The mGlu2/3 Receptor Agonists LY354740 and LY379268 Differentially Regulate Restraint-Stress-Induced Expression of c-Fos in Rat Cerebral Cortex.

Metabotropic glutamate 2/3 (mGlu2/3) receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL) and infralimbic (IL) cortex. LY354740 (10 and 30 mg/kg, i.p.) showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3-10 mg/kg, i.p.). Because both compounds inhibit serotonin 2A receptor (5-HT2AR)-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that 5-HT2AR activation and restraint stress induce c-Fos through distinct mechanisms.

Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats.

Studies suggest that behavioral, genomic, and endocrine functions mediated by central corticotropin-releasing factor (CRF)-containing circuits may be differentially regulated. However, this hypothesis has never been tested directly by simultaneous assessment of distinct CRF-mediated responses within the same animal. The present study addressed this issue by concurrently examining the effects of central CRF infusions on anxiety responses, plasma corticosterone release, and c-fos mRNA induction within limbic brain circuits. Bilateral intracerebroventricular (icv) infusions of CRF (0.1-10 microg total) dose-dependently reduced exploratory behavior in a novel open field, increased circulating corticosterone (CORT) levels and augmented c-fos mRNA expression in the central nucleus of the amygdala (CeA) and the hypothalamic paraventricular nucleus (PVN). Plasma CORT levels increased significantly after 0.1 microg CRF, whereas behavioral and genomic responses required at least 1 microg CRF, suggesting that the distinct responses mediated by CRF are differentially regulated. Further characterization of intracerebroventricular CRF at 1 microg also demonstrated a disruption of social interaction behavior. The majority of behavioral effects and the elevated c-fos mRNA expression were attenuated by 10 mg/kg DMP696, a CRF(1) antagonist. However, plasma CORT elevation required 30 mg/kg DMP696 for attenuation. Thus, our studies demonstrate a greater sensitivity of the hypothalamic-pituitary-adrenal axis to intracerebroventricular CRF compared with the induction of innate fear-like responses and associated genomic changes.

Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype.

Postmortem AD brains exhibit dendritic spine loss in the hippocampus. To determine whether this pathology may be associated with amyloid burden, the present study used the Golgi stain technique to assess age- and genotype-dependent changes in dendritic spine density in CA1 hippocampus of two transgenic mouse lines that produce high levels of Abeta. Tg2576 and PDAPP mice, as well as a group of Tg2576 mice crossed with human apoE2-expressing transgenic mice, were compared to respective transgene-negative controls. Since the time course of amyloid plaque deposition in the PDAPP and Tg2576 mice is well characterized, we examined changes in spine density at ages that corresponded to different levels of amyloid plaque load. The data show age- and genotype-dependent reductions in spine density in both Tg2576 and PDAPP mice, albeit at somewhat different time courses. The spine loss occurred prior to plaque deposition and was ameliorated by the overexpression of human apoE2. These results suggest that a soluble Abeta species may affect hippocampal synapses and thereby contribute to functional deficits evident in these animals.

Rapid habituation of hippocampal serotonin and norepinephrine release and anxiety-related behaviors, but not plasma corticosterone levels, to repeated footshock stress in rats.

Prior stress exposure is known to alter the activation response to a subsequent stressor. In the present study, we examined neurochemical, neuroendocrinological, and behavioral correlates of short-term adaptation to homotypic stressors administered 60 min apart. An initial electric footshock significantly induced extracellular levels of both serotonin (5-HT) and norepinephrine (NE) in the rat hippocampus (650% and 200% above baseline, respectively), as measured by in vivo microdialysis. A rapid habituation in this response was evident in the inability of a second footshock to evoke similar increases. In contrast, the hypothalamic-pituitary-adrenal (HPA) response was augmented further after the second shock session: plasma corticosterone (CORT) levels were 18.1, 316.5, and 441.6 mg/ml in nonstressed, one-footshock-, or two-footshock-treated rats, respectively. In a social interaction paradigm, rats subjected to a single footshock showed several fear- and anxiety-related behaviors such as increases in freezing and decreases in rearing and active approach for social interaction. Exposure to a second footshock completely blocked the freezing response and restored rearing behavior without affecting the disruption in social interactions. Taken together, these data raise the possibility that neurochemical and neuroendocrine adaptations to short-term homotypic stressors differentially contribute to expression of different fear and anxiety-like responses in the rat.

Maternal height and newborn size relative to risk of intrapartum caesarean delivery and perinatal distress.

OBJECTIVE: To estimate the changes, in risk of intrapartum caesalrean delivery and perinatal distress that may be introduced through increased birth size, resulting from interventions such as improving nutrition of the mother; and to characterise delivery risk relative to maternal stature by birth size. DESIGN: Model these risks using data from the Guatemalan Perinatal Study. SETTING: The antenatal clinic of the Gynaecology and Obstetrics Hospital of the Guatemalan Social Security Institute in Guatemala City serving predominantly working class women. POPULATION: Women who had their first prenatal visit between April 1984 and January 1986. METHODS: Multivariate logistic regression models were developed to estimate incidence of intrapartum caesarean delivery and perinatal distress and used to calculate changes in risk associated with changes in size. MAIN OUTCOME MEASURES: Incidences of intrapartum caesarean delivery and perinatal distress. RESULTS: A woman of 146cm height (-1 SD) relative to another of 160 cm (+1 SD) has a 2.5 times higher risk of intrapartum caesarean delivery. An increase in newborn head circumference and weight (from -1 SD to +1 SD) are each independently associated with an increase in risk of intrapartum caesarean delivery (2.0 times and 1.5 times. respectively). An increase in birthweight from 2,450 g to 2,550 g is associated with a decrease in risk of perinatal distress of 34/1,000 cases and an increase in risk of intrapartum caesarean delivery of 8/1,000 cases. CONCLUSIONS: Increases in fetal growth comparable to those attributable to improved nutrition during pregnancy are associated with a larger decrease in risk of perinatal distress relative to the increase in risk of intrapartum caesarean delivery for the mother. Greater maternal stature is associated with lower risk of intrapartum caesarean delivery.

Increased levels of proneurotensin/neuromedin N mRNA in rat striatum and nucleus accumbens induced by 7-OH-DPAT and nafadotride.

The D3 dopamine receptor has been proposed as a potential antipsychotic site. In this study, the effects of the D3-preferring compounds 7-OH-DPAT and nafadotride on levels of proneurotensin/neuromedin N (proNT/N) were assessed. Adult, male, Sprague-Dawley rats were injected subcutaneously (s.c.) with the agonist 7-OH-DPAT (0.1 mg/kg) or antagonist nafadotride (1 mg/kg) at doses previously shown to produce negligible occupancy of D2 receptors in vivo. As a positive control, an additional group of animals was treated with haloperidol (3 mg/kg, s.c.). ProNT/N mRNA levels were determined by in situ hybridization. 7-OH-DPAT increased proNT/N mRNA in the nucleus accumbens shell. Nafadotride increased proNT/N mRNA levels in the nucleus accumbens shell and dorsomedial caudate nucleus to levels comparable to those produced by haloperidol. Nafadotride also increased proNT/N mRNA in the anterior and dorsal caudate but to a lesser extent than haloperidol. These data indicate that 7-OH-DPAT and nafadotride increase proNT/N mRNA levels in brain areas affected by antipsychotic drugs and suggest that the D3 receptor may regulate proNT/N mRNA expression in the nucleus accumbens shell.

Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats.

Behavioral sensitization resulting from repeated, intermittent exposure to psychostimulants such as amphetamine (Amp) is hypothesized to model pathophysiology of psychotic disorders. The present study was designed to characterize the effects of a typical and an atypical antipsychotic drug, haloperidol and clozapine, respectively, on the induction of context-independent sensitization to Amp. Peripheral Amp treatment for five days (2 mg/kg/day, s.c.) produced an augmented stimulant response to an acute Amp challenge (2 mg/kg, s.c.) given seven days after the last pretreatment injection. Interestingly, preexposure to high doses of either clozapine (20 mg/kg) or haloperidol (0.5 mg/kg) alone also led to a sensitized behavioral response to an acute Amp challenge. The cross-sensitization between Amp and high doses of the haloperidol and clozapine may have occluded any blockade of Amp behavioral sensitization by the antipsychotics. Indeed, administration of a lower dose of clozapine (4 mg/kg) or haloperidol (0.1 mg/kg) with Amp during the preexposure phase clearly blocked the induction of behavioral sensitization. In addition to the behavioral sensitization, Amp-pretreated rats showed a reduction in the ability of the acute Amp challenge to induce c-fos mRNA in the medial prefrontal cortex and neurotensin/neuromedin N (NT/N) mRNA in the nucleus accumbens-shell. At doses that blocked the initiation of behavioral sensitization to Amp, clozapine fully and haloperidol partially restored the capacity of acute Amp to induce c-fos and NT/N gene expression. These data lend support to the psychostimulant-sensitization model of psychosis and a role of dopamine D2-like receptors in the phenomenon.

The role of dopamine D4 receptor in the induction of behavioral sensitization to amphetamine and accompanying biochemical and molecular adaptations.

Our studies examined the role of dopamine D4 receptors in the induction of behavioral sensitization to amphetamine (Amp) and accompanying neurochemical and molecular adaptive responses using a highly selective D4 antagonist, PNU-101387G. Behavioral sensitization to an acute challenge of Amp (2 mg/kg, s.c.) was observed in rats pretreated with five daily doses of Amp (2 mg/kg/d, s.c.) followed by 7-day withdrawal. Interestingly, coadministration of PNU-101387G with Amp during pretreatment completely blocked the sensitized response to an acute Amp challenge. The behavioral sensitization and its blockade by the D4 antagonist were observed in the absence of significant differences in cerebellar Amp levels among the various pretreatment groups. Accompanying behavioral sensitization were two postsynaptic neuroadaptive responses: reduction in the ability of Amp to induce c-fos gene expression in the infralimbic/ventral prelimbic cortex and NT/N mRNA in the accumbal shell. However, concurrent blockade of D4 receptors during Amp pretreatment prevented the refractoriness in c-fos and NT/N responsiveness to acute Amp. We observed also a presynaptic neuroplastic response associated with the behavioral sensitization: a significant augmentation in the ability of Amp to increase extracellular dopamine concentrations in the nucleus accumbens shell. As with the behavioral sensitization and associated postsynaptic adaptive responses, concurrent administration of PNU-101387G with Amp during pretreatment blocked the augmentation in Amp-induced dopamine release. Taken together, these data demonstrate that dopamine D4 receptors play an important role in the induction of behavioral sensitization to Amp and accompanying adaptations in pre- and postsynaptic neural systems associated with the mesolimbocortical dopamine projections.

EEDQ reduces the striatal neurotensin mRNA response to haloperidol.

Haloperidol is believed to induce neurotensin/neuromedin N (NT/ N) gene expression in the dorsolateral striatum (DLST) of the rat brain via dopamine D2 receptor blockade, but is also known to interact with other receptors as well. To further characterize haloperidol's effects, rats were treated with the irreversible monoaminergic receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2 hydroxyquinolone (EEDQ). In situ hybridization was performed for NT/N mRNA. D2-like and sigma receptor autoradiography was performed using 125I-sulpride and 3H-1,3-di-o-tolylguanidine (DTG), respectively. Despite antagonism of D2 receptors, pretreatment with EEDQ failed to significantly reduce the NT/N mRNA response when given 3 days prior to the haloperidol challenge. These data suggest that the acute effects of haloperidol on NT/N mRNA expression in large part result from D2 receptor antagonism. Nonetheless, a contribution of other receptors can not be excluded.

Pharmacological characterization of U-101387, a dopamine D4 receptor selective antagonist.

Dopamine D2-like receptors play an important role in the pharmacotherapy of psychotic disorders. Molecular and cellular techniques have identified distinct gene products (D2-long, D2-short, D3 and D4) displaying the D2 receptor pharmacology. However, the contribution of each subtype in antipsychotic effects of or their physiological role remain unclear. Here we describe the pharmacological effects of a selective D4 antagonist, U-101387. U-101387 displayed moderately high affinity (Ki = 10 nM) and selectivity for the dopamine D4.2 receptor expressed in clonal cell lines. It lacked measurable affinity for not only other dopamine receptors but also noradrenalin, serotonin and histamine receptor families (Ki > 2000 nM). It fully and dose-dependently antagonized quinpirole-induced cAMP inhibition (without producing any effect by itself) in stably transfected cells. U-101387 also displayed excellent oral bioavailability, brain penetration and other pharmacokinetic characteristics. Unlike classical neuroleptics (e.g., haloperidol), U-101387 neither blocked acute behavioral effects of amphetamine or apomorphine nor did it alter spontaneous locomotion by itself. Additionally, U-101387 was without effect in behavioral and biochemical tests predictive of extrapyramidal and neuroendocrine side effects. Consistent with the lack of autoreceptor function of D4, acute administration of U-101387 failed to alter dopamine neuronal firing by itself or reverse the inhibition produced by dopamine agonists and to affect monoamine turnover in areas innervated by the mesencephalic or hypothalamic dopamine neurons. However, U-101387 potently induced c-fos mRNA expression in the infralimbic/ventral prelimbic cortex to a level similar to that produced by the atypical antipsychotic, clozapine. This is consistent with the predominantly cortical distribution of the D4 receptor. Taken together, these results demonstrate that the D4-selective antagonist, U-101387, produces effects that are distinct from those of the nonselective D2 antagonists as well as D3-preferring agents. U-101387 offers a unique tool to understand the role of dopamine D4 receptors in diseases involving central dopamine systems.

Induction of c-fos mRNA in rat medial prefrontal cortex by antipsychotic drugs: role of dopamine D2 and D3 receptors.

The present studies compared the effects of acute and chronic administration of haloperidol or clozapine on c-fos mRNA expression in the rat medial prefrontal cortex. Acute administration of clozapine, but not haloperidol robustly increased c-fos mRNA expression in the infralimbic and prelimbic cortex of the rat. Even though most c-fos mRNA-expressing neurons in the clozapine- treated animals were localized in deep cortical layers, labeled neurons were found organized into several cell bridges connecting the superficial and deep layers of the cortex. After chronic treatment with clozapine, c-fos mRNA was reduced by approximately 60% of that seen acutely; however, the columns of c-fos mRNA expressing neurons did not show the same magnitude of tolerance. Haloperidol had no significant effect even after chronic treatment. We examined further the role of dopamine D2 versus D3 receptors in c-fos gene induction in the infralimbic cortex by studying the acute effects of remoxipride and U-99194A. Remoxipride, a selective D2 antagonist in vitro, induced c-fos mRNA at very low doses and lost its ability to alter c-fos mRNA at higher doses. Interestingly, U-99194A, an antagonist with 20-fold selectivity for D3 over D2 receptors, also produced greater induction of c-fos mRNA at lower doses. We hypothesize that blockade of D3 receptors may enhance c-fos gene expression in the medial prefrontal cortex but that of D2 receptors may prevent the same.

Differential distribution of gamma-aminobutyric acidA receptor subunit (alpha 1, alpha 2, alpha 3, alpha 5 and beta 2 + 3) immunoreactivity in the medial prefrontal cortex of the rat.

A detailed mapping of the gamma-aminobutyric acid (GABA)A receptor subunits (alpha 1, alpha 2, alpha 3, alpha 5 and beta 2 + 3) in the infralimbic/ventral prelimbic region (IL/vPL) of the rat frontal cortex was carried out using subunit-specific antibodies. The alpha 1 and beta 2 + 3 subunit antibodies immunostained all layers of the IL/vPL region. Layers II and III displayed immunostaining of cell bodies whereas I, V and VI showed predominantly neuropil staining. The size of the alpha 1-positive cell bodies corresponded to that of small interneurons (range, 20-55 microns2; mean +/- SEM, 37 +/- 5.5 microns2) as well as pyramidal cells or large interneurons (range, 87-135 microns2; mean +/- SEM, 103.4 +/- 9.7 microns2). However, beta 2 + 3 antibody immunostained only small cell bodies. Immunoreactivity for alpha 2 was restricted to layers I and II, whereas alpha 3 and alpha 5 subunit expression was seen only in layer VI. The antibody to the alpha 2 subunit immunostained small cell bodies (range, 29-63 microns2; mean +/- SEM, 32 +/- 4.5 microns2) in layer II, resembling interneurons. Conversely, both alpha 3 and alpha 5 antibodies immunostained large cell bodies (range, 94-151 microns2; mean +/- SEM, 115.7 +/- 13.4 microns2), consistent with pyramidal cell labelling in layer VI.

Effect of muscimol on haloperidol-induced alteration of neurotensin gene expression in the striatum and nucleus accumbens in the rat.

Acute neuroleptic administration increases the expression of neurotensin/neuromedin (NT/N) gene in rat dorsolateral striatum and shell sector of the nucleus accumbens. The purpose of this study was to examine modulation of neuroleptic induction of NT/N and the proto-oncogene c-fos expression by the GABAA agonist muscimol. Adult male Sprague-Dawley rats were treated with saline, haloperidol (1 mg/kg); muscimol (3.2 mg/kg); or haloperidol (1 mg/kg) plus muscimol (3.2 mg/kg). Animals were sacrificed 1 h after drug administration. Expression of NT/N and c-fos mRNA was examined by in situ hybridization using 35S-antisense probes. Muscimol alone had no measurable effect on basal levels of NT/N or c-fos mRNA in either the dorsolateral striatum or the nucleus accumbens. However, co-administration of muscimol with haloperidol reduced haloperidol-induced increases in NT/N as well as c-fos mRNA in the dorsolateral striatum. In contrast, NT/N mRNA expression in accumbal shell induced by haloperidol was not modulated by co-administration of muscimol. These data suggest that GABAA receptors may be involved in regulation of NT/N gene expression in the DLSt, but not in the nucleus accumbens.

Effects of chronic haloperidol and clozapine treatment on neurotensin and c-fos mRNA in rat neostriatal subregions.

Previous studies have shown elevation of neurotensin neuromedin N (NT/N) and c-fos mRNA in the dorsolateral region of the rat neostriatum (DLSt) by acute administration of only typical antipsychotic drugs. However, NT/N mRNA in the nucleus accumbens-shell is enhanced acutely by several clinically efficacious antipsychotic drugs, regardless of their motor side effect liability. In the present study, induction of NT/N mRNA in the DLSt was observed again after 28 days of continuous administration (via osmotic minipumps) of haloperidol, but not clozapine. However, this response was only about 50% of that caused by acute haloperidol and c-fos mRNA levels in the DLSt were not elevated after the chronic treatment. An acute challenge of haloperidol 24 hr after chronic haloperidol treatment did not affect the tolerant response of NT neurons but caused a small increase in c-fos mRNA in the DLSt. Similar to the DLSt, chronic haloperidol (but not clozapine) significantly enhanced NT/N gene expression in the ventrolateral striatum, a region thought to be involved in abnormal oral movements, perhaps related to tardive dyskinesia. Interestingly, dopamine D2 receptor binding using [125I]iodosulpride nearly doubled in all regions of the striatum after chronic haloperidol but not clozapine. In contrast to the lateral neostriatum, NT/N mRNA expression in the nucleus accumbens-shell was elevated similarly by chronic treatment with haloperidol and clozapine to a level observed after acute haloperidol treatment. These results demonstrate further that region-specificity of NT/N mRNA regulation discriminate between typical and atypical antipsychotic drugs.

c-fos antisense oligonucleotide specifically attenuates haloperidol-induced increases in neurotensin/neuromedin N mRNA expression in rat dorsal striatum.

Acute administration of neuroleptic drugs such as haloperidol robustly increases transcription of the gene encoding the neuroactive peptide, neurotensin, in the dorsolateral striatum of the rat. This induction of neurotensin/neuromedin (NT/N) mRNA by haloperidol is preceded by increases in c-fos mRNA expression in the same region. Our recent studies demonstrate that a vast majority of haloperidol-sensitive NT/N mRNA expressing cells in the dorsolateral striatum coexpress c-fos mRNA. These data suggest that the transcription factor, Fos, may participate in NT/N gene induction by neuroleptics. Present studies investigated this possibility using an antisense c-fos oligodeoxynucleotide (which has been shown to block the expression of Fos protein in vivo) or its sense sequence oligomer injected into opposite caudate-putamen of awake, freely moving rats. Eight hours following the injection of the oligomers, the animals were challenged with a systemic injection of haloperidol (1 mg/kg) and were sacrificed 1 h later. Examination of NT/N mRNA by in situ hybridization histochemistry revealed approximately 50% attenuation in the NT/N mRNA expression in the dorsolateral striatum injected with the antisense oligomer compared to the contralateral side which received the sense oligomer. On the other hand, expression of proenkephalin mRNA in the dorsolateral striatal neurons or NT/N mRNA in the nucleus accumbens shell was not altered following the c-fos antisense oligomer injection. These data demonstrate a specific role of Fos in the regulation of the neurotensin/neuromedin N gene in the rat dorsolateral striatal neurons by acute haloperidol treatment.

Coexpression of neurotensin and c-fos mRNAs in rat neostriatal neurons following acute haloperidol.

Our previous studies have shown several fold induction of neurotensin/neuromedin N (NT/N) primary transcripts and mature cytosolic mRNA in the dorsolateral region of the rat neostriatum (DLSt) following a single dose of the neuroleptic, haloperidol. The apparent enhancement of NT/N gene transcription by haloperidol is preceded by increases in the expression of c-fos mRNA in the same region. The present study used double-labeling in situ hybridization technique to study cellular localization of NT/N and c-fos mRNA following acute haloperidol treatment. Simultaneous detection of NT mRNA and c-fos mRNA was achieved using cRNA probes synthesized in vitro with digoxigenin- and 35S-labeled UTP, respectively. Interestingly, approximately 75% of DLSt neurons expressing NT/N mRNA also displayed c-fos mRNA in rats treated with haloperidol (1 mg/kg, i.p.) for 1 h. Colocalization of c-fos mRNA in haloperidol-responsive NT neurons in the DLSt suggests that haloperidol's induction of NT/N gene transcription may involve participation of the transcription factor Fos and the AP-1 consensus sequence in regulatory region of the NT/N gene.

Induction of neurotensin and c-fos mRNA in distinct subregions of rat neostriatum after acute methamphetamine: comparison with acute haloperidol effects.

Large increases of neurotensin (NT)-like immunoreactivity in the rat neostriatum have been reported previously after treatment with either dopamine D2 receptor antagonists (e.g., haloperidol) or potent indirect dopamine agonists (e.g., methamphetamine). Combined administration of these two opposite classes of drugs results in additive increases in striatal NT-like immunoreactivity suggesting that distinct mechanisms may underlie increases in NT content after haloperidol and methamphetamine. Our recent studies demonstrate that acute haloperidol treatment increases NT immunoreactivity in the striatum, at least in part, by enhancing the expression of the NT/neuromedin N (NT/N) gene in neurons confined to the dorsolateral sector of the striatum. Additionally, this induction of NT/N gene transcription in the dorsolateral striatum by haloperidol appears to involve participation of the immediate early gene, c-fos. The present study investigated alterations in NT/N and c-fos gene expression after acute methamphetamine (10 mg/kg s.c.) treatment and compared these changes to those observed after acute haloperidol (1 mg/kg i.p.) administration. Unlike haloperidol, methamphetamine increased NT/N mRNA expression in the periventricular dorsomedial quadrant of the striatum and induced c-fos mRNA primarily in the medial aspects of the central core of the neostriatum. These data suggest that Fos may not act as a primary transcription factor in methamphetamine-induced NT/N gene expression in the dorsomedial striatum. The results also indicate that additive increases in striatal NT-like immunoreactivity after simultaneous treatment with haloperidol and methamphetamine may be due to induction of NT/N gene expression in distinct neostriatal neuronal populations.

Maternal nutritional depletion.

PIP: The author discusses maternal nutritional depletion, the negative energy balance and/or micronutrient deficiencies resulting from the energetic burden of frequent reproductive cycling combined with undernutrition and overexertion, and its impact upon a woman's health and nutritional status and that of her offspring. The article is therefore concerned with the impact of nutritional depletion which occurs during a woman's life cycle, as opposed to the effects of nutritional depletion which occur intergenerationally. A brief summary is presented of the recognition and controversy regarding the effects of reproductive stress followed by a description of the factors which make assessment and identification of specific consequences so complex, with approaches suggested to alleviate maternal nutritional depletion. Policy directions and areas for research are suggested.^ieng

Blunting of the neurotensin mRNA response to haloperidol in the striatum of aging rats: possible relationship to decline in dopamine D2 receptor expression.

Neuroleptic drugs such as haloperidol (H) induce a rapid increase in neurotensin/neuromedin N (NT/N) gene expression in the dorsolateral striatum (DLSt) and nucleus accumbens (NA) in young adult rats. This effect may be mediated by post-receptor effectors that are activated by dopamine D2 receptor antagonism. The regional pattern of induction of neurotensin gene expression correlates with the side effect profile of particular neuroleptics. As motor side effects of H differ in aged animals, we hypothesized that the regional expression of the neurotensin gene may differ between young and old animals. We administered H or saline acutely to 3, 14, and 25 month-old Fischer 344 rats, followed by in situ hybridization and quantitative autoradiography for NT/N mRNA. There was a significant age effect on the H-induced NT/N mRNA response in the DLSt, but not the NA, of older animals. In addition to the blunted NT/N mRNA response, significant decreases in D2 receptor mRNA were observed in the lateral striatum of another group of young, middle-aged, and aged rats. Age-related blunting of the NT/N mRNA response to H in the DLSt may be due in part to a decrease in D2 receptors in this structure.

Differential loss of dopamine D2 receptor mRNA isoforms during aging in Fischer-344 rats.

Effects of aging on the expression of dopamine D2 receptor isoforms (D2-long and -short) in neostriatal subregions was examined by in situ hybridization histochemistry. Hybridization of a probe selective for the D2-long transcript was compared with signal generated by a probe recognizing both variants of D2 mRNA. Lateral quadrants of the neostriatum in old rats appeared to show declines in primarily the long transcripts. On the other hand, decreases in the expression of D2-short transcripts appeared to occur during aging in the ventromedial region of the striatum. These data suggest that the mechanisms involved in alternative splicing of D2 mRNA may be differentially altered in neostriatal subregions during aging.