Chlorzoxazone, an SK-type potassium channel activator used in humans, reduces excessive alcohol intake in rats

Background Alcoholism imposes a tremendous social and economic burden. There are relatively few pharmacological treatments for alcoholism, with only moderate efficacy, and there is considerable interest in identifying additional therapeutic options. Alcohol exposure alters SK-type potassium channel (SK) function in limbic brain regions. Thus, positive SK modulators such as chlorzoxazone (CZX), a US Food and Drug Administration–approved centrally acting myorelaxant, might enhance SK function and decrease neuronal activity, resulting in reduced alcohol intake. Methods We examined whether CZX reduced alcohol consumption under two-bottle choice (20% alcohol and water) in rats with intermittent access to alcohol (IAA) or continuous access to alcohol (CAA). In addition, we used ex vivo electrophysiology to determine whether SK inhibition and activation can alter firing of nucleus accumbens (NAcb) core medium spiny neurons. Results Chlorzoxazone significantly and dose-dependently decreased alcohol but not water intake in IAA rats, with no effects in CAA rats. Chlorzoxazone also reduced alcohol preference in IAA but not CAA rats and reduced the tendency for rapid initial alcohol consumption in IAA rats. Chlorzoxazone reduction of IAA drinking was not explained by locomotor effects. Finally, NAcb core neurons ex vivo showed enhanced firing, reduced SK regulation of firing, and greater CZX inhibition of firing in IAA versus CAA rats. Conclusions The potent CZX-induced reduction of excessive IAA alcohol intake, with no effect on the more moderate intake in CAA rats, might reflect the greater CZX reduction in IAA NAcb core firing observed ex vivo. Thus, CZX could represent a novel and immediately accessible pharmacotherapeutic intervention for human alcoholism. Key Words: Alcohol intake; intermittent; neuro-adaptation; nucleus accumbens; SK potassium channel

Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats

BACKGROUND: There has been some difficulty getting standard laboratory rats to voluntarily consume large amounts of ethanol without the use of initiation procedures. It has previously been shown that standard laboratory rats will voluntarily consume high levels of ethanol if given intermittent-access to 20% ethanol in a 2-bottle-choice setting [Wise, Psychopharmacologia 29 (1973), 203]. In this study, we have further characterized this drinking model. METHODS: Ethanol-naïve Long-Evans rats were given intermittent-access to 20% ethanol (three 24-hour sessions per week). No sucrose fading was needed and water was always available ad libitum. Ethanol consumption, preference, and long-term drinking behaviors were investigated. Furthermore, to pharmacologically validate the intermittent-access 20% ethanol drinking paradigm, the efficacy of acamprosate and naltrexone in decreasing ethanol consumption were compared with those of groups given continuous-access to 10 or 20% ethanol, respectively. Additionally, ethanol consumption was investigated in Wistar and out-bred alcohol preferring (P) rats following intermittent-access to 20% ethanol. RESULTS: The intermittent-access 20% ethanol 2-bottle-choice drinking paradigm led standard laboratory rats to escalate their ethanol intake over the first 5 to 6 drinking sessions, reaching stable baseline consumption of high amounts of ethanol (Long-Evans: 5.1 +/- 0.6; Wistar: 5.8 +/- 0.8 g/kg/24 h, respectively). Furthermore, the cycles of excessive drinking and abstinence led to an increase in ethanol preference and increased efficacy of both acamprosate and naltrexone in Long-Evans rats. P-rats initiate drinking at a higher level than both Long-Evans and Wistar rats using the intermittent-access 20% ethanol paradigm and showed a trend toward a further escalation in ethanol intake over time (mean ethanol intake: 6.3 +/- 0.8 g/kg/24 h). CONCLUSION: Standard laboratory rats will voluntarily consume ethanol using the intermittent-access 20% ethanol drinking paradigm without the use of any initiation procedures. This model promises to be a valuable tool in the alcohol research field.

Partial agonists of the [alpha]3[beta]4[ast] neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2(*) nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats

Abstract RATIONALE: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking. MATERIALS AND METHODS: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day). The orexin-1 receptor antagonist SB334867 (0, 5, 10, 15, 20 mg/kg, i.p.) was administered 30 min before the operant self-administration sessions. After these experiments, the operant self-administration behaviors were extinguished in both the ethanol and sucrose-trained rats. Upon reaching extinction criteria, SB334867 (0, 5, 10 mg/kg, i.p.) was administered 30 min before yohimbine (0 or 2 mg/kg, i.p.). In a separate experiment, the effect of SB334867 (0, 15, or 20 mg/kg, i.p.) on general locomotor activity was determined using the open-field test. RESULTS: The orexin-1 receptor antagonist, SB334867 (10, 15 and 20 mg/kg) decreased operant self-administration of 10% ethanol but not 5% sucrose self-administration. Furthermore, SB334867 (5 and 10 mg/kg) significantly decreased yohimbine-induced reinstatement of both ethanol and sucrose seeking. SB334867 did not significantly affect locomotor activity measured using the open-field test. CONCLUSIONS: The results suggest that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

Serum bone formation marker correlation with improved osseointegration in osteoporotic rats treated with simvastatin

Objective: Simvastatin has been shown to enhance osseointegration of pure titanium implants in osteoporotic rats. This study aimed to evaluate the relationship between the serum level of bone formation markers and the osseointegration of pure titanium implants in osteoporotic rats treated with simvastatin. Materials and methods: Fifty-four female Sprague Dawley rats, aged 3 months old, were randomly divided into three groups: Sham-operated group (SHAM; n=18), ovariectomized group (OVX; n=18), and ovariectomized with Simvastatin treatment group (OVX+SIM; n=18). Fifty-six days after ovariectomy, screw-shaped titanium implants were inserted into the tibiae. Simvastatin was administered orally at 5mg/kg each day after the placement of the implant in the OVX+SIM group. The animals were sacrificed at either 28 or 84 days after implantation and the undecalcified tissue sections were processed for histological analysis. Total alkaline phosphatase (ALP), bone specific alkaline phosphatase (BALP) and bone Gla protein (BGP) were measured in all animal sera collected at the time of euthanasia and correlated with the histological assessment of osseointegration. Results: The level of ALP in the OVX group was higher than the SHAM group at day 28, with no differences between the three groups at day 84. The level of BALP in the OVX+SIM group was significantly higher than both OVX and SHAM groups at days 28 and 84. Compared with day 28, the BALP level of all three groups showed a significant decrease at day 84. There were no significant differences in BGP levels between the three groups at day 28, but at day 84 the OVX+SIM group showed significantly higher levels than both the OVX and SHAM groups. There was a significant increase in BGP levels between days 28 and 84 in the OVX+SIM group. The serum bone marker levels correlated with the histological assessment showing reduced osseointegration in the OVX compared to the SHAM group which is subsequently reversed in the OVX+SIM group.

Caregiving experience and its influencing factors : rural versus urban adult-child caregivers caring for parents with dementia in China

Background: It is predicted that China will have the largest number of cases of dementia in the world by 2025 (Ferri et al., 2005). Research has demonstrated that caring for family members with dementia can be a long-term, burdensome activity resulting in physical and emotional distress and impairment (Pinquart & Sorensen, 2003b). The establishment of family caregiver supportive services in China can be considered urgent; and the knowledge of the caregiving experience and related influencing factors is necessary to inform such services. Nevertheless, in the context of rapid demographic and socioeconomic change, the impact of caregiving for rural and urban Chinese adult-child caregivers may be different, and different needs in supportive services may therefore be expected. Objectives: The aims of this research were 1) to examine the potential differences existing in the caregiving experience between rural and urban adult-child caregivers caring for parents with dementia in China; and 2) to examine the potential differences existing in the influencing factors of the caregiving experience for rural as compared with urban adult-child caregivers caring for parents with dementia in China. Based on the literature review and Kramer.s (1997) caregiver adaptation model, six concepts and their relationships of caregiving experience were studied: severity of the care receivers. dementia, caregivers. appraisal of role strain and role gain, negative and positive well-being outcomes, and health related quality of life. Furthermore, four influencing factors (i.e., filial piety, social support, resilience, and personal mastery) were studied respectively. Methods: A cross-sectional, comparative design was used to achieve the aims of the study. A questionnaire, which was designed based on the literature review and on Kramer.s (1997) caregiver adaptation model, was completed by 401 adult-child caregivers caring for their parents with dementia from the mental health outpatient departments in five hospitals in the Yunnan province, P.R. China. Structural equation modelling (SEM) was employed as the main statistical technique for data analyses. Other statistical techniques (e.g., t-tests and Chi-Square tests) were also conducted to compare the demographic characteristics and the measured variables between rural and urban groups. Results: For the first research aim, the results indicated that urban adult-child caregivers in China experienced significantly greater strain and negative well-being outcomes than their rural peers; whereas, the difference on the appraisal of role gain and positive outcomes was nonsignificant between the two groups. The results also indicated that the amounts of severity of care receivers. dementia and caregivers. health related quality of life do not have the same meanings between the two groups. Thus, the levels of these two concepts were not comparable between the rural and urban groups in this study. Moreover, the results also demonstrated that the negative direct effect of gain on negative outcomes in urban caregivers was stronger than that in rural caregivers, suggesting that the urban caregivers tended to use appraisal of role gain to protect themselves from negative well-being outcomes to a greater extent. In addition, the unexplained variance in strain in the urban group was significantly more than that in the rural group, suggesting that there were other unmeasured variables besides the severity of care receivers. dementia which would predict strain in urban caregivers compared with their rural peers. For the second research aim, the results demonstrated that rural adult-child caregivers reported a significantly higher level of filial piety and more social support than their urban counterparts, although the two groups did not significantly differ on the levels of their resilience and personal mastery. Furthermore, although the mediation effects of these four influencing factors on both positive and negative aspects remained constant across rural and urban adult-child caregivers, urban caregivers tended to be more effective in using personal mastery to protect themselves from role strain than rural caregivers, which in turn protects them more from the negative well-being outcomes than was the case with their rural peers. Conclusions: The study extends the application of Kramer.s caregiving adaptation process model (Kramer, 1997) to a sample of adult-child caregivers in China by demonstrating that both positive and negative aspects of caregiving may impact on the caregiver.s health related quality of life, suggesting that both aspects should be targeted in supportive interventions for Chinese family caregivers. Moreover, by demonstrating partial mediation effects, the study provides four influencing factors (i.e., filial piety, social support, resilience, and personal mastery) as specific targets for clinical interventions. Furthermore, the study found evidence that urban adult-child caregivers had more negative but similar positive experience compared to their rural peers, suggesting that the establishment of supportive services for urban caregivers may be more urgent at present stage in China. Additionally, since urban caregivers tended to use appraisal of role gain and personal mastery to protect themselves from negative well-being outcomes than rural caregivers to a greater extend, interventions targeting utility of gain or/and personal mastery to decrease negative outcomes might be more effective in urban caregivers than in rural caregivers. On the other hand, as cultural expectations and expression of filial piety tend to be more traditional in rural areas, interventions targeting filial piety could be more effective among rural caregivers. Last but not least, as rural adult-child caregivers have more existing natural social support than their urban counterparts, mobilising existing natural social support resources may be more beneficial for rural caregivers, whereas, formal supports (e.g., counselling services, support groups and adult day care centres) should be enhanced for urban caregivers.