Medial geniculate body and primary auditory cortex differentially contribute to striatal sound representations.

The dorsal striatum has emerged as a key region in sensory-guided, reward-driven decision making. A posterior sub-region of the dorsal striatum, the auditory striatum, receives convergent projections from both auditory thalamus and auditory cortex. How these pathways contribute to auditory striatal activity and function remains largely unknown. Here we show that chemogenetic inhibition of the projections from either the medial geniculate body (MGB) or primary auditory cortex (ACx) to auditory striatum in mice impairs performance in an auditory frequency discrimination task. While recording striatal sound responses, we find that transiently silencing the MGB projection reduced sound responses across a wide-range of frequencies in striatal medium spiny neurons. In contrast, transiently silencing the primary ACx projection diminish sound responses preferentially at the best frequencies in striatal medium spiny neurons. Together, our findings reveal that the MGB projection mainly functions as a gain controller, whereas the primary ACx projection provides tuning information for striatal sound representations.

Escin attenuates behavioral impairments, oxidative stress and inflammation in a chronic MPTP/probenecid mouse model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that results mainly due to the death of dopaminergic neurons in the substantia nigra (SN), and subsequently has an effect on one's motor function and coordination. The current investigation explored the neuroprotective potential of escin, a natural triterpene-saponin on chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) induced mouse model of PD. Administration of MPTP led to the depleted striatal dopamine content, impaired patterns of behavior, enhanced oxidative stress and diminished expression of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2). The expressions of interleukin-6 and -10, glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1 (IBA-1), tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) in SN were also enhanced. Oral treatment of escin significantly attenuated MPTP/p induced dopaminergic markers depletion, physiological abnormalities, oxidative stress and inhibit neuroinflammatory cytokine expressions in SN. The result of our study confirmed that escin mediated its protection against experimental PD through its antioxidant and anti-inflammatory properties.

Neurochemical and behavioral effects elicited by bupropion and diethylpropion in rats.

This study is an attempt to demonstrate whether bupropion (BP) and diethylpropion (DEP) exert their pharmacological actions by similar neurochemical mechanisms in the dorsal striatum. In this regard, the release of dopamine (DA), glutamate (Glu), and GABA, was determined in the rat dorsal striatum after acute (5 min) and chronic (15 consecutive days) treatments, and subsequently correlated with the locomotor activities produced by these drugs. The results from the acute experiments indicate that BP and DEP (40 mg/kg) increase locomotor activity, whereas chronic DEP treatment decreases locomotor activity by unspecific mechanisms. Acute BP treatment produces significant DA and Glu, but not GABA, releases. A lesser extent of DA release and tissue content of DA and its metabolites, and consequently less locomotor activity, was observed after chronic BP treatment. Acute DEP (5mg/kg) was only able to slightly increase DA release and to decrease the tissue levels of DA, but no other markers, with practically nil locomotor activity, whereas chronic DEP produced even less neurotransmitter release. The observed difference between BP and DEP might be based on that although both drugs inhibit the DA and norepinephrine transporters, the BP-induced nicotinic receptor inhibition has yet to be demonstrated for DEP.

Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal.

In this study, we investigated the effects of acute morphine administration, chronic intermittent escalating-dose morphine administration and spontaneous withdrawal from chronic morphine on mRNA levels of mu opioid receptor (MOP-r), and the opioid peptides pro-opiomelanocortin (POMC) and preprodynorphin (ppDyn) in several key brain regions of the rat, associated with drug reward and motivated behaviors: lateral hypothalamus (lat.hyp), nucleus accumbens (NAc) core, amygdala, and caudate-putamen (CPu). There was no effect on MOP-r mRNA levels in these brain regions 30 min after either a single injection of morphine (10 mg/kg, i.p.) or chronic intermittent escalating-dose morphine (from 7.5 mg/kg per day on day 1 up to 120 mg/kg per day on day 10). Activation of the stress-responsive hypothalamic-pituitary-adrenal axis by 12 h withdrawal from chronic morphine was confirmed; both POMC mRNA levels in the anterior pituitary and plasma adrenocorticotropic hormone levels were significantly elevated. Under this withdrawal-related stress condition, there was an increase in MOP-r mRNA levels in the lat.hyp, NAc core, and CPu. Recent studies have demonstrated a novel role for the lat.hyp orexin (or hypocretin) activation in both drug-related positive rewarding, and withdrawal effects. Around 50% of lat.hyp orexin neurons express MOP-r. Therefore, we also examined the levels of lat.hyp orexin mRNA, and found them increased in morphine withdrawal, whereas there was no change in levels of the lat.hyp ppDyn mRNA, a gene coexpressed with the lat.hyp orexin. Our results show that there is an increase in MOP-r gene expression in a region-specific manner during morphine withdrawal, and support the hypothesis that increased lat.hyp orexin activity plays a role in morphine-withdrawal-related behaviors.

Co-localization and functional interaction between adenosine A(2A) and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum.

The anti-Parkinsonian effect of glutamate metabotropic group 5 (mGluR5) and adenosine A(2A) receptor antagonists is believed to result from their ability to postsynaptically control the responsiveness of the indirect pathway that is hyperfunctioning in Parkinson's disease. mGluR5 and A(2A) antagonists are also neuroprotective in brain injury models involving glutamate excitotoxicity. Thus, we hypothesized that the anti-Parkinsonian and neuroprotective effects of A(2A) and mGluR5 receptors might be related to their control of striatal glutamate release that actually triggers the indirect pathway. The A(2A) agonist, CGS21680 (1-30 nM) facilitated glutamate release from striatal nerve terminals up to 57%, an effect prevented by the A(2A) antagonist, SCH58261 (50 nM). The mGluR5 agonist, CHPG (300-600 mum) also facilitated glutamate release up to 29%, an effect prevented by the mGluR5 antagonist, MPEP (10 microm). Both mGluR5 and A(2A) receptors were located in the active zone and 57 +/- 6% of striatal glutamatergic nerve terminals possessed both A(2A) and mGluR5 receptors, suggesting a presynaptic functional interaction. Indeed, submaximal concentrations of CGS21680 (1 nM) and CHPG (100 microm) synergistically facilitated glutamate release and the facilitation of glutamate release by 10 nM CGS21680 was prevented by 10 microm MPEP, whereas facilitation by 300 microm CHPG was prevented by 10 nM SCH58261. These results provide the first direct evidence that A(2A) and mGluR5 receptors are co-located in more than half of the striatal glutamatergic terminals where they facilitate glutamate release in a synergistic manner. This emphasizes the role of the modulation of glutamate release as a likely mechanism of action of these receptors both in striatal neuroprotection and in Parkinson's disease.

Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice.

Nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic (DA) neurons have long been considered as potential therapeutic targets for the treatment of several neuropsychiatric diseases, including nicotine and cocaine addiction or Parkinson's disease. However, DA neurons express mRNAs coding for most, if not all, neuronal nAChR subunits, and the subunit composition of functional nAChRs has been difficult to establish. Immunoprecipitation experiments performed on mouse striatal extracts allowed us to identify three main types of heteromeric nAChRs (alpha4beta2*, alpha6beta2*, and alpha4alpha6beta2*) in DA terminal fields. The functional relevance of these subtypes was then examined by studying nicotine-induced DA release in striatal synaptosomes and recording ACh-elicited currents in DA neurons fromalpha4, alpha6, alpha4alpha6, and beta2 knock-out mice. Our results establish that alpha6beta2* nAChRs are functional and sensitive to alpha-conotoxin MII inhibition. These receptors are mainly located on DA terminals and consistently do not contribute to DA release induced by systemic nicotine administration, as evidenced by in vivo microdialysis. In contrast, (nonalpha6)alpha4beta2* nAChRs represent the majority of functional heteromeric nAChRs on DA neuronal soma. Thus, whereas a combination of alpha6beta2* and alpha4beta2* nAChRs may mediate the endogenous cholinergic modulation of DA release at the terminal level, somato-dendritic (nonalpha6)alpha4beta2* nAChRs most likely contribute to nicotine reinforcement.

Simultaneous determination of the monoamine neurotransmitters and glucose in rat brain by microdialysis sampling coupled with liquid chromatography-dual electrochemical detector.

A new type of chemically modified electrode based ring-disk electrode as the dual electrochemical detector (DECD) for high-performance liquid chromatography (HPLC) to simultaneously determine the monoamine neurotransmitters and glucose is described. The ring electrode was modified with an ion-exchange polymer-overoxidized polypyrrole (OPPy) and the disk electrode was modified with nano Au colloid and glucose oxidase (GOD). The electrochemical behaviors of dopamine (DA) and ascorbic acid (AA) at the OPPy chemically modified electrode (CME) were investigated by differential pulse voltammetry (DPV). It was found that the CME could permeate dopamine cations and repelled the ascorbate anions, which could be used to determine the monoamine neurotransmitters and avoid the interference of AA. The electrochemical behavior of glucose at the Nafion/GOD-Au colloid/GC CME was investigated by amperometry and flow injection analysis (FIA). It was found that the sensitivity of the CME increased apparently in determination of glucose. In order to obtain better separation and current responses of the analytes in HPLC-DECD, several operational parameters have been investigated. Under the optimum conditions, the method showed good stability and reproducibility. The application of this method coupled with microdialysis sampling for in vivo simultaneous determination of monoamine neurotransmitters and glucose in rat brain was satisfactory.

Alteration of cyclic adenosine monophosphate response element binding protein in rat brain after hypoglycemic coma.

In the current study, the temporal and regional changes of the transcription factor cyclic adenosine monophosphate response element binding protein (CREB) were investigated in rat brains subjected to 30 minutes of hypoglycemic coma followed by varied periods of recovery using Western blot and confocal microscopy. The total amount of CREB was not altered in any area examined after coma. The level of the phosphorylated form of CREB decreased during coma but rebounded after recovery. In the relatively resistant areas, such as the inner layers of the neocortex and the inner and outer blades of the dentate gyms (DG), phospho-CREB increased greater than the control level after 30 minutes of recovery and continued to increase up to 3 hours of recovery. In contrast, little or no increase of phospho-CREB was observed during the recovery period in the outer layers of the neocortex and at the tip of the DG, that is, regions that are selectively vulnerable to hypoglycemic insults. The current findings suggest that a neuroprotective signaling pathway may be more activated in the resistant regions than in the vulnerable ones after hypoglycemic coma.

Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication.

Striatal nicotinic acetylcholine receptors with high affinity for nicotinic agonists are involved with the release of a number of neurotransmitters, including dopamine. Previous findings as to whether these receptors are changed in Parkinson's disease and Alzheimer's disease are inconsistent and no previous investigations have focused on these receptors in dementia with Lewy bodies and schizophrenia, which are also associated with disorders of movement. The present autoradiographic study of striatal [3H]nicotine binding in Alzheimer's and Parkinson's diseases, dementia with Lewy bodies and schizophrenia was conducted with particular reference to the potentially confounding variables of tobacco use and neuroleptic medication. [3H]Nicotine binding in both dorsal and ventral caudate and putamen was significantly reduced in Parkinson's disease (43-67%, n=13), Alzheimer's disease (29-37%, n=13) and dementia with Lewy bodies (50-61%, n=20) compared to age-matched controls (n=42). Although tobacco use in the control group was associated with increased [3H]nicotine binding (21-38%), and neuroleptic treatment in dementia with Lewy bodies and Alzheimer's disease was associated with reduced [3H]nicotine binding (up to 29%), differences between neurodegenerative disease groups and controls persisted in subgroups of Alzheimer's disease cases (26-33%, n=6, in the ventral striatum) and dementia with Lewy body cases (30-49%, n=7, in both dorsal and ventral striatum) who had received no neuroleptic medication compared to controls who had not smoked (n=10). In contrast, striatal [3H]nicotine binding in a group of elderly (56-85 years) chronically medicated individuals with schizophrenia (n=6) was elevated compared with the entire control group (48-78%, n=42) and with a subgroup that had smoked (24-49%, n=8). The changes observed in [3H]nicotine binding are likely to reflect the presence of these receptors on multiple sites within the striatum, which may be differentially modulated in the different diseases. Further study is warranted to explore which nicotinic receptor subunits and which neuronal compartments are involved in the changes in [3H]nicotine binding reported, to aid development of potential nicotinic receptor therapy.

Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons.

Despite the importance of dopamine signaling, it remains unknown if the two major subclasses of dopamine receptors exist on the same or distinct populations of neurons. Here we used confocal microscopy to demonstrate that virtually all striatal neurons, both in vitro and in vivo, contained dopamine receptors of both classes. We also provide functional evidence for such colocalization: in essentially all neurons examined, fenoldopam, an agonist of the D1 subclass of receptors, inhibited both the Na+/K+ pump and tetrodotoxin (TTX)-sensitive sodium channels, and quinpirole, an agonist of the D2 subclass of receptors, activated TTX-sensitive sodium channels. Thus D1 and D2 classes of ligands may functionally interact in virtually all dopamine-responsive neurons within the basal ganglia.

Regulation of striatal dopamine receptors by estrogen.

The ability of estrogen to modulate the expression of ventral and dorsal striatal dopamine receptors D(1), D(2,) and D(3) was examined in vivo using semi-quantitative in situ hybridization and ligand binding autoradiography. Two-week treatment with subcutaneous pellets of 17beta-estradiol (25 mg) downregulated D(2) dopamine receptor mRNA in both dorsal and ventral striatum (shell and core regions of nucleus accumbens). No significant changes in D(1) or D(3) mRNA expression were detected. Ligand binding autoradiography did not reveal changes in D(1), D(2,) or D(3) receptor protein expression. We also assessed the ability of 17beta-estradiol to regulate D(2) gene promoter activity in NB41A3 neuroblastoma cells that express this gene endogenously using co-transfections with an estrogen receptor expression vector. While a small fragment of the D(2) promoter could be activated 2.5-fold by estrogen, a larger portion of the D(2) gene was not regulated by this treatment. Estrogens do not appear to have a net effect on striatal dopamine receptor expression. The observed downregulation of D(2) receptor mRNA in the dorsal and ventral striatum in vivo could be secondary to the increased striatal dopamine release induced by estrogen. Synapse 34:222-227, 1999. Published 1999 Wiley-Liss, Inc.

Thyroid hormone coadministration inhibits the estrogen-stimulated elevation of preproenkephalin mRNA in female rat hypothalamic neurons.

Expression of the enkephalin gene in ventromedial hypothalamus (VMH) of the female rat has been correlated with the performance of lordosis behavior. By antisense DNA evidence, it has been drawn into a causal role as well. Here, we explored whether, parallel to earlier molecular and behavioral results, thyroid hormone coadministration could disrupt the estrogenic induction of preproenkephalin (PPE) mRNA. As expected, estradiol benzoate treatment to ovariectomized rats led to a large and significant increase in PPE gene expression in the VMH. This increase was inhibited by coadministration of thyroid hormone. The thyroid hormone interference in PPE gene expression was specific to the VMH, as there were no significant effects in the central nucleus of the amygdala or in the caudate/putamen. These in situ hybridization histochemical results form a direct parallel both to previous transcriptional measurements and to reproductive behavior assays in which thyroid hormones were able to oppose estrogenic facilitation. Previous evidence supports the notion of competitive DNA binding and protein/protein interactions providing mechanisms for nuclear thyroid hormone receptors to affect estrogen receptor function, but other, additional mechanisms cannot be ruled out. To date, both oxytocin and PPE gene expression represent potential hypothalamic systems by which thyroid hormones could interfere with estrogen-stimulated female rat reproductive behavior.

Sexual dimorphism in the response to N-methyl-D-aspartate receptor antagonists and morphine on behavior and c-Fos induction in the rat brain.

It has been suggested that there are sex differences in the neural response to drugs of abuse. Previous studies have shown that, upon administration of morphine, the immediate early gene c-Fos is induced in the striatum, nucleus accumbens and cortex of the rat brain. This induction of c-Fos is reduced by administration of the N-methyl-D-aspartate receptor antagonist dizocilpine maleate. However, in studies using immunocytochemistry, we found that the pattern of this expression differed markedly between the sexes. In male rats treated with morphine (10 mg/kg, s.c.) and killed 2 h later, there was an induction of c-Fos in the dorsomedial caudate-putamen, the nucleus accumbens and in the intralaminar nuclei of the thalamus. Administration of dizocilpine maleate (0.2 mg/kg, i.p.; 30 min before morphine) partially blocked the response in the caudate-putamen, but not in the thalamus. In females, morphine induced c-Fos in the caudate-putamen, but with more inter-animal variability than in males. In the midline intralaminar thalamic nuclei, female rats showed less induction than males. In male rats, dizocilpine maleate alone caused negligible induction of c-Fos, whereas in female rats, it caused a large induction in the rhomboid, reuniens and central medial nuclei of the thalamus, and in the cortex. Whereas dizocilpine maleate partially blocked the morphine-induced c-Fos expression in the caudate-putamen of males, it completely blocked this response in females. With dizocilpine maleate alone, there was little or no effect on behavior in male rats, whereas in female rats, it caused head bobbing, thrashing, hyperactivity and uncoordinated movements. These behavioral sex differences were not seen on treatment of rats with the competitive N-methyl-D-aspartate receptor antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphoheptanoic acid (NPC-17742; 10 mg/kg, i.p.) and this drug did not induce c-Fos expression in either sex. In the caudate-putamen, morphine-induced c-Fos expression was significantly reduced by NPC-17742 (30 min before morphine) in males and completely blocked in females. These results suggest that the responses to both morphine and N-methyl-D-aspartate receptor antagonists differ between the sexes and emphasize that glutamate is involved in morphine-induced immediate early gene expression in the brain. These studies thus have important implications for gender differences in drug addiction.

Distribution, biochemistry and function of striatal adenosine A2A receptors.

It is well known that the nucleoside adenosine exerts a modulatory influence in the central nervous system by activating G protein coupled receptors. Adenosine A2A receptors, the subject of the present review, are predominantly expressed in striatum, the major area of the basal ganglia. Activation of A2A receptors interferes with effects mediated by most of the principal neurotransmitters in striatum. In particular, the inhibitory interactions between adenosine acting on A2A receptors and dopamine acting on D2 receptors have been well examined and there is much evidence that A2A receptors may be a possible target for future development of drugs for treatment of Parkinson's disease, schizophrenia and affective disorders. Our understanding of the role of striatal A2A receptors has increased dramatically over the last few years. New selective antibodies, antagonist radioligands and optimized in situ hybridization protocols have provided detailed information on the distribution of A2A receptors in rodent as well as primate striatum. Studies on the involvement of A2A receptors in the regulation of DARPP-32 and the expression of immediate early genes, such as nerve growth factor-induced clone A and c-fos, have pointed out an important role for these receptors in regulating striatopallidal neurotransmission. Moreover, by using novel selective antagonists for A2A receptors and transgenic mice lacking functional A2A receptors, crucial information on the behavioral role of striatal A2A receptors has been provided, especially concerning their involvement in the stimulatory action of caffeine and the anti-Parkinsonian properties of A2A receptor antagonists. In the present review, current knowledge on the distribution, biochemistry and function of striatal A2A receptors is summarized.

Rapid effects of estrogen or progesterone on the amphetamine-induced increase in striatal dopamine are enhanced by estrogen priming: a microdialysis study.

There are estrous cycle-dependent differences in amphetamine-stimulated behaviors and striatal dopamine (DA) release; intact female rats exhibit a greater behavioral response to amphetamine on estrus than on other days of the cycle. Following ovariectomy amphetamine-induced behavior is attenuated, as is the striatal DA response to amphetamine in vitro. Repeated estrogen treatment in ovariectomized rats reinstates both of these responses to a level comparable to estrous females. In addition, 30 min after a single treatment with a physiological dose of estrogen there is enhanced amphetamine-induced behavior and increased amphetamine-induced striatal DA detected during microdialysis. This experiment was conducted to determine whether the acute effect of estradiol and the effect of repeated exposure to estrogen are functionally related. We report here that prior treatment with estrogen (three daily treatments of 5 microg estradiol benzoate) results in a significant enhancement of the effect of acute estrogen (5 microg estradiol benzoate) or progesterone (500 microg) on amphetamine-induced striatal DA release and stereotyped behaviors. Both the peak response and the duration of the response are greater in estrogen-primed animals treated with estrogen or progesterone 30 min prior to amphetamine, than in all other groups. Either prior treatment with estrogen (last dose 24 h before) or a single acute injection of estrogen result in an enhanced peak response to amphetamine, with no effect on the duration of amphetamine-induced striatal DA release. Treatment with progesterone in animals not primed with estrogen was not different from treatment with oil vehicle. These results demonstrate that there are both acute and long-term effects of estrogen on the striatum that underlie the dynamic changes in stimulated DA release and amphetamine-induced behaviors during the reproductive cycle.

Neurochemical evidence for at least two regional subdivisions within the homing pigeon (Columba livia) caudolateral neostriatum.

The distributions of one neurotransmitter, two neurotransmitter-related substances, and five neuropeptides were examined within the homing pigeon caudolateral neostriatum (NCL). All eight neuroactive substances were found within a tyrosine hydroxylase (TH)-dense region that defines the NCL. Overall regional variation in the relative density of these substances suggested at least two neurochemically distinct portions of NCL. Dorsal NCL contained relatively dense staining for TH, choline acetyltransferase, and substance P, whereas vasoactive intestinal polypeptide was more abundant in ventral portions of NCL. Serotonin and cholecystokinin were found to be densest in intermediate portions of NCL. Somatostatin and leucine-enkephalin were homogeneously distributed throughout NCL. The results suggest that NCL may consist of multiple subdivisions. Investigations into the behavioral importance of these regions are necessary to clarify the role of this brain region in avian behavior.

Metabotropic glutamate receptor modulation of excitotoxicity in the neostriatum: role of calcium channels.

We have previously shown that metabotropic glutamate receptor (mGluR) activation can attenuate N-methyl-d-aspartate (NMDA)-induced excitotoxic injury in the neostriatum both in vivo and in vitro. Our earlier studies made use of the non-subtype selective mGluR agonist 1-amino-cyclopentane-1,3-dicarboxylic acid (tACPD). In the present study, we extended these observations by identifying the subtype of mGluR involved. Using selective mGluR agonists, we provide evidence that the Group II mGluRs are responsible for inhibition of NMDA excitotoxicity in the neostriatum. In addition, we provide evidence that the inhibitory effects of tACPD on excitotoxicity are dependent upon calcium influx as they are blocked by a low calcium solution as well as the broad-spectrum calcium channel blocker cadmium. The tACPD-induced attenuation was also blocked by omega-conotoxin GVIA suggesting participation of N-type calcium channels. Whole cell voltage clamp recordings were made to directly determine the effects of mGluRs on voltage-gated calcium channels in neostriatal neurons. As predicted, both tACPD and the Group II agonist 3C4HPG inhibited calcium currents in neostriatal neurons. Again this effect was blocked by omega-conotoxin GVIA. Overall the results suggest that mGluR regulation of voltage-gated calcium channels can limit NMDA toxicity in the neostriatum.

Blockade of neurotensin receptors suppresses the dopamine D1/D2 synergism on immediate early gene expression in the rat brain.

A remarkable feature of dopamine functioning is that the concomitant activation of D1-like and D2-like receptors acts to intensify the expression of various dopamine-dependent effects, in particular the expression of the immediate-early genes, c-fos and zif268. Using non-peptide neurotensin receptor antagonists, including SR48692, we have determined that blockade of neurotensin receptors reduced the cooperative responses of direct acting D2-like (quinpirole) and partial D1-like (SKF38393) dopamine agonists on the expression of Fos-like antigens and zif268 mRNA. Pretreatment with SR48692 (3 and 10 mg/kg) reduced the number of Fos-like immunoreactive cells produced by the combined administration of SKF38393 (20 mg/kg) and quinpirole (1 mg/kg) in the caudate-putamen, nucleus accumbens, globus pallidus and ventral pallidum. High-affinity neurotensin receptors are likely to be involved in these D1-like/D2-like cooperative responses, as compounds structurally related to SR48692, SR48527 (3 mg/kg) and its (-)antipode, SR49711 (3 mg/kg), exerted a stereospecific antagonism in all selected brain regions. Pretreatment with SR48692 (10 mg/kg) also diminished Fos induction by the indirect dopamine agonist, cocaine (25 mg/kg), particularly at the rostral level of the caudate-putamen. In situ hybridization experiments in the caudate-putamen indicated that SR48692 (10 mg/kg) markedly reduced zif268 mRNA labelling produced by SKF38393 plus quinpirole in cells not expressing enkephalin mRNA, but was unable to affect the concomitant decrease of zif268 mRNA labelling in enkephalin-positive cells. Taken together, the results of the present study indicate that neurotensin is a key element for the occurrence of cooperative responses of D2-like and partial D1-like agonists on immediate-early gene expression.

The sexually dimorphic expression of androgen receptors in the song nucleus hyperstriatalis ventrale pars caudale of the zebra finch develops independently of gonadal steroids.

The development of sex differences in brain structure and brain chemistry ("brain sex") of vertebrates is frequently thought to depend entirely on gonadal steroids such as androgens and estrogens, which act on the brain at the genomic level by binding to intracellular transcription factors, the androgen receptors (ARs) and estrogen receptors (ERs). These hormone actions are thought to shift the brain from a monomorphic to a dimorphic phenotype. One prominent such example is the nucleus hyperstriatalis ventrale pars caudale (HVc) of the zebra finch (Poephila guttata), a set of cells in the caudal forebrain involved in the control of singing. In contrast with previous studies using nonspecific cell staining techniques, the size and neuron number of the HVc measured by the distribution of AR mRNA is already sexually dimorphic on posthatching day (P)9. No ARs or ERs are expressed in the HVc before day 9. Slice cultures of the caudal forebrain of P5 animals show that the sexually dimorphic expression of AR mRNA in HVc is independent of the direct action of steroids on this nucleus or any of its immediate presynaptic or postsynaptic partners. Therefore, gonadal steroids do not appear to be directly involved in the initial sex difference in the expression pattern of AR mRNA, size, and neuron number of the HVc. Furthermore, we demonstrate that the initial steroid-independent size and its subsequent steroid-independent growth by extension linearly with the extension of the forebrain explains 60-70% of the masculine development of the HVc. Thus, we suggest that epigenetic factors such as the gonadal steroids modify but cannot overwrite the sex difference in HVc volume determined autonomously in the brain.

Elevated Fos-like immunoreactivity in the brains of postpartum female prairie voles, Microtus ochrogaster.

This study investigated the expression of the protein product of the immediate early gene c-fos in the brains of female prairie voles (Microtus ochrogaster) in association with pregnancy and postparturient activities including maternal behavior, lactation and postpartum estrus. Fos expression was assessed in female voles that were late in pregnancy, nonpregnant or at one of three different times postpartum (0-8, 12-24, and 24-48 h, respectively). A significant increase in the number of cells displaying Fos immunoreactivity (Fos-ir) was observed during the 0-8 h and 12-24 h postpartum time periods in the accessory olfactory bulbs, medial preoptic area, hypothalamus (specifically, the supraoptic nucleus, ventro-medial hypothalamus, and paraventricular nucleus), lateral septum, bed nucleus of the stria terminalis, and primary somatosensory area of the brain. The number of Fos-ir cells decreased after 24 h postpartum. There were no significant changes in Fos-ir cell numbers in the primary olfactory bulbs, hippocampus, or caudate putamen. The neural activation of the medial preoptic area, accessory olfactory bulbs, hypothalamus, and bed nucleus is consistent with reports in rats of Fos induction associated with the onset of maternal behavior. In voles postpartum estrous behavior begins and ends 0-12 h after parturition. Maternal behavior, including lactation, is initiated at the same time but persists for several weeks. The highest Fos-ir cell numbers reported here coincide with the timing of postpartum estrous behavior in this species.