Individual variation creates diverse migratory portfolios in native populations of a mountain ungulate.

Ecological theory and empirical studies have demonstrated population-level demographic benefits resulting from a diversity of migratory behaviors with important implications for ecology, conservation, and evolution of migratory organisms. Nevertheless, evaluation of migratory portfolios (i.e., the variation in migratory behaviors across space and time among individuals within populations) has received relatively little attention in migratory ungulates, where research has focused largely on the dichotomous behaviors (e.g., resident and migrant) of partially migratory populations. Using GPS data from 361 female bighorn sheep (Ovis canadensis) across 17 (4 restored, 6 augmented, 7 native) populations in Montana and Wyoming, USA, we (1) characterized migratory portfolios based on behavioral and spatial migratory characteristics and (2) evaluated the relative influence of landscape attributes and management histories on migratory diversity. Native populations, which had been extant on the landscape for many generations, had more diverse migratory portfolios, higher behavioral switching rates, reduced seasonal range fidelity, and broad dispersion of individuals across summer and winter ranges. In contrast, restored populations with an abbreviated history on the landscape were largely non-migratory with a narrow portfolio of migratory behaviors, less behavioral switching, higher fidelity to seasonal ranges, and less dispersion on summer and winter ranges. Augmented populations were more variable and contained characteristics of both native and restored populations. Differences in migratory diversity among populations were associated with management histories (e.g., restored, augmented, or native). Landscape characteristics such as the duration and regularity of green-up, human landscape alterations, topography, and snow gradients were not strongly associated with migratory diversity. We suggest a two-pronged approach to restoring migratory portfolios in ungulates that first develops behavior-specific habitat models and then places individuals with known migratory behaviors into unoccupied areas in an effort to bolster migratory portfolios in restored populations, potentially with synergistic benefits associated with variation among individuals and resulting portfolio effects. Management efforts to restore diverse migratory portfolios may increase the abundance, resilience, and long-term viability of ungulate populations.

[Recommendations from the German Respiratory Society for Pulmonary Rehabilitation in Patients with COVID-19]. / DGP-Empfehlungen zur pneumologischen Rehabilitation bei COVID-19.

The German Respiratory Society (DGP) has commissioned Assembly 12 "Rehabilitation, Prevention and Tobacco Control" to develop recommendations for the implementation of pulmonary rehabilitation in COVID-19 patients. This position paper is based on the current state of knowledge, which develops daily. This position paper describes the health consequences in COVID-19 as well as the indications for pulmonary rehabilitation. Rehabilitative therapies in COVID-19 are already indicated on the ward or intensive care unit, continue as early pulmonary rehabilitation in the acute hospital and as pulmonary rehabilitation in pulmonary rehabilitation centers. The main focus of this position paper is to propose recommendations for the content-related implementation of a multimodal, interdisciplinary pulmonary rehabilitation in COVID-19 patients.

Resynchronization strategies to improve fertility in lactating dairy cows utilizing a presynchronization injection of GnRH or supplemental progesterone: I. Pregnancy rates and ovarian responses.

Objectives were to evaluate 3 resynchronization protocols for lactating dairy cows. At 32+/-3 d after pre-enrollment artificial insemination (AI; study d -7), 1 wk before pregnancy diagnosis, cows from 2 farms were enrolled and randomly assigned to 1 of 3 resynchronization protocols after balancing for parity, days in milk, and number of previous AI. All cows were examined for pregnancy at 39+/-3 d after pre-enrollment AI (study d 0). Cows enrolled as controls (n=386) diagnosed not pregnant were submitted to a resynchronization protocol (d 0-GnRH, d 7-PGF2alpha, and d 10-GnRH and AI) on the same day. Cows enrolled in the GGPG (GnRH-GnRH-PGF2alpha-GnRH) treatment (n=357) received a GnRH injection at enrollment (d -7) and if diagnosed not pregnant were submitted to the resynchronization protocol for control cows on d 0. Cows enrolled in CIDR treatment (n=316) diagnosed not pregnant received the resynchronization protocol described for control cows with addition of a controlled internal drug release (CIDR) insert containing progesterone (P4) from d 0 to 7. In a subgroup of cows, ovaries were scanned and blood was sampled for P4 concentration on d 0 and 7. After resynchronized AI, cows were diagnosed for pregnancy at 39+/-3 and 67+/-3 d (California herds) or 120+/-3 d (Arizona herds). Cows in the GGPG treatment had more corpora lutea than CIDR and control cows on d 0 (1.30+/-0.11, 1.05+/-0.11, and 1.05+/-0.11, respectively) and d 7 (1.41+/-0.14, 0.97+/-0.13, and 1.03+/-0.14, respectively). A greater percentage of GGPG cows ovulated to GnRH given on d 0 compared with CIDR and control cows (48.4, 29.6, and 36.6%, respectively), but CIDR and control did not differ. At 39+/-3 d after resynchronized AI, pregnancy per AI (P/AI) was increased in GGPG (33.6%) and CIDR (31.3%) cows compared with control (24.6%) cows. At 67 or 120+/-3 d after resynchronized AI, P/AI of GGPG and CIDR cows was increased compared with control cows (31.2, 29.5, and 22.1%, respectively). Presynchronizing the estrous cycle of lactating dairy cows with a GnRH 7 d before the start of the resynchronization protocol or use of a CIDR insert within the resynchronization protocol resulted in greater P/AI after resynchronized AI compared with control cows.

Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET.

The regional distributions of monoamine oxidase (MAO) types A and B have been identified in human brain in vivo with intravenously injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and positron emission tomography. The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in one subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO B for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.

Antipredator response diminishes during periods of resource deficit for a large herbivore.

The starvation-predation hypothesis predicts that, during resource shortages, prey forego antipredator behavior and forage as much as possible to avoid starvation, even when risk of predation is high. We tested this hypothesis using GPS locations collected simultaneously from moose (Alces alces) and wolves (Canis lupus) in the Greater Yellowstone Ecosystem of North America. We assessed shifts in the speed, displacement, and habitat selection of moose 24 h following encounter with wolves (0-1,500 m distance). We examined whether the strength of antipredator behaviors would weaken as winter progressed and the nutritional condition of moose declined. Moose responded to wolf encounters by increasing their rate of movement in early winter, but only within 500 m distance. Importantly, these responses attenuated as winter progressed. Moose did not avoid their preferred foraging habitat (riparian areas) following encounters with wolves at any distance, and instead they more strongly selected riparian areas, especially in early winter. Our findings support theoretical predictions that resource deficits should dampen prey antipredator behavior, and suggest that nutritional condition of prey may buffer against run-away risk effects in food webs involving large mammalian predators and prey.

Calibration drift in a laboratory high purity germanium detector spectrometry system.

For unknown radionuclide identification, it is important that a high purity germanium (HPGe) spectrometry system be calibrated correctly for energy. The energy calibration of an HPGe spectrometry system will drift over time due to a variety of factors including the ambient temperature, the line voltage applied to the system, variation in the electronics, and other possible influences. In order to better understand the nature of this energy calibration drift, calibration spectra were collected over a period of several months from a laboratory HPGe spectrometry system. System parameters, including detector voltage, amplifier gain, and preamplifier gain, were not deliberately modified during the course of the experiment. The system was calibrated routinely over the 90 days, and the results of the calibrations were compared in order to assess the drift in the energy calibration of the detector over time. The analysis of a 36% high purity germanium system demonstrated the energy calibration drifted an average of 0.014 keV d(-1) to 0.041 keV d(-1) depending upon energy. At 1,332 keV, one day after calibration, it was shown that up to half of the total error in energy calibration was as a result of calibration drift.

Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain.

BACKGROUND: The purposes of this study were to investigate the pharmacokinetics of methylphenidate hydrochloride (Ritalin) in the human brain, to compare them with those of cocaine, and to evaluate whether cocaine and methylphenidate compete for the same binding sites. METHODS: We used positron emission tomography to measure the temporal and spatial distribution of carbon 11 (11C)-labeled methylphenidate. These results were compared with those obtained previously for [11C]cocaine. Eight healthy male subjects, 20 to 51 years of age, were scanned with [11C]methylphenidate. Three were tested twice to assess test-retest variability, four were tested at baseline and after administration of methylphenidate, and one was tested with [11C]methylphenidate and [11C]cocaine. Two baboons were scanned to evaluate whether there was competition between cocaine and methylphenidate for the same binding sites in the brain. RESULTS: The uptake of [11C]methylphenidate in the brain was high (mean +/- SD, 7.5% +/- 1.5%), and the maximal concentration occurred in striatum. Pretreatment with methylphenidate decreased binding only in striatum (40%). Although the regional distribution of [11C]methylphenidate, was identical to that of [11C]cocaine and they competed with each other for the same binding sites, these two drugs differed markedly in their pharmacokinetics. Clearance of [11C]methylphenidate from striatum (90 minutes) was significantly slower than that of [11C]cocaine (20 minutes). For both drugs, their fast uptake in striatum paralleled the experience of the "high." For methylphenidate, the high decreased very rapidly despite significant binding of the drug in the brain. In contrast, for cocaine, the decline in the high paralleled its fast rate of clearance from the brain. CONCLUSION: We speculate that because the experience of the high is associated with the fast uptake of cocaine and methylphenidate in the brain, the slow clearance of methylphenidate from the brain may serve as a limiting factor in promoting its frequent self-administration.

Effects of blood flow on [11C]raclopride binding in the brain: model simulations and kinetic analysis of PET data.

To assess the stability of different measures of receptor occupancy from [11C]raclopride (a D2 antagonist) studies with positron emission tomography, we analyze data from five test/retest studies in normal volunteers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems. The DV ratio showed the smallest variation. Individual differences were reflected in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measurements were addressed both experimentally and by simulation studies using three models that explicitly incorporate blood flow into a compartmental model that also includes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simulation. Experimentally, blood flow was significantly reduced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyperventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which PCO2 was varied. Some variability in the DV ratio was observed but was not correlated with changes in blood flow. This raises the possibility that other factors indirectly related to changes in blood flow (or PCO2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.

Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects.

A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t after which a plot of integral of t0ROI(t')dt'/ROI(t) versus integral of t0Cp(t')dt'/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume,.Vp. For a two-compartment model, the slope is given by lambda + Vp, where lambda is the partition coefficient and the intercept is -1/[kappa 2(1 + Vp/lambda)]. For a three-compartment model, the slope is lambda(1 + Bmax/Kd) + Vp and the intercept is -[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 +/- 0.20, in agreement with literature values.

Decreased cerebral response to inhibitory neurotransmission in alcoholics.

OBJECTIVE: Changes in gamma-aminobutyric acid (GABA)-benzodiazepine receptor function have been implicated in alcohol tolerance, withdrawal, and dependence. The purpose of this study was to investigate whether recently detoxified alcoholic subjects had abnormalities in brain GABA-benzodiazepine receptor function. METHOD: The effect of 30 micrograms/kg of lorazepam on regional brain glucose metabolism was studied in 12 normal subjects and 10 alcoholic subjects with the use of positron emission tomography and [18F]fluorodeoxyglucose. RESULTS: Lorazepam decreased whole brain glucose metabolism in both the normal subjects (13% change) and the alcoholic subjects (10% change), and the response was correlated with the concentration of lorazepam in plasma. Whereas the normal and alcoholic subjects showed similar responses to lorazepam in occipital and cerebellar metabolism, the alcoholic subjects showed significantly less of a response than the comparison subjects in the thalamus, basal ganglia, and orbitofrontal cortex. The rate of response in the orbitofrontal cortex was significantly correlated with cerebellar metabolism at baseline. CONCLUSIONS: The alcoholic subjects had a blunted response to lorazepam that was specific to certain brain regions. The association between cerebellar metabolism and response to lorazepam suggests that the cerebellum may contribute to the decreased sensitivity to lorazepam which was seen in the alcoholic subjects.

Effects of chronic cocaine abuse on postsynaptic dopamine receptors.

To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [18F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [18F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.

Decreased brain metabolism in neurologically intact healthy alcoholics.

OBJECTIVE: The extent to which cerebral dysfunction in alcoholics is related to the direct effects of alcohol in the brain rather than to indirect mechanisms and/or alcohol withdrawal remains unclear. The purpose of this study was to evaluate whether healthy alcoholics with no evidence of alcohol-associated complications showed changes in brain glucose metabolism. METHOD: Positron emission tomography and [18F]-fluorodeoxyglucose were used to measure regional brain metabolism. The study group consisted of 22 normal, healthy, right-handed volunteers and 22 neurologically intact, healthy, right-handed alcoholics tested 6 to 32 days after alcohol discontinuation. RESULTS: Alcoholics showed significantly lower whole brain metabolism than normal control subjects. Normalization of regional metabolic values to the whole brain metabolic rate revealed that the left parietal and right frontal cortices were the most affected regions. Although the whole brain metabolic rate was correlated with the amount of time since alcohol discontinuation, the "normalized" decreases in left parietal and right frontal glucose metabolism were not. CONCLUSIONS: These findings support the contribution of the direct effect of alcohol as well as alcohol withdrawal on the changes in regional brain metabolism seen in alcoholics. They also provide evidence of cerebral changes in neurologically intact healthy alcoholics.

Changes in brain glucose metabolism in cocaine dependence and withdrawal.

OBJECTIVE: The authors investigated changes in brain function associated with cocaine dependence and withdrawal to provide clues regarding the processes that lead to the uncontrollable self-administration of cocaine. METHOD: They measured regional brain metabolism with [18F]-fluorodeoxyglucose (FDG) and positron emission tomography in 15 outpatients with the diagnosis of cocaine abuse and 17 normal comparison subjects. Ten of the patients were studied less than 1 week after they had last had cocaine, and five were studied 2-4 weeks after withdrawal. RESULTS: Patients studied within 1 week of cocaine withdrawal but not those studied within 2-4 weeks of cocaine withdrawal had higher levels of global brain metabolism as well as higher levels of regional brain metabolism in the basal ganglia and orbitofrontal cortex than did normal subjects, probably as a consequence of less brain dopamine activity. There was also a significant relationship between the number of days since cocaine withdrawal and regional brain glucose metabolism in the orbitofrontal cortex and in the basal ganglia, and the correlations between cocaine craving and metabolic activity were significant in the prefrontal cortex and the orbitofrontal cortex. CONCLUSIONS: Although the time-dependent fall in metabolic activity suggests that the higher metabolic activity observed less than a week after cocaine withdrawal may represent a nonspecific expression of drug withdrawal, the selectivity of changes in glucose metabolism for the basal ganglia and for the orbitofrontal cortex suggests that the regional metabolic changes seen in cocaine abusers during detoxification are related to changes in brain dopamine activity.

Enhanced sensitivity to benzodiazepines in active cocaine-abusing subjects: a PET study.

OBJECTIVE: Because cocaine enhances dopamine brain activity and dopamine signals are transferred through gamma-aminobutyric acid pathways, the authors hypothesized GABA-ergic disruption in cocaine-abusing subjects. This study tests this hypothesis. METHOD: GABA brain function was assessed indirectly by measuring the brain metabolic responses to lorazepam, a drug that facilitates GABA neurotransmission. Thirteen current cocaine-abusing subjects and 14 comparison subjects were scanned twice with positron emission tomography and [18F]fluorodeoxyglucose; the first scan was obtained after placebo administration and the second after lorazepam administration (30 micrograms/kg). RESULTS: Despite significantly higher plasma lorazepam concentrations in comparison subjects than in cocaine-abusing subjects, lorazepam-induced decrements in whole brain metabolism were significantly greater in cocaine-abusing (mean = 21%, SD = 13%) than in comparison (mean = 13%, SD = 7%) subjects. These differences were largest in striatum, thalamus, and parietal cortex. Lorazepam-induced sleepiness in cocaine-abusing subjects was intense and was significantly greater than in comparison subjects, and it was correlated with lorazepam-induced changes in thalamic metabolism. Whereas regional metabolic measures during placebo administration were significantly higher in cocaine-abusing subjects than in comparison subjects, the measures during lorazepam administration were equivalent for both groups. CONCLUSIONS: The enhanced sensitivity to lorazepam in cocaine-abusing subjects suggests disruption of GABA pathways that may reflect, in part, cocaine withdrawal. The intense sleepiness induced by lorazepam in some of the abusers, despite their significantly lower plasma concentrations, should alert clinicians of the potential toxicity from accentuated responses to sedative hypnotics in active cocaine-abusing subjects.

Effect of a haloperidol challenge on regional brain metabolism in neuroleptic-responsive and nonresponsive schizophrenic patients.

OBJECTIVE: The CNS metabolic response to a neuroleptic challenge in treatment-responsive and nonresponsive schizophrenic patients was measured in order to examine the relation between treatment outcome and the capacity to alter neurochemical function in response to acute receptor blockade. METHOD: Positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) were used to measure regional cerebral metabolism in seven schizophrenic patients judged to have been responsive to drug treatment previously and seven nonresponsive schizophrenic patients after a drug-free period of at least 3 weeks (baseline) and again 12 hours after administration of 5.0 mg of haloperidol. RESULTS: The haloperidol challenge caused widespread decreases in absolute metabolism in the nonresponsive patients but not the responsive patients. These group differences reflect the findings on the second (challenge) scans, since metabolic values at baseline were not statistically different in the two groups. The pattern of decreased metabolic activity in the nonresponders after the haloperidol challenge is similar to that previously observed in normal subjects. CONCLUSIONS: The metabolic response to drug challenge separates treatment responders from nonresponders and normal subjects. The results suggest that subtyping of schizophrenia (and other psychiatric disorders) can be achieved by measuring the physiologic response to a pharmacologic challenge in vivo with chemical brain-imaging techniques.

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects.

OBJECTIVE: This study was undertaken to measure serotonergic modulation of dopamine in vivo by using positron emission tomography (PET), a radiotracer for the striatal dopamine D2 receptor ([11C]raclopride), and a pharmacologic challenge of the serotonin system (d,l-fenfluramine). METHOD: Two PET studies using [11C]raclopride were performed in 11 normal male subjects before administration of the serotonin-releasing agent and reuptake inhibitor fenfluramine (60 mg p.o.) and 3 hours afterward. A graphical analysis method was used with the [11C]raclopride data to derive the distribution volume of D2 receptors. Plasma levels of fenfluramine, norfenfluramine, homovanillic acid (HVA), cortisol, and prolactin were determined. RESULTS: Levels of fenfluramine and prolactin were elevated 2 hours after fenfluramine administration and remained significantly elevated during the second scan, while levels of HVA and cortisol were not altered significantly during the time of scanning. A significant decrease in the specific binding (striatum) and the nonspecific binding subtracted from the specific binding (striatum minus cerebellum) of [11C]raclopride was observed. The rate of metabolism of [11C]raclopride and the nonspecific binding (cerebellum) were not significantly altered by the fenfluramine intervention. CONCLUSIONS: The observed decrease in [11C]raclopride binding is consistent with an increase in dopamine concentrations and with the ability of serotonin to stimulate dopamine activity. The ability to measure serotonergic modulation of dopamine in vivo may have implications for the study of etiologic and therapeutic mechanisms in schizophrenia, major depressive disorder, obsessive-compulsive disorder, and substance abuse.

Effects of haloperidol challenge on regional cerebral glucose utilization in normal human subjects.

OBJECTIVE: Positron emission tomography and the fluorodeoxyglucose (FDG) method were used to determine the brain's metabolic response to neuroleptic challenge in a normal, disease-free state. METHOD: FDG measurements were obtained before and 12 hours after administration of 5 mg of haloperidol to 12 young normal men. These values were compared with test-retest FDG measures obtained from nine normal male control subjects who received no drug intervention. RESULTS: After haloperidol administration, the haloperidol subjects showed significantly lower glucose utilization in the neocortex, limbic cortex, thalamus, and caudate nucleus but not in the putamen or cerebellum. After adjustment for global effects, significant reductions were still evident in the frontal, occipital, and anterior cingulate cortex, whereas the putamen and cerebellum showed significant increases. CONCLUSIONS: This study, measuring the brain's metabolic response to acute receptor blockade, is a first step in the development of an assay of CNS pharmacological activity. By determining the response to neuroleptic challenge in a normal state, the study establishes a comparison group for determining response to challenge in various psychiatric conditions.

Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates.

The pharmacologic treatment of many neuropsychiatric disorders (Alzheimer's disease, schizophrenia, depressive illness) has been targeted at the central hypothesis that defects in a single neurotransmitter system underlie the pathophysiology of the disease state. With the recognition that such treatments have not been efficacious consistently, recent drug development has been directed at altering other functionally linked neurotransmitters involved in these diseases. Using positron emission tomography, we have noninvasively investigated the effects of two noncholinergic drugs on the release of acetylcholine. By examining the effects of gamma-vinyl gamma-aminobutyric acid (GABA) (a GABA transaminase inhibitor) or altanserin (a serotonergic antagonist) on the regional binding of 11C-benztropine in the primate brain (Papio anubis), we demonstrated that drugs acting upon either GABAergic or serotonergic neurons produce profound regional changes in acetylcholine release. These findings indicate that the mechanisms of action and the subsequent therapeutic efficacy of these centrally acting drugs may be linked to their multitransmitter effects. This application of positron emission tomography represents an extremely promising experimental approach that can be directed towards elucidating abnormalities in neurotransmitter modulation relevant to disease progression and pharmacologic treatment.

Gamma vinyl-GABA differentially modulates NMDA antagonist-induced increases in mesocortical versus mesolimbic DA transmission.

To explore the role of endogenous GABA in NMDA antagonist induced dopamine (DA) release, we used in vivo microdialysis to study the effects of pretreatment with gamma-vinyl GABA (GVG) on phencyclidine (PCP)-induced DA release in terminal regions of midbrain DA neurons. GVG, an irreversible inhibitor of the GABA catabolizing enzyme GABA-AT, significantly reduced the DA response to PCP (7.0 mg/kg) in freely moving animals. Preferential increases in PCP-induced DA release in the PFC (four-fold those of NAcc) were dose-dependently inhibited by acute pretreatment with GVG at doses of 150 (51% inhibition), 300 (68% inhibition), and 500 (82% inhibition) mg/kg, whereas NAcc PCP-induced DA activity was unresponsive to 150 mg/kg and only partially inhibited by 300 and 500 mg/kg. Subchronic treatment with GVG did not enhance the inhibitory capacity of the GABAergic system. While GVG evidently modulates PCP-induced increases in mesocorticolimbic DA transmission, the character of this modulation is regionally specific, with cortical NMDA-antagonist induced increases appearing more sensitive to inhibition by endogenous GABA than subcortical areas.

Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects.

Subanesthetic doses of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine exacerbate psychosis in schizophrenic patients, and ketamine has significant abuse liability. These observations indicate that a secondary effect of ketamine may be to increase dopamine concentrations. The present study was undertaken using positron emission tomography (PET) and the dopamine (D2) radiotracer 11C-raclopride to determine whether ketamine would decrease D2 receptor availability, indicative of an increase in dopamine concentrations. Two scans were performed in seven male control subjects before and after administration of ketamine (0.5 mg/kg, i.v. infused over 20 min). Ketamine significantly increased cortisol levels and decreased dopamine receptor availability in the striatum (specific binding), but not in the cerebellum (nonspecific binding). In addition, the cerebellar binding subtracted from the striatal binding (to account for changes in nonspecific binding) was significantly decreased after ketamine administration. These results provide in vivo evidence for the ability of ketamine to increase striatal dopamine concentrations, consistent with the role of the NMDA receptor in modulating dopamine function.