Central infusion of angiotensin IV or its more stable analogues facilitates memory retention and retrieval in normal animals and reverses amnesia induced by scopolamine or by bilateral perforant pathway lesions. These peptides bind with high affinity and specificity to a novel binding site designated the angiotensin AT₄ receptor. Until now, the AT₄ receptor has eluded molecular characterization. Here we identify the AT₄ receptor, by protein purification and peptide sequencing, to be insulin-regulated aminopeptidase (IRAP). HEK 293T cells transfected with IRAP exhibit typical AT₄receptor binding characteristics; the AT₄ receptor ligands, angiotensin IV and LVV-hemorphin 7, compete for the binding of [¹²⁵I]Nle¹-angiotensin IV with IC₅₀ values of 32 and 140 nm, respectively. The distribution of IRAP and its mRNA in the brain, determined by immunohistochemistry and hybridization histochemistry, parallels that of the AT₄ receptor determined by radioligand binding. We also show that AT₄ receptor ligands dose-dependently inhibit the catalytic activity of IRAP. We have therefore demonstrated that the AT₄ receptor is IRAP and propose that AT₄ receptor ligands may exert their effects by inhibiting the catalytic activity of IRAP thereby extending the half-life of its neuropeptide substrates.

Males and females sometimes significantly differ in their propensity to develop neurological disorders. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson’s disease (PD), attention-deficit hyperactivity disorder (ADHD) and autism. Despite this, biological sex is rarely considered when making treatment decisions in neurological disorders. A better understanding of the molecular mechanism(s) underlying sex differences in the healthy and diseased brain will help to devise diagnostic and therapeutic strategies optimal for each sex. Thus, the aim of this review is to discuss the available evidence on sex differences in neuropsychiatric and neurodegenerative disorders regarding prevalence, progression, symptoms and response to therapy. We also discuss the sex-related factors such as gonadal sex hormones and sex chromosome genes and how these might help to explain some of the clinically observed sex differences in these disorders. In particular, we highlight the emerging role of the Y-chromosome gene, SRY, in the male brain and its potential role as a male-specific risk factor for disorders such as PD, autism, and ADHD in many individuals.

J. Neurochem. (2012) 122, 260–271. The male gender is determined by the sex‐determining region on the Y chromosome (SRY) transcription factor. The unexpected action of SRY in the control of voluntary movement in male rodents suggests a role in the regulation of dopamine transmission and dopamine‐related disorders with gender bias, such as Parkinson’s disease. We investigated SRY expression in the human brain and function in vitro. SRY immunoreactivity was detected in the human male, but not female substantia nigra pars compacta, within a sub‐population of tyrosine hydroxylase (TH) positive neurons. SRY protein also co‐localized with TH positive neurons in the ventral tegmental area, and with GAD‐positive neurons in the substantia nigra pars reticulata. Retinoic acid‐induced differentiation of human precursor NT2 cells into dopaminergic cells increased expression of TH, NURR1, D₂R and SRY. In the human neuroblastoma cell line, M17, SRY knockdown resulted in a reduction in TH, DDC, DBH and MAO‐A expression; enzymes which control dopamine synthesis and metabolism. Conversely, SRY over‐expression increased TH, DDC, DBH, D₂R and MAO‐A levels, accompanied by increased extracellular dopamine levels. A luciferase assay demonstrated that SRY activated a 4.6 kb 5′ upstream regulatory region of the human TH promoter/nigral enhancer. Combined, these results suggest that SRY plays a role as a positive regulator of catecholamine synthesis and metabolism in the human male midbrain. This ancillary genetic mechanism might contribute to gender bias in fight‐flight behaviours in men or their increased susceptibility to dopamine disorders, such as Parkinson’s disease and schizophrenia.

Failed storage capacity, leading to pulsatile delivery of dopamine (DA) in the striatum, is used to explain the emergence of ‘wearing off’ and dyskinaesia in Parkinson's disease. In this study, we show that surviving DA neurons in 6-OHDA lesioned rats sprout to re-innervate the striatum, and maintain terminal density until ∼60% of neurons are lost. We demonstrate that DA terminal density correlates with baseline striatal DA concentration ([DA]). Electrochemical and synaptosome studies in 6-OHDA lesioned rats and primates suggest that impaired striatal DA re-uptake and increased DA release from medial forebrain bundle fibres contribute to maintaining striatal DA levels. In lesioned rats where terminal density fell by 60% or more, l-DOPA administration increased striatal DA levels markedly. The striatal [DA] produced by l-DOPA directly correlated with the extent of dyskinaesia, suggesting that dyskinaesia was related to high striatal [DA]. While sprouting and decreased dopamine uptake transporter function would be expected to contribute to the marked increase in l-DOPA induced [DA], the increased [DA] was most marked when DAergic fibres were >60% denervated, suggesting that other release sites, such as serotonergic fibres might be contributing. In conclusion, the extent of dyskinaesia was directly proportional to the extent of DA terminal denervation and levels of extra-synaptic striatal DA. We propose that sprouting of DA terminals and decreased dopamine uptake transporter function prevent the appearance of Parkinsonian symptoms until about 60% loss of nigral neurons, but also contribute to dysregulated striatal DA release that is responsible for the emergence of dyskinaesia and ‘wearing off’.