Association between striatal accumulation of FosB/ΔFosB and long-term psychomotor sensitization to amphetamine in mice depends on the genetic background

Previous results demonstrated association between increased FosB/ΔFosB immunostaining in the ventromedial striatum and behavioral sensitization to amphetamine promoted by repeated stress or by repeated pairings of the psychostimulant and the testing cage in mice of the C57BL/6J strain. The present experiments tested this association in an additional protocol, its stability following the end of the sensitizing procedure and its generalization to mice from a different inbred strain. Eleven days after repeated administration of amphetamine within their home-cages, mice of the C57BL/6J strain expressed sensitization to the psychomotor effects of the psychostimulant when tested in a novel cage. At this time-point the same mice showed increased FosB/ΔFosB immunostaining in the ventromedial striatum. Instead, mice of the genetically unrelated DBA/2J inbred strain expressing robust sensitization in the same protocol did not show changes in FosB/ΔFosB immunostaining throughout the striatal complex. Lack of effects in FosB/ΔFosB immunostaining was also observed in DBA/2J mice behaviorally sensitized by repeated pairings of amphetamine with the test cage. These results demonstrate that mice, depending on the genetic background, can develop robust and long-lasting behavioral sensitization to amphetamine in the absence of striatal ΔFosB accumulation.     

Differential time course of effects of κ-opioid agonist treatment on dynorphin a levels and κ-opioid receptor density

The effects of κ-opioid agonist treatment on κ-opioid receptor density and on dynorphin A levels in the rat brain were studied. Rats were treated with the selective κ-opioid agonist U-69593 or vehicle for 5 d. Dynorphin A levels and κ-opioid receptor binding were measured on day 8 (3 d after the last injection) or 22 (17 d after the last injection). On day 8, κ-opioid receptor density was increased in the hypothalamus of rats treated with U-69593; there were no changes in the frontal cortex or caudate putamen. In contrast, there was an increase in dynorphin A levels in the frontal cortex and no changes in hypothalamus and caudate putamen in response to U-69593. On day 22, B _max was decreased in frontal cortex and caudate putamen of U-69593-treated rats, whereas dynorphin A levels were increased in the caudate putamen and in the frontal cortex. These findings suggest that κ-opioid receptor agonist treatment has long-term, continually changing effects on the κ-opioid system.     

Involvement of p38/NF-κB signaling pathway in the nucleus accumbens in the rewarding effects of morphine in rats

The nucleus accumbens (NAc) is one of the important brain regions for the acquisition of morphine-induced conditioned place preference (CPP), which is a valuable paradigm for detecting the rewarding effects of drugs. However, the underlying molecular mechanisms remain largely unknown. In the present study, we investigated the role of p38 and nuclear factor kappa B (NF-κB) in the NAc in the acquisition of morphine-induced CPP. The results showed that repeated morphine treatment induced the acquisition of CPP and increased the phosphorylation of p38, IκB-α and NF-κB p65 in the NAc. Microinjection of p38 inhibitor SB203580 into the NAc prior to the application of morphine prevented the acquisition of CPP and inhibited the activation of p38, IκB-α and NF-κB p65. Furthermore, pre-infusion of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, into the NAc blocked the CPP but also the phosphorylation of NF-κB p65 induced by morphine. It is concluded that the activation of p38/NF-κB p65 signaling pathway in the NAc plays a critical role in the morphine CPP.     

The role of peroxisome proliferator-activated receptor γ, and effects of its agonist, rosiglitazone, on transient cerebral ischemic damage

Peroxisome proliferator-activated receptor γ (PPARγ) is expressed in neurons and glia, and its synthetic agonist, rosiglitazone (RSG), regulates inflammatory process and has neuroprotective effects against neurological disorders. In the present study, we examined the role of PPARγ in the hippocampal CA1 region (CA1) after transient cerebral ischemia and the neuroprotective effects of RSG on ischemic damage. RSG attenuated neuronal damage in the ischemic CA1, not showing perfect neuroprotection: the RSG appeared to delay neuronal death after ischemia/reperfusion (I/R). PPARγ immunoreactivity and protein levels were increased after I/R, and most of PPARγ-immunoreactive cells colocalized with microglia, not astrocytes. In addition, RSG attenuated glial activation and increased IL-4 and IL-13 levels in the ischemic CA1. These results indicate that PPARγ increases and expresses in microglia after I/R, and that RSG delays neuronal damage by interfering with glial activations and increases anti-inflammatory cytokines in response to ischemic damage.     

Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants. The most toxic PCBs are the non-ortho-substituted (“dioxin-like”) congeners that act through the aryl hydrocarbon receptor (AHR) pathway. In humans, perinatal exposure to dioxin-like PCBs is associated with neurodevelopmental toxicity in children. Yet, the full potential for later-life neurobehavioral effects that result from early-life low level exposure to dioxin-like PCBs is not well understood. The objective of this study was to determine the effects of developmental exposure to low levels of dioxin-like PCBs on early- and later-life behavioral phenotypes using zebrafish as a model system. We exposed zebrafish embryos to either vehicle (DMSO) or low concentrations of PCB126 (0.3, 0.6, 1.2 nM) for 20 h (4–24 h post fertilization), and then reared them to adulthood in clean water. Locomotor activity was tested at two larval stages (7 and 14 days post fertilization). Adult fish were tested for anxiety-related behavior using the novel tank and shoaling assays. Adult behavioral assays were repeated several times on the same group of fish and effects on intra- and inter-trial habituation were determined. While there was no effect of PCB126 on larval locomotor activity in response to changes in light conditions, developmental exposure to PCB126 resulted in impaired short- and long-term habituation to a novel environment in adult zebrafish. Cyp1a induction was measured as an indicator for AHR activation. Despite high induction at early stages, cyp1a expression was not induced in the brains of developmentally exposed adult fish that showed altered behavior, suggesting that AHR was not activated at this stage. Our results demonstrate the effectiveness of the zebrafish model in detecting subtle and delayed behavioral effects resulting from developmental exposure to an environmental contaminant.     

An examination of the effects of subthalamic nucleus inhibition or μ-opioid receptor stimulation on food-directed motivation in the non-deprived rat

The subthalamic nucleus (STN) serves important functions in regulating movement, cognition, and motivation and is connected with cortical and basal ganglia circuits that process reward and reinforcement. In order to further examine the role of the STN on motivation toward food in non-deprived rats, these experiments studied the effects of pharmacological inhibition or μ-opioid receptor stimulation of the STN on the 2-h intake of a sweetened fat diet, the amount of work exerted to earn sucrose on a progressive ratio 2 (PR-2) schedule of reinforcement, and performance on a differential reinforcement of low-rate responding (DRL) schedule for sucrose reward. Separate behavioral groups (N=6-9) were tested following bilateral inhibition of the STN with the GABA(A) receptor agonist muscimol (at 0-5 ng/0.5 μl/side) or following μ-opioid receptor stimulation with the agonist D-Ala2, N-MePhe?, Gly-ol-enkephalin (DAMGO; at 0, 0.025 or 0.25 μg/0.5 μl/side). Although STN inhibition increased ambulatory behavior during 2-h feeding sessions, it did not significantly alter intake of the sweetened fat diet. STN inhibition also did not affect the breakpoint for sucrose pellets during a 1-h PR-2 reinforcement schedule or impact the number of reinforcers earned on a 1-h DRL-20s reinforcement schedule in non-deprived rats. In contrast, STN μ-opioid receptor stimulation significantly increased feeding on the palatable diet and reduced the reinforcers earned on a DRL-20 schedule, although DAMGO microinfusions had no effect on PR-2 performance. These data suggest that STN inhibition does not enhance incentive motivation for food in the absence of food restriction and that STN μ-opioid receptors play an important and unique role in motivational processes.     

AQW051, a novel and selective nicotinic acetylcholine receptor α7 partial agonist,reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys

Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (l-Dopa)-induced dyskinesias (LID). This study investigated the novel selective α7 nAChR partial agonist (R)-3-(6-ρ-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo(2.2.2)octane (AQW051) for its antidyskinetic activity in l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus monkeys. Six MPTP monkeys were repeatedly treated with l-Dopa to develop reproducible dyskinesias. AQW051 (2, 8, and 15 mg/kg) administered 1 h before l-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the l-Dopa antiparkinsonian response, by 30 min at the highest AQW051 dose (15 mg/kg). Dyskinesias were significantly reduced for the total period of l-Dopa effect following treatment with 15 mg/kg; achieving a reduction of 60% in median values. Significant reductions in 1 h peak dyskinesia scores and maximal dyskinesias were also observed with AQW051 (15 mg/kg). To understand the exposure–effect relationship and guide dose selection in clinical trials, plasma concentration-time data for the 15 mg/kg AQW051 dose were collected from three of the MPTP monkeys in a separate pharmacokinetic experiment. No abnormal behavioral or physiological effects were reported following AQW051 treatment. Our results show that AQW051 at a high dose can reduce LID without compromising the benefits of l-Dopa and extend the duration of the l-Dopa antiparkinsonian response in MPTP monkeys. This supports the clinical testing of α7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of l-Dopa.     

Blockade of the NMDA and AMPA/kainate receptors in the dorsal raphe nucleus prevents the 5-HT₃ receptor agonist m-chlorophenylbiguanide-induced suppression of REM sleep in the rat

The effects of the selective 5-HT₃ receptor agonist m-chlorophenylbiguanide (m-CPBG), and of the NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate)/kainate antagonists AP-5 [(±)-2-amino-5-phosphono-pentanoic acid] and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), respectively, were studied in adult male Wistar rats implanted for chronic sleep recordings. The compounds were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of m-CPBG (2 and 4 mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Local infusion of AP-5 (0.5-1 mM) and CNQX (2 mM) significantly increased slow wave sleep (SWS). Pretreatment with AP-5 (0.5 mM) or CNQX (0.5 mM) antagonized the m-CPBG-induced suppression of REMS. It is proposed that the reduction of REMS after microinjection of m-CPBG into de DRN is related to the activation of glutamatergic interneurons that express the 5-HT₃ receptor and make synaptic contacts with serotonergic cells. The resultant increase of serotonin release at postsynaptic sites involved in the induction of REMS would provoke the suppression of the behavioral state. Our findings provide, in addition, new details concerning the pharmacology of DRN serotonergic neurons in the rat that may become relevant to the development of drugs for enhancing cortical and subcortical serotonergic neurotransmission.     

Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats

[3H]CUMI-101 is a 5-HT(1A) partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [3H]CUMI-101 ex vivo in awake rats and determine if [3H]CUMI-101 can measure changes in synaptic levels of serotonin after different challenge paradigms. [3H]CUMI-101 shows good uptake and good specific binding ratio (SBR) in frontal cortex 5.18 and in hippocampus 3.18. Binding was inhibited in a one-binding-site fashion by WAY100635 and unlabeled CUMI-101. The ex vivo B(max) of [3H]CUMI-101 in frontal cortex (98.7 fmol/mg) and hippocampus (131 fmol/kg) agree with the ex vivo B(max) of [3H]MPPF in frontal cortex (147.1 fmol/mg) and hippocampus (72.1 fmol/mg) and with in vitro values reported with 8-OH-DPAT. Challenges with citalopram, a selective serotonin reuptake inhibitor, fenfluramine, a serotonin releaser, and 4-chloro-DL-phenylalanine, a serotonin synthesis inhibitor, did not show any effect on the standardized uptake values (SUVs) in any region. Citalopram did alter SBR, but this was due to changes in cerebellar SUVs. Our results indicate that [3H]CUMI-101 is a good radioligand for imaging 5-HT(1A) high-density regions in rats; however, the results from pharmacological challenges remain inconclusive.     

The central versus peripheral antinociceptive effects of μ-opioid receptor agonists in the new model of rat visceral pain

This study describes the antinociceptive effects of μ-opioid agonists, d-Ala(2),N-Me-Phe(4),Gly(5)-ol-enkephalin (DAMGO) and morphine in a model of rat visceral pain in which nociceptive responses were triggered by 2% acetic acid intraperitoneal (i.p.) injections. DAMGO and morphine were administered i.p., to the same site where acetic acid was delivered or intracerebroventricularly (i.c.v.). The antinociceptive actions of i.p. versus i.c.v. administered DAMGO or morphine were evaluated in the late phase of permanent visceral nociceptive responses. Both compounds inhibited the nociceptive responses in a dose-dependent manner and exhibited more potent agonist activity after i.c.v. than i.p. administration. DAMGO and morphine showed comparable ED(50) values after i.p. injections. However, DAMGO was much stronger than morphine after central administration. Co-administration of the peripherally restricted opioid antagonist, naloxone methiodide (NAL-M), significantly attenuated the antinociceptive effects of i.p. DAMGO or morphine. On the other hand, i.c.v. injections of NAL-M partially antagonized the antinociceptive effect of i.p. morphine and failed to affect the antinociceptive action of i.p. DAMGO indicating the partial and pure peripheral antinociceptive effects of morphine and DAMGO, respectively. These results suggest the role of either central or peripheral μ-opioid receptors (MOR) in mediating antinociceptive effects of i.p. μ-opioid agonists in the rat late permanent visceral pain model which closely resembles the clinical situation.     

Neuron-specific effects of interleukin-1β are mediated by a novel isoform of the IL-1 receptor accessory protein

In the CNS, interleukin-1β (IL-1β) is synthesized and released during injury, infection, and disease, mediating inflammatory responses. However, IL-1β is also present in the brain under physiological conditions, and can influence hippocampal neuronal function. Several cell-specific IL-1-mediated signaling pathways and functions have been identified in neurons and astrocytes, but their mechanisms have not been fully defined. In astrocytes, IL-1β induced both the p38 MAPK and NF-κB (nuclear factor κB) pathways regulating inflammatory responses, however in hippocampal neurons IL-1β activated p38 but not NF-κB. Additionally, IL-1β induced Src phosphorylation at 0.01 ng/ml in hippocampal neurons, a dose 1000-fold lower than that used to stimulate inflammatory responses. IL-1 signaling requires the type 1 IL-1 receptor and the IL-1 receptor accessory protein (IL-1RAcP) as a receptor partner. We previously reported a novel isoform of the IL-1RAcP, IL-1RAcPb, found exclusively in CNS neurons. In this study, we demonstrate that AcPb specifically mediates IL-1β activation of p-Src and potentiation of NMDA-induced calcium influx in mouse hippocampal neurons in a dose-dependent manner. Mice lacking the AcPb, but retaining the AcP, isoform were deficient in IL-1β regulation of p-Src in neurons. AcPb also played a modulatory role in the activation of p38 MAPK, but had no effect on NF-κB signaling. The restricted expression of AcPb in CNS neurons, therefore, governs specific neuronal signaling and functional responses to IL-1β.     

Molecular effects of interleukin-1β on dorsal root ganglion neurons: prevention of ligand-induced internalization of the bradykinin 2 receptor and downregulation of G protein-coupled receptor kinase 2

In dorsal root ganglion sections numerous small-to medium-sized neurons were found to exhibit extensive colocalization of the bradykinin receptor 2, the interleukin-1 receptor 1 and G protein-coupled receptor kinase 2. Application of bradykinin to cultured DRG neurons caused substantial internalization of the bradykinin 2 receptor which significantly reduced the responsiveness of DRG neurons to a second application of bradykinin. Such an internalization was not observed in DRG neurons which were exposed to long-term pretreatment with interleukin-1β. The long-term incubation with interleukin-1β on its own did neither change the proportion of neurons which expressed the bradykinin 2 receptor in the cytoplasma nor the proportion of neurons expressing the bradykinin 2 receptor in the membrane but it reduced the proportion of neurons expressing G protein-coupled receptor kinase 2, an enzyme which facilitates the internalization of G protein-coupled receptors. These results show that interleukin-1β maintains the responsiveness of DRG neurons to bradykinin in the long-term range, and they suggest that the downregulation of G protein-coupled receptor kinase 2 could be a cellular mechanism involved in this interleukin-1β effect.     

In vivo effects of pardoprunox (SLV308), a partial D₂/D₃ receptor and 5-HT1A receptor agonist, on rat dopamine and serotonin neuronal activity

The nonergot ligand pardoprunox (SLV308) is a dopamine (DA) D₂/D₃ and serotonin (5‐HT)_1A receptor agonist and a new candidate for the treatment of Parkinson's disease. We used in vivo electrophysiological paradigm in the rat to assess the effects of pardoprunox on DA neuronal activity in ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) as well as on 5‐HT neuronal activity in dorsal raphe nucleus (DRN). In the VTA, pardoprunox (2–20 μg kg^?1, i.v.) decreased partially the firing activity of DA neurons. Interestingly, the bursting activity of VTA DA neurons was completely suppressed. This compound both reversed and prevented the inhibition of firing rate induced by the full D₂‐like receptor agonist apomorphine, confirming its partial D₂‐like receptor agonistic property. Surprisingly in the SNc, pardoprunox (10 μg kg^?1, i.v.) either partially or fully suppressed the firing activity in two separate populations of DA neurons. Finally, in the DRN, pardoprunox (5–40 μg kg^?1, i.v.) completely suppressed the firing activity of 5‐HT neurons. Moreover, the selective 5‐HT_1A receptor antagonist WAY‐100,635 prevented and reversed the effects of pardoprunox. The present study shows that pardoprunox acts in the VTA as a potent partial D₂‐like receptor agonist reducing preferentially the burst activity linked to the phasic activity of DA neurons. Unexpectedly in the SNc, pardoprunox behaves either as apartial or a full D₂‐like receptor agonist. Finally in the DRN, pardoprunox is a potent full 5‐HT_1A receptor agonist. Hence, this in vivo study suggests that pardoprunox represents a promising approach for the treatment of Parkinson's disease. Synapse, 2011. © 2011 Wiley‐Liss, Inc.     

Modifications of local cerebral glucose utilization in thalamic structures following injection of a dopaminergic agonist in the nucleus accumbens--involvement in antiepileptic effects?

Dopaminergic transmission in the nucleus accumbens (NAcc) is implicated in different aspects of reward and motivational mechanisms. More recently, it has been suggested that this nucleus could also be involved in the modulation of generalized epileptic seizures. In particular, microinjection of dopaminergic agonists in the NAcc suppresses the occurrence of epileptic seizures in a model of absence seizures, the GAERS (generalized absence epileptic rats from Strasbourg). The aim of this study was to identify the structures involved in this effect. Local cerebral metabolic rates for glucose utilization (LCMRglc) were measured in different parts of the basal ganglia and output structures after apomorphine injection in the NAcc in GAERS and in the inbred non-epileptic rats (NE), concomitantly with seizure suppression. Apomorphine injection in the NAcc induced a significant increase of glucose intake in the anteromedial, mediodorsal and ventrolateral nuclei of the thalamus in NE rats, while no significant changes were observed in the basal ganglia structures (globus pallidus, subthalamic nucleus, substantia nigra). Furthermore, microinjections of muscimol (100 and 200 pmol/side) in the mediodorsal nucleus of the thalamus in GAERS rats suppressed seizures. These results suggest that the mediodorsal nucleus of the thalamus could be involved in absence seizures modulation. Along with data from the literature, our data suggest that this nucleus could participate in the control of the basal ganglia over generalized epileptic seizures.     

The role of melatonin and melatonin receptor agonist in the prevention of sleep disturbances and delirium in intensive care unit – a clinical review

AimThe intensive care unit (ICU) environment contributes to the development of sleep disturbances. Sleep disturbances, sleep fragmentation, and multiple awakening episodes lead to the circadian rhythm disorder, which increases the risk of delirium. Melatonin and melatonin receptor agonist is widely used agent in the therapy of sleep disturbances. However, there is also some for its efficacy in ICU delirium. Enteral melatonin and ramelteon supplementation eliminates (partially) the delirium inducing factors.MethodsPubMed/MEDLINE, OVID, Embase, Cochrane Library, and Web of Science databases were searched using adequate key words. We reviewed the literature on the role of melatonin and ramelteon in the prevention of sleep disturbances and delirium in intensive care units and analysed the methods of melatonin therapy in an ICU setting. Review followed the PRISMA statement. A review written protocol was not drafted.ResultsOriginally 380 studies were searched in five scientific databases. After rejecting the duplicate results, 125 results were obtained. Finally, 10 scientific studies were included in the review. In selected articles, the leading topics analysed were the role of melatonin and ramelteon in the prevention of delirium and sleep disorders. In addition, the noted effect of therapy with these agents on reducing the ventilation time of mechanical time and the demand for psychoactive substances in the ICU environment.ConclusionReduction of either the incidence or the severity of delirium course is possible by eliminating its risk factors. Risk factors are directly related to sleep disorders. To reduce the problem, therefore, a holistic approach to the source is necessary. The efficacy of melatonin therapy in an ICU setting requires confirmation in studies including a greater number of participants as the impact of melatonin on these factors is yet to be fully elucidated. However, the prognosis is predictive because this concept provides patients with a minimally invasive and natural form of therapy.     

Age-related effects of estrogen on the expression of estrogen receptor （ER） α and βmRNA in the ovariectomized （OVX） monkey hypothalamus

In the present study, we reported distribution of ERα and ER β mRNAs in the hypothalamus of young and old ovariectomized （OVX） rhesus macaques. The ERα were detected in all six major vestiblular nuclei which included arcuate nucleus （ARC） , paraventricularis nucleus （PVN） , periventricular nucleus （PeriV） , supraoptic nucleus （SON）, medial prioptic nucleus （MPN） and lateral hypotbalamus area （LHA）. However, the ERβ mRNA can also detected in those nuclei excerpt SON, but the signals of ERβ mRNA were weaker than those of ERα mRNA. We observed that the degree of expression of ERs mRNA were different in most nucleus of old and young monkeys. The ERα mRNAs were highly expressed in ARC and SON in young monkeys compared with old monkeys. Moderate amount of ERα mRNAs hybridization signals and weak signals were observed in LHA, and MPN both in young and old monkeys. In contrast, only lower level of ERα hybridization signal were observed in PVN and PeriV in young monkeys, and the signals of ERα were very low in those nucleus of old monkeys. In general, the expression of ERβ mRNA were weaker than that of ERα mRNA in above nucleus excerpt LHA. The relatively higher density of ERβ hybridization signals have been observed in the LHA in young monkey compared with old monkeys. Low amount of. ERβ mRNA hybridization signals were observed in the ARC, PVN and MPN, and no age differences were seen in PVN and MPN of those monkeys. In PeriV, we observed some signals in young monkey and a few signals in old monkeys. It was different from the rodent in which we did not found ERβ hybridization signal in SON. This study showed that both of the two estrogen receptors not only had the same pattern of expression but also had many different patterns of expression. The different expression of ERα and ERβ mRNAs in the young and old monkey brain may imply diverse functions in different regions of the monkey brain.     

Age-related effects of estrogen on the expression of estrogen receptor (ER) α and β mRNA in the ovariectomized (OVX) monkey hypothalamus

In the present study, we reported distribution of ERα and ERβ mRNAs in the hypothalamus of young and old ovariectomized (OVX) rhesus macaques. The ERα were detected in all six major vestiblular nuclei which included arcuate nucleus (ARC) , paraventricularis nucleus (PVN) , periventricular nucleus (PeriV) , supraoptic nucleus (SON) , medial prioptic nucleus (MPN) and lateral hypothalamus area (LHA). However, the ERβ mRNA can also detected in those nuclei excerpt SON, but the signals of ERβ mRNA were weaker than those of ERα mRNA. We observed that the degree of expression of ERs mRNA were different in most nucleus of old and young monkeys. The ERα mRNAs were highly expressed in ARC and SON in young monkeys compared with old monkeys. Moderate amount of ERα mRNAs hybridization signals and weak signals were observed in LHA, and MPN both in young and old monkeys. In contrast, only lower level of ERα hybridization signal were observed in PVN and PeriV in young monkeys, and the signals of ERα were very low in those nucleus of old monkeys. In general, the expression of ERβ mRNA were weaker than that of ERα mRNA in above nucleus excerpt LHA. The relatively higher density of ERβ hybridization signals have been observed in the LHA in young monkey compared with old monkeys. Low amount of ERβ mRNA hybridization signals were observed in the ARC, PVN and MPN, and no age differences were seen in PVN and MPN of those monkeys. In PeriV, we observed some signals in young monkey and a few signals in old monkeys. It was different from the rodent in which we did not found ERβ hybridization signal in SON. This study showed that both of the two estrogen receptors not only had the same pattern of expression but also had many different patterns of expression. The different expression of ERα and ERβ mRNAs in the young and old monkey brain may imply diverse functions in different regions of the monkey brain.