Background The phenotype of Parkinson disease (PD) patients with and without LRRK2 G2019S mutations is reported to be similar; however large uniformly evaluated series are lacking. Objective To characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. Methods We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). GBA mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the geriatric depression scale (GDS) and the non-motor symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. Results LRRK2 G2019S carriers (n=97) and non-carriers (n=391) were similar in age and age-at-onset of PD. Carriers had longer disease duration (8.6years versus 6.1years, p<0.001), were more likely to be women (51.5% versus 37.9%, p=0.015) and more often reported first symptoms in lower extremities (40.0% versus 19.2%, p<0.001). In logistic models adjusted for age, disease duration, gender, education, and site, carriers were more likely to have lower extremity onset (p<0.001), postural instability gait difficulty (PIGD, p=0.043) and persistent levodopa response for>5 years (p=0.042). Performance on UPDRS, MoCA, GDS and NMS did not differ by mutation status. Conclusion PD in AJ-LRRK2 G2019S mutation carriers is similar to idiopathic PD, but characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Sex differences in biological substrates of drug use and addiction are poorly understood. The present study investigated sexual dimorphisms in motor behavior following acute cocaine administration (10, 20, or 40 mg/ kg, i.p Little is known about sex differences in biologic substrates of drug taking and addiction. However, an emerging literature documents that sex differences in the behavioral responses to addictive drugs exist in humans. A sex difference in human affective responses to cocaine has been reported in one study in which females reported more nervousness than males following intranasal cocaine (Kosten et al. 1996). Lukas and coworkers (1996) showed that cocaine induced similar cardiovascular and affective responses in men and women, although plasma concentrations of cocaine were lower in women. In a laboratory setting, cocaine cues induced more drug craving in female than male addicts (Robbins et al. 1999). These results suggest that women may be more sensitive to cocaine than men. In fact, women begin using cocaine and enter treatment at earlier ages than men (Griffin et al. 1989;Mendelson et al. 1991) and have more severe cocaine use at intake than men (Kosten et al. 1993). .). Cocaine increased stereotypy rating, horizontal and vertical activity in both sexes, and effects were always greater in females than males. A population analysis using data from multiple experiments indicated that horizontal activity scores were normally distributed in males butSex differences in spontaneous and drug-stimulated behavior have been carefully studied in animals. Probably the most robust sex difference in behavior is the observation that female rats exhibit more running wheel activity than males (for review see Beatty 1979). Female rats are also often reported to be more active than males in open-field situations (Beatty 1979). These sex differences in basal or non-stimulated behavior are likely related to the reported sex differences in open-field behavior following psychomotor stimulant administration (van Hartesveldt and Joyce 1986 25 , NO . 1 Sex Differences in Cocaine Effects 119 particularly well known for producing greater behavioral effects in female rats following acute administration (Schneider and Norton 1979;Savageau and Beatty 1981;Becker et al. 1982;Camp et al. 1986;Camp and Robinson 1988a). Acute cocaine administration has also been reported to induce greater behavioral effects in female rats (van Haaren and Meyer 1991;Haney et al. 1994;Bowman and Kuhn 1996) and in mice (Sershen et al. 1998). However, in other reports, sex differences in acute cocaine-stimulated motor behavior were not observed in naïve Sprague-Dawley rats (Craft and Stratman 1996) and in three other rat strains (Cailhol and Mormede 1999). Thus, better evidence of sex-differences in acute behavioral effects in intact animals exists for amphetamine than cocaine. Gonadal and especially ovarian hormones have been investigated as likely modulators of these sex differences in behavior. Ovarian hormone effects on stimulant respon...

The present study investigated the effect of the selective cannabinoid agonist, WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on body temperature. WIN 55212-2 (1, 2.5, 5, and 10 mg/kg, i.m.) induced hypothermia in a dose-dependent manner. The peak hypothermia occurred 60 to 180 min postinjection. Body temperature was still suppressed 5 h after the injection of the highest dose of WIN 55212-2. The selective hypothermia. Neither SR141716A nor SR144528 alone altered body temperature. WIN 55212-2 (1-30 g/l) injected directly into the preoptic anterior hypothalamic nucleus (POAH) induced hypothermia in an immediate and dose-dependent fashion. The hypothermia produced by intra-POAH injection of WIN 55212-2 was brief, with body temperature returning to baseline 60 min postinjection. SR141716A (5 mg/kg, i.m.) abolished the hypothermia induced by intra-POAH injection of WIN 55212-2 (30 g/l), indicating that CB 1 receptors in the POAH mediated the hypothermia. The present results confirm the idea that CB 1 receptors mediate the hypothermic response to cannabinoid agonists. Moreover, the present data suggest that 1) the POAH is the central locus for thermoregulation, and 2) CB 1 receptors within the POAH are the primary mediators of cannabinoid-induced hypothermia.