RESUMO
INTRODUCTION: Existing treatments can aid tobacco smoking cessation, but they have low efficacy. Because there is a network of neural systems involved in tobacco addiction, combination treatments may provide greater efficacy. Chronic nicotine and amitifadine have each been shown to significantly reduce nicotine self-administration in rats. This study was conducted to determine if the combination of chronic nicotine with amitifadine, a triple monoamine reuptake inhibitor with CYP2B inhibitory effects, would reduce nicotine self-administration to a greater extent than either alone or placebo. METHODS: This study tested the combination of nicotine plus amitifadine in young adult female Sprague-Dawley rats self-administering nicotine (0.03 mg/kg/infusion). This combination was compared with each treatment alone and the vehicle during continuing nicotine self-administration as well as during resumption of self-administration after a week of enforced abstinence, modeling a quit attempt. Finally, we studied the residual effects of these therapies after discontinuation of treatment. RESULTS: Treatment with either chronic nicotine or amitifadine alone significantly reduced nicotine self-administration relative to controls. The combination of the treatments significantly enhanced this effect. After treatment withdrawal, all of the groups showed increases in nicotine self-administration, but only the combined treatment group remained significantly below control rates of nicotine self-administration. CONCLUSIONS: This study showed the promise of amitifadine as a possible new treatment for smoking cessation and suggested that amitifadine is more effective when given with chronic nicotine. The improved efficacy of the amitifadine and nicotine combination may be potentiated by amitifadine's inhibitory effects on CYP2B, which slows nicotine metabolism. IMPLICATIONS: This study replicated the effects that chronic nicotine or chronic amitifadine, a triple reuptake inhibitor, significantly reduces nicotine self-administration in rats. It extends those findings by showing that the combination of chronic nicotine plus amitifadine causes significantly greater reduction in nicotine self-administration than either drug treatment alone. The combination of chronic amitifadine and chronic nicotine also causes a persistent significant reduction in nicotine self-administration after the end of treatment. The amitifadine and nicotine treatment should be assessed in humans to determine whether this combination provides greater efficacy in smoking cessation than transdermal nicotine treatment alone.
Assuntos
Compostos Aza/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Inibidores do Citocromo P-450 CYP2B6/administração & dosagem , Citocromo P-450 CYP2B6 , Nicotina/administração & dosagem , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Citocromo P-450 CYP2B6/metabolismo , Quimioterapia Combinada/métodos , Feminino , Ratos , Ratos Sprague-Dawley , Autoadministração , Abandono do Hábito de Fumar/métodos , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
Multiple interacting neural systems are involved in sustaining nicotine reinforcement. We and others have shown that dopamine D1 receptors and glutamate NMDA receptors both play important roles in nicotine reinforcement. Blockade of D1 receptors with the antagonist SCH-23390 (0.02 mg/kg) both acutely and chronically significantly decreased nicotine self-administration in rats. Blockade of NMDA receptors (10 mg/kg) acutely with memantine significantly increased nicotine self-administration, but chronic blockade of NMDA receptors with memantine significantly decreased nicotine self-administration. The current study examined the interactions of acute and chronic administration of SCH-23390 and memantine on nicotine self-administration in female rats. Replicating earlier studies, acute and chronic SCH-23390 significantly decreased nicotine self-administration and memantine had a biphasic effect with acute administration increasing nicotine self-administration and chronic memantine showed a non-significant trend toward decreasing it. However, chronic interaction study showed that memantine significantly attenuated the decrease in nicotine self-administration caused by chronic SCH-23390. These studies provide important information that memantine attenuates the efficacy of D1 antagonist SCH 23390 in reducing nicotine-self-administration. These two drugs do not appear to have mutually potentiating effects to aid tobacco cessation.
Assuntos
Antagonistas de Dopamina , Nicotina , Ratos , Feminino , Animais , Nicotina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Dopamina , N-Metilaspartato , Memantina/farmacologia , Receptores de N-Metil-D-Aspartato , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Benzazepinas/farmacologiaRESUMO
Repeated paternal preconception exposure to Δ9-tetrahydrocannabinol (Δ9-THC) alone or together with the other constituents in a cannabis extract has been shown in our earlier studies in rats to cause significant neurobehavioral impairment in their offspring. In the current study, we compared the effects of daily cannabis extract (CE) exposure to cannabis on two consecutive days per week, modeling weekend cannabis use in human. The CE contained Δ9-THC as well as cannabidiol and cannabinol. We also extended the investigation of the study to cross-generational effects of grand-paternal cannabis exposure on the F2 generation and included testing the effects of paternal cannabis exposure on responding for opiate self-administration in F1 and F2 generation offspring. We replicated the findings of neurobehavioral impairment in F1 offspring of male rats exposed to cannabis extract containing 4â¯mg/kg/day of Δ9-THC daily for four weeks prior to mating with drug naïve females. The 4-week cannabis extract exposure caused a significant decrease in weight gain in the male rats exposed daily. In contrast, their offspring showed significantly greater body weights and anogenital distances (AGD) in the third to fourth weeks after birth. The behavioral effects seen in the F1 generation were increased habituation of locomotor activity in the figure-8 maze in female offspring and increased lever pressing for the opiate drug remifentanil in male offspring. The F2 generation showed significantly impaired negative geotaxis and an elimination of the typical sex-difference in locomotor activity, with effects not seen in the F1 generation. This study shows that daily paternal cannabis exposure for four weeks prior to mating causes significant neurobehavioral impairment in the F1 and F2 offspring. Intermittent exposure on two consecutive days per week for four weeks caused comparable neurobehavioral impairment. In sum, there should be concern about paternal as well as maternal exposure to cannabis concerning neurobehavioral development of their offspring.
Assuntos
Dronabinol , Exposição Paterna , Animais , Masculino , Feminino , Exposição Paterna/efeitos adversos , Ratos , Dronabinol/administração & dosagem , Dronabinol/toxicidade , Gravidez , Cannabis , Comportamento Animal/efeitos dos fármacos , Autoadministração , Peso Corporal/efeitos dos fármacosRESUMO
The habenula is an epithalamic structure through which descending connections go from the telencephalon to the brainstem, putting it in a key location to provide feedback control over the ascending projections from the brainstem to the telencephalon. The medial habenula has a high concentration of nicotinic receptors. We assessed the role of medial habenular nicotinic receptors for nicotine self-administration (SA) in female young adult Sprague-Dawley rats. The rats had bilateral chronic infusion cannulae placed into the medial habenula nucleus. Each cannula was connected to a slow delivery osmotic minipump to chronically infuse mecamylamine (100 µg/side/day) or vehicle for four consecutive weeks. The rats were tested for nicotine SA for the first two weeks of mecamylamine infusion. Then, they had one week of enforced abstinence, during which they had no access to the nicotine SA. Finally, they had one week of resumed nicotine SA access. There was a significantly differential mecamylamine effects in animals with lower and higher pretreatment baseline nicotine SA. Rats with lower baseline nicotine SA levels showed a nearly significant mecamylamine-induced reduction in SA while those with higher baseline levels of SA showed a significant mecamylamine-induced increase in nicotine SA. This study determined that medial habenular nicotinic receptors are important for nicotine reinforcement. Baseline level of performance makes a crucial difference for the involvement of habenular mechanisms in nicotine reinforcement with nicotinic activation being important for maintaining nicotine self-administration for those with lower levels of baseline self-administration and the opposite effect with subjects with higher levels of baseline self-administration.
Assuntos
Habenula/efeitos dos fármacos , Mecamilamina/farmacologia , Nicotina/farmacologia , Receptores Nicotínicos/metabolismo , Autoadministração , Animais , Feminino , Habenula/fisiologia , Infusões Intraventriculares , Nicotina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reforço PsicológicoRESUMO
Lorcaserin, a selective 5-hydroxytryptamine(2C) (5-HT(2C)) agonist, has been shown to facilitate weight loss in obese populations. It was assessed for its efficacy in reducing nicotine self-administration in young adult female Sprague-Dawley rats. The effect of short-term doses (subcutaneous) on nicotine self-administration (0.03 mg/kg per infusion) with a fixed ratio 1 schedule was assessed in 3-h sessions. Short-term lorcaserin doses (0.3125-20 mg/kg) were administered in a counterbalanced order. Significant reduction of nicotine self-administration was achieved with all of the short-term doses in this range. Tests of lorcaserin on locomotor activity detected prominent sedative effects at doses greater than 1.25 mg/kg with more modest transient effects seen at 0.625 to 1.25 mg/kg. Long-term effects of lorcaserin on locomotor activity were tested with repeated injections with 0.625 mg/kg lorcaserin 10 times over 2 weeks. This low lorcaserin dose did not cause an overall change in locomotor activity relative to that of saline-injected controls. Long-term lorcaserin (0.625 mg/kg) significantly reduced nicotine self-administration over a 2-week period of repeated injections. Long-term lorcaserin at this same dose had no significant effects on food self-administration over the same 2-week period of repeated injections. These studies support development of the 5-HT(2C) agonist lorcaserin to aid tobacco smoking cessation.
Assuntos
Benzazepinas/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Tabagismo/tratamento farmacológico , Tabagismo/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Alimentos , Motivação , Atividade Motora/efeitos dos fármacos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Recompensa , Autoadministração , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Abandono do Hábito de FumarRESUMO
BACKGROUND: Nicotine has reinforcing effects, but there are thousands of other compounds in tobacco, some of which might interact with nicotine reinforcement. AIMS: This rat study was conducted to determine if nicotine self-administration is altered by co-administration of the complex mixture of compounds in tobacco smoke extract (TSE). METHODS: Female Sprague-Dawley rats were tested for self-administration of low doses of nicotine (3 or 10 µg/kg/infusion) at three different rates of reinforcement (FR1, FR3 and FR5) over three weeks either alone or together with the complex mixture of tobacco smoke extract (TSE). RESULTS: Rats self-administering 3 µg/kg/infusion of nicotine alone showed a rapid initiation on an FR1 schedule, but declined with FR5. Rats self-administering nicotine in TSE acquired self-administration more slowly, but increased responding over the course of the study. With 10 µg/kg/infusion rats self-administered significantly more nicotine alone than rats self-administering the same nicotine dose in TSE. Rats self-administering nicotine alone took significantly more infusions with the 10 than the 3 µg/kg/infusion dose, whereas rats self-administering nicotine in TSE did not. Nicotine in TSE led to a significantly greater locomotor hyperactivity at a dose of 0.1 mg/kg compared to rats that received nicotine alone. Rats self-administering nicotine alone had significantly more responding on the active vs. inactive lever, but rats self-administering the same nicotine doses in TSE did not. CONCLUSIONS: Self-administration of nicotine in a purer form appears to be more clearly discriminated and dose-related than nicotine self-administered in the complex mixture of TSE.
Assuntos
Nicotina , Poluição por Fumaça de Tabaco , Animais , Condicionamento Operante , Relação Dose-Resposta a Droga , Feminino , Ratos , Ratos Sprague-Dawley , Autoadministração , Fumaça , NicotianaRESUMO
Opioid use disorder (OUD) has a variety of adverse effects on both the users and their offspring. In the current study, a random group of Sprague-Dawley rats (25 females and 15 males) were tested for intravenous self-administration of the opioid agonist remifentanil to determine the range of acquisition for opioid. One-month after the end of self-administration of remifentanil, rats with the highest intake were mated together and rats with lowest intake were mated together. Then, the offspring of the two groups were tested for anxiety-like behavior, locomotor activity, nociception and intravenous remifentanil self-administration. The parents showed a range of remifentanil self-administration, especially in the female rats. The offspring of the parents with low and high remifentanil self-administration showed significant differences in specific behavioral functions. On the hotplate test of nociception, the female offspring parents with high remifentanil self-administration had significantly longer hotplate latencies, indicating reduced nociception, than the female offspring of parents with low remifentanil-self-administration, whereas there was no difference in the male offspring of low and high responding parents. In the elevated plus maze test of anxiety-like behavior, the offspring of the parents with high remifentanil intake showed more anxiety-like behavior than the offspring of the parents with low remifentanil intake regardless of sex. Locomotor activity was not significantly different. Interestingly, no significant differences in remifentanil self-administration in the offspring of parents with low and high remifentanil self-administration were detected. Overall, our data suggest a considerable range in remifentanil self-administration in rats and the offspring of rats with high opioid self-administration exhibit different behaviors vs offspring of rats with low opioid self-administration.
Assuntos
Analgésicos Opioides/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Remifentanil/efeitos adversos , Analgésicos Opioides/administração & dosagem , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Ratos , Remifentanil/administração & dosagem , AutoadministraçãoRESUMO
Adequate treatment of tobacco addiction remains problematic. Part of the problem with treatment is a poor understanding of the pharmacologic aspects of nicotine contributing to addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also desensitizes them. It is currently not known how much of each of nicotine's actions contribute to its particular behavioral effects. Sazetidine-A (saz-A) is a novel nicotinic receptor-desensitizing agent and partial agonist with high selectivity for alpha4beta2 receptors. The current experiments were conducted to determine whether saz-A would reduce nicotine self-administration in rats and to characterize its ancillary effects. Adult male Sprague-Dawley rats were allowed to self-administer nicotine. After initial food pellet training followed by 10 sessions of nicotine self-administration training, the rats were administered saz-A (0.1-3 mg/kg s.c.) or the saline vehicle in a repeated-measures counterbalanced design. Saz-A at the 3 mg/kg dose significantly decreased nicotine self-administration relative to performance of the same rats after saline injections. In a second study, long-term administration of this dose of sazetidine-A over the course of 10 sessions significantly reduced nicotine self-administration with no apparent diminution of effect. Saz-A in this dose range had only modest effects on locomotor activity, without any overall decrease in activity over a 1-h-long session. Saz-A significantly reduced food self-administration, but this effect was smaller than its effect on nicotine self-administration. Saz-A, which is a selective alpha4beta2-desensitizing agent and partial agonist, effectively reduces nicotine self-administration. This type of treatment holds promise for a new therapy to aid smoking cessation.
Assuntos
Azetidinas/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/fisiologia , Animais , Azetidinas/efeitos adversos , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Agonismo Parcial de Drogas , Alimentos , Masculino , Motivação/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Piridinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
Farmers are often chronically exposed to insecticides, which may present health risks including increased risk of neurobehavioral impairment during adulthood and across aging. Experimental animal studies complement epidemiological studies to help determine the cause-and-effect relationship between chronic adult insecticide exposure and behavioral dysfunction. With the zebrafish model, we examined short and long-term neurobehavioral effects of exposure to either an organochlorine insecticide, dichlorodiphenyltrichloroethane (DDT) or an organophosphate insecticide chlorpyrifos (CPF). Adult fish were exposed continuously for either two or 5 weeks (10-30 nM DDT, 0.3-3 µM CPF), with short- and long-term effects assessed at 1-week post-exposure and at 14 months of age respectively. The behavioral test battery included tests of locomotor activity, tap startle, social behavior, anxiety, predator avoidance and learning. Long-term effects on neurochemical indices of cholinergic function were also assessed. Two weeks of DDT exposure had only slight effects on locomotor activity, while a longer five-week exposure led to hypoactivity and increased anxiety-like diving responses and predator avoidance at 1-week post-exposure. When tested at 14 months of age, these fish showed hypoactivity and increased startle responses. Cholinergic function was not found to be significantly altered by DDT. The two-week CPF exposure led to reductions in anxiety-like diving and increases in shoaling responses at the 1-week time point, but these effects did not persist through 14 months of age. Nevertheless, there were persistent decrements in cholinergic presynaptic activity. A five-week CPF exposure led to long-term effects including locomotor hyperactivity and impaired predator avoidance at 14 months of age, although no effects were apparent at the 1-week time point. These studies documented neurobehavioral effects of adult exposure to chronic doses of either organochlorine or organophosphate pesticides that can be characterized in zebrafish. Zebrafish provide a low-cost model that has a variety of advantages for mechanistic studies and may be used to expand our understanding of neurobehavioral toxicity in adulthood, including the potential for such toxicity to influence behavior and development during aging.
Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Clorpirifos/toxicidade , DDT/toxicidade , Inseticidas/toxicidade , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Peixe-ZebraRESUMO
Opiate addiction has risen substantially during the past decade. New treatments to combat opiate addiction are sorely needed. The current study was conducted to determine the acute individual and interactive effects of bupropion and dextromethorphan in a rat model of opiate self-administration using the short-acting synthetic opioid remifentanil. Both of these drugs have been found to reduce self-administration of nicotine. Bupropion and dextromethorphan and their combination had differential effects depending on whether the rats showed higher or lower baseline remifentanil self-administration. The rats with higher initial remifentanil self-administration showed a significant decrease in remifentanil self-administration with bupropion or dextromethorphan treatment, compared to the vehicle control condition. This decrease in self-remifentanil administration was most pronounced when combination of the higher doses of bupropion and dextromethorphan were administered. In contrast, the rats with lower baseline remifentanil self-administration showed the opposite effect of drug treatment with an increase in remifentanil self-administration with bupropion treatment compared to the vehicle control condition. Dextromethorphan had no significant effect inthis group. This study shows that combination bupropion and dextromethorphan affects remifentanil self-administration in a complex fashion with differential effects on low and high baseline responders. In subjects with high baseline remifentanil self-administration, bupropion and dextromethorphan treatment significantly reduced self-administration, whereas in subjects with low baseline remifentanil self-administration, bupropion increased remifentanil self-administration and dextromethorphan had no discernible effect. This finding suggests that combination bupropion-dextromethorphan should be tested in humans, with a focus on treating people with high-level opiate use.
Assuntos
Analgésicos Opioides/administração & dosagem , Bupropiona/administração & dosagem , Dextrometorfano/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Remifentanil/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Locomoção/efeitos dos fármacos , Motivação/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/etiologia , Ratos , Ratos Sprague-Dawley , Remifentanil/efeitos adversos , Autoadministração , Resultado do TratamentoRESUMO
RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.
Assuntos
Analgésicos Opioides/administração & dosagem , Compostos Aza/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Inibidores da Captação de Dopamina/uso terapêutico , Norepinefrina/antagonistas & inibidores , Remifentanil/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Animais , Compostos Aza/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Motivação/efeitos dos fármacos , Motivação/fisiologia , Nicotina/administração & dosagem , Norepinefrina/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Autoadministração , Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , EstereoisomerismoRESUMO
The potential health risks of cannabis are of growing concern, including effects on reproduction and development. Extensive research has investigated risks associated with maternal exposure to THC during gestation and its impacts on the development of offspring, but little research has been done regarding paternal THC exposure effects prior to conception. We have previously found that paternal THC exposure in rats causes changes in sperm methylation. In an initial study we also showed that a 12-day paternal THC exposure prior to conception alters locomotor activity and impairs cognitive function of their offspring. This study investigated the cross-generational effects of chronic paternal THC exposure in rats (0, 2, or 4 mg/kg/day SC for 28 days) prior to mating with drug naïve females. The offspring of THC-exposed male rats had significant alterations in locomotor activity and cognitive function. Specifically, during adolescence there was significant locomotor hyperactivity in the offspring of males exposed to 2 mg/kg/day of THC. During the novel object recognition task, the controls maintained their relative preference for the novel object across the duration of the ten-min session while the rats whose fathers received THC (2 mg/kg/day) showed a significantly greater drop-off in interest in the novel object during the second half of the session. Learning in the radial-arm maze was significantly delayed in the offspring of males exposed to 4 mg/kg/day of THC. This study shows that premating chronic paternal THC exposure at multiple dose regimens can cause long-lasting detrimental behavioral effects in their offspring, including abnormal locomotor activity and impaired cognitive function. Future studies should investigate the underlying mechanisms driving these aberrant developmental outcomes and seek to identify possible treatments of alleviation in the presence of paternal THC exposure.
Assuntos
Comportamento Animal/efeitos dos fármacos , Dronabinol/toxicidade , Exposição Paterna , Animais , Feminino , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Maternal toxicant exposure during gestation can have deleterious effects on neurobehavioral development of the offspring. The potential risks engendered by paternal toxicant exposure prior to conception have been largely understudied. Recently, we found that chronic THC exposure prior to conception in male rats causes long-lasting behavioral impairment in their offspring. The current study examined the effects of chronic preconception exposure to cannabis smoke extract in Sprague-Dawley rats at two different phases in sperm development. One group received daily subcutaneous (sc) injections of THC in cannabis extract at 4 mg/kg/day for 28 days until three days prior to mating with untreated females (late exposure group). Another group received the same regimen except they underwent 56 days of drug abstinence prior to mating (early exposure group). These were compared with a control group treated with vehicle. The offspring underwent a battery of tests for behavioral function to assess motor, emotional and cognitive function. On the elevated plus maze test, the offspring of both paternal cannabis smoke extract (CSE) exposure groups had significantly more time on the open arms than control offspring, indicative of greater risk-taking behavior. No significant main effects of CSE exposure were seen on adolescent or adult locomotor activity in the figure-8 apparatus. In the novel object recognition test, there was a significantly greater drop-off in novel object preference across the session in the male, but not female offspring of the late exposure group. There was also a sex-selective effect of paternal CSE treatment in the 16-arm radial maze test of memory function. Female offspring of the late exposure group had significantly more working memory errors than control females in the first half of the 12-session training sequence. No significant effects were seen in the operant visual signal sustained detection test of attention. This study shows that there are long-lasting behavioral consequences of preconception CSE exposure through the paternal lineage in rats.
Assuntos
Comportamento Animal/efeitos dos fármacos , Dronabinol/toxicidade , Alucinógenos/toxicidade , Exposição Paterna/efeitos adversos , Espermatogênese/efeitos dos fármacos , Animais , Cognição/efeitos dos fármacos , Teste de Labirinto em Cruz Elevado , Emoções/efeitos dos fármacos , Feminino , Locomoção , Masculino , Atividade Motora/efeitos dos fármacos , Teste de Campo Aberto , Ratos Sprague-Dawley , Fatores SexuaisRESUMO
Sazetidine-A selectively desensitizes α4ß2 nicotinic receptors and also has partial agonist effects. We have shown that subcutaneous acute and repeated injections as well as chronic infusions of sazetidine-A significantly reduce intravenous (IV) nicotine self-administration in rats. To further investigate the promise of sazetidine-A as a smoking cessation aid, it is important to determine sazetidine-A effects with oral administration and the time-effect function for its action on nicotine self-administration. Young adult female Sprague-Dawley rats were trained to self-administer IV nicotine at the benchmark dose of 0.03â¯mg/kg/infusion dose in an operant FR1 schedule in 45-min sessions. After five sessions of training, they were tested for the effects of acute oral doses of sazetidine-A (0, 0.3, 1 and 3â¯mg/kg) given 30â¯min before testing. To determine the time-effect function, these rats were administered 0 or 3â¯mg/kg of sazetidine-A 1, 2, 4 or 23â¯h before the onset of testing. Our previous study showed that with subcutaneous injections, only 3â¯mg/kg of sazetidine-A significantly reduced nicotine self-administration, however, with oral administration of sazetidine-A lower dose of 1â¯mg/kg was also effective in reducing nicotine intake. A similar effect was seen in the time-effect study with 3â¯mg/kg of oral sazetidine-A causing a significant reduction in nicotine self-administration across all the time points of 1, 2, 4 or 23â¯h after oral administration. These results advance the development of sazetidine-A as a possible aid for smoking cessation by showing effectiveness with oral administration and persistence of the effect over the course of a day.
Assuntos
Azetidinas/farmacologia , Nicotina/administração & dosagem , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/uso terapêutico , Feminino , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacologia , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Tobacco addiction each year causes millions of deaths worldwide. Brain nicotinic acetylcholine receptors have been shown to be central to tobacco addiction. Nicotine replacement therapy aids tobacco cessation, but the success rate is still far too low. This may in part be due to the fact that neurons with nicotinic receptors are not the only neural systems involved in tobacco addiction. Interacting neural systems also play important roles in tobacco addiction. Nicotine increases the release of a variety of neurotransmitters, including dopamine and serotonin. Dopamine, in particular dopamine D1 receptors, has been shown to be involved in the reinforcing action of nicotine. Serotonin through its actions on 5-HT2C receptors has been shown to play a key role in modulating the reinforcement of addictive drugs, including nicotine and alcohol. Combination of treatments could provide greater treatment efficacy. These studies were conducted to evaluate combination therapies utilizing nicotine replacement therapy in conjunction with either a dopamine D1 receptor antagonist SCH-23390 or a serotonin 5-HT2C receptor agonist, lorcaserin. Female Sprague-Dawley rats were given access to self-administer nicotine via IV infusions. Osmotic pumps were implanted to reproduce the kinetic of chronic nicotine patch therapy. SCH-23390 (0.02â¯mg/kg) or lorcaserin (0.6â¯mg/kg) were administered prior to nicotine self-administration sessions. Reproducing earlier findings SCH-23390, lorcaserin and nicotine replacement therapy were effective at reducing IV nicotine self-administration. 5HT2C agonist treatment had additive effects with chronic nicotine infusion for significantly lowering nicotine self-administration. This study demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors as treatment options for tobacco addiction.
Assuntos
Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Nicotina/administração & dosagem , Receptores de Dopamina D1/antagonistas & inibidores , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Tabagismo/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/administração & dosagem , Quimioterapia Combinada , Feminino , Bombas de Infusão Implantáveis , Nicotina/farmacologia , Ratos , Ratos Sprague-Dawley , Autoadministração , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de TabacoRESUMO
Developmental neurotoxicity of a wide variety of toxicants mediated via maternal exposure during gestation is very well established. In contrast, the impacts of paternal toxicant exposure on offspring neurobehavioral function are much less well studied. A vector for paternal toxicant exposure on development of his offspring has been identified. Sperm DNA can be imprinted by chemical exposures of the father. Most but not all of the epigenetic marks in sperm are reprogrammed after fertilization. The persisting epigenetic marks can lead to abnormal genetic expression in the offspring. We have found that paternal delta-9-tetrohydrocannabinol (THC) exposure in rats causes changes in methylation of sperm (Murphy et al., 2018). This is similar to cannabis-associated changes in sperm DNA methylation we found in human males who smoke cannabis (Murphy et al., 2018). In the current study we investigated the intergeneration effects of THC exposure of young adult male rats (0 or 2â¯mg/kg/day orally for 12â¯days) to the neurobehavioral development of their offspring. This paternal THC exposure was not found to significantly impact the clinical health of the offspring, including litter size, sex ratio, pup birth weight, survival and growth. However, it did cause a long-lasting significant impairment in attentional performance in the offspring relative to controls when they were tested in adulthood. There was also a significant increase in habituation of locomotor activity in the adult offspring of the males exposed to THC prior to mating. This study shows that premating paternal THC exposure even at a modest dose for a brief period can cause deleterious long-term behavioral effects in the offspring, notably significant impairment in an operant attention task. Further research should be conducted to determine the degree to which this type of risk is seen in humans and to investigate the mechanisms underlying these effects and possible treatments to ameliorate these long-term adverse behavioral consequences of paternal THC exposure.
Assuntos
Comportamento Animal/efeitos dos fármacos , Dronabinol/toxicidade , Epigênese Genética/fisiologia , Exposição Paterna , Animais , Ansiedade/induzido quimicamente , Atenção/efeitos dos fármacos , Feminino , Habituação Psicofisiológica/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a selective α4ß2 nicotinic receptor desensitizing agent and partial agonist. Sazetidine-A has been shown in our previous studies to significantly reduce nicotine and alcohol self-administration in rats. The question arises whether sazetidine-A would reduce self-administration of other addictive drugs as well. Nicotinic receptors on the dopaminergic neurons in the ventral tegmental area play an important role in controlling the activity of these neurons and release of dopamine in the nucleus accumbens, which is critical mechanism for reinforcing value of drugs of abuse. Previously, we showed that the nonspecific nicotinic antagonist mecamylamine significantly reduces cocaine self-administration in rats. In this study, we acutely administered systemically sazetidine-A and two other selective α4ß2 nicotinic receptor-desensitizing agents, VMY-2-95 and YL-2-203, to young adult female Sprague-Dawley rats and determined their effects on IV self-administration of cocaine and methamphetamine. Cocaine self-administration was significantly reduced by 0.3â¯mg/kg of sazetidine-A. In another set of rats, sazetidine-A (3â¯mg/kg) significantly reduced methamphetamine self-administration. VMY-2-95 significantly reduced both cocaine and methamphetamine self-administration with threshold effective doses of 3 and 0.3â¯mg/kg, respectively. In contrast, YL-2-203 did not significantly reduce cocaine self-administration at the same dose range and actually significantly increased cocaine self-administration at the 1â¯mg/kg dose. YL-2-203 (3â¯mg/kg) did significantly decrease methamphetamine self-administration. Sazetidine-A and VMY-2-95 are promising candidates to develop as new treatments to help addicts successfully overcome a variety of addictions including tobacco, alcohol as well as the stimulant drugs cocaine and methamphetamine.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Azetidinas/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Azetidinas/administração & dosagem , Cocaína/administração & dosagem , Feminino , Metanfetamina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
Neurobehavioral bases of tobacco addiction and nicotine reinforcement are complex, involving more than only nicotinic cholinergic or dopaminergic systems. Memantine is an NMDA glutamate antagonist used to improve cognitive function in people with Alzheimer's disease. Glutamate may be an important component of the reinforcing effects of nicotine, so memantine was evaluated as a potential smoking cessation aid. Two studies were conducted with adult female rats, one testing acute effects of memantine over a range of doses for changing nicotine self-administration and the other testing the chronic effects of memantine to reduce nicotine self-administration. Acute memantine injections slightly, but significantly, increased nicotine self-administration in a dose-related manner. In contrast, chronic memantine treatment significantly reduced nicotine self-administration. During the first day of memantine administration in the chronic study, nicotine self-administration was significantly elevated replicating the acute study. Starting in the second week of treatment there was a significant reduction of nicotine self-administration relative to controls. This was seen because memantine treatment prevented the increase in nicotine self-administration shown by controls. There even continued to be a memantine-induced lowered nicotine self-administration during the week after the cessation of memantine treatment. Memantine or other drugs affecting NMDA glutamate receptors may be useful aids to smoking cessation. Full efficacy for reducing nicotine self-administration was seen as the NMDA drug treatment is given chronically. Importantly, the effect persisted even after treatment is ended, indicating the high potential for NMDA glutamate receptors to impact nicotine addiction.
Assuntos
Memantina/farmacologia , Nicotina/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Memantina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Autoadministração , Fatores de Tempo , Tabagismo/tratamento farmacológicoRESUMO
A variety of neural systems are involved in the brain bases of tobacco addiction. Animal models of nicotine addiction have helped identify a variety of interacting neural systems involved in the pathophysiology of tobacco addiction. We and others have found that drug treatments affecting many of those neurotransmitter systems significantly decrease nicotine self-administration. These treatments include dopamine D1 receptor antagonist, histamine H1 antagonist, serotonin 5HT2C agonist, glutamate NMDA antagonist, nicotinic cholinergic α4ß2 partial agonist and nicotinic cholinergic α3ß4 antagonist acting drugs. It may be the case that combining treatments that affect different neural systems underlying addiction may be more efficacious than single drug treatment. In the current study, we tested the interactions of the D1 antagonist SCH-23390 and the serotonin 5HT2c agonist lorcaserin, both of which we have previously shown to significantly reduce nicotine self-administration. In the acute interactions study, both SCH-23390 and lorcaserin significantly reduced nicotine self-administration when given alone and had additive effects when given in combination. In the chronic study, each drug alone caused a significant decrease in nicotine self-administration. No additive effect was seen in combination because SCH-23390 given alone chronically was already highly effective. Chronic administration of the combination was not seen to significantly prolong reduced nicotine self-administration into the post-treatment period. This research shows that unlike lorcaserin and SCH-23390 interactions when given acutely, when given chronically in combination they do not potentiate or prolong each other's effects in reducing nicotine self-administration.
Assuntos
Nicotina/administração & dosagem , Receptor 5-HT2C de Serotonina/fisiologia , Receptores de Dopamina D1/fisiologia , Autoadministração , Animais , Benzazepinas/farmacologia , Feminino , Ratos , Ratos Sprague-Dawley , Tabagismo/reabilitaçãoRESUMO
BACKGROUND: Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the early 2000s, mainly in home furnishings and electronics. The persistence of PBDEs in the environment leads to continued ubiquitous exposure to low levels, with infants and children experiencing higher exposures than adults. Accumulating evidence suggest that low-level exposures during early life stages can affect brain development and lead to long-term behavioral impairments. We investigated the effects of zebrafish exposure to low doses of the two prominent PBDEs; 2,2',4,4',5,-Pentabromodiphenyl ether (BDE-99) and 2,2',4,4',-Tetrabromodiphenyl ether (BDE-47), during embryo-development on short- and long-term behavioral endpoints. We included the organophosphate pesticide chlorpyrifos (CPF) due to its well documented neurotoxicity across species from zebrafish to humans. METHODS: Zebrafish embryos were exposed to the following individual treatments; 0.1% DMSO (vehicle control); 0.3µM CPF; 0.01, 0.03, 0.1, 0.3µM BDE-47; 0.003, 0.03, 0.3, 1, 3, 10, 20µM BDE-99 from 5 until 120h post fertilization (hpf). Low exposure levels were determined as those not causing immediate overt toxicity, and behavior assays were conducted in the low-level range. At 144 hpf the larvae were tested for locomotor activity. At approximately 6 months of age adult zebrafish were tested in a behavioral battery including assays for anxiety-related behavior, sensorimotor response and habituation, social interaction, and predator avoidance. RESULTS: In the short-term, larval locomotor activity was reduced in larvae treated with 0.3µM CPF and 0.1µM BDE-47. BDE-99 treatment caused non-monotonic dose effects, with 0.3µM causing hyperactivity and 1µM or higher causing hypoactivity. In the long-term, adult anxiety-related behavior was reduced in all treatments as measured in both the novel tank dive test and tap test. DISCUSSION: We show that exposure of zebrafish embryos to low concentrations of the brominated flame retardants BDE-47 and BDE-99, and the organophosphate pesticide CPF, caused both short- and long-term behavioral impairments. Interestingly, we also found that at very low exposure concentrations, where there were no visible effects on larval activity, adult behavior was still strongly affected.