Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or C(min). The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D(1)-like or D(2)-like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA(2) (orK(dose)) to be measured. Antagonist K(dose) values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self-administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects.

Copyright © 2010. Published by Elsevier B.V.

Involvement of the pituitary BMP system in the modulation of prolactin (PRL) secretion regulated by somatostatin analogs, including octreotide (OCT) and pasireotide (SOM230), and a dopamine agonist, bromocriptine (BRC), were examined in GH3 cells. GH3 cells are rat pituitary somato-lactotrope tumor cells that express somatostatin receptors (SSTRs) and BMP system molecules including BMP-4 and -6. Treatment with BMP-4 and -6 increased PRL and cAMP secretion by GH3 cells. The BMP-4 effects were neutralized by adding a BMP-binding protein Noggin. These findings suggest the activity of endogenous BMPs in augmenting PRL secretion by GH3 cells. BRC and SOM230 reduced PRL secretion, but OCT failed to reduce the PRL level. In GH3 cells activated by forskolin, BRC suppressed forskolin-induced PRL secretion with reduction in cAMP levels. OCT did not affect forskolin-induced PRL level, while SOM230 reduced PRL secretion and PRL mRNA expression induced by forskolin. BMP-4 treatment enhanced the reducing effect of SOM230 on forskolin-induced PRL level while BMP-4 did not affect the effects of OCT or BRC. Noggin treatment had no significant effect on the BRC actions reducing PRL levels by GH3 cells. However, in the presence of Noggin, OCT elicited an inhibitory effect on forskolin-induced PRL secretion and PRL mRNA expression, whereas the SOM230 effect on PRL reduction was in turn impaired. It was further found that BMP-4 and -6 suppressed SSTR-2 but increased SSTR-5 mRNA expression of GH3 cells. These findings indicate that Noggin rescues SSTR-2 but downregulates SSTR-5 by neutralizing endogenous BMP actions, leading to an increase in OCT sensitivity and a decrease in SOM230 sensitivity of GH3 cells. In addition, BMP signaling was facilitated in GH3 cells treated with forskolin. Collectively, these findings suggest that BMPs elicit differential actions in the regulation of PRL release dependent on cellular cAMP-PKA activity. BMPs may play a key role in the modulation of SSTR sensitivity of somato-lactotrope cells in an autocrine/paracrine manner.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

This review of recent research on prenatal depression suggests that it is a strong predictor of postpartum depression and is more common than postpartum depression. Prenatal depression has been associated with excessive activity and growth delays in the fetus as well as prematurity, low birthweight, disorganized sleep and less responsiveness to stimulation in the neonate. Infants of depressed mothers have difficult temperament, and later in development attentional, emotional and behavioral problems have been noted during childhood and adolescence, as well as chronic illnesses in adulthood. Several variables have confounded the effects of prenatal depression including comorbid anxiety and anger as well as stressful life events. Potential mediating variables are low prenatal maternal dopamine and serotonin levels and elevated cortisol and norepinephrine. The associated intrauterine artery resistance may limit blood flow, oxygen and nutrients to the fetus. Some studies also suggest the heritability of developmental problems for the children of prenatally depressed mothers, including ADHD and antisocial behavior. Multivariate, longitudinal research is needed to disentangle these confounding and mediating variables.

Copyright © 2010. Published by Elsevier Inc.

Intermittent hypoxia (IH) associated with sleep apnea leads to cardio-respiratory morbidities. Previous studies have shown that IH alters the synthesis of neurotransmitters including catecholamines and neuropeptides in brainstem regions associated with regulation of cardio-respiratory functions. GABA, a major inhibitory neurotransmitter in the central nervous system, has been implicated in cardio-respiratory control. GABA synthesis is primarily catalyzed by glutamic acid decarboxylase (GAD). Here, we tested the hypothesis that IH like its effect on other transmitters also alters GABA synthesis. The impact of IH on GABA synthesis was investigated in pheochromocytoma 12 (PC12) cells, a neuronal cell line which is known to express active form of GAD67 in the cytosolic fraction and also assessed the underlying mechanisms contributing to IH-evoked response. Exposure of cell cultures to IH decreased GAD67 activity and GABA level. IH-evoked decrease in GAD67 activity was due to increased cAMP – protein kinase A (PKA) – dependent phosphorylation of GAD67, but not as a result of changes in either GAD67 mRNA or protein expression. PKA inhibitor restored GAD67 activity and GABA levels in IH treated cells. PC12 cells express dopamine 1 receptor (D1R), a G-protein coupled receptor whose activation increased adenylyl cyclase (AC) activity. Treatment with either D1R antagonist or AC inhibitor reversed IH-evoked GAD67 inhibition. Silencing D1R expression with siRNA reversed cAMP elevation and GAD67 inhibition by IH. These results provide evidence for the role of D1R-cAMP-PKA signaling in IH mediated inhibition of GAD67 via protein phosphorylation resulting in down regulation of GABA synthesis.

Journal of Neurochemistry © 2010 International Society for Neurochemistry.

The basal ganglia have a local renin-angiotensin system and it has been shown that the loss of dopaminergic neurons induced by neurotoxins is amplified by local angiotensin II (AII) via angiotensin type 1 receptors (AT1) and nicotinamide adenine dinucleotide phosphate (NADPH) complex activation. Recent studies have revealed a high degree of counter-regulatory interactions between dopamine and AII receptors in non-neural cells such as renal proximal tubule cells. However, it is not known if this occurs in the basal ganglia. In the striatum and nigra, depletion of dopamine with reserpine induced a significant increase in the expression of AT1, angiotensin type 2 receptors (AT2) and the NADPH subunit p47(phox) , which decreased as dopamine function was restored. Similarly, 6-hydroxydopamine-induced chronic dopaminergic denervation induced a significant increase in expression of AT1, AT2 and p47(phox) , which decreased with L-dopa administration. A significant reduction in expression of AT1 mRNA was also observed after administration of dopamine to cultures of microglial cells. Transgenic rats with very low levels of brain AII showed increased AT1, decreased p47 (phox) and no changes in AT2 expression, whereas mice deficient in AT1 exhibited a decrease in the expression of p47 (phox) and AT2. The administration of relatively high doses of AII (100?nm) decreased the expression of AT1, and the increased expression of AT2 and p47(phox) in primary mesencephalic cultures. The results reveal an important interaction between the dopaminergic and local renin-angiotensin system in the basal ganglia, which may be a major factor in the progression of Parkinson’s disease.

© 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Knowledge of the reproducibility of striatal [(11)C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine during pharmacological and cognitive challenges. To our knowledge, no baseline test-retest data exist for nontreatment-seeking alcoholics (NTS). We determined the test-retest reproducibility of baseline RAC binding potential (BP(ND)) in twelve male NTS subjects. Subjects were scanned twice with single-bolus RAC PET on separate days. Striatal RAC binding potential (BP(ND)) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis with a reference region (LGA). Test-retest variability (TRV), % change in BP(ND) between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was ± 6.5%, and ± 7.1% for LGA. Average striatal ICCs were 0.94 for both methods (p < 0.0001). Striatal BP(ND) values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects. Synapse, 2010. © 2010 Wiley-Liss, Inc.

The objective of this study was to evaluate characteristics that discriminate prolactinoma from non-functioning pituitary macroadenoma with hyperprolactinemia. We included 117 patients with hyperprolactinemic pituitary macroadenomas. Patients were divided into three groups according to treatment outcomes and pathologic results: (A) prolactinoma that responded to dopamine agonist (DA) treatment (PRDA); (B) prolactinoma requiring surgical treatment (PRS); and (C) non-functioning pituitary adenoma with hyperprolactinemia (NFPAH). Old age, low serum prolactin levels, and extrasellar extension were associated with NFPAH. Most patients with NFPAH had serum prolactin levels less than 100 ng/ml. Visual defects and GH deficiency were more common in patients with NFPAH compared with patients with PRS and PRDA, without difference of tumor size. Galactorrhea and amenorrhea were less frequent in patients with NFPAH than in patients with PRS and PRDA. Post-operative remission of hyperprolactinemia was achieved in 100% of patients with NFPAH and in 72.5% of patients with PRS. DA administration was required in 25.5% of patients with PRS; however, no patients with NFPAH required DA administration. In conclusion, old age, extrasellar tumor extension with relatively low prolactin levels, visual defect, and GH deficiency were considered suggestive of non-functioning pituitary adenoma rather than prolactinoma in hyperprolactinemic pituitary macroadenoma.

Chronic treatment with the indirect dopamine agonist d-amphetamine can reduce cocaine use in clinical trials and, in preclinical studies in laboratory animals, attenuates daily cocaine self-administration. The present study extended previous results to conditions designed to reflect a more clinically relevant experience of cocaine exposure and d-amphetamine treatment. Each morning, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement. After determining a dose-response curve for cocaine (0.003-0.56?mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule of reinforcement in the evening, cocaine self-administration sessions were suspended and d-amphetamine (0.01-0.056?mg/kg/h, i.v.) was administered continuously for at least 24 days, except during cocaine self-administration sessions, which were conducted using the PR schedule once every 8 days. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was redetermined. Cocaine- and food-maintained responding were also examined after discontinuation of d-amphetamine. Although individual differences in sensitivity were observed, d-amphetamine produced selective, qualitatively similar decreases in the reinforcing strength of cocaine in all monkeys that persisted at least 4 weeks. Moreover, cocaine dose-effect curves were shifted downward and/or to the right. For 2 weeks following discontinuation of d-amphetamine treatment, the reinforcing strength of cocaine varied within and across individuals, however, on the whole no increased sensitivity was apparent. These data provide further support for the use of agonist medications for cocaine abuse, and extend the conditions under which such treatment is successful to those that incorporate clinically relevant patterns of cocaine use and drug treatment.Neuropsychopharmacology advance online publication, 20 October 2010; doi:10.1038/npp.2010.185.

Human immunodeficiency virus-associated neurological disease (HAND) still causes significant morbidity, despite success reducing viral loads with combination antiretroviral therapy. The dopamine (DA) system is particularly vulnerable in HAND. We hypothesize that early, “reversible” DAergic synaptic dysfunction occurs long before DAergic neuron loss. As such, aging human immunodeficiency virus (HIV)-infected individuals may be vulnerable to other age-related neurodegenerative diseases like Parkinson’s disease (PD), underscoring the need to understand shared molecular targets in HAND and PD. Previously, we reported that the neurotoxic HIV-1 transactivating factor (Tat) acutely disrupts mitochondrial and endoplasmic reticulum calcium homeostasis via ryanodine receptor (RyR) activation. Here, we further report that Tat disrupts DA transporter (DAT) activity and function, resulting in increased plasma membrane (PM) DAT and increased DAT V(max), without changes in K(m) or total DAT protein. Tat also increases calpain protease activity at the PM, demonstrated by total internal reflection fluorescence microscopy of a cleavable fluorescent calpain substrate. Tat-increased PM DAT and calpain activity are blocked by the RyR antagonists ryanodine and dantrolene, the calpain inhibitor calpastatin, and by a specific inhibitor of GSK-3?. We conclude that Tat activates RyRs via a calcium- and calpain-mediated mechanism that upregulates DAT trafficking to the PM, and is independent of DAT protein synthesis, reinforcing the feasibility of RyR and GSK-3? inhibition as clinical therapeutic approaches for HAND. Finally, we provide key translational relevance for these findings by highlighting published human data of increased DAT levels in striata of HAND patients and by demonstrating similar findings in Tat-expressing transgenic mice.