Learning to PERSEVERE: A pilot study of peer mentor support and caregiver education in Lewy body dementia.

BACKGROUND: Lewy Body Disease (LBD) is the second most common neurodegenerative disorder. Despite high family caregiver strain and adverse patient and caregiver outcomes, few interventions exist for LBD family caregivers. Based on a successful peer mentoring pilot study in advanced Parkinson's Disease, we revised the curriculum of this peer-led educational intervention incorporating LBD caregiver input. OBJECTIVE: We assessed feasibility of a peer mentor-led educational intervention and its impact on LBD family caregivers' knowledge, dementia attitudes, and mastery. METHODS: Using community-based participatory research, we refined a 16-week peer mentoring intervention and recruited caregivers online through national foundations. Experienced LBD caregiver mentors were trained and matched with newer caregiver mentees with whom they spoke weekly for 16 weeks, supported by the intervention curriculum. We measured intervention fidelity biweekly, program satisfaction, and change in LBD knowledge, dementia attitudes, and caregiving mastery before and after the 16-week intervention. RESULTS: Thirty mentor-mentee pairs completed a median of 15 calls (range: 8-19; 424 total calls; median 45 min each). As satisfaction indicators, participants rated 95.3% of calls as useful, and at week 16, all participants indicated they would recommend the intervention to other caregivers. Mentees' knowledge and dementia attitudes improved by 13% (p < 0.05) and 7% (p < 0.001), respectively. Training improved mentors' LBD knowledge by 32% (p < 0.0001) and dementia attitudes by 2.5% (p < 0.001). Neither mentor nor mentee mastery changed significantly (p = 0.36, respectively). CONCLUSIONS: This LBD caregiver-designed and -led intervention was feasible, well-received, and effective in improving knowledge and dementia attitudes in both seasoned and newer caregivers. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04649164ClinicalTrials.gov Identifier: NCT04649164; December 2, 2020.

Community-based neuropalliative care.

Community-based palliative care is defined as palliative care delivered outside of the hospital and outpatient clinics. These settings include the home, nursing homes, day programs, volunteer organizations, and support groups. There is strong evidence outside of the neuropalliative context that community-based palliative care can reduce hospital costs and admissions at the end of life. Research that focuses on specialized community-based palliative care for neurologic disease have similar findings, although with significant variability across conditions and geographic locations. Several of these studies have investigated home-based care for neurologic conditions including dementia, Parkinson's disease, multiple sclerosis, brain tumors, and motor neuron disease. Other work has focused on incorporating palliative care models into the treatment of patients with neurologic diseases within nursing home settings. Similar to nonneurologic community-based palliative care, little has been published on patient and caregiver quality-of-life outcomes in such models of care, although the emerging data are generally positive. Future studies should explore how best to provide comprehensive, cost-effective, scalable, and replicable models of community-based neuropalliative care, patient and caregiver outcomes in such models, and how care can be adapted between and within specific patient populations and healthcare systems.

Differentiating the primary reinforcing and reinforcement-enhancing effects of varenicline.

RATIONALE: Varenicline (VAR), a smoking cessation aid that is a partial agonist at nicotinic receptors, mimics the reinforcement-enhancing effects of nicotine. Varenicline, when accompanied by non-drug cues, is self-administered by rats, though it is unclear whether this results from varenicline acting as a primary reinforcer or a reinforcement enhancer of the cues. OBJECTIVES: This study sought to disentangle these two potential actions. METHODS: Rats were allowed to self-administer intravenous nicotine, saline, or varenicline during 1-h sessions in operant chambers equipped with two levers. Five groups had concurrent access to drug infusions and a moderately reinforcing visual stimulus (VS) for responding on separate levers. Meeting the reinforcement schedule on one lever was reinforced with VAR (0.01, 0.06, 0.1 mg/kg/infusion), nicotine (0.06 mg/kg/infusion), or saline, while meeting the same schedule on the other lever delivered the VS. Additional groups were reinforced for pressing a single "active" lever and received VAR paired with the VS, the VS with response-independent infusions of VAR, or VAR alone (0.1 mg/kg/infusion). RESULTS: Rats readily responded for VAR paired with VS on a single lever. However, when VAR was the only reinforcer contingent on a response, rats did not respond more than for saline. CONCLUSIONS: These findings show that VAR does not serve as a primary reinforcer in rats at doses that increase responding for non-drug reinforcers. These data are consistent with research showing that the primary reinforcing effects of VAR are weak, at best, and that the primary reinforcing and reinforcement-enhancing actions of nicotinic drugs are pharmacologically distinct.

Nicotine enhances the expression of a sucrose or cocaine conditioned place preference in adult male rats.

Nicotine has been shown to enhance the motivational properties of non-nicotine stimuli. This reinforcement-enhancing property of nicotine has the potential to promote the use of other illicit substances as well as maladaptive patterns of food intake. Therefore, the current study aimed to examine whether nicotine enhances preference for contexts paired with cocaine or sucrose utilizing a place conditioning procedure. Separate groups of adult male rats were administered sucrose or cocaine in one of two compartments of a standard CPP chamber on four consecutive days. Preference was then assessed following no injection, a single subcutaneous (s.c.) injection of nicotine, and a s.c. saline injection. The animals preferred the chamber paired with either sucrose or cocaine, as evident from an increased time spent in the paired chamber compared to baseline. Nicotine further increased the time spent in the sucrose- or cocaine-paired chamber, consistent with a reinforcement-enhancement effect. Previous results demonstrate an interaction between nicotine and intake of other drugs or food. The present findings provide an additional mechanism that may underlie these effects and which may have implications for drug dependence and obesity.

Gradual and immediate nicotine reduction result in similar low-dose nicotine self-administration.

INTRODUCTION: Food and Drug Administration-mandated product standards that drastically reduce nicotine content in cigarettes aim to decrease smoking and thus improve health outcomes for millions of U.S. smokers. Researchers have suggested that nicotine reduction should be implemented gradually, but a gradual nicotine reduction may shift the minimum level of nicotine required to reinforce behavior or may result in different levels of compensatory smoking behavior. METHOD: Rats were given the opportunity to acquire nicotine self-administration at 60 µg/kg/infusion nicotine with a cocktail of other tobacco constituents included as the vehicle. Rats were subsequently assigned to one of six immediate dose reductions (30, 15, 7.5, 3.75, 1.875, or 0.0 µg/kg/infusion) for 10 sessions (n = 9-15). Rats in the 30 µg/kg/infusion reduction group continued to have their nicotine dose reduced by half after at least 10 sessions at each dose until reaching 1.875 µg/kg/infusion (i.e., gradual reduction). RESULTS: For both methods of reduction, reduction to 3.75 µg/kg/infusion resulted in significant decreases in behavior. Reduction to doses above 3.75 µg/kg/infusion resulted in only limited compensation. The largest compensation was temporary. There was no compensation following reduction to 3.75 µg/kg/infusion or below. CONCLUSION: This study suggests that reduction to the same nicotine dose will result in similar reductions in behavior for both gradual and immediate reductions, and both methods result in similar compensation. Future studies using humans should investigate differences in other outcomes such as withdrawal and craving.

Adolescent exposure to nicotine results in reinforcement enhancement but does not affect adult responding in rats.

BACKGROUND: Adolescence is a period of development associated with a peak in an organism's responsiveness to reward. Epidemiological data indicate that the initiation of smoking is high during adolescence and that earlier age of onset is associated with increased incidence of dependence as adults. In rats, nicotine is known to have primary reinforcing and reinforcement enhancing effects. Although the primary reinforcing effects of nicotine have been demonstrated in adolescent rats (self-administration), less is known about its reinforcement enhancing effects during this period. Moreover, the impact of adolescent nicotine exposure on its reinforcement enhancing effects during adulthood has not yet been examined. The objectives of this study were to assess whether (1) nicotine enhances operant responding for an unconditioned visual reinforcer (VS) in adolescent rats, and (2) exposure to nicotine during adolescence affects responsiveness to the VS in adulthood. METHODS: Rats were exposed to nicotine (0.32 mg/kg, subcutaneous injection) or saline during adolescence (postnatal day 29-42) and adulthood. Nose-poking for the VS was assessed under fixed and progressive ratio schedules. RESULTS: Nicotine increased responding for the VS during adolescence. Adolescent nicotine exposure failed to significantly affect adult responsiveness for the VS, regardless of adult nicotine exposure, but early exposure to the VS affected responsiveness to the VS in adulthood. CONCLUSIONS: Nicotine exhibits reinforcement enhancing effects in adolescent rats. Long-term effects of adolescent nicotine on reinforcement enhancement are minimal, but the impact of early exposure to the VS and/or the primary reinforcing effects of nicotine requires further investigation.

Varenicline dose dependently enhances responding for nonpharmacological reinforcers and attenuates the reinforcement-enhancing effects of nicotine.

INTRODUCTION: Varenicline (VAR), a partial nicotinic agonist, is one of the most effective smoking cessation pharmacotherapies. The therapeutic efficacy of VAR could be partly the result of substituting for and/or blocking the reinforcement-enhancing effects of nicotine (NIC). We assessed the effects of VAR alone and in combination with NIC (0.4 mg/kg) while rats pressed the lever for a moderately reinforcing visual stimulus (VS). METHODS: Rats were injected with placebo (0.9% saline), NIC, VAR (0.1-1 mg/kg), or NIC + VAR. A follow-up study was conducted with a broader dose range of VAR-alone dosages (0.01-3.0 mg/kg). All drug manipulations were conducted in a between-subjects design to prevent confounding effects of repeated exposure. RESULTS: There was a dose-dependent effect of VAR alone. Moderate doses of VAR (0.1 and 1.0 mg/kg) increased the number of VS presentations earned, while lower and higher VAR doses (0.01 and 3.0 mg/kg) did not change responding for the VS. VAR dose dependently attenuated the reinforcement-enhancing effects of NIC, with the highest dose (1.0 mg/kg) exhibiting the greatest antagonist effect. CONCLUSIONS: The results of these studies support the assertion that the therapeutic efficacy of VAR may be due to the partial agonist characteristics of the drug, specifically, its ability to partially replace the reinforcement-enhancing effects of NIC as well as antagonize these effects.

The reinforcement-enhancing effects of nicotine: implications for the relationship between smoking, eating and weight.

Concerns about body weight represent an important barrier to public health efforts aimed at reducing smoking. Epidemiological studies have found that current smokers weigh less than non-smokers, smoking cessation results in weight gain, and weight restriction is commonly cited as a reason for smoking. The mechanisms underlying the relationship between smoking and weight are complex and may involve a number of factors including changes in caloric intake, physical activity, metabolic rate, and lipogenesis. Amongst these possible mechanisms, nicotine-induced enhancement of food reinforcement may be particularly important. In this paper, we first review data from our laboratory that highlight two distinct ways in which nicotine impacts reinforced behavior: 1) by acting as a primary reinforcer; and 2) by directly (non-associatively) enhancing the reinforcing effects of other stimuli. We then elaborate on the reinforcement-enhancing effects of nicotine as they pertain to behaviors and stimuli related to food. Data from both laboratory animals and humans support the assertion that nicotine enhances the reinforcing efficacy of food and suggest that the influence of these effects on eating may be most important after nicotine cessation when nicotine's effects on satiety subside. Finally, we discuss the theoretical and clinical implications of this perspective for understanding and addressing the apparent tradeoff between smoking and weight gain. Better understanding of the mechanisms underlying the reinforcement-enhancing effects of nicotine broadly, and the effects on food reinforcement per se, may aid in the development of new treatments with better long term outcomes.

Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats.

RATIONALE: Nicotine serves as a primary reinforcer but also potently enhances responding for nonnicotine stimuli with reinforcing properties. One of the most successful pharmacotherapies for smoking cessation, bupropion, also increases responding for nondrug reinforcers such as food and brain stimulation rewards. OBJECTIVE: The present studies investigated whether treatment with bupropion and nicotine had similar effects on responding for a reinforcing visual stimulus (VS). They also investigated whether the effects of bupropion and nicotine depended on common pharmacological substrates. RESULTS: Nicotine (0.4 mg/kg base) enhanced responding for the VS, and this enhancing effect increased across testing sessions, replicating our previous findings. Bupropion (3, 10, and 30 mg/kg salt) dose-dependently increased responding for the VS. Treatment with 10 and 30 mg/kg bupropion resulted in a profile similar to nicotine; operant responding increased over repeated drug treatments. The reinforcement enhancing effect of nicotine, but not bupropion, was blocked by pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine. In contrast, the reinforcement enhancing effect of bupropion, but not nicotine, was blocked by pretreatment with the alpha noradrenergic antagonist prazosin. CONCLUSION: The reinforcement enhancing effects of nicotine and bupropion increased over time and repeated treatments suggesting a shared mechanism of action. However, the reinforcement enhancing effects of nicotine are mediated by nicotinic acetylcholine receptors, whereas the reinforcement enhancing effects of bupropion were mediated by alpha noradrenergic receptors.