RESUMO
Varenicline (Chantix) is an FDA-approved smoking cessation aid that is pharmacologically similar to nicotine, the primary addictive component found within tobacco. In support of this similarity, previous drug discrimination research in rats has reported that the internal or interoceptive stimulus effects of nicotine and varenicline share stimulus elements. Those shared elements appear to be mediated, in part, by overlapping action at alpha4beta2-containing nicotinic acetylcholine receptors (nAChRs). The research supporting this conclusion, however, has only used nicotine, and not varenicline, as the training drug. Accordingly, we used the discriminated goal tracking (DGT) task in which 1 mg/kg varenicline signaled intermittent access to sucrose. On separate intermixed saline days, sucrose was not available. Rats acquired the discrimination as measured by a differential increase in dipper entries (goal tracking) evoked by varenicline. These rats then received a series of tests with several doses of varenicline, nicotine, nornicotine (a metabolite of nicotine and tobacco alkaloid), sazetidine-A (a partial alpha4beta2 agonist), PHA-543613 (an alpha7 agonist), and bupropion (a norepinephrine and dopamine reuptake inhibitor). Control of goal tracking by varenicline was dose-dependent. Nicotine and nornicotine evoked responding comparable to the varenicline training dose indicating full substitution. Sazetidine-A partially substituted for the varenicline stimulus, whereas bupropion and PHA-543613 evoked little to no varenicline-like responding. These findings indicate that varenicline can serve as the training stimulus in the DGT task. Further, stimulus control of varenicline in the DGT task is driven by its partial agonist activity at alpha4beta2-containing nAChRs. The use of this approach could lead to a better understanding of the pharmacological action of varenicline and help guide treatment geared towards tobacco cessation through a more targeted development of novel synthetically designed, subunit-specific pharmacological interventions.
Assuntos
Motivação , Receptores Nicotínicos , Agentes de Cessação do Hábito de Fumar , Vareniclina , Animais , Ratos , Benzazepinas/farmacologia , Bupropiona , Objetivos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Quinoxalinas/farmacologia , Receptores Nicotínicos/metabolismo , Vareniclina/farmacologia , Agentes de Cessação do Hábito de Fumar/farmacologia , Motivação/efeitos dos fármacosRESUMO
BACKGROUND: Alcohol is often consumed with tobacco, and dependence to alcohol and tobacco are highly comorbid. In addition, there are differences in the prevalence of nicotine- and alcohol-abuse between the sexes. Nicotine produces enhancing effects on the value of other reinforcers, which may extend to alcohol. METHODS: Male and female Wistar rats were trained to self-administer 15% ethanol solution in 30-minute sessions. Once ethanol self-administration was established, demand for ethanol was evaluated using an exponential reinforcer demand method, in which the response cost per reinforcer delivery was systematically increased over blocks of several sessions. Within each cost condition, rats were preinjected with nicotine (0.05, 0.1, 0.2, or 0.4 mg/kg base, SC) or saline 5 minutes before self-administration sessions. The effects of nicotine dose and biological sex were evaluated using the estimates generated by the reinforcer demand model. RESULTS: Under saline conditions, males showed greater sensitivity to ethanol reinforcement than females. Nicotine enhanced the reinforcement value of alcohol and this varied with sex. In both sexes, 0.4 mg/kg nicotine decreased intensity of ethanol demand. However, 0.05, 0.1, and 0.2 mg/kg nicotine decreased elasticity of ethanol demand in females, but not in males. CONCLUSIONS: Nicotine enhances ethanol reinforcement, which may partially drive comorbidity between nicotine-abuse and alcohol-abuse. Males showed signs of greater ethanol reinforcement value than females under saline conditions, and nicotine attenuated this effect by increasing ethanol reinforcement value in the females. These findings highlight that a complete understanding of alcohol-abuse must include a thorough study of alcohol use in the context of other drug use, including nicotine. IMPLICATIONS: Nicotine dose dependently enhances the alcohol reinforcement value in a manner that is clearly influenced by biological sex. Under saline baseline conditions, males show lower elasticity of demand for alcohol reinforcement than females, indicative of greater reinforcement value. However, nicotine attenuated this difference by enhancing alcohol reward in the females. Specifically, low-to-moderate doses (0.05-0.2 mg/kg) of nicotine decreased elasticity of alcohol demand in female rats, increasing the perseverance of their alcohol taking behavior. These data indicate that the well-documented reward-enhancing effects of nicotine on sensory reinforcement extend to alcohol reinforcement and that these vary with biological sex.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Etanol/administração & dosagem , Nicotina/administração & dosagem , Reforço Psicológico , Recompensa , Caracteres Sexuais , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar , AutoadministraçãoRESUMO
Nicotine and varenicline (Chantix®; the leading non-nicotine cessation pharmacotherapy) can come to control appetitive behaviors such as goal-tracking. We tested rats (N = 48) in a drug-discriminated goal-tracking (DGT) task where each rat received daily subcutaneous injections of either nicotine (0.4 mg/kg) or saline (0.9% [w/v]) interspersed across the acquisition phase (Phase 1). On saline days, sucrose was intermittently available. On nicotine days, sucrose was withheld. All rats acquired the discrimination with increased goal-tracking rates on saline days relative to nicotine days. Following acquisition, rats were separated into four groups to assess drug-substitution and discrimination reversal in Phase 2. The first group maintained the stimulus-reinforcer relation from acquisition (NIC-). The reversal group was now given access to sucrose on nicotine days (NIC+). The substitution group replaced nicotine with varenicline (1 mg/kg) while maintaining the acquisition stimulus-reinforcer relation (VAR-). The substitution and reversal group had nicotine replaced by varenicline and the stimulus-reinforcer relation reversed (VAR+). Rats in all groups learned or maintained their Phase 1 discriminations. For Phase 2, the reversal groups (+ conditions) acquired their discriminations within 10 sessions. The VAR- group displayed a pattern of disrupted discrimination at the outset of Phase 2 but was reestablished after continued training. In substitution testing, VAR groups received nicotine and NIC groups received varenicline. The NIC- and VAR- groups displayed full substitution of the test stimulus whereas the NIC+ and VAR+ groups displayed partial substitution of the test stimulus. Rats underwent nicotine extinction in Phase 3. Initial responding for each group mimicked Phase 2 training (i.e., higher responding by the reversal groups). All rats maintained similarly low levels of responding after six sessions. In conclusion, initial learning history with nicotine (i.e., + or -) influenced drug-stimulus substitution and the rate at which new learning (e.g., reversal) occurs with the varenicline and nicotine interoceptive stimuli.
Assuntos
Aprendizagem por Discriminação , Substituição de Medicamentos , Objetivos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Agentes de Cessação do Hábito de Fumar/farmacologia , Vareniclina/farmacologia , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The HIV-1 transgenic (Tg) rat model is valuable for understanding HIV-associated neurocognitive disorders (HAND) and accompanying substance use and misuse. Tg and F344/NHsd wildtype (WT) rats were allowed to self-administer intrajugular cocaine. For the first 7 sessions, neither genotype self-administered cocaine (0.1 mg/kg/infusion) on a fixed ratio 1 schedule. We thus implemented a lever-cocaine "autoshaping" session followed by a series of manipulations changing dose and reinforcement schedule. Tg rats self-administered much less cocaine than WT rats throughout the study. Of 8 Tg rats, 5 modestly increased self-administration from sessions 36-50. Of those, only 3 showed a lever discrimination. Of 10 WT rats, 8 acquired robust self-administration by session 19; all WT rats self-administered cocaine by the end of the study. WT and Tg rats had similar baseline locomotor activity in the self-administration chamber suggesting that the low levels of cocaine intake in the Tg rats did not reflect a nonspecific motor impairment in this rat strain. Concomitant measurement of activity with self-administration revealed activity increases that followed increased cocaine intake. That relation held in Tg rats. Therefore, the present study provides evidence that HIV-1 Tg rats are less sensitive to the reinforcing effects of cocaine than their F344 WT counterparts.
Assuntos
Complexo AIDS Demência/complicações , Transtornos Relacionados ao Uso de Cocaína/complicações , HIV-1 , Complexo AIDS Demência/psicologia , Animais , Transtornos Relacionados ao Uso de Cocaína/virologia , Condicionamento Operante , Locomoção , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos TransgênicosRESUMO
Learning processes associated with nicotine influence the development of addiction to tobacco products. In the present report, we are interested in the interoceptive stimulus effects of nicotine acquiring control over appetitive behaviors - specifically, reward seeking. Also of interest is the current smoking cessation drug, varenicline (Chantix®). Varenicline, with its nicotine-like stimulus effects, can decrease withdrawal and cravings for a subset of individuals addicted to nicotine, though relapse is still common. We trained rats (Nâ¯=â¯48) with nicotine (0.4â¯mg/kg, SC) as an excitatory stimulus (i.e., paired with sucrose) in a drug-discriminated goal-tracking (DGT) task. There was no access to sucrose on interspersed saline days. After acquisition of the initial nicotine-saline discrimination, rats were separated into four groups to test discrimination reversal and drug substitution. The control group maintained nicotine as the excitatory stimulus (NIC+). The substitution group had varenicline (1â¯mg/kg) replace nicotine as the stimulus paired with sucrose (VAR+). One reversal group had nicotine signal the absence of sucrose (i.e., now available on intermixed saline sessions; NIC-). The last group was similar to the NIC- group except varenicline replaced nicotine on non-reinforced sessions (VAR-). We found that varenicline fully substituted as the training stimulus when the drug-sucrose relation remained in place (VAR+). Both reversal groups acquired the new discrimination, albeit slowly and more variable for the VAR- group in comparison to NIC-. There was an effect of group during substitution testing. Specifically, nicotine fully substituted for varenicline regardless of condition. However, varenicline only partially substituted for the nicotine stimulus. At the start of extinction, responding mimicked that of the rats training condition. However, by extinction session 12, all groups maintained similarly low levels of responding. These findings show nicotine and varenicline share stimulus elements, yet the conclusion of partial to full substitution depends on the nature of the testing protocol.
Assuntos
Comportamento Apetitivo/efeitos dos fármacos , Interocepção/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Vareniclina/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Substituição de Medicamentos , Extinção Psicológica/efeitos dos fármacos , Injeções Subcutâneas , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Solução Salina/farmacologia , Abandono do Hábito de Fumar , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Sacarose/farmacologia , Vareniclina/administração & dosagemRESUMO
BACKGROUND: Smoking constitutes a significant public health risk. Alcohol and methamphetamine use disorders are also highly co-morbid with smoking, further increasing negative health outcomes. An important question in determining the underlying neurobiology of nicotine poly-drug use is understanding whether having a positive history with nicotine effects alters later drug-taking behavior. METHODS: The current experiments sought to elucidate whether having an appetitive nicotine conditioning history would affect later alcohol or methamphetamine self-administration. Adult male and female Long-Evans rats were first trained on a discriminated goal-tracking task in which the interoceptive effects of nicotine predicted sucrose reinforcement. As a control, pseudo-conditioned groups were included that had equated nicotine and sucrose experience. Rats were then shifted to either alcohol self-administration or methamphetamine self-administration. RESULTS: Nicotine conditioning history had no effect on acquisition or maintenance of alcohol self-administration in males or females. In contrast, an appetitive nicotine conditioning history decreased methamphetamine self-administration in female rats, but not males. CONCLUSIONS: In female, but not male, rats, an appetitive conditioning history with nicotine decreases methamphetamine, but not alcohol, self-administration. This dissociation suggests that the effects may be due to a specific increase in the reinforcing value of methamphetamine. This may have implications for better understanding the progression of drug use from nicotine to methamphetamine.
Assuntos
Condicionamento Operante , Etanol/administração & dosagem , Metanfetamina/administração & dosagem , Nicotina/farmacologia , Animais , Feminino , Masculino , Ratos , Ratos Long-Evans , AutoadministraçãoRESUMO
With the signing of H.R. 1256, the Family Smoking Prevention and Tobacco Control Act, the United States Food and Drug Administration (FDA) gained regulatory authority over the tobacco industry. A notable clause in this Act permits the FDA to regulate nicotine yields. However, they cannot completely remove this addictive constituent from tobacco products. This restriction has prompted the FDA to seek research on the threshold dose of nicotine that does not support dependence. This idea of threshold dose has led to an interesting reframing of scientific questions. For example, some researchers studying nicotine from this regulatory perspective translated the notion of an addiction threshold to a construct thought to play a role in addiction but which can be more readily operationalized. Examples include reinforcement threshold, discrimination threshold, and reinforcer-enhancement threshold. In this Perspective Paper, we highlight the importance of behavioral pharmacology and, specifically, the experimental analysis of behavior to help establish a scientific basis for policy decisions regarding nicotine yields. Recent research, including exemplars provided herein, note vast individual differences in the effects of nicotine at a known dose. Unfortunately, the behavioral and biological factors that contribute to such individual variations remain to be understood. We believe that behavior analysts are uniquely well-positioned to contribute to this understanding.
Assuntos
Pesquisa Comportamental , Indústria do Tabaco/legislação & jurisprudência , Produtos do Tabaco/legislação & jurisprudência , Uso de Tabaco/psicologia , Regulamentação Governamental , Humanos , Individualidade , Nicotina/análise , Nicotina/farmacologia , Reforço Psicológico , Produtos do Tabaco/análise , Uso de Tabaco/prevenção & controle , Estados Unidos , United States Food and Drug AdministrationRESUMO
In several laboratory meetings, we discussed the challenges that face trainees in behavioral pharmacology. Major concerns, such as a difficult funding climate and limited academic job prospects were discussed at first. However, we decided to concentrate on ways to meet these challenges; versus focusing on negatives and listing gripes. Within this more constructive framework, we identified the importance of broadening training to aligned areas to enhance the capacity of behavioral pharmacologists to collaborate in multidisciplinary teams. With increased breadth of training comes the concern for a balance that does not cheat trainees out of the depth of training also needed for success. We believe that behavioral pharmacologists trained in this manner will be ideally positioned to be leaders of these translational research teams. Related to the breadth and depth of training is the recent concerns over replicability and reproducibility of published research. Behavioral pharmacologists, with the rigors of training in behavioral analysis and experimental design, can be at the forefront of this conversation. This will be especially true if current training is reinforced with additional experience in the use of cutting-edge statistical tools that address the complex experimental designs and large data sets that emerge from modern multidisciplinary collaborations. Finally, communicating the import and potential societal impact of our research to legislators, other scientists, educators, school children, neighbors, and acquaintances is needed to ensure that our field thrives. In closing, the process of explicitly discussing the challenges and potential solutions with current trainees will enhance their mentoring and training.