Susceptibility to a parkinsonian toxin varies during primate development.

Symptoms of Parkinson's disease typically emerge later in life when loss of nigrostriatal dopamine neuron function exceeds the threshold of compensatory mechanisms in the basal ganglia. Although nigrostriatal dopamine neurons are lost during aging, in Parkinson's disease other detrimental factors must play a role to produce greater than normal loss of these neurons. Early development has been hypothesized to be a potentially vulnerable period when environmental or genetic abnormalities may compromise central dopamine neurons. This study uses a specific parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to probe the relative vulnerability of nigrostriatal dopamine neurons at different stages of primate development. Measures of dopamine, homovanillic acid, 1-methyl-pyridinium concentrations and tyrosine hydroxylase immunoreactive neurons indicated that at mid-gestation dopamine neurons are relatively vulnerable to MPTP, whereas later in development or in the young primate these neurons are resistant to the neurotoxin. These studies highlight a potentially greater risk to the fetus of exposure during mid-gestation to environmental agents that cause oxidative stress. In addition, the data suggest that uncoupling protein-2 may be a target for retarding the progressive loss of nigrostriatal dopamine neurons that occurs in Parkinson's disease and aging.

Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease.

Methamphetamine is a CNS stimulant with limited therapeutic indications, but is widely abused. Short-term exposure to higher doses, or long-term exposure to lower doses, of methamphetamine induces lasting damage to nigrostriatal dopamine neurons in man and animals. Strong evidence indicates that the mechanism for this detrimental effect on dopamine neurons involves oxidative stress exerted by reactive oxygen species. This study investigates the relative susceptibility of dopamine neurons in mid-gestation, young, and adult (not aged) monkeys to four treatments with methamphetamine over 2 days. Primate dopamine neurons undergo natural cell death at mid-gestation, and we hypothesized that during this event they are particularly vulnerable to oxidative stress. The results indicated that at mid-gestation and in adults, dopamine neurons were susceptible to methamphetamine-induced damage, as indicated by loss of striatal tyrosine hydroxylase (TH) immunoreactivity and dopamine concentration. However, dopamine neurons in young animals appeared totally resistant to the treatment, despite this group having higher brain levels of methamphetamine 3 h after administration than the adults. As a possible explanation for the protection, striatal glial-derived neurotrophic factor (GDNF) levels were elevated in young animals 1 week after treatment, but not in adults following methamphetamine treatment. Implications of these primate studies are: (1) the susceptibility of dopamine neurons at mid-gestation to methamphetamine warns against the risk of exposing pregnant women to the drug or oxidative stressors, and supports the hypothesis of Parkinson's disease being associated with oxidative stress during development, (2) elucidation of the mechanism of resistance of dopamine neurons in the young animals to methamphetamine-induced oxidative stress may provide targets for slowing or preventing age- or disease-related loss of adult nigrostriatal dopamine (DA) neurons, and (3) the increased striatal production of GDNF in young animals, but not in adults, in response to methamphetamine, suggests the possibility of an age-related change in the neurotrophic capacity of the striatal dopamine system.

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.

Prenatal cocaine exposure increases mesoprefrontal dopamine neuron responsivity to mild stress.

Children whose mothers used cocaine during pregnancy appear to have an increased incidence of certain neurobehavioral deficits. Rodent models of prenatal cocaine exposure have mimicked these deficits in the offspring, yet the biochemical basis of the behavioral abnormalities is unknown. We have been able to reproduce short-term memory deficits in our rat intravenous model of prenatal cocaine exposure, and as short-term memory is dependent on the function of dopamine neurons innervating the medial prefrontal cortex, we hypothesized that prenatal cocaine induces a dysfunction in the regulation of this pathway. Here we report that mild footshock stress, which preferentially activates the mesoprefrontal dopamine system, leads to an enhanced increase in dopamine turnover in the ventromedial prefrontal cortex of adolescent (postnatal day 35-37) rats exposed to cocaine in utero, suggesting that the dopamine neurons innervating this region are hyperresponsive in these rats. Thus, this biochemical alteration may be central to some of the cognitive deficits exhibited by offspring that were exposed to cocaine during fetal development.

Prenatal exposure to cocaine reduces the number and enhances reactivity of A10 dopaminergic neurons to environmental stress.

Prenatal exposure to cocaine has been shown to result in poor cognitive performance in the resulting offspring in humans and laboratory animals. The underlying biochemical changes that contribute to these behavioral effects are not known but have been proposed to involve changes in dopaminergic function. In these studies, we exposed rats to cocaine in utero using the clinically relevant intravenous model and report a mean loss of 24.8% of the tyrosine hydroxylase immunoreactive, presumed dopaminergic, neurons in the A10, but not A9 and A8, cell groups of the young adult offspring. Additionally, in prenatal cocaine-exposed rats dopaminergic neurons in the ventral, midline A10, and lateral A9 regions demonstrated a hyperreactivity to environmental stress, as measured by activation of the immediate-early gene, Fos. Mild, intermittent footshock did not further increase the number of dopamine neurons expressing Fos in prenatal cocaine-exposed rats, as it did in the prenatal saline controls. Because the exposure to cocaine took place during development, other potential changes in dopaminergic and nondopaminergic neuronal systems could result from the cocaine-induced reduction in numbers of A10 dopamine neurons. We hypothesize that a perinatal loss of A10 dopamine neurons, and subsequent developmental changes, contributes to a dysregulation of the adult mesoprefrontal system, resulting in the reported cognitive deficits.

TMT, a predator odor, elevates mesoprefrontal dopamine metabolic activity and disrupts short-term working memory in the rat.

Working memory has been proposed to require the proper functioning of the medial prefrontal cortex and its dopaminergic innervation. The dopaminergic input to the medial prefrontal cortex has been demonstrated to be sensitive to physical and psychological stress. In this report, we demonstrate that a brief exposure to 2, 5-dihydro-2,4,5-trimethylthiazoline (TMT), an odor derived from a predator of the rat, the fox, resulted in elevated dopamine metabolism in the medial prefrontal cortex and elevated serum corticosterone. We tested the effects of this olfactory stress on working memory using a spontaneous, delayed, non-matching-to-sample task using object recognition methods. Rats were exposed to one set of objects and, after a delay of 1, 15 or 60 min, later demonstrated a robust working memory of the familiar object compared to a novel object. When rats were exposed to TMT during the 15-min delay, working memory was disrupted without altering exploratory behavior. We conclude from these studies that (1) TMT selectively activates mesoprefrontal dopamine neurons, (2) TMT exposure can disrupt working memory and (3) this disruption in working memory is not due to an overall suppression of exploratory behavior but may involve altered mesoprefrontal dopaminergic activity.

The predator odor, TMT, displays a unique, stress-like pattern of dopaminergic and endocrinological activation in the rat.

Predator odors may provide a species relevant aversive stimuli to study the central effects of stress in rats and may have several benefits over currently applied models. Here, we examined one such odor, TMT, isolated from the fox, a predator of the rat, on fear-induced behaviors, serum corticosterone, and central dopamine metabolism. Habituated rats were exposed to TMT, or a control odor, butyric acid, in an open field. For comparison, other rats were subjected to a model of conditioned fear - a traditional fear model. Several similarities between the two stresses were observed including increased serum corticosterone and increased dopamine metabolism in the medial prefrontal cortex. Differences were also observed. TMT, but not conditioned fear, activated dopamine metabolism in the amygdala, but not the nucleus accumbens core and shell. Rats exposed to conditioned fear, but not TMT odor, demonstrated altered behaviors associated with fear, including locomotion, grooming and immobility. Finally, rats reexposed to TMT after a 24-h delay did not demonstrate any of the changes observed with acute exposure to TMT. These data indicate acute exposure to a predator odor, TMT, can result in a unique pattern of biochemical activation that is similar, but not identical, to conditioned fear. The differences may indicate unique features of a central 'fear arousal' pathway that responds to innate, unlearned stressful stimuli, such as predator odors.

Divergent effects of putative anxiolytics on stress-induced fos expression in the mesoprefrontal system of the rat.

Previously, we reported that R(+)HA-966, a weak partial agonist for the glycine/NMDA receptor, and guanfacine, a noradrenergic alpha2 agonist, have anxiolytic-like actions on the biochemical activation of the mesoprefrontal dopamine neurons and fear-induced behaviors. Here, we examined these two putative anxiolytic agents, both with primary actions independent of GABAergic systems, for their ability to alter stress-induced Fos-like immunoreactivity in the mesoprefrontal cortex and in tyrosine hydroxylase-stained, presumed dopaminergic, neurons in the ventral tegmental area. The benzodiazepine agonist, lorazepam, and partial agonist, bretazenil, were also tested in this footshock paradigm [10 x 0.5 sec, 0.8 mA paired with a 5-sec tone]. In saline-treated rats, footshock resulted in an increase in Fos-li in the prelimbic and infralimbic cortices and tyrosine hydroxylase-labeled cells in the ventral tegmental area. Treatment with lorazepam or bretazenil prevented the stress-induced activation in Fos-li nuclei in all regions of the medial prefrontal cortex and in dopaminergic neurons in the ventral tegmental area. In contrast, the actions of the novel anxiolytic-like agents on stress-induced Fos-li were different than those observed with benzodiazepine agonists. Both putative anxiolytics, R(+)HA-966 and guanfacine, did not reduce, but significantly enhanced the stress-induced Fos-li in the prelimbic region of the medial prefrontal cortex. Additionally, treatment with R(+)HA-966 completely blocked, while guanfacine attenuated, the stress-induced increase in the number of Fos-li, TH-li cells in the ventral tegmental area. These results indicate that the putative anxiolytics, R(+)HA-966 and guanfacine, have actions on the stress-sensitive mesoprefrontal system which appear distinct from those of traditional anxiolytics.

Chronic clozapine, but not haloperidol, alters the response of mesoprefrontal dopamine neurons to stress and clozapine challenges in rats.

Previously, we demonstrated that serotonin-lesioned rats had an enhanced mesoprefrontal dopaminergic response to restraint stress. This study attempted to extend our knowledge regarding this serotonin/dopamine interaction by seeing if suppression of serotonin metabolism by chronic administration of the atypical antipsychotic, clozapine, would have similar effects. Both typical and atypical neuroleptics require chronic administration in humans before antipsychotic activity is seen. Rats treated for 21 days with clozapine or haloperidol, a typical antipsychotic without significant binding affinity for serotonergic receptors, showed lowered basal dopamine metabolism in the medial prefrontal cortex, the nucleus accumbens, and the striatum, as expected. Basal serotonin metabolism in the prefrontal cortex was also lowered by clozapine treatment, but not haloperidol. One of two challenges were given to chronically treated rats: 30 min of restraint stress or an acute challenge of clozapine. When corrected for baseline differences, both challenges significantly elevated dopamine metabolism in the prefrontal cortex of the clozapine group more than the saline or haloperidol groups. No hyperresponsiveness was seen with serotonin metabolism in the prefrontal cortex or either dopamine or serotonin metabolism in the nucleus accumbens in clozapine-treated, challenged rats. Additionally, this augmentation of the dopaminergic stress response was not seen with a single, acute administration of clozapine. The significance of the clozapine-induced hyperresponsiveness of the mesoprefrontal dopamine system is discussed with regard to clinical efficacy of clozapine.

The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat.

The mesoprefrontal dopamine neurons are sensitive to physical, pharmacological and psychological stressors. In this report, the role of these neurons in the response to classical fear conditioning was investigated. 6-Hydroxydopamine lesions to the medial prefrontal cortex reduced dopamine levels to about 13% of controls but did not alter behavior during the acquisition of fear conditioning. As expected, conditioned fear increased dopamine metabolism (3,4-dihydroxyphenylacetic acid/dopamine ratio) in the nucleus accumbens in sham-lesion rats. The medial prefrontal 6-hydroxydopamine lesions did not alter this effect. During the expression, however, lesioned rats demonstrated a delayed extinction of the conditioned response without an overall increase in the initial conditioned response. This effect was consistent in rats receiving 6-hydroxydopamine lesions before or after the acquisition period. The calculated rates of extinction showed that the 6-hydroxydopamine lesioned rats had a reduced rate of extinction, but not acquisition, of fear conditioning. The results presented in this manuscript indicate that the mesoprefrontal dopamine neurons are involved in co-ordinating the normal extinction of a fear response but do not alter the acquisition of fearful behaviors. These data are consistent with the conclusion that the mesoprefrontal dopamine neurons are involved in maintaining the animal's response adaptability with regards to stress-related changes in the external environment.

Biochemical and behavioral anxiolytic-like effects of R(+)HA-966 at the level of the ventral tegmental area in rats.

RATIONALE: R(+) HA-966, a weak partial agonist at the glycine/NMDA receptor complex, has been shown to have anxiolytic-like actions on restraint stress-induced mesoprefrontal dopamine metabolism. OBJECTIVE: This study investigates the putative anxiolytic, R(+) HA-966, applied locally at the level of the mesocorticolimbic dopamine cell bodies in the ventral tegmental area (VTA), on the acquisition and expression of conditioned fear. METHODS: Ten to 14 days after cannula implantation, rats were subjected to the acquisition session (10x5 s tone paired with 0.5 s, 0.8 mA footshock) followed about 24 h later by the expression session (ten tones only) of a conditioned fear protocol. Rats were treated with R(+) HA-966 (15 microg/VTA) or saline before either the acquisition or expression sessions. Other rats were injected with saline or R(+) HA-966 (10 microg/side), intra-medial prefrontal cortex, on the expression day. RESULTS: R(+)HA-966, intra-VTA, prevented stress-induced changes in mesoprefrontal, but not mesoaccumbal, dopamine metabolism and was associated with a reduction in fearful responses to physical (footshock) and psychological (conditioned fear) stressors. Additionally, rats treated with R(+)HA-966 intra-VTA before the acquisition session were less fearful at the beginning of the expression session. Local injection of R(+)HA-966 into medial prefrontal cortex did not have anxiolytic-like behavioral or biochemical actions but diminished the expression of exploratory behavior in non-stress, control rats. CONCLUSIONS: These studies indicate that the stress-induced activation of the mesoprefrontal dopamine neurons is necessary for the normal expression of fearful behaviors.

An antisense oligonucleotide reverses the footshock-induced expression of fos in the rat medial prefrontal cortex and the subsequent expression of conditioned fear-induced immobility.

The immediate-early genes, including c-fos, have been proposed to be involved in learning and memory. In this report, we examine stress-induced Fos-like immunoreactivity (Fos-li) in subregions of the prefrontal cortex during a conditioned fear paradigm. During the acquisition phase, the rats were conditioned to fear a formerly neutral tone by pairing the tone with a mild footshock. The rats were then tested for fearful behavior by reexposure to the tone without additional footshock. During acquisition, Fos-li was increased in the medial prefrontal cortex (infralimbic and prelimbic) but not the anterior cingulate and M1 motor cortex. However, during the extinction phase, no significant increase in Fos-li was observed in any region. These findings indicate that acquisition, but not extinction, of conditioned fear is associated with an increase in Fos-li in subregions of the medial prefrontal cortex. In other animals, an antisense oligonucleotide directed against the c-fos mRNA was injected into the infralimbic/prelimbic cortex 12 or 72 hr before the acquisition session. Antisense treatment given 12, but not 72, hr earlier suppressed Fos production without altering behavior during the acquisition session. Three days after the acquisition session, rats were tested for fearful behavior as before. The antisense oligonucleotide blockade of Fos production during acquisition was associated with a significantly less fearful response during the extinction session. These results support a role for Fos in the medial prefrontal cortex during the acquisition of aversive learning.

(S)-(-)-HA-966, a gamma-hydroxybutyrate-like agent, prevents enhanced mesocorticolimbic dopamine metabolism and behavioral correlates of restraint stress, conditioned fear and cocaine sensitization.

This report investigates the effect of the negative enantiomer of 1-hydroxy-3-aminopyrrolidone-2 (HA-966) on behavioral and biochemical changes elicited by pharmacological or experimental paradigms which activate mesocorticolimbic dopaminergic neurotransmission. Several paradigms were used, including cocaine sensitization and two stressors: restraint for 30 min and an aversive conditioning model. (S)-(-)-HA-966 (3 and 5 mg/kg i.p.) prevented restraint stress-induced dopamine utilization in both the medial prefrontal cortex and nucleus accumbens, in contrast to the positive enantiomer. Conditioned fear increased dopamine metabolism in both the core and shell subdivisions of the nucleus accumbens, an effect blocked by (S)-(-)-HA-966. The conditioned stress-induced increase in dopamine metabolism in the medial prefrontal cortex was also blocked by (S)-(-)-HA-966. In addition, (S)-(-)-HA-966 suppressed fear-induced behaviors: immobility and defecation. In other studies, (S)-(-)-HA-966 (3 mg/kg i.p.) prevented locomotor sensitization without altering the acute motoric response elicited by cocaine. The highest dose of (S)-(-)-HA-966 (5 mg/kg i.p.) blocked acute cocaine-induced locomotion but resulted in sedation. In addition, the highest dose of (S)-(-)-HA-966 tested suppressed weight gain in control rats, unlike its enantiomer, (R)-(+)-HA-966. Because (S)-(-)-HA-966 has been proposed to act at the gamma-aminobutyric acid (GABA)B receptor, we examined the ability of (S)-(-) and (R)-(+)-HA-966 to displace [3H]-(-)-baclofen from cortical membranes to assess GABAB receptor binding. Neither enantiomer significantly altered [3H]-(-)-baclofen binding at relevant concentrations, indicating the actions of (S)-(-)-HA-966 reported here are the results of a mechanism apparently independent of the baclofen binding site on the GABAB receptor.

Serotonergic lesions alter cocaine-induced locomotor behavior and stress-activation of the mesocorticolimbic dopamine system.

The aim of this study was to examine the effects of serotonergic lesions to the dorsal raphe on midbrain dopaminergic systems. 5,7-Dihydroxytryptamine lesions of the dorsal raphe resulted in a substantial loss of serotonin in the medial prefrontal cortex (about 75%) and the nucleus accumbens (about 50%), while no change in DA levels or DA metabolism were noted in either region at 12 days postlesion. A transient basal locomotor activation was noted in the lesioned animals compared to the sham controls 7 to 12 days after the lesions. The locomotor response to an acute dose of cocaine was also enhanced in 5,7-dihydroxytryptamine lesioned rats, however, no change in the time course or magnitude of the behavioral locomotor response to repeated cocaine administration was observed. Restraint for 30 min increased DA metabolism in both the NAS and mPFC of sham rats, as expected. However, in 5,7-dihydroxytryptamine lesioned rats, restraint stress enhanced the usual stress-induced increase in DA metabolism by about 50 and 150% in the medial prefrontal cortex and nucleus accumbens, respectively. Our results indicate the 5,7-dihydroxytryptamine lesions of the dorsal raphe lower serotonin in both the mPFC and NAS leading to an enhanced responsiveness of the DA projections in both regions. This effect may be explained by a loss of sensitivity of DA receptors in 5,7-dihydroxytryptamine denervated rats. This interpretation implies that the stimulated, but not basal, release of DA in the mPFC and NAS is dependent on serotonin tone.

Tyrosine enhances behavioral and mesocorticolimbic dopaminergic responses to aversive conditioning.

Tyrosine is a precursor in the biosynthesis of catecholamines and, when administered systemically, has been shown to enhance the in vivo rate of tyrosine hydroxylation in the medial prefrontal cortex. Additionally, exogenous tyrosine has been demonstrated to enhance the pharmacologically-induced increase in dopamine metabolism seen following administration of haloperidol or the anxiogenic B-carboline, FG-7142. In this report, we examine the effect of a physiologically relevant dose of tyrosine (25 mg/kg) on biochemical and behavioral consequences of aversive conditioning. Rats were conditioned to fear a tone by pairing it with footshock, so that when challenged with the tone alone, rats responded with immobility, defecation, and elevated dopamine metabolism in the medial prefrontal cortex and nucleus accumbens. When tyrosine was administered on the test day (tones alone), the rats displayed an even greater elevation of dopamine metabolism in the nucleus accumbens and prolonged immobility to the tone, compared to the saline/conditioned controls. Tyrosine did not alter mobility or dopamine utilization in the nucleus accumbens in nonconditioned controls. However, dopamine metabolism in the medial prefrontal cortex of nonconditioned rats treated with tyrosine was increased to levels similar to those in the conditioned groups. This may be accounted for by handling and by exposure to an unfamiliar environment necessary for nonconditioned controls. We conclude that exogenous tyrosine is able to 1) elevate stress-induced dopamine metabolism in the nucleus accumbens, 2) alter dopamine utilization in the medial prefrontal cortex of handled, nonconditioned controls, and 3) enhance fear-induced immobilization. These data suggest a role for dietary tyrosine in biochemical and behavioral responses to aversive stimuli.

Prior exposure to cocaine diminishes behavioral and biochemical responses to aversive conditioning: reversal by glycine/N-methyl-D-aspartate antagonist co-treatment.

Animals will respond with stress-like behavioral and biochemical changes when exposed to a neutral stimulus that had previously been paired with a stressful stimulus. This phenomenon is generally known as aversive conditioning or conditioned fear. We tested the effect of prior exposure to cocaine on rats subjected to an aversive conditioning paradigm. Rats were given repeated doses of cocaine to develop a reverse tolerance or sensitization to the locomotor stimulant properties of cocaine. We blocked this sensitization to cocaine in one cocaine-exposed group by co-administering an antagonist of the strychinine-insensitive glycine site of the N-methyl-D-aspartate receptor complex, R-(+)-HA-966, which prevented the development of locomotor sensitization to cocaine. After about three weeks, we examined the effect of cocaine sensitization and the prevention of sensitization by R-(+)-HA-966 on aversive conditioning. Rats were exposed to 10 tones (neutral stimuli) paired with footshock (stressful stimuli) over 30 min for the conditioning session. The following day, rts were returned to the cages, received 10 tones only over 30 min and were killed. No drugs were given to any rat before either session and control rats received the tones without footshock in both sessions. Prior exposure to cocaine caused an attenuation of the behavioral effects of aversive conditioning, namely the amount of time spent immobilized and the number of fecal boli expelled. Additionally, the elevated metabolic activity of dopamine in the medial prefrontal cortex, nucleus accumbens and ventral tegmental area associated with aversive conditioning was diminished in rats pre-exposed to cocaine. The behavioral and biochemical effects of pre-exposure to cocaine were reversed in rats that receive R-(+)-HA-966 co-treatment with the five day cocaine sensitization regimen. These data suggest that prior behavioral sensitization to cocaine diminishes the stressful effect of conditioned fear and that these effects are reversed when sensitization is prevented with R-(+)-HA-966.

R-(+)-HA-966, an antagonist for the glycine/NMDA receptor, prevents locomotor sensitization to repeated cocaine exposures.

Repeated administration of cocaine results in a reverse tolerance or sensitization to the locomotor stimulant properties of cocaine. In this study, we examined the effect of an antagonist for the strychinine-insensitive glycine receptor of the NMDA receptor complex, R-(+)-HA-966, on the development of locomotor sensitization to cocaine. Co-administration of R-(+)-HA-966 with repeated cocaine prevented locomotor sensitization to a subsequent challenge dose of cocaine. However, R-(+)-HA-966 (15 mg/kg i.p.) did not attenuate locomotor activation to an acute dose of cocaine (15 mg/kg). These results indicate that the glycine/NMDA receptor is involved in locomotor sensitization to repeated cocaine administration but not in the locomotor activation to the acute stimulant effects of cocaine administration.

Dexamethasone and ergonovine effects on cerebrospinal fluid pressure in conscious rats.

Prior work showed that intracerebroventricular (i.c.v.) infusions of artificial cerebrospinal fluid (aCSF), at a rate of 8 microliters/min x 10 min, elevated CSF pressure (CSFp) of conscious rats after a 2-hour delay. The rise was associated with an increased resistance to outflow and decreased intracranial compliance. When maintained by a continuous infusion of 0.25 microliter/min into each lateral ventricle, CSFp recordings can be made for 24 h and a higher CSFp occurs. Here, we pretreated rats with ergonovine or dexamethasone to determine their effects on the delayed CSFp rise. Ergonovine (0.5 mg/kg i.p.) pretreatment, in a 6-hour protocol using only the 10-min infusion, slightly reduced CSFp (p < 0.05, one-tail test) but the time course of the delayed rise in CSFp was unchanged (p > 0.05). Ergonovine increased intracranial compliance (p < 0.05) 20 min after infusion when CSFp was normal, but not when CSFp was elevated at 4 h (p > 0.05). Dexamethasone (40 micrograms i.m.) pretreatment was tested in the 24-hour protocol. It reduced (p < 0.05) normal CSFp during the 2-hour lag after infusion and the CSFp rise was reduced (p < 0.05) for about 8 h. However, the time course and ending CSFp were unchanged (p > 0.05). Thus, prior cerebral vasoconstriction or a steroidal anti-inflammatory drug have partial efficacy in reducing CSFp, but do not prevent the unknown events that precede the delayed CSFp rise after i.c.v. infusions.

Stress activation of mesocorticolimbic dopamine neurons: effects of a glycine/NMDA receptor antagonist.

Restraint of brief duration causes a metabolic activation of mesocortical and some mesolimbic dopaminergic systems with little effect on the nigrostriatal system. We have examined the ability of an antagonist of the allosteric glycine site of the N-methyl-D-aspartate receptor complex to block the stress-induced response in dopamine utilization. Thirty minutes of restraint stress elevated dopamine metabolism, as measured by the ratio between 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine, in both the medial prefrontal cortex and nucleus accumbens. An antagonist for the glycine/N-methyl-D-aspartate receptor complex, 1-hydroxy-3-aminopyrrolidone-2 ((+)-HA-966), given systemically or injected into the ventral tegmental area, prevents the stress-induced increase in dopamine metabolism in the prefrontal cortex without altering the response in the nucleus accumbens. Similarly, systemic administration of the non-competitive antagonist for the N-methyl-D-aspartate receptor, dizocilpine ((+)-MK-801), blocked the stress-induced rise in dopamine metabolism in the medial prefrontal cortex but not the nucleus accumbens. The negative enantiomer of HA-966 did not produce a selective antagonism of the stress-induced dopamine metabolism in the medial prefrontal cortex. These results support previous work which suggest the mesocortical and mesoaccumbens dopamine neurons respond to excitatory input through different glutamate receptor mechanisms. Additionally, the specific blockade of the stress-induced change in dopamine metabolism in the medial prefrontal cortex by a glycine antagonist implies a role for such an antagonist in treatment of disease states which may involve disruptions of N-methyl-D-aspartate receptor function.

Mechanism of delayed intracranial hypertension after cerebroventricular infusions in conscious rats.

Prior studies showed that cerebroventricular infusions of artificial cerebrospinal fluid, 8 microliter/min for 10 min, followed by a 10 min rest and a 24 h infusion of 0.5 microliters/min, raised cerebrospinal fluid pressure (CSFp) of conscious, unrestrained rats after about 2 h. Here, we report that the 10 min infusion alone evoked a delayed, prolonged rise in CSFp. Pressure during the infusion itself rose and recovered quickly, as is usually reported. Pressure/volume tests, used to calculate resistance to outflow (Ro) and compliance (C), revealed that infusions increased Ro and decreased C, after a delay (P less than 0.05). The rise in CSFp after infusion was blocked by pretreatment with acetazolamide + ouabain (P less than 0.05), but the delayed changes in Ro and C were unaffected. We suggest that the 10 min infusion of a sterile, balanced salt solution has a primary effect that increases Ro; as CSF synthesis continues, C is exhausted and the delayed rise in CSFp ensues. This non-traumatic method of raising CSFp may be a useful method to study intracranial fluid dynamics.