Ovarian hormones differentially influence immunoreactivity for dopamine beta- hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys.

Recent studies have shown that ovariectomy reduces, and subsequent hormone replacement restores the density of axons immunoreactive for tyrosine hydroxylase in the dorsolateral prefrontal cortex of adult female rhesus monkeys. The present study indicates that three additional extrathalamic frontal lobe afferents are also sensitive to changes in the ovarian hormone environment. Specifically, the combination of hormone manipulation with qualitative and quantitative analysis of immunocytochemistry for dopamine beta-hydroxylase, choline acetyltransferase, and serotonin in the primate prefrontal cortex revealed quantitative responses in both cholinergic and monoaminergic axons to changing ovarian hormone levels. However, whereas ovariectomy produced a modest net decrease in the density of fibers immunoreactive for choline acetyltransferase, this same treatment markedly increased the density of axons immunoreactive for dopamine beta-hydroxylase and for serotonin. Further, the effects of ovariectomy on these afferent systems were differentially attenuated by estrogen verses estrogen plus progesterone hormone replacement. Estrogen was as effective as estrogen plus progesterone in stimulating normal prefrontal immunoreactivity for choline acetyltransferase and dopamine beta-hydroxylase. The dual replacement of estrogen plus progesterone, however, was a much more potent influence than estrogen alone for serotonin immunoreactivity. Thus, ovarian hormones appear to provide stimulation that differentially affects each of four chemically identified extrathalamic prefrontal afferent systems examined to date, and may have roles in maintaining the normal balance and functional interactions between these neurotransmitter systems.     

Effects of acute and chronic gonadectomy on the catecholamine innervation of the cerebral cortex in adult male rats: insensitivity of axons immunoreactive for dopamine-beta-hydroxylase to gonadal steroids, and differential sensitivity of axons immunoreactive for tyrosine hydroxylase to ovarian and testicular hormones

Previous studies have shown that gonadectomy in adult male rats induces a complex series of region- and time-specific changes in the density of presumed cerebral cortical dopamine axons that are immunoreactive for tyrosine hydroxylase. The present study asked whether noradrenergic cortical afferents also show hormone sensitivity by assaying axons immunoreactive for the enzyme dopamine-beta-hydroxylase in representative areas of acutely and chronically gonadectomized and sham-operated adult male rats. Catecholamine afferents (both tyrosine hydroxylase-immunoreactive and dopamine-beta-hydroxylase-immunoreactive) were also quantified in gonadectomized rats supplemented with testosterone propionate, with 17-beta-estradiol, or with 5-alpha-dihydrotestosterone. Analyses of noradrenergic (dopamine-beta-hydroxylase) afferents revealed no differences in axon appearance or density among the hormonally intact and hormonally manipulated groups. However, analyses of tyrosine hydroxylase immunoreactivity revealed an unexpected division of labor among ovarian and testicular hormones in ameliorating the effects of acute verses chronic hormone deprivation on these afferents. Estradiol replacement attenuated the decreases in immunoreactivity induced by acute gonadectomy, but was ineffective in suppressing changes in immunoreactivity stimulated by chronic gonadectomy. In contrast, supplementing gonadectomized animals with dihydrotestosterone provided no protection from acute decreases in innervation, but fully attenuated both the supragranular decreases and infragranular increases in tyrosine hydroxylase-immunoreactive axon density that mark the association cortices of chronically gonadectomized rats. Together these findings indicate both long- and short-term effects of gonadectomy on cortical catecholamines, principally target dopamine afferents, and that chronic gonadectomy, which selectively disturbs dopamine innervation in the prefrontal cortices, involves a compromise in androgen signaling pathways.     

Effects of two years of estrogen loss or replacement on nucleus basalis cholinergic neurons and cholinergic fibers to the dorsolateral prefrontal and inferior parietal cortex of monkeys

The present study examined the long-term (2 years) effects of estrogen loss or estrogen replacement therapy (ERT) on cholinergic neurons in the nucleus basalis of Meynert and on cholinergic fibers in the prefrontal and parietal cortex of adult female cynomolgus monkeys. Cholinergic fiber density in layer II of the prefrontal cortex was decreased in monkeys who were ovariectomized and treated with placebo for 2 years. In contrast, ovariectomized monkeys receiving ERT for 2 years had fiber densities that were comparable to those of intact controls. No differences in parietal cholinergic fiber density or nucleus basalis cholinergic neuron number or volume were found among intact, ovariectomized, or ERT monkeys. Our results suggest that ERT is effective in preventing region-specific changes in cortical cholinergic fibers that result from the loss of circulating ovarian hormones. These modest but appreciable effects on cholinergic neurobiology following long-term estrogen loss and ERT may contribute to changes in visuospatial attention function that is mediated by the prefrontal cortex.     

Administration of tamoxifen but not flutamide to hormonally intact, adult male rats mimics the effects of short-term gonadectomy on the catecholamine innervation of the cerebral cortex

Gonadectomy in adult male rats induces a series of changes in cortical catecholamine innervation that begins with a large, but transient decrease in the density of tyrosine hydroxylase- but not dopamine-beta-hydroxylase-immunoreactive axons in sensory, motor, and association cortices. More recent studies have shown that estradiol maintains these presumed dopamine afferents but that supplementing acutely gonadectomized rats with dihydrotestosterone provides no protective effects for innervation. These findings suggest that the depression of mesocortical dopamine axons that follows gonadectomy is stimulated by changes in estrogen signaling. The studies presented here examined tyrosine hydroxylase and dopamine-beta-hydroxylase innervation in hormonally intact adult male rats treated for 4 days with the nonsteroidal antiestrogen tamoxifen or with the nonsteroidal antiandrogen flutamide to probe for additional evidence for this selective hormone sensitivity and for insights into the intracellular mechanisms that may govern it. Qualitative and quantitative comparisons of innervation with corresponding data from control and acutely gonadectomized rats revealed that administration of the antiestrogen tamoxifen in hormonally intact rats produced deficits in catecholamine innervation that mirrored those induced by short-term gonadectomy. The antiandrogen flutamide, however, had no discernible impact on cortical afferents. When considered within the context of the known pharmacology and sites of action of tamoxifen, these findings not only provide additional support for an initial phase of selective estrogen sensitivity among the cortical catecholamines but also suggest that it is stimulation of intracellular estrogen receptors that confers this sensitivity in the adult rat cerebrum.     

Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: A tyrosine hydroxylase immunohistochemical analysis

The mature functional architecture of the primate prefrontal cortex arises during a protracted period of postnatal development. Although catecholaminergic afferents arrive in the primate cortex quite early during fetal development, several lines of evidence suggest that substantial changes in the dopaminergic innervation of prefrontal cortex may occur during postnatal development. In this study, we used immunocytochemical techniques and antibodies against tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, to examine the precise time course from birth to adulthood of the maturational changes of tyrosine hydroxylase-labeled axons in prefrontal cortical areas 9 and 46 and primary motor cortex (area 4) of rhesus monkeys. In area 9, the densities of tyrosine hydroxylase-labeled axons and varicosities in the superficial and deep cortical layers remained relatively constant during postnatal development. In contrast, marked developmental changes in innervation density occurred in the middle cortical layers. For example, in deep layer III, the density of tyrosine hydroxylase-positive varicosities was relatively low and uniform in animals under 1 month of age but then increased by a factor of three in animals 2–3 months of age. The density of labeled varicosities continued to increase, reaching a peak (sixfold greater than in the youngest animals) in aninuds 2–3 years of age before declining to stable adult levels. Similar laminar-specific patterns of change also occurred in areas 46 and 4, although regional differences were present in the magnitude and precise time course of these developmental changes. These findings demonstrate that the innervation of monkey frontal cortex by tyrosine hydroxylase-immunoreactive axons undergoes a protracted, laminar-specific pattern of change during postnatal development that continues through adolescence and into early adulthood. These developmental refinements may interact with other modifications of cortical circuitry that underlie the functional maturation of these regions. © 1995 Wiley-Liss, Inc.     

Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time-dependent manner

In previous work, we have demonstrated that cell proliferation in the adult hippocampal formation is regulated by estrogen under both natural and experimental conditions. To determine the extent to which this regulation is affected by the dose or schedule of hormone treatment, or progesterone administration, we examined the impact of different acute and chronic ovarian hormone replacement regimens on cell production using the S-phase marker bromodeoxyuridine. Additionally, we investigated the long-term impact of surgical ovarian hormone depletion on the capacity of estrogen to stimulate cell proliferation and the production of new cells that express either TuJ1 (a marker of neuronal phenotype) or glial fibrillary acidic protein (GFAP; a marker of astroglial phenotype). Acute treatment with a moderate, but not a low or a high, dose of estrogen rapidly increased cell proliferation in ovariectomized (OVX) animals, an effect that was reversed by the administration of progesterone. In contrast, OVX animals that were chronically replaced with either estrogen alone (continuous or cyclic) or estrogen plus progesterone (cyclic) did not exhibit an estrogen-induced increase in cell proliferation 3 weeks following the onset of hormone replacement. In animals that were subjected to a prolonged absence of ovarian hormones, acute treatment with the moderate dose of estrogen failed to stimulate cell proliferation, and a decrease in the number of new cells expressing a neuronal phenotype was evident. Collectively, these results indicate that a prolonged reduction in ovarian hormones results in 1) a diminished responsiveness to estrogen over time in this system and 2) a decrease in neuron production that is unlikely to be reversible by standard regimens of hormone replacement.     

Effects of an epinephrine synthesis inhibitor, SKF64139, on the secretion of luteinizing hormone in ovariectomized female rats

In order to test the involvement of central epinephrine systems in luteinizing hormone (LH) secretion, the epinephrine synthesis inhibitor, SKF64139, was administered to ovariectomized rats treated with ovarian hormones. This agent significantly decreased resting LH concentrations in ovariectomized, hormonally untreated rats and completely suppressed the stimulatory feedback effects of estrogen plus progesterone. In these animals, hypothalamic concentrations of epinephrine, but not norepinephrine or dopamine, were significantly decreased. It is suggested that brain epinephrine may participate in the neural control of LH secretion in rats.     

Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects.

OBJECTIVE: Abnormalities in dopamine neurotransmission in the prefrontal cortex have been implicated in the pathophysiology of schizophrenia. However, the integrity of the dopamine projections to the prefrontal cortex in this disorder has not been directly examined. METHOD: The authors employed immunocytochemical methods and antibodies against tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, and the dopamine membrane transporter to examine dopamine axons in the dorsomedial prefrontal cortex (area 9) from 16 pairs of schizophrenic and matched control subjects. RESULTS: Compared to the control subjects, the total length of tyrosine hydroxylase-immunoreactive axons was unchanged in the superficial and middle layers of the schizophrenic subjects but was reduced by an average of 33.6% in layer 6. The total length of tyrosine hydroxylase-positive axons in layer 6 was decreased in 13 of the schizophrenic subjects compared to their control subjects. Axons immunoreactive for the dopamine membrane transporter showed a similar pattern of change. In contrast, axons labeled for the serotonin transporter did not differ between schizophrenic and control subjects in any layer examined. In addition, the density of tyrosine hydroxylase-containing axons did not differ between monkeys chronically treated with haloperidol and matched control animals. CONCLUSIONS: These findings reveal that schizophrenia is associated with an altered dopamine innervation of prefrontal cortex area 9 that is lamina- and neurotransmitter-specific and that does not appear to be a consequence of pharmacological treatment. Together, these data provide direct evidence for a disturbance in dopamine neurotransmission in the prefrontal cortex of schizophrenic subjects.     

Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area.

Physiological and pharmacological studies indicate that descending projections from the prefrontal cortex modulate dopaminergic transmission in the nucleus accumbens septi and ventral tegmental area. We investigated the ultrastructural bases for these interactions in rat by examining the synaptic associations between prefrontal cortical terminals labeled with anterograde markers (lesion-induced degeneration or transport of Phaseolus vulgaris leucoagglutinin; PHA-L) and neuronal processes containing immunoreactivity for the catecholamine synthesizing enzyme, tyrosine hydroxylase. Prefrontal cortical terminals in the nucleus accumbens and ventral tegmental area contained clear, round vesicles and formed primarily asymmetric synapses on spines or small dendrites. In the ventral tegmental area, these terminals also formed asymmetric synapses on large dendrites and a few symmetric axodendritic synapses. In the nucleus accumbens septi, degenerating prefrontal cortical terminals synapsed on spiny dendrites which received convergent input from terminals containing peroxidase immunoreactivity for tyrosine hydroxylase, or from unlabeled terminals. In single sections, some tyrosine hydroxylase-labeled terminals formed thin and punctate symmetric synapses with dendritic shafts, or the heads and necks of spines. Close appositions, but not axo-axonic synapses, were frequently observed between degenerating prefrontal cortical afferents and tyrosine hydroxylase-labeled or unlabeled terminals. In the ventral tegmental area, prefrontal cortical terminals labeled with immunoperoxidase for PHA-L were in synaptic contact with dendrites containing immunogold reaction product for tyrosine hydroxylase, or with unlabeled dendrites. These results suggest that: (1) catecholaminergic (mainly dopaminergic) and prefrontal cortical terminals in the nucleus accumbens septi dually synapse on common spiny neurons; and (2) dopaminergic neurons in the ventral tegmental area receive monosynaptic input from prefrontal cortical afferents. This study provides the first ultrastructural basis for multiple sites of cellular interaction between prefrontal cortical efferents and mesolimbic dopaminergic neurons.     

Alterations of dopaminergic and noradrenergic innervations in motor cortex in Parkinson's disease.

The motor areas of the cerebral cortex contain dense dopaminergic and noradrenergic innervation in humans. We looked for changes of these innervations in cases with Parkinson's disease (PD). The density of fibers immunolabeled with tyrosine hydroxylase or dopamine-beta-hydroxylase was evaluated in the primary motor, premotor, and prefrontal cortical regions in 6 cases with PD and 7 control cases. Reductions of both noradrenergic and dopaminergic cortical innervations were observed, with similar magnitudes of reduction found in the motor and prefrontal regions of the cortex. Depletion of noradrenergic innervation was diffuse, involving all cortical laminae. Depletion of dopaminergic innervation was laminar specific, with the most significant reductions in layers I and II; reductions in layers V and VI were either less marked (prefrontal cortex) or not detectable (primary motor). The results suggest the existence of two separate mesocortical dopaminergic systems in humans, with the one distributing to upper cortical layers being preferentially involved in PD.     

Effects of exposure to an estrous female on forebrain monoaminergic neurotransmission in the non-copulating male rat

Regional changes in the rate of brain monoamine synthesis were monitored in male rats exposed to, but prevented from physical contact with, an estrous or an ovariectomized female. The in vivo rate of tyrosine and tryptophan hydroxylase activities were estimated by measuring the accumulation of DOPA and 5-HTP following inhibition of cerebral aromatic l-amino acid decarboxylase by means of 3-hydroxybenzylhydrazine (NSD-1015) treatment (100 mg/kg i.p.) 5 min upon NSD-1015 treatment, the males were exposed to an intact estrous female or an ovariectomized female for 20 min before decapitation and brain dissections. Exposure to an estrous female produced an increased rate of tyrosine and tryptophan hydroxylase activity in the medial prefrontal cortex, the dorso-lateral neostriatum and in the ventral neostriatum, in comparison with home-cage controls. By the same comparison, exposure to an ovariectomized female resulted in an increased rate of tyrosine hydroxylase activity in the medial prefrontal cortex, byt not in the neostriatal areas, whereas tryptophan hydroxylase activity was unaffected. Finally, exposure to the empty test cage, with no stimulus females present, did not produce any statistically significant changes in the rate of tyrosine or tryptophan hydroxylase activity in any of the brain areas sampled. Taken together with recent findings from this laboratory, the present results demonstrate that the level of sexual motivation brought about by the olfactory, auditory and/or visual stimulation of a receptive female is associated with an increased demand on catecholamine and 5-hydroxytryptamine synthesis in the limbic forebrain of the male rat. The finding that the presence of an unestrous female produced an enhanced demand on tyrosine hydroxylase activity in the medial prefrontal neocortex demonstrates that the sexual incentive provided by the estrous female may not be the only factor responsible for all the effects observed in the present study. In fact, there is a distinct possibility that the intense challenge produced by sexually significant stimuli is but an endpoint, and that the changes found in forebrain monoamine synthesis is a reflection of an environmental challenge not necessarily specifically linked to the sexual behavior.     

Tyrosine hydroxylase and norepinephrine transporter in sympathetic ganglia of female rats vary with reproductive state

In females, sympathetic activity varies with changes in reproductive status, but whether expression of proteins critical to the function of sympathetic neurons is also altered is unknown. Therefore, the present study tested the hypothesis that, in rat adrenal gland and superior cervical ganglia, the expression of tyrosine hydroxylase (TH) and the norepinephrine transporter (NET), measured using Western analysis, are changed during pregnancy and the estrous cycle. Compared to diestrus, pregnancy increased TH levels in both superior cervical ganglia and adrenal gland. Pregnancy was also associated with decreased NET levels in the superior cervical ganglia, but increased levels in the adrenal gland. Relative to diestrus, the pattern of changes of TH and the NET in rats during proestrus was generally similar to changes observed during pregnancy. To assess whether gonadal hormones were involved, ovariectomized rats were also studied and changes in serum estrogen and progesterone were assayed in a subset of animals in all groups. Variations in TH and the NET among all groups did not correlate with changes in either estrogen or progesterone, suggesting that the steroids were not exclusively responsible. In conclusion, reproductive status alters the expression of TH and the NET in adrenal gland and superior cervical ganglia of female rats, which could significantly influence the function of the sympathetic nervous system. However, the mechanism for these changes does not depend solely on changes in estrogen or progesterone.     

Diverse actions of ovarian steroids in the serotonin neural system

All of the serotonin-producing neurons of the mammalian brain are located in 10 nuclei in the mid- and hindbrain regions. The cells of the rostal nuclei project to almost every area of the forebrain and regulate diverse neural processes from higher order functions in the prefrontal cortex such as integrative cognition and memory, to limbic system control of arousal and mood, to diencephalic functions such as pituitary hormone secretion, satiety, and sexual behavior. The more caudal serotonin neurons project to the spinal cord and interact with numerous autonomic and sensory systems. All of these neural functions are sensitive to the presence or absence of the ovarian hormones, estrogen and progesterone. We have shown that serotonin neurons in nonhuman primates contain estrogen receptor beta and progestin receptors. Thus, they are targets for ovarian steroids which in turn modify gene expression. Any change in serotoninergic neural function could be manifested by a change in any of the projection target systems and in this manner, serotonin neurons integrate steroid hormone information and partially transduce their action in the CNS. This article reviews the work conducted in this laboratory on the actions of estrogens and progestins in the serotonin neural system of nonhuman primates. Comparisons to results obtained in other laboratory animal models are made when available and limited clinical data are referenced. The ability of estrogens and progestins to alter the function of the serotonin neural system at various levels provides a cellular mechanism whereby ovarian hormones can impact cognition, mood or arousal, hormone secretion, pain, and other neural circuits.     

Gender-Specific Reduction of Estrogen-Sensitive Small RNA,miR-30b,in Subjects With Schizophrenia

Estrogen signaling pathways affect cortical function and metabolism, are thought to play a role in the pathophysiology of schizophrenia, and exert neuroprotective effects in female subjects at risk. However, the molecular signatures of estrogen signaling in normal and diseased cerebral cortex remain largely unexplored. Expression of the estrogen-sensitive small RNA, microRNA-30b (miR-30b), was studied in 30 controls and 30 matched samples from subjects diagnosed with schizophrenia from prefrontal cortex (PFC), as well as in 23 samples from parietal cortex (12 controls and 11 schizophrenia cases). The majority of case and control samples were genotyped for an estrogen receptor α (Esr1) sequence variant (rs2234693) previously associated with genetic risk, and a subset of them were subjected to further analysis to determine expression of mature and precursor forms of miR-30b (pre/pri-miR-30b). Gender-dimorphic expression was also explored in mouse frontal cortex and hippocampus. A significant interaction between gender and diagnosis was discovered for changes in mature miR-30b levels, so that miR-30b expression was significantly reduced in the cerebral cortex of female but not male subjects with schizophrenia. In addition, disease-related changes in miR-30b expression in a subset of female subjects were further modulated by Esr1 genotype. Changes after antipsychotic drug exposure remained insignificant. These preliminary findings point to the possibility that disease-related changes in the expression of small noncoding RNAs such as miR-30b in schizophrenia could be influenced by gender and potentially regulated by estrogen signaling.     

Antipsychotic medication,prolactin elevation,and ovarian function in women with schizophrenia and schizoaffective disorder

Some, but not all, antipsychotics elevate serum prolactin. Antipsychotic-induced hyperprolactinemia is thought to account for high rates of menstrual dysfunction and diminished estrogen levels in women with schizophrenia. However, few studies have directly assessed the relationships between prolactin, menstrual function, and ovarian hormone levels in this population. Sixteen premenopausal women with schizophrenia and schizoaffective disorder, eight treated with an antipsychotic with prolactin-elevating potential (five with typical antipsychotics and three with risperidone) and eight treated with an antipsychotic with prolactin-sparing potential (seven with olanzapine and one with clozapine), were studied for eight weeks. Data were collected on menstrual functioning and on serum prolactin, estradiol, and progesterone levels, and were compared between subjects who received an antipsychotic with prolactin-elevating potential and an antipsychotic with prolactin-sparing potential, and between subjects with hyperprolactinemia (N=6) and normoprolactinemia (N=10). Additionally, peak ovarian hormone levels were compared to normal values. While mean prolactin levels of subjects who received an antipsychotic with prolactin-elevating potential were significantly greater than those of subjects who received an antipsychotic with prolactin-sparing potential, there were no differences in rates of menstrual dysfunction or in ovarian hormone values between the two groups. Additionally, similar rates of menstrual dysfunction and ovarian hormone values were observed between the hyperprolactinemic and normoprolactinemic subjects. Moreover, irrespective of medication type or prolactin status, most subjects had peak estradiol levels below normal reference values for the periovulatory phase of the menstrual cycle. While our sample size is small, warranting the need for further investigation, the findings of this preliminary study suggest that antipsychotic-induced hyperprolactinemia, alone, may not adequately explain the observed ovarian dysfunction in women with schizophrenia.     

The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female

It is clear from both clinical observations of women, and research in laboratory animals, that gonadal hormones exert a profound influence on neuronal excitability, seizures, and epilepsy. These studies have led to a focus on two of the primary ovarian steroid hormones, estrogen and progesterone, to clarify how gonadal hormones influence seizures in women with epilepsy. The prevailing view is that estrogen is proconvulsant, whereas progesterone is anticonvulsant. However, estrogen and progesterone may not be the only reproductive hormones to consider in evaluating excitability, seizures, or epilepsy in the female. It seems unlikely that estrogen and progesterone would exert single, uniform actions given our current understanding of their complex pharmacological and physiological relationships. Their modulatory effects are likely to depend on endocrine state, relative concentration, metabolism, and many other factors. Despite the challenges these issues raise to future research, some recent advances have helped clarify past confusion in the literature. In addition, testable hypotheses have developed for complex clinical problems such as "catamenial epilepsy." Clinical and animal research, designed with the relevant endocrinological and neurobiological issues in mind, will help advance this field in the future.     

Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects.

BACKGROUND: We recently reported a laminar-specific reduction in the density of tyrosine hydroxylase (TH)-immunoreactive axons in the prefrontal cortex of subjects with schizophrenia. In this report, we extend these investigations to the entorhinal cortex (ERC), another candidate site of dysfunction in this disorder. METHODS: Using immunocytochemical techniques and blind quantitative analyses, we determined the density of TH-immunoreactive axons in the rostral subdivision of the ERC from seven matched pairs of schizophrenic and control subjects. RESULTS: The relative density of TH-labeled axons was significantly decreased by over 60% in layers 3 and 6, but not in layer 1, of the ERC in schizophrenic subjects. In contrast, in the prefrontal cortex of the same subjects, labeled axon density was significantly decreased by 62% only in layer 6. Furthermore, the length of TH-labeled axons did not differ between six matched pairs of nonschizophrenic psychiatric and control subjects in any layer of the ERC. Finally, the density of TH-labeled axons in the ERC of cynomolgus monkeys chronically treated with haloperidol was not reduced relative to control animals. CONCLUSIONS: These findings reveal regional- and laminar-specific alterations in TH-immunoreactive axons that appear to be specific to the pathophysiology of schizophrenia.     

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

Summary The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease.     

Distribution of neurotensin-containing fibers in the frontal cortex of the macaque monkey.

The distribution of neurotensin-containing fibers was examined in the frontal cortex of the monkey Macaca fuscata using the immunoperoxidase histochemical technique. An extremely dense network of neurotensin-containing fibers was observed in the medial prefrontal regions. The majority of cortical neurotensin fibers was observed in the anterior cingulate cortex (Walker's area 24) and adjacent medial prefrontal regions (areas 6 and 32). In area 24, the fiber density was similar to that in the nucleus accumbens. Immunoreactive fibers were particularly dense in two pyramidal layers (III, V). The medial prefrontal regions, areas 6 and 32, contained a moderate density of immunoreactive fibers. This regional distribution of neurotensin-containing fibers was not observed in other cortical fiber systems that contained substance P, somatostatin, or tyrosine hydroxylase. No neurotensin-containing cell bodies were observed in the frontal cortex. The present study demonstrates that the laminar and regional distributions of neurotensin-containing fibers are unique when compared to those of substance P- or somatostatin-containing fibers, and also distinct from that of catecholaminergic fibers. The distribution of telencephalic neurotensin fibers points to a relationship with limbic structures.     

Deficit in decision making in catatonic schizophrenia: an exploratory study

Catatonic schizophrenia can be distinguished from paranoid schizophrenia by prominent behavioral and motor anomalies. As demonstrated in recent imaging studies, behavioral symptoms may be related to dysfunction in the ventral prefrontal cortex. However, the neuropsychological correlates of ventral prefrontal cortical dysfunction remain unclear. In an exploratory study, we investigated eight patients with catatonic schizophrenia and compared them with 19 patients with paranoid schizophrenia and 26 healthy subjects. The Iowa Gambling Task (IGT) and the Object Alternation Task (OAT) served as measures of ventral prefrontal cortical function. In addition, other prefrontal cortical tests such as a visual working memory task, a Go-NoGo task, and the Wisconsin Card Sorting Test, as well as attentional tasks, were included in the test battery. Catatonic patients showed significant deficits in the IGT characterized by an inability to shift from the initial preference for high-risk cards to a more advantageous strategy with low-risk cards. Moreover, catatonic patients showed significant deficits in the OAT. In conclusion, our preliminary results suggest a specific deficit in catatonic schizophrenia in those neuropsychological measures that are associated with ventral prefrontal cortical function.