Brain serotonin and catecholamine responses to repeated stress in rats

This study was designed to compare the effects of single and repeated administration of a discrete 2-min restraint stress on serotonin (5-HT) and catecholamine neuron activity in various regions of rat brain. A single 2-min restraint stress significantly increased the 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT responses in hypothalamus and cerebral cortex and the 5-HIAA response in brainstem. A second 2-min restraint stress applied 90 min after the initial stress did not appreciably alter the steady-state concentrations of 5-HIAA and 5-HT nor did it produce any further changes in the 5-HIAA and 5-HT responses compared to those seen following a single stress in these 3 brain regions. In addition, the synthesis rate of 5-HT in anterior hypothalamus, posterior hypothalamus, hippocampus and brainstem was not altered by a second stress applied 90 min after the initial stress. In contrast, a second 2-min restraint stress applied 30 or 60 min after the initial stress significantly increased the 5-HIAA concentration in hypothalamus, cerebral cortex and brainstem. Also, the synthesis rate of 5-HT was greater following application of a second stress at 30 min than following either a single stress or a second stress applied at 90 min. Following application of a single 2-min restraint stress the hypothalamic concentration of norepinephrine (NE) was significantly decreased at 5 min after onset of the stress and returned to prestress levels by 15 min; the hypothalamic dopamine (DA) concentration was significantly increased at 30 min after the onset of the stress, while the hypothalamic epinephrine (EPI) concentration remained unchanged. A second 2-min restraint stress applied at 30 min markedly lowered NE concentrations in whole and mediobasal hypothalamus but not in laterobasal hypothalamus, and the NE concentrations remained decreased for a period lasting at least 60 min; there was a significant decrease in the hypothalamic EPI concentration 60 min after application of the second stress at 30 min. In addition, the synthesis rate of catecholamines was significantly greater in anterior but not in posterior hypothalamus after application of a second stress 30 min after the initial stress than following either a single stress or a second stress applied at 90 min. Negative correlations were demonstrated between increased synthesis rates of both hypothalamic 5-HT and anterior hypothalamic catecholamines and decreased corticosterone response to single and repeated stress.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of Oestrogen Receptors on Brain NMDA Receptors of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine Mice

Parkinson’s disease (PD) is characterised by the loss of nigrostriatal dopamine (DA) neurones and glutamate overactivity. There is substantial evidence to suggest that oestrogens prevent or delay the disease. 17β‐oestradiol has neuroprotective effects in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD and modulates brain NMDA receptors. In MPTP‐lesioned mice, oestrogen receptor (ER)α and ERβ are important in 17β‐oestradiol‐induced neuroprotection. To evaluate the role of ERs in the response of NMDA receptors to lesion, we compared wild‐type (WT) with ER knockout (KO) C57Bl/6 male mice that received 7, 9 or 11 mg/kg of MPTP. These mice were also treated with MPTP (9 mg/kg) and 17β‐oestradiol. [³H]Ro 25‐6981 specific binding autoradiography was used to label NMDA receptors containing NR2B subunits. In the frontal and cingulate cortex and striatum, vehicle‐treated WT mice had higher [³H]Ro 25‐6981 specific binding compared to ERKO mice. Cortical [³H]Ro 25‐6981 specific binding decreased with increasing doses of MPTP in WT and ERKOα but not ERKOβ mice, whereas a dose‐related decrease was only observed in the striatum of WT mice remaining low in ERKOα and ERKOβ mice. No effect of 17β‐oestradiol treatment in intact or MPTP‐lesioned mice of all three genotypes was observed in the cortex, whereas it increased striatal specific binding of intact ERKOβ and MPTP‐lesioned WT mice. Striatal [³H]Ro 25‐6981 specific binding positively correlated with striatal DA concentrations only in WT mice. MPTP and 17β‐oestradiol treatments had more limited effects in the hippocampus. Only in the CA3 and dentate gyrus did vehicle and 17β‐oestradiol‐treated ERKOα mice have higher [³H]Ro 25‐6981 specific binding than WT and ERKOβ mice, whereas MPTP decreased this specific binding only in the CA1, CA2 and CA3 of ERKOα mice. Hence, brain NMDA receptors were affected by the deletion of ERs, which affect the response to MPTP and 17β‐oestradiol treatments with brain region specificity.     

Differential effects of serotonin (5‐HT)2 receptor‐targeting ligands on locomotor responses to nicotine‐repeated treatment

We verified the hypothesis that serotonin (5‐HT)₂ receptors control the locomotor effects of nicotine (0.4 mg kg⁻¹) in rats by using the 5‐HT_2A receptor antagonist M100907, the preferential 5‐HT_2A receptor agonist DOI, the 5‐HT_2C receptor antagonist SB 242084, and the 5‐HT_2C receptor agonists Ro 60‐0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5‐HT₂ receptor ligands, M100907 (2 mg kg⁻¹) or DOI (1 mg kg⁻¹) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg⁻¹), Ro 60‐0175 (1 mg kg⁻¹), and WAY 163909 (1.5 mg kg⁻¹) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1–5, 10) with nicotine, none of 5‐HT₂ receptor ligands administered during the second withdrawal period (Days: 11–14) to nicotine‐treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5‐HT_2A receptors (but not 5‐HT_2C receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5‐HT_2A receptors enhances the development of nicotine sensitization and activation of 5‐HT_2C receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5‐HT₂ receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization. Synapse 64:511–519, 2010. © 2010 Wiley‐Liss, Inc.     

Antipsychotic‐induced DRD2 upregulation and its prevention by α‐lipoic acid in SH‐SY5Y Neuroblastoma cells

Most antipsychotic (AP) drugs are dopamine (DA) D2 receptor (DRD2) antagonists and remain the main pharmacological treatment of schizophrenia. Long‐term AP use can give rise to tardive dyskinesia. It has been reported that chronic treatment with APs induces DRD2 upregulation and oxidative stress, which have been associated with tardive dyskinesia. We showed previously that H₂O₂‐induced oxidative stress increased DRD2 expression in human SH‐SY5Y neuroblastoma cells. We report here the effects of AP drugs on DRD2 expression levels in the same cell line and the effects of the inhibition of oxidative phenomena by (±)‐α‐lipoic acid treatment. Haloperidol, a first‐generation AP, induced an increase in DRD2 protein and mRNA levels, whereas amisulpride, a second‐generation AP, had no significant effect. (±)‐α‐Lipoic acid pretreatment reversed the haloperidol‐induced DRD2 upregulation in mRNA and protein levels. Furthermore, haloperidol induced a larger increase of oxidative stress biomarkers (protein carbonylation, lipid peroxidation, and superoxide anion production) than amisulpride. (±)‐α‐Lipoic acid also attenuated AP‐induced oxidative stress. Inhibition of catecholamine synthesis by α‐methyl‐DL ‐tyrosine (AMPT) increased DRD2 expression and prevented further increase by APs. Our results suggest that haloperidol‐induced DRD2 upregulation is linked to oxidative stress and provide potential mechanisms by which (±)‐α‐lipoic acid can be considered as a therapeutic agent to prevent and treat side effects related to the use of first‐generation APs. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Differentiation of forebrain and hippocampal dopamine 1‐class receptors,D1R and D5R,in spatial learning and memory

Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1‐class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water‐maze spatial learning task remains unknown. D1R‐ and D5R‐specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F‐D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F‐D1R/D5R KO mice were given water‐maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F‐D1R KO) and D5R KO (F‐D5R KO) mice were trained on the water‐maze task. F‐D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F‐D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F‐D5R KO animals did not present observable deficits on the water‐maze task. Because F‐D1R KO mice showed water‐maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG‐D1R KO) mice on the water‐maze task. DG‐D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory. © 2015 Wiley Periodicals, Inc.     

Early‐life‐stress affects the homeostasis of glutamatergic synapses

Early‐life stress induces several neuropsychological disorders in adulthood, including depression. Such disorders may be induced by functional alteration of the glutamatergic system. However, their underlying mechanisms have not yet been fully clarified. Furthermore, the involvement of glucocorticoids, which are representative stress hormones, has not yet been fully clarified. In this study, we used maternal deprivation (MD) mice as an early‐life‐stress model, and studied the changes in the glutamatergic system in adulthood. The glutamate concentration and neuronal activity in the somatosensory cortex (SSC) increased under basal conditions in MD mice. Stressful physical stimulation (SPS) increased the concentration of corticosterone, but not of glutamate, in the control mouse SSC. On the other hand, in the MD mice, although the basal concentration of corticosterone in the SSC increased, no SPS‐induced increase was observed. In contrast, the concentration of glutamate increased greatly during SPS. It was significantly high for 30 min after stimulation. The expression level of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid/N‐methyl‐d ‐aspartate receptors in the MD mice was also changed compared with that in the control mice after stimulation. These findings indicate that early‐life stress disrupts the homeostasis of glutamatergic synapses.     

Enhancement of some 5-HT-dependent behavioural responses following repeated immobilization in rats

Responses to drugs affecting 5-hydroxytryptamine (5-HT) and dopaminergic (DA) systems have been examined in rats after repeated immobilization. Groups of rats were immobilized for 2 h per day for up to 7 days. Twenty-four hours later their behavioural responses to various drugs were tested. Rats immobilized for 7 days showed decreased sniffing and increased grooming and body shakes. When given amphetamine (3 mg/kg, i.p.) the intensity of classical dopamine-dependent behaviours was similar to that of non-immobilized controls. Some responses to the 5-HT releaser p-chloroamphetamine (PCA) (4 and 10 mg/kg, i.p.) and the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MEODMT) (5 mg/kg, i.p.) (forepaw treading and tremor) were enhanced after 7 days immobilization. Backward walking and body shakes induced by PCA were also enhanced after 7 days immobilization. Concentrations of 5-HT, DA and their metabolites in striatum, cortex, hippocampus, hypothalamus and midbrain of non-drug-treated control and immobilized groups were comparable. Brain PCA concentrations 30 min after injection were also comparable. The above biochemical and behavioural data suggest that repeated immobilization increases some 5-HT postsynaptic functions. These results are discussed in relation to non-drug-provoked behavioural abnormalities occurring 24 h after the first immobilization but no longer evident after 7 periods of immobilization.     

Cross‐sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens

Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre‐exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione microinjection into the core prevented both the behavioral cross‐sensitization and the augmented increase in cocaine‐induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre‐stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long‐term expression of restraint stress‐induced behavioral cross‐sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long‐term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross‐sensitization to cocaine.     

Serotonin (5‐HT) regulates neurite outgrowth through 5‐HT1A and 5‐HT7 receptors in cultured hippocampal neurons

Serotonin (5‐HT) production and expression of 5‐HT receptors (5‐HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5‐HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5‐HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G‐protein‐coupled 5‐HT_1AR and 5‐HT₇R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5‐HT promotes neurite outgrowth through 5‐HT_1AR and 5‐HT₇R. The involvement of 5‐HT_1AR and 5‐HT₇R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5‐HT and specific antagonists for 5‐HT_1AR and 5‐HT₇R (WAY‐100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5‐HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT₇R was blocked, the addition of 5‐HT increased the number of primary neurites, suggesting that 5HT₇R could inhibit neuritogenesis. In contrast, 5‐HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY‐100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5‐HT_1AR and 5‐HT₇R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth. © 2014 Wiley Periodicals, Inc.     

Pituitary-adrenal response to acute and repeated mild restraint, forced swim and change in environment stress in arginine vasopressin receptor 1b knockout mice

Arginine vasopressin and corticotrophin-releasing hormone synthesised and released from the hypothalamic paraventricular nucleus are the prime mediators of the hypothalamic-pituitary-adrenal (HPA) axis response to stress. These neurohormones act synergistically to stimulate adrenocorticotophin (ACTH) secretion from the anterior pituitary, culminating in an increase in circulating glucocorticoids. Arginine vasopressin mediates this action at the arginine vasopressin 1b receptor (Avpr1b) located on pituitary corticotrophs. Arginine vasopressin is regarded as a minor ACTH secretagogue in rodents but evidence suggests that it has a role in mediating the neuroendocrine response to some acute and chronic stressors. To investigate the role of the Avpr1b in the HPA axis response to an acute and chronic (repeated) stress, we measured the plasma ACTH and corticosterone concentrations in three stress paradigms in both Avpr1b knockout and wild-type mice. Single acute exposure to restraint, forced swim and change in environment stressors elevated both plasma ACTH and corticosterone concentrations in wild-type animals. Conversely, the ACTH response to the acute stressors was significantly attenuated in Avpr1b knockout mice compared to their wild-type counterparts. Plasma corticosterone concentrations were reduced in Avpr1b knockout mice in response to change in environment but not to mild restraint or forced swim stress. Irrespective of genotype, there was no difference in the plasma ACTH or corticosterone concentrations in response to acute and repeated stressors. The data show that a functional Avpr1b is required for an intact pituitary ACTH response to the acute and chronic stressors used in this study. Furthermore, the normal corticosterone response to repeated exposure to change in environment stress also requires the Avpr1b to drive HPA axis responsiveness.     

Oestradiol Alters Central 5‐HT1A Receptor Binding Potential Differences Related to Psychosocial Stress but not Differences Related to 5‐HTTLPR Genotype in Female Rhesus Monkeys

Social subordination in female macaques represents a well‐described model of chronic psychosocial stress. Additionally, a length polymorphism (5‐HTTLPR) in the regulatory region of the serotonin (5‐HT) transporter (5‐HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5‐HTTLPR polymorphism. The present study determined the effects of social status and the 5‐HTTLPR genotype on 5‐HT1A receptor binding potential (5‐HT1A BP_ND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β‐oestradiol (E₂) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p‐[¹⁸F]MPPF was performed to determine the levels of 5‐HT1A BP_ND under a non‐E₂ and a 3‐week E₂ treatment condition. The short variant (s‐variant) 5‐HTTLPR genotype produced a significant reduction in 5‐HT1A BP_ND in the mPFC regardless of social status, and subordinate s‐variant females showed a reduction in 5‐HT1A BP_ND within the ACC. Both these effects of 5‐HTTLPR were unaffected by E₂. Additionally, E₂ reduced 5‐HT1A BP_ND in the dorsal raphe of all females irrespective of psychosocial stress or 5‐HTTLPR genotype. Hippocampal 5‐HT1A BP_ND was attenuated in subordinate females regardless of 5‐HTTLPR genotype during the non‐E₂ condition, an effect that was normalised with E₂. Similarly, 5‐HT1A BP_ND in the hypothalamus was significantly lower in subordinate females regardless of 5‐HTTLPR genotype, an effect reversed with E₂. Taken together, the data indicate that the effect of E₂ on modulation of central 5HT1A BP_ND may only occur in brain regions that show no 5‐HTTLPR genotype‐linked control of 5‐HT1A binding.     

Methamphetamine induces striatal neurokinin‐1 receptor endocytosis primarily in somatostatin/NPY/NOS interneurons and the role of dopamine receptors in mice

Methamphetamine (METH) is a psychostimulant that induces long‐term deficits of dopamine terminal markers and apoptotic cell death in the striatum. Our laboratory demonstrated that pharmacological blockade of the neurokinin‐1 receptor attenuated the METH‐induced damage to the striatal dopamine terminals and the apoptotic cell death of some striatal neurons. Here, we used histological methods to assess the effect of METH on neurokinin‐1 receptor trafficking in the striatum as an indirect index of signaling by the neuropeptide substance P (natural ligand for this receptor). Male mice received a single injection of METH (30 mg/kg, i.p.) and were sacrificed 30 min later. Immunohistofluorescence confocal microscopy confirmed that the neurokinin‐1 receptor is located on cholinergic and somatostatin interneurons of the striatum. METH induced the trafficking of the neurokinin‐1 receptor from the membrane into cytoplasmic endosomes primarily in the somatostatin/NPY/NOS interneurons, and this phenomenon was attenuated by antagonists of the dopamine D1 (SCH‐23390), D2 (raclopride), or neurokinin‐1 (WIN‐51,708) receptors. These data demonstrate that METH induces the trafficking of the striatal neurokinin‐1 receptors principally in the somatostatin/NPY/NOS interneurons and that this phenomenon is dependent on the activity of dopamine D1 and D2 receptors. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Pharmacological characterization of 2‐methoxy‐N‐propylnorapomorphine's interactions with D2 and D3 dopamine receptors

Dopaminergic signaling pathways have been extensively investigated using PET imaging, primarily with antagonist radioligands of D₂ and D₃ dopamine receptors (DARs). Recently, agonist radioligands of D₂/D₃ DARs have begun to be developed and employed. One such agonist is (R)‐2‐¹¹CH₃O‐N‐n‐propylnorapomorphine (MNPA). Here, we perform a pharmacological characterization of MNPA using recombinant D₂ and D₃ DARs expressed in HEK293 cells. MNPA was found to robustly inhibit forskolin‐stimulated cAMP accumulation to the same extent as dopamine in D₂ or D₃ DAR‐transfected cells, indicating that it is a full agonist at both receptors. MNPA is ～50‐fold more potent than dopamine at the D₂ DAR, but equally potent as dopamine at the D₃ DAR. MNPA competition binding curves in membrane preparations expressing D₂ DARs revealed two binding states of high and low‐affinity. In the presence of GTP, only one binding state of low affinity was observed. Direct saturation binding assays using [³H]MNPA revealed similar results as with the competition experiments leading to the conclusion that MNPA binds to the D₂ DAR in an agonist‐specific fashion. In contrast to membrane preparations, using intact cell binding assays, only one site of low affinity was observed for MNPA and other agonists binding to the D₂ DAR. MNPA was also found to induce D₂ DAR internalization to an even greater extent than dopamine as determined using both cell surface receptor binding assays and confocal fluorescence microscopy. Taken together, our data indicate that the PET tracer, MNPA, is a full and potent agonist at both D₂ and D₃ receptors. Synapse 63:462–475, 2009. © 2009 Wiley‐Liss, Inc.     

Regulation of dynamin 2 and G protein‐coupled receptor kinase 2 in rat nucleus accumbens during acute and repeated cocaine administration

Exposure to cocaine causes many neuroadaptations including alterations in several neurotransmitter receptors and transporters. This study investigated potential mechanisms of cocaine‐induced receptor and transporter regulation by measuring levels of two proteins involved in receptor and transporter trafficking, dynamin 2 and G protein‐coupled receptor kinase 2 (GRK2). Male Fischer rats received three daily injections of cocaine, 15 mg/kg, in a binge‐pattern (at 1 h intervals) for 1, 3, or 14 days. Brain regions of interest were collected 30 min after the last injection and proteins measured by Western blot. Acute binge‐pattern cocaine administration produced a significant increase in both dynamin 2‐ and GRK2‐immunoreactivity (227% and 358% of control) in the nucleus accumbens and GKR2 (150% of control) in the caudate putamen. Tolerance to this effect occurred, as levels of both proteins returned to baseline after 3 days of cocaine. In contrast, dynamin 2 and GRK2 were significantly decreased in the nucleus accumbens after chronic cocaine. This pattern of regulation was unique to the nucleus accumbens and not seen in the frontal cortex or substantia nigra. Pretreatment with either the dopamine (DA) D1 receptor antagonist SCH 23390 or D2 receptor antagonist eticlopride prior to acute cocaine blocked the upregulation of dynamin 2 and GRK2 in the nucleus accumbens. However, only eticlopride was effective in attenuating the decrease in these proteins following chronic cocaine exposure. These results demonstrate that two proteins involved in receptor and transporter trafficking are selectively regulated in the nucleus accumbens following acute versus chronic cocaine exposure, and dopamine receptor activation is required for this regulation. Synapse 63:863–870, 2009. © 2009 Wiley‐Liss, Inc.     

Effects of serotonin 5-HT1A agonist in advanced Parkinson's disease.

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskinesias and prolonged its antiparkinsonian response (P < or = 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD.     

Conversion of psychological stress into cellular stress response: Roles of the sigma‐1 receptor in the process

Psychiatrists empirically recognize that excessive or chronic psychological stress can result in long‐lasting impairments of brain functions that partly involve neuronal cell damage. Recent studies begin to elucidate the molecular pathways activated/inhibited by psychological stress. Activation of the hypothalamic–pituitary–adrenal axis under psychological stress causes inflammatory oxidative stresses in the brain, in part due to elevation of cytokines. Psychological stress or neuropathological conditions (e.g., accumulation of β‐amyloids) trigger ‘cellular stress responses’, which promote upregulation of molecular chaperones to protect macromolecules from degradation. The unfolded protein response, the endoplasmic reticulum (ER)‐specific cellular stress response, has been recently implicated in the pathophysiology of neuropsychiatric disorders and the pharmacology of certain clinically used drugs. The sigma‐1 receptor is an ER protein whose ligands are shown to exert antidepressant‐like and neuroprotective actions. Recent studies found that the sigma‐1 receptor is a novel ligand‐operated ER chaperone that regulates bioenergetics, free radical generation, oxidative stress, unfolded protein response and cytokine signaling. The sigma‐1 receptor also regulates morphogenesis of neuronal cells, such as neurite outgrowth, synaptogenesis, and myelination, which can be perturbed by cellular stress. The sigma‐1 receptor may thus contribute to a cellular defense system that protects nervous systems against chronic psychological stress. Findings from sigma receptor research imply that not only cell surface monoamine effectors but also intracellular molecules, especially those at the ER, may provide novel therapeutic targets for future drug developments.