Antipsychotic drug action in schizophrenic patients: effect on cortical dopamine metabolism after long-term treatment.

In the brains of deceased schizophrenics who underwent long-term treatment with antipsychotic drugs, the concentration of homovanillic acid (a dopamine metabolite) was significantly increased in the orbital frontal, cingulate, and temporal tip areas of the cortex, but not in the putamen or the nucleus accumbens. The concentration of homovanillic acid was normal in the brains of schizophrenics who were not treated with drugs.

Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine.

The effects of the psychotomimetic drug phencyclidine on the neurochemistry and function of the prefrontal cortex in vervet monkeys were investigated. Monkeys treated with phencyclidine twice a day for 14 days displayed performance deficits on a task that was sensitive to prefrontal cortex function; the deficits were ameliorated by the atypical antipsychotic drug clozapine. Repeated exposure to phencyclidine caused a reduction in both basal and evoked dopamine utilization in the dorsolateral prefrontal cortex, a brain region that has long been associated with cognitive function. Behavioral deficits and decreased dopamine utilization remained after phencyclidine treatment was stopped, an indication that these effects were not simply due to direct drug effects. The data suggest that repeated administration of phencyclidine in monkeys may be useful for studying psychiatric disorders associated with cognitive dysfunction and dopamine hypofunction in the prefrontal cortex, particularly schizophrenia.

Cryopreservation, culture, and transplantation of human fetal mesencephalic tissue into monkeys.

Studies in animals suggest that fetal neural grafts might restore lost neurological function in Parkinson's disease. In monkeys, such grafts survive for many months and reverse signs of parkinsonism, without attendant graft rejection. The successful and reliable application of a similar transplantation procedure to human patients, however, will require neural tissue obtained from human fetal cadavers, with demonstrated cellular identity, viability, and biological safety. In this report, human fetal neural tissue was successfully grafted into the brains of monkeys. Neural tissue was collected from human fetal cadavers after 9 to 12 weeks of gestation and cryopreserved in liquid nitrogen. Viability after up to 2 months of storage was demonstrated by cell culture and by transplantation into monkeys. Cryopreservation and storage of human fetal neural tissue would allow formation of a tissue bank. The stored cells could then be specifically tested to assure their cellular identity, viability, and bacteriological and virological safety before clinical use. The capacity to collect and maintain viable human fetal neural tissue would also facilitate research efforts to understand the development and function of the human brain and provide opportunities to study neurological diseases.

Embryonic substantia nigra grafts show directional outgrowth to cografted striatal grafts and potential for pathway reconstruction in nonhuman primate.

Transplantation of embryonic dopamine (DA) neurons has been tested as a therapy for Parkinson's disease. Most studies placed DA neurons into the striatum instead of the substantia nigra (SN). Reconstruction of this DA pathway could serve to establish a more favorable environment for control of DA release by grafted neurons. To test this we used cografts of striatum to stimulate growth of DA axons from embryonic SN that was implanted adjacent to the host SN in African green monkeys. Embryonic striatum was implanted at one of three progressive distances rostral to the SN. Immunohistochemical analysis revealed DA neuron survival and neuritic outgrowth from the SN grafts at 12-36 weeks after grafting. Each animal showed survival of substantial numbers of DA neurons. Most fibers that exited SN grafts coursed rostrally. Striatal grafts showed evidence of target-directed outgrowth and contained dense patterns of DA axons that could be traced from their origin in the SN grafts. A polarity existed for DA neurites that exited the grafts; that is, those seen caudal to the grafts did not appear to be organized into a directional outflow while those on the rostral side were arranged in linear profiles coursing toward the striatal grafts. Some TH fibers that reached the striatal grafts appeared to arise from the residual DA neurons of the SN. These findings suggest that grafted DA neurons can extend neurites toward a desired target over several millimeters through the brain stem and caudal diencephalon of the monkey brain, which favors the prospect of circuit reconstruction from grafted neurons placed into appropriate locations in their neural circuitry. Further study will assess the degree to which this approach can be used to restore motor balance in the nonhuman primate following neural transplantation.

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: role of autoreceptors.

Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily i.v. injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [125I]-para-iodoclonidine, a radioligand with specificity for high affinity alpha2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared with prenatal saline controls. As alpha2-adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.

Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson's disease and memory.

There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinson's disease and dementia. These differences, as well as direct experimental data in rodents, suggest that gonadal hormones play a role in modulating this system. To determine whether circulating estrogen might have long-term effects by altering the number of dopamine neurons, the density of dopamine neurons was calculated in the compact zone of the substantia nigra of male and intact female short- (10 d) and longer-term (30 d) ovariectomized and short- and longer-term ovariectomized but estrogen-replaced nonhuman primates (African green monkeys). Furthermore, the number of tyrosine hydroxylase-expressing neurons, the total number of all types of neurons, and the volume of the compact zone of the substantia nigra were calculated in 30 d ovariectomized and in 30 d ovariectomized and estrogen-replaced monkeys. Unbiased stereological analyses demonstrated that a 30 d estrogen deprivation results in an apparently permanent loss of >30% of the total number of substantia nigra dopamine cells. Furthermore, the density calculations showed that brief estrogen replacement restores the density of tyrosine hydroxylase-immunoreactive cells after a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms of memory-impairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.

Neural stem cells implanted into MPTP-treated monkeys increase the size of endogenous tyrosine hydroxylase-positive cells found in the striatum: a return to control measures.

Neural stem cells (NSC) have been shown to migrate towards damaged areas, produce trophic factors, and replace lost cells in ways that might be therapeutic for Parkinson's disease (PD). However, there is very little information on the effects of NSC on endogenous cell populations. In the current study, effects of implanted human NSC (hNSC) on endogenous tyrosine hydroxylase-positive cells (TH+ cells) after treatment with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) were explored in nonhuman primates. After MPTP damage and in PD, the primate brain is characterized by decreased numbers of dopamine neurons in the substantia nigra (SN) and an increase in neurons expressing TH in the caudate nucleus. To determine how implanted NSC might affect these cell populations, 11 St. Kitts African green monkeys were treated with the selective dopaminergic neurotoxin, MPTP. Human NSC were implanted into the left and right caudate nucleus and the right SN of eight of the MPTP-treated monkeys. At either 4 or 7 months after NSC implants, the brains were removed and the size and number of TH+ cells in the target areas were assessed. The results were compared to data obtained from normal untreated control monkeys and to the three unimplanted MPTP-treated monkeys. The majority of hNSC were found bilaterally along the nigrostriatal pathway and in the substantia nigra, while relatively few were found in the caudate. In the presence of NSC, the number and size of caudate TH+ cells returned to non-MPTP-treated control levels. MPTP-induced and hNSC-induced changes in the putamen were less apparent. We conclude that after MPTP treatment in the primate, hNSC prevent the MPTP-induced upregulation of TH+ cells in the caudate and putamen, indicating that hNSC may be beneficial to maintaining a normal striatal environment.

Panic-induced elevation of plasma MHPG levels in phobic-anxious patients. Effects of clonidine and imipramine.

Six subjects with the phobic-anxiety syndrome were treated in a controlled, crossover trial of clonidine hydrochloride v imipramine hydrochloride for periods of four weeks each. During each drug trial and during baseline placebo treatment, each patient exposed himself or herself to a situation that previously elicited panic attacks. Self-rated anxiety and plasma levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured to study the effect of the drug treatments on noradrenergic activity and anxiety. Plasma MHPG level correlated highly with rated anxiety under all conditions, and was consistent with significant symptom reduction by clonidine or imipramine. Diminished suppression of plasma MHPG concentrations in two subjects was associated with the continued emergence of panic symptoms in response to phobic stimuli.

Presynaptic adrenergic receptor sensitivity in depression. The effect of long-term desipramine treatment.

Stimulation of presynaptic alpha 2-adrenergic receptors located on norepinephrine (NE)-containing cells in the brain decreases the firing rate and turnover of NE in these neurons. To assess whether abnormalities in the regulation of the NE system during desipramine hydrochloride treatment may be present in depressed patients, the effects of an alpha 2-agonist, clonidine hydrochloride, on plasma levels of the NE metabolite 3-methoxy-4-hydroxy/phenethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in ten depressed patients before and during long-term desipramine treatment. Long-term desipramine treatment significantly attenuated the effects of clonidine on plasma MHPG level and BP, indicating that during desipramine treatment alpha 2-adrenergic receptors had become subsensitive. In addition, plasma MHPG levels were significantly reduced during long-term desipramine treatment. These findings are discussed in relation to the hypothesized therapeutic mechanism of action of desipramine and the hypotheses relating noradrenergic function and depression.

Object retrieval/detour deficits in monkeys produced by prior subchronic phencyclidine administration: evidence for cognitive impulsivity.

BACKGROUND: Impulsivity associated with frontal cortical dysfunction appears to be a direct consequence of chronic consumption of drugs of abuse, though few investigations in animals have attempted to directly address this issue. In this study the effects of repeated, intermittent administration of a psychotomimetic drug of abuse, phencyclidine, on the acquisition and performance of a task sensitive to corticostriatal function was examined in nonhuman primates. METHODS: Monkeys were repeatedly exposed to phencyclidine (0.3 mg/kg) twice daily for 14 days. Acquisition and performance on an object-retrieval detour task was subsequently examined for up to 28 days after drug withdrawal. RESULTS: Animals treated with phencyclidine exhibited impaired acquisition of the task. The performance of trials requiring inhibitory control (as opposed to solely sensory-guided responding) was specifically impaired by prior phencyclidine administration. Impairments were found to be due to increased perseveration and barrier reaching. As is the case after frontal cortex ablation, the behavioral deficits were particularly evident during acquisition and appeared to be alleviated by prolonged training. CONCLUSIONS: The current data demonstrate that subchronic administration of phencyclidine can produce deficits in inhibitory response control that are manifest as impulsivity (increased control of behavior by unconditioned, appetitive stimuli). These data suggest that long-term phencyclidine exposure induces frontostriatal-like cognitive impairments and may represent a potential (drug induced) model for the study of prefrontal cortical cognitive and dopaminergic dysfunction.

14C-homovanillic acid in the cerebrospinal fluid of parkinsonian patients after intravenous 14C-L-dopa.

Six patients with Parkinson's disease and five controls were premedicated with probenecid and the peripheral decarboxylase inhibitor alpha-methyldopathydrazine (Carbidopa) before intravenous administration of 50 muc of 14C-L-dopa in tracer quantity. Seven-and-one-half hours later lumbar CSF was obtained. 14C-homovanillic acid (HVA), a major metabolite of brain dopamine, was isolated by thin-layer chromatography and measured. The statistically significant positive correlation between endogenous HVA and 14C-HVA in the entire patient group and the slightly lower values of endogenous HVA and 14C-HVA in the CSF of the parkinsonians support the assumption that the concentration of HVA in the CSF after probenecid treatment reflects brain dopamine turnover. Measurement of labeled HVA here seems to have little advantage over measurement of endogenous HVA alone.

Effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in rats: dissociation of biochemical and behavioral effects.

BACKGROUND: We have examined the effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in the rat. METHODS: Rats were pretreated daily with saline or nicotine for 20 days then challenged with nicotine or saline on day 21. Animals were trained in a classical conditioned fear paradigm. Dopamine utilization in the medial prefrontal cortex and nucleus accumbens shell and conditioned fear stress-induced immobility responses were assessed. RESULTS: Saline pretreated animals rapidly acquired the conditioned fear stress response as assessed by preferential activation of mesoprefrontal dopamine metabolism and tone-elicited immobility responses. Repeated, but not acute, nicotine pretreatment significantly reduced conditioned fear stress-induced dopamine metabolism in the medial prefrontal cortex and nucleus accumbens shell. Repeated nicotine pretreatment did not modify the acquisition or expression of conditioned fear stress responses, however. CONCLUSIONS: The dissimilar effects of repeated nicotine exposure on the cortical dopamine and behavioral responses to conditioned fear stress suggest that nicotine differs from other agents with anxiolytic activity that produce coordinated changes in conditioned fear stress-induced cortical dopaminergic and behavioral responses. Furthermore, compared with results of acute footshock stress, repeated nicotine pretreatment appears to have differential effects on physical versus psychological stressors. Results are discussed within the clinical context of stress-related psychopathology syndromes and comorbid nicotine dependence.

Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease.

This report describes the prospective and systematic psychiatric assessment of nine patients who received transplantation of human fetal mesencephalic tissue into the caudate nucleus for treatment of Parkinson's disease. Unlike adrenal medullary transplantation, which often causes psychosis or delirium, this procedure appeared to have few perioperative sequelae. On longer-term follow-up, there was some statistical evidence of deterioration in psychiatric status, as manifested primarily in depressive and nonspecific emotional and behavioral symptoms. This group effect was partly attributable to the occurrence of discrete episodes of illness (major depression and panic disorder with agoraphobia) in some patients, but it was unclear whether such episodes occurred more often than would ordinarily be expected in Parkinson's disease. Differences in the neurobiological effects of fetal mesencephalic and adrenal medullary grafts may account for differences in the psychiatric sequelae of patients receiving these procedures.

GABA levels in CSF of patients with psychiatric disorders.

The authors measured gamma-aminobutyric acid (GABA) levels in the lumbar CSF of patients with depression, with psychosis, or undergoing evaluation for a neurologic disorder. GABA levels in the CSF from depressed patients were significantly decreased compared with neurologic control patients. CSF GABA levels in psychotic patients were not different from those in neurologic patients, although the data suggested a decrease in CSF GABA levels in patients with schizoaffective disorder.

Neuroactive metabolites of L-tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid. Effect of tryptophan loading.

Extracellular fluid levels of the neurotoxin quinolinic acid in the corpus striatum of rats, measured by in vivo microdialysis, were increased in a dose-dependent manner following the intraperitoneal administration of tryptophan. The lowest dose of tryptophan (12.5 mg/kg), equivalent to about 5% of the normal daily intake, increased peak quinolinic acid levels nearly 3-fold. At higher doses of tryptophan (up to 250 mg/kg), concentrations of quinolinic acid increased over 200-fold and exceeded potentially neurotoxic levels (10 microM). In contrast, the increase in extracellular serotonin following even the highest tryptophan dose was small (less than 2-fold). These data indicate that quinolinic acid is present in the extracellular fluid where it may function as a neuromodulator and that it is very responsive to physiological changes in precursor availability.

Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin.

The purpose of the present investigation was to examine the topographical organization of efferent projections from the cytoarchitectonic divisions of the mPFC (the medial precentral, dorsal anterior cingulate and prelimbic cortices). We also sought to determine whether the efferents from different regions within the prelimbic division were organized topographically. Anterograde transport of Phaseolus vulgaris leucoagglutinin was used to examine the efferent projections from restricted injection sites within the mPFC. Major targets of the prelimbic area were found to include prefrontal, cingulate, and perirhinal cortical structures, the dorsomedial and ventral striatum, basal forebrain nuclei, basolateral amygdala, lateral hypothalamus, mediodorsal, midline and intralaminar thalamic nuclei, periaqueductal gray region, ventral midbrain tegmentum, laterodorsal tegmental nucleus, and raphe nuclei. Previously unreported projections of the prelimbic region were also observed, including efferents to the anterior olfactory nucleus, the piriform cortex, and the pedunculopontine tegmental-cuneiform region. A topographical organization governed the efferent projections from the prelimbic area, such that the position of terminal fields within target structures was determined by the rostrocaudal, dorsoventral, and mediolateral placement of the injection sites. Efferent projections from the medial precentral and dorsal anterior cingulate divisions (dorsomedial PFC) were organized in a similar topographical fashion and produced a pattern of anterograde labeling different from that seen with prelimbic injection sites. Target structures innervated primarily by the dorsomedial PFC included certain neocortical fields (the motor, somatosensory, and visual cortices), the dorsolateral striatum, superior colliculus, deep mesencephalic nucleus, and the pontine and medullary reticular formation. Previously unreported projections to the paraoculomotor central gray area and the mesencephalic trigeminal nucleus were observed following dorsomedial PFC injections. These results indicate that the efferent projections of the mPFC are topographically organized within and across the cytoarchitectonic divisions of the medial wall cortex. The significance of topographically organized and restricted projections of the rat mPFC is discussed in light of behavioral and physiological studies indicating functional heterogeneity of this region.

General cognitive ability following unilateral and bilateral fetal ventral mesencephalic tissue transplantation for treatment of Parkinson's disease.

OBJECTIVE: To contrast the neuropsychological profiles of Parkinsonian patients, before and after fetal ventral mesencephalic tissue transplantation. DESIGN: Case series of personally examined patients. SETTING: Patients were evaluated by neurologists, neurosurgeons, and neuropsychologists as outpatients at a university hospital. PATIENTS: Fetal mesencephalic tissue was implanted in the right caudate nucleus of three patients and both nuclei of one patient. These patients were evaluated prior to surgery and at 12, 24, and 26 months postoperatively. RESULTS: Factor analysis of the test battery identified four statistically orthogonal test clusters. No statistically significant changes were identified postoperatively for clusters assessing verbal cognitive ability, nonverbal cognitive ability, and information-processing speed. An improvement of verbal memory cluster index was observed 12 months after surgery, and the improvement reached the level of statistical significance at 24 months after surgery. However, the verbal memory of all patients declined between 24 and 36 months after surgery. CONCLUSIONS: Fetal tissue transplantation to one or both caudate nuclei did not permanently arrest cognitive dysfunction. Although there is some evidence of improved cognitive ability after transplantation, it is improbable that normal cognitive function can be restored by this procedure because the impairments of cognitive ability associated with Parkinson's disease do not appear to originate solely from dopamine deficiency.

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.

Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys.

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.

Subchronic phencyclidine administration increases mesolimbic dopaminergic system responsivity and augments stress- and psychostimulant-induced hyperlocomotion.

Previous studies have shown that repeated exposures to phencyclidine (PCP) induces prefrontal cortical dopaminergic and cognitive deficits in rats and monkeys, producing a possible model of schizophrenic frontal cortical dysfunction. In the current study, the effects of subchronic PCP exposure on forebrain dopaminergic function and behavior were further explored. Prefrontal cortical dopamine utilization was reduced 3 weeks after subchronic PCP administration, and the cortical dopaminergic deficit was mimicked by repeated dizocilpine exposure. In contrast, stress- and amphetamine-induced hyperlocomotion, behavior believed to be mediated by activation of mesolimbic dopamine transmission, was enhanced after PCP exposures. Furthermore, haloperidol-induced increases in nucleus accumbens dopamine utilization were larger in magnitude in PCP-treated rats relative to control subjects. These data are the first to demonstrate that repeated exposures to PCP causes prefrontal cortical dopaminergic hypoactivity and subcortical dopaminergic hyper-responsivity in rats, perhaps mimicking alterations in dopaminergic transmission that underlie the behavioral pathology of schizophrenia.