if tested at a later post-administration interval. In Experiment 2, adolescent rats were assessed for ethanol-induced locomotor activation on postnatal Day 28. These animals were then evaluated for ethanol-mediated conditioned taste aversion and underwent a 16-day-long ethanol intake protocol. Ethanol-mediated aversive effects were unrelated to ethanol locomotor stimulation or subsequent ethanol consumption patterns. Ethanol intake during late adolescence was greatest in animals initiated to ethanol earliest at postnatal Day 28. Females that were more sensitive to ethanol's locomotor-activating effects showed a transient increase in ethanol self-administration. Blood ethanol concentrations during initiation were not related to ethanol-induced locomotor activation. Adolescent rats appeared sensitive to the locomotor-stimulatory effects of ethanol. Even brief ethanol exposure during adolescence may promote later ethanol intake.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Intoxicação Alcoólica/psicologia , Período Crítico Psicológico , Etanol/toxicidade , Atividade Motora/efeitos dos fármacos , Fatores Etários , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Etanol/sangue , Feminino , Masculino , Motivação , Ratos , Ratos Wistar , Fatores Sexuais , Paladar/efeitos dos fármacosRESUMO
Endogenous opioid systems are implicated in the reinforcing effects of ethanol and may play a substantial role in modulating the central reinforcing effects of ethanol early in ontogeny. This possibility was explored in the present study through the use of an olfactory conditioning paradigm with centrally administered ethanol serving as an unconditioned stimulus (US). In Experiment 1, newborn rat pups were treated with either a selective mu antagonist CTOP or kappa selective antagonist nor-BNI prior to olfactory conditioning. Experiment 2 tested the effectiveness of an alternative, shorter-duration kappa opioid antagonist GNTI in altering ethanol reinforcement. Experiment 3 investigated whether the effectiveness of pharmacological blockade of opioid receptors was due to the disruption of learning per se using an olfactory aversive conditioning paradigm with intraoral quinine serving as a US. Central administration of either mu or kappa opioid antagonists prior to conditioning disrupted the reinforcing effects of ethanol in newborn rats. The kappa opioid antagonist GNTI was as effective as nor-BNI. These effects of opioid antagonists on ethanol reinforcement are unlikely to be due to a disruption of all types of conditioning, since CTOP did not affect aversive reinforcement to intraoral infusions of quinine. The present results support the hypothesis that in newborn rats, the reinforcing properties of ethanol are mediated by the endogenous activity at mu and kappa opioid receptors.