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Ca2+ entry into nigrostriatal dopamine (DA) neurons and axons via L‐type voltage‐gated Ca2+ channels (LTCCs) contributes, respectively, to pacemaker activity and DA release and has long been thought to contribute to vulnerability to degeneration in Parkinson's disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, α‐synuclein, DA transporters (DATs) and calbindin‐D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast‐scan cyclic voltammetry and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations, we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, α‐synuclein, DAT and a dorsolateral co‐ordinate, but limited by factors associated with protection, that is, female sex, glucocerebrosidase activity, Calb1 and ventromedial co‐ordinate. Together, these data show that LTCC function in DA axons and isradipine effect are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration. [ABSTRACT FROM AUTHOR]

Background: Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and dyslipidaemia is well established, while evidence on antidepressants is mixed. Aims: To investigate if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants and if CYP2C19 and CYP2D6 genetic variation plays a role. Methods: Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein cholesterol (L/HDL-C) and triglycerides derived from blood samples. CYP2C19 and CYP2D6 metabolic phenotypes were assigned from genetic data. Linear regression investigated aims, adjusted for key covariates. Results: Of 469,739 participants, 36,043 took antidepressants (53% female, median age 58, 17% taking cholesterol-lowering medications) and 3255 took antipsychotics (58% female, median age 57, 27% taking cholesterol-lowering medications). Significant associations were found between use of each amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine and venlafaxine with higher total cholesterol, LDL-C, and triglycerides and lower HDL-C, compared to participants not taking each medication. Venlafaxine was associated with the worst lipid profile (total cholesterol, adjusted mean difference: 0.21 mmol/L, 95% confidence interval (CI): 0.17 to 0.26, p < 0.001). Antipsychotic use was significantly associated with lower HDL-C and higher triglycerides. In participants taking sertraline, CYP2C19 intermediate metabolisers had higher HDL-C (0.05 mmol/L, 95% CI: 0.01 to 0.09, p = 0.007) and lower triglycerides (−0.17 mmol/L, 95% CI: −0.29 to −0.05, p = 0.007), compared to normal metabolisers. Conclusions: Antidepressants were significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring. Further research should investigate the mechanistic pathways underlying the protective effects of the CYP2C19 intermediate metaboliser phenotype on HDL-C and triglycerides in people taking sertraline. [ABSTRACT FROM AUTHOR]

The calcium-binding protein calbindin-D28K, or calb1, is expressed at higher levels by dopamine (DA) neurons originating in the ventral tegmental area (VTA) than in the adjacent substantia nigra pars compacta (SNc). Calb1 has received attention for a potential role in neuroprotection in Parkinson's disease. The underlying physiological roles for calb1 are incompletely understood. We used cre-loxP technology to knock down calb1 in mouse DA neurons to test whether calb1 governs axonal release of DA in the striatum, detected using fast-scan cyclic voltammetry ex vivo. In the ventral but not dorsal striatum, calb1 knockdown elevated DA release and modified the spatiotemporal coupling of Ca 2+ entry to DA release. Furthermore, calb1 knockdown enhanced DA uptake but attenuated the impact of DA transporter (DAT) inhibition by cocaine on underlying DA release. These data reveal that calb1 acts through a range of mechanisms underpinning both DA release and uptake to limit DA transmission in the ventral but not dorsal striatum.