The Environmental Sustainability of Plant-Based Dietary Patterns: A Scoping Review.

BACKGROUND: A large part of the existential threat associated with climate change is the result of current human feeding patterns. Over the last decade, research evaluating the diet-related environmental impacts of plant-based diets has emerged, and a synthesis of the available data is now due. OBJECTIVES: The objectives of the study were as follows: 1) to compile and summarize the literature on diet-related environmental impacts of plant-based dietary patterns; 2) to assess the nature of the data on impacts of plant-based dietary patterns on both environmental parameters and health (e.g., if land use is reduced for a particular diet, is cancer risk also reduced?); and 3) to determine where sufficient data exist for meta-analyses, in addition to identifying gaps within the literature. METHODS: Global peer-reviewed studies on the environmental impacts of plant-based diets were searched in Ovid MEDLINE, EMBASE, and Web of Science. After removing duplicates, the screening identified 1553 records. After 2 stages of independent review by 2 reviewers, 65 records met the inclusion criteria and were eligible to be used in synthesis. RESULTS: Evidence suggests that plant-based diets may offer lower greenhouse gas emissions (GHGEs), land use, and biodiversity loss than offered by standard diets; however, the impact on water and energy use may depend on the types of plant-based foods consumed. Further, the studies were consistent in demonstrating that plant-based dietary patterns that reduce diet-related mortality also promote environmental sustainability. CONCLUSIONS: Overall, there was agreement across the studies regarding the impact of plant-based dietary patterns on GHGE, land used, and biodiversity loss despite varied plant-based diets assessed.

Association of glycaemic index and glycaemic load with type 2 diabetes, cardiovascular disease, cancer, and all-cause mortality: a meta-analysis of mega cohorts of more than 100 000 participants.

BACKGROUND: There is debate over whether the glycaemic index of foods relates to chronic disease. We aimed to assess the associations between glycaemic index (GI) and glycaemic load (GL) and type 2 diabetes, cardiovascular disease, diabetes-related cancers, and all-cause mortality. METHODS: We did a meta-analysis of large cohorts (≥100 000 participants) identified from the Richard Doll Consortium. We searched the Cochrane Library, MEDLINE, PubMed, Embase, Web of Science, and Scopus for cohorts that prospectively examined associations between GI or GL and chronic disease outcomes published from database inception to Aug 4, 2023. Full-article review and extraction of summary estimates data were conducted by three independent reviewers. Primary outcomes were incident type 2 diabetes, total cardiovascular disease (including mortality), diabetes-related cancers (ie, bladder, breast, colorectal, endometrial, hepatic, pancreatic, and non-Hodgkin lymphoma), and all-cause mortality. We assessed comparisons between the lowest and highest quantiles of GI and GL, adjusting for dietary factors, and pooling their most adjusted relative risk (RR) estimates using a fixed-effects model. We also assessed associations between diets high in fibre and whole grains and the four main outcomes. The study protocol is registered with PROSPERO, CRD42023394689. FINDINGS: From ten prospective large cohorts (six from the USA, one from Europe, two from Asia, and one international), we identified a total of 48 studies reporting associations between GI or GL and the outcomes of interest: 34 (71%) on various cancers, nine (19%) on cardiovascular disease, five (10%) on type 2 diabetes, and three (6%) on all-cause mortality. Consumption of high GI foods was associated with an increased incidence of type 2 diabetes (RR 1·27 [95% CI 1·21-1·34]; p<0·0001), total cardiovascular disease (1·15 [1·11-1·19]; p<0·0001), diabetes-related cancer (1·05 [1·02-1·08]; p=0·0010), and all-cause mortality (1·08 [1·05-1·12]; p<0·0001). Similar associations were seen between high GL and diabetes (RR 1·15 [95% CI 1·09-1·21]; p<0·0001) and total cardiovascular disease (1·15 [1·10-1·20]; p<0·0001). Associations between diets high in fibre and whole grains and the four main outcomes were similar to those for low GI diets. INTERPRETATION: Dietary recommendations to reduce GI and GL could have effects on health outcomes that are similar to outcomes of recommendations to increase intake of fibre and whole grain. FUNDING: Banting and Best and the Karuna Foundation.

Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors.

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients.

Systematic review and meta-analysis examining the relationship between postprandial hypotension, cardiovascular events, and all-cause mortality.

BACKGROUND: Postprandial hypotension (PPH) has been reported to be associated with syncope, falls, adverse cardiovascular outcomes, and increased all-cause mortality. It has been reported to have an incidence as high as 30% in the elderly and persons with diabetes. We therefore performed a meta-analysis to determine the relation of PPH with cardiovascular disease (CVD) events and all-cause mortality. OBJECTIVES: Our objective was to conduct a systematic review and meta-analysis of cohort and cross-sectional studies to determine the association of PPH with CVD and all-cause mortality. METHODS: We searched the databases MEDLINE, EMBASE, and Cochrane library up to 13 April 2022 for prospective cohort and cross-sectional studies that examined the association of PPH with CVD outcomes and all-cause mortality. Data were analyzed using the generic inverse variance method with a random-effects model. Grading of Recommendations, Assessment, Development, and Evaluation approach assessed the certainty of evidence. RESULTS: Seven studies that included 2389 participants met our inclusion criteria. PPH was associated with each outcome individually, including increased all-cause mortality, total CVD, CVD mortality, and stroke. CVD outcomes and all-cause mortality combined were also associated with PPH (RR: 1.52; 95% CI: 1.05, 2.18; P = 0.03; I2 = 77%). The certainty of evidence was graded as very low due to significant heterogeneity and the limited number of studies. CONCLUSIONS: This assessment indicates an association of PPH with CVD and all-cause mortality. Further studies are required to improve CVD and mortality estimates, but the potential seriousness of CVD and all-cause mortality as outcomes of PPH justifies more screening, diagnosis, and research.

Low-carbohydrate vegan diets in diabetes for weight loss and sustainability: a randomized controlled trial.

BACKGROUND: Low-carbohydrate, high animal fat and protein diets have been promoted for weight loss and diabetes treatment. We therefore tested the effect of a low-carbohydrate vegan diet in diabetes as a potentially healthier and more ecologically sustainable low-carbohydrate option. OBJECTIVES: We sought to compare the effectiveness of a low-carbohydrate vegan diet with a moderate-carbohydrate vegetarian diet on weight loss and metabolic measures in diabetes. METHODS: One hundred and sixty-four male and female participants with type 2 diabetes were randomly assigned to advice on either a low-carbohydrate vegan diet, high in canola oil and plant proteins, or a vegetarian therapeutic diet, for 3 mo, with both diets recommended at 60% of calorie requirements. Body weight, fasting blood, blood pressure, and 7-d food records, to estimate potential greenhouse gas emissions, were obtained throughout the study with tests of cholesterol absorption undertaken at baseline and end of study on 50 participants. RESULTS: Both low-carbohydrate vegan and vegetarian diets similarly but markedly reduced body weight (-5.9 kg; 95% CI: -6.5, -5.28 kg; and -5.23 kg; 95% CI: -5.84, -4.62 kg), glycated hemoglobin (-0.99%; 95% CI: -1.07, -0.9%; and -0.88%; 95% CI: -0.97, -0.8%), systolic blood pressure (-4 mmHg; 95% CI: -7, -2 mmHg; and -6 mmHg; 95% CI: -8, -3 mmHg), and potential greenhouse gas emissions, but only for potential greenhouse gas emissions was there a significant treatment difference of -0.63 kgCO2/d (95% CI: -0.99, -0.27 kgCO2/d) favoring the low-carbohydrate vegan diet. CONCLUSIONS: Low-carbohydrate vegan and vegetarian diets reduced body weight, improved glycemic control and blood pressure, but the more plant-based diet had greater potential reduction in greenhouse gas emissions. TRIAL REGISTRATION NUMBER: clinicaltrials.gov identifier NCT02245399.

Glycemic Index Versus Wheat Fiber on Arterial Wall Damage in Diabetes: A Randomized Controlled Trial.

OBJECTIVE: High cereal fiber and low-glycemic index (GI) diets are associated with reduced cardiovascular disease (CVD) risk in cohort studies. Clinical trial evidence on event incidence is lacking. Therefore, to make trial outcomes more directly relevant to CVD, we compared the effect on carotid plaque development in diabetes of a low-GI diet versus a whole-grain wheat-fiber diet. RESEARCH DESIGN AND METHODS: The study randomized 169 men and women with well-controlled type 2 diabetes to counseling on a low GI-diet or whole-grain wheat-fiber diet for 3 years. Change in carotid vessel wall volume (VWV) (prespecified primary end point) was assessed by MRI as an indication of arterial damage. RESULTS: Of 169 randomized participants, 134 completed the study. No treatment differences were seen in VWV. However, on the whole-grain wheat-fiber diet, VWV increased significantly from baseline, 23 mm3 (95% CI 4, 41; P = 0.016), but not on the low-GI diet, 8 mm3 (95% CI -10, 26; P = 0.381). The low-GI diet resulted in preservation of renal function, as estimated glomerular filtration rate, compared with the reduction following the wheat-fiber diet. HbA1c was modestly reduced over the first 9 months in the intention-to-treat analysis and extended with greater compliance to 15 months in the per-protocol analysis. CONCLUSIONS: Since the low-GI diet was similar to the whole-grain wheat-fiber diet recommended for cardiovascular risk reduction, the low-GI diet may also be effective for CVD risk reduction.

Development of a Portfolio Diet Score and Its Concurrent and Predictive Validity Assessed by a Food Frequency Questionnaire.

The Portfolio Diet, a plant-based portfolio of cholesterol-lowering foods, has been shown to reduce low-density lipoprotein cholesterol (LDL-C), and other cardiovascular risk factors, in randomized controlled trials (RCTs). It is not known if these beneficial effects translate to a lower incidence cardiovascular disease (CVD) risk. To support examinations between Portfolio Diet adherence and disease, a Portfolio Diet score (PDS) was developed and its predictive and concurrent validity was assessed within the Toronto Healthy Diet Study, a six-month RCT in overweight adults. Predictive validity was assessed using change in the PDS measured by food frequency questionnaire (FFQ) and concomitant change in LDL-C from baseline to six months using multiple linear regression, adjusted for potential confounders (n = 652). Concurrent validity was assessed in a subset of participants (n = 50) who completed the FFQ and a 7-day diet record (7DDR) at baseline. The PDS determined from each diet assessment method was used to derive correlation coefficients and Bland-Altman plots to assess the between-method agreement. The change in PDS was inversely associated with change in LDL-C (ß coefficients: -0.01 mmol/L (95% confidence intervals (CIs): -0.02, -0.002; p =0.02). The correlation between the PDS from the FFQ and 7DDR was 0.69 (95% CIs: 0.48, 0.85). The Bland-Altman plot showed reasonable agreement between the score from the FFQ and 7DDR. These findings indicate predictive validity of the PDS with lower LDL-C, and reasonable concurrent validity of the PDS as assessed by an FFQ against a 7DDR.

Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment: JACC Focus Seminar.

This is an update of the previous 2018 systematic review and meta-analysis of vitamin and mineral supplementation on cardiovascular disease outcomes and all-cause mortality. New randomized controlled trials and meta-analyses were identified by searching the Cochrane library, Medline, and Embase, and data were analyzed using random effects models and classified by the Grading of Recommendations Assessment Development and Evaluation approach. This updated review shows similar findings to the previous report for preventive benefits from both folic acid and B vitamins for stroke and has been graded with moderate quality. No effect was seen for the commonly used multivitamins, vitamin D, calcium, and vitamin C, and an increased risk was seen with niacin (with statin) for all-cause mortality. Conclusive evidence for the benefit of supplements across different dietary backgrounds, when the nutrient is sufficient, has not been demonstrated.

Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Antioxidants have been promoted for cardiovascular disease (CVD) risk reduction and for the prevention of cancer. Our preliminary analysis suggested that only when selenium was present were antioxidant mixtures associated with reduced all-cause mortality. OBJECTIVE: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effect of selenium supplementation alone and of antioxidant mixtures with or without selenium on the risk of CVD, cancer, and mortality. METHODS: We identified studies using the Cochrane Library, Medline, and Embase for potential CVD outcomes, cancer, and all-cause mortality following selenium supplementation alone or after antioxidant supplement mixtures with and without selenium up to June 5, 2020. RCTs of ≥24 wk were included and data were analyzed using random-effects models and classified by the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: The meta-analysis identified 9423 studies, of which 43 were used in the final analysis. Overall, no association of selenium alone or antioxidants was seen with CVD and all-cause mortality. However, a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mix (RR: 0.77; 95% CI: 0.62, 0.97; P = 0.02), with no association when selenium was absent. Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality (RR: 0.90; 95% CI: 0.82, 0.98; P = 0.02) as opposed to an increased risk when selenium was absent (RR: 1.09; 95% CI: 1.04, 1.13; P = 0.0002). CONCLUSION: The addition of selenium should be considered for supplements containing antioxidant mixtures if they are to be associated with CVD and all-cause mortality risk reduction. This trial was registered at https://www.crd.york.ac.uk/PROSPERO/ as CRD42019138268.

Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias.

Levodopa (L-DOPA) is the 'gold standard' to treat Parkinson's disease. Unfortunately, dyskinesias detract from its efficacy. Current dyskinesia treatments, including amantadine and dextromethorphan, are thought to work via N-methyl-D-aspartate (NMDA) antagonism, but this hypothesis has not been tested. The NMDA antagonists MK-801 and HA-966 failed to suppress expression of dyskinesias in the 6-hydroxydopamine rat. Dyskinesias, however, were suppressed by the NMDA and sigma (sigma)-1 receptor ligand dextromethorphan and by the sigma-1 antagonist BMY-14802. Antidyskinetic effects of dextromethorphan may be mediated via mechanisms other than NMDA, including the sigma-1 receptor and other binding sites common to dextromethorphan and BMY-14802.

Supplemental Vitamins and Minerals for CVD Prevention and Treatment.

The authors identified individual randomized controlled trials from previous meta-analyses and additional searches, and then performed meta-analyses on cardiovascular disease outcomes and all-cause mortality. The authors assessed publications from 2012, both before and including the U.S. Preventive Service Task Force review. Their systematic reviews and meta-analyses showed generally moderate- or low-quality evidence for preventive benefits (folic acid for total cardiovascular disease, folic acid and B-vitamins for stroke), no effect (multivitamins, vitamins C, D, ß-carotene, calcium, and selenium), or increased risk (antioxidant mixtures and niacin [with a statin] for all-cause mortality). Conclusive evidence for the benefit of any supplement across all dietary backgrounds (including deficiency and sufficiency) was not demonstrated; therefore, any benefits seen must be balanced against possible risks.

Effect of Current Dietary Recommendations on Weight Loss and Cardiovascular Risk Factors.

BACKGROUND: Dietary recommendations emphasize increased consumption of fruit, vegetables, and whole grain cereals for prevention of chronic disease. OBJECTIVES: This study assessed the effect of dietary advice and/or food provision on body weight and cardiovascular disease risk factors. METHODS: Healthy overweight men (n = 209) and women (n = 710), mean age 44.7 years, body mass index [BMI] 32.4 kg/m2, were randomized between November 2005 and August 2009 to receive Health Canada's food guide (control, n = 486) or 1 of 3 interventions: dietary advice consistent with both Dietary Approaches to Stop Hypertension (DASH) and dietary portfolio principles (n = 145); weekly food provision reflecting this advice (n = 148); or food delivery plus advice (n = 140). Interventions lasted 6 months with 12-month follow-up. Semiquantitative food frequency questionnaires and fasting blood, anthropometric and blood pressure measurements were obtained at baseline, 6 months, and 18 months. RESULTS: Participant retention at 6 and 18 months was 91% and 81%, respectively, after food provision compared to 67% and 57% when no food was provided (p < 0.0001). Test and control treatments showed small reductions in body weight (-0.8 to -1.2 kg), waist circumference (-1.1 to -1.9 cm), and mean arterial pressure (0.0 to -1.1 mm Hg) at 6 months and Framingham coronary heart disease risk score at 18 months (-0.19 to -0.42%), which were significant overall. Outcomes did not differ among test and control groups. CONCLUSIONS: Provision of foods increased retention but only modestly increased intake of recommended foods. Current dietary recommendations showed small overall benefits in coronary heart disease risk factors. Additional dietary strategies to maximize these benefits are required. (Fruits, Vegetables, and Whole Grains: A Community-based Intervention; NCT00516620).

Assessment of recovery in the hemiparkinson rat: drug-induced rotation is inadequate.

Recovery from apomorphine-induced rotational behavior was compared to sensorimotor and motor function in hemiparkinsonian rats receiving intrastriatal grafts of astrocytes expressing recombinant tyrosine hydroxylase (TH) or control beta-galactosidase (beta-gal). Rats received unilateral intranigral infusions of 6-hydroxydopamine (6-OHDA). Animals with large lesions, as determined by apomorphine-induced rotation, received grafts of astrocytes into the denervated striatum. Behavioral recovery was assessed on days 14-16 post-transplantation using apomorphine-induced rotation, somatosensory neglect, and reaching for pellets using the Montoya staircase method. Rats that received transplants of TH-transfected astrocytes showed a 34% decrease in rotational behavior, but no consistent recovery of somatosensory neglect or skilled reaching. Post-mortem histological analyses revealed survival of grafted astrocytes in host striatum and expression of TH at 17 days post-transplantation. We suggest that TH-expressing astrocytes may reverse post-synaptic dopamine (DA) receptor supersensitivity; however, sensorimotor and motor abilities are not restored due to a failure by TH-expressing astrocytes to reestablish dopaminergic circuitry. The present results demonstrate the need to utilize a variety of sensory and motor behavioral tests that cohesively provide greater interpretability than a single behavioral measure used in isolation, such as drug-induced rotational behavior, to assess the efficacy of experimental gene therapies.

The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat.

RATIONALE: L-DOPA continues to be the primary treatment for patients with Parkinson's disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT1A receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce L-DOPA induced dyskinesia in a 5-HT1A receptor dependent manner. OBJECTIVE: In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against L-DOPA, the D1 receptor agonist SKF81297 and the D2 receptor agonist, quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802's effects was evaluated using WAY-100635, a 5-HT1A receptor antagonist. RESULTS: Results confirmed the dose-dependent (20 > 10 > 5 mg/kg) anti-dyskinetic effects of BMY-14802 against L-DOPA with preservation of anti-parkinsonian efficacy at 10 mg/kg. BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D1 and D2 receptor agonists. Additionally, BMY-14802's anti-dyskinetic effects against L-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0.5 mg/kg). CONCLUSION: Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against L-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD.

MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism.

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-D-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIMs. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the anti-dyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIMs or contraversive rotation. In addition, in L-DOPA-primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIMs, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2-0.3 mg/kg) suppressed expression of AIMs. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed L-DOPA-induced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with L-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism.

Amphetamine-evoked rotation requires newly synthesized dopamine at 14 days but not 1 day after intranigral 6-OHDA and is consistently dissociated from sensorimotor behavior.

Immediately after unilateral, intranigral 6-hydroxydopamine (6-OHDA), amphetamine (AMPH) evokes "paradoxical" contraversive rotation, whereas 14 days later, AMPH evokes the traditional ipsiversive rotation used to model the chronic Parkinsonian state. In this study, the hypothesis was that accelerated dopamine (DA) synthesis ipsilateral to the lesion augments cytoplasmic DA to produce paradoxical rotation. Therefore, the sensitivity to synthesis inhibition of AMPH-evoked rotation at 1 or 14 days after 6-OHDA was assessed. To determine the functional status that might be reflected by paradoxical rotation, sensorimotor abilities were examined at 1 and 14 days following unilateral 6-OHDA using the elevated swing, paw placement, grip strength, ladder walking, somatosensory neglect, and cylinder tests. At 14 days after 6-OHDA when AMPH-evoked ipsiversive rotation is mediated by the intact hemisphere, rotation was dose-dependently reduced by tyrosine hydroxylase (TH) inhibition with alpha-methyl-p-tyrosine (alpha-MPT) or dopa decarboxylase (DDC) inhibition with 3-hydroxybenzyl hydrazine (NSD-1015), indicating dependence upon newly synthesized DA. Conversely, at 1 day after 6-OHDA, paradoxical rotation, presumably mediated by the treated hemisphere, was completely resistant to synthesis blockade, indicating an abundant supply of intracellular DA that is independent from synthesis rates. Sensorimotor behaviors were not correlated with AMPH-evoked rotation. The present data do not support the hypothesis that enhanced DA synthesis is required to express paradoxical rotation. Therefore, alternative mechanisms that may enhance cytoplasmic DA to produce paradoxical rotation are discussed.

The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism.

RATIONALE: Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model. OBJECTIVES: Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic alpha-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects. RESULTS: Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the alpha-1 antagonist prazosin. CONCLUSIONS: BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia.