Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone.

Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [(18)F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.

The neuropharmacology of prolactin secretion elicited by 3,4-methylenedioxymethamphetamine ("ecstasy"): a concurrent microdialysis and plasma analysis study.

3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug "ecstasy". Racemic MDMA (S,R(+/-)-MDMA) and its stereoisomers elicit complex spectrums of psychobiological, neurochemical, and hormonal effects. In this regard, recent findings demonstrated that S,R(+/-)-MDMA and its stereoisomer R(-)-MDMA elicit increases in striatal extracellular serotonin levels and plasma levels of the hormone prolactin in rhesus monkeys. In the present mechanistic study, we evaluated the role of the serotonin transporter and the 5-HT(2A) receptor in S,R(+/-)-MDMA- and R(-)-MDMA-elicited prolactin secretion in rhesus monkeys through concurrent microdialysis and plasma analysis determinations and drug interaction experiments. Concurrent neurochemical and hormone determinations showed a strong positive temporal correlation between serotonin release and prolactin secretion. Consistent with their distinct mechanisms of action and previous studies showing that the serotonin transporter inhibitor fluoxetine attenuates the behavioral and neurochemical effects of S,R(+/-)-MDMA, pretreatment with fluoxetine attenuated serotonin release elicited by either S,R(+/-)-MDMA or R(-)-MDMA. As hypothesized, at a dose that had no significant effects on circulating prolactin levels when administered alone, fluoxetine also attenuated prolactin secretion elicited by S,R(+/-)-MDMA. In contrast, combined pretreatment with both fluoxetine and the selective 5-HT(2A) receptor antagonist M100907 was required to attenuate prolactin secretion elicited by R(-)-MDMA, suggesting that this stereoisomer of S,R(+/-)-MDMA elicits prolactin secretion through both serotonin release and direct agonism of 5-HT(2A) receptors. Accordingly, these findings inform our understanding of the neuropharmacology of both S,R(+/-)-MDMA and R(-)-MDMA and the regulation of prolactin secretion.

Integrative proteomic analysis of the nucleus accumbens in rhesus monkeys following cocaine self-administration.

The reinforcing effects and long-term consequences of cocaine self-administration have been associated with brain regions of the mesolimbic dopamine pathway, namely the nucleus accumbens (NAc). Studies of cocaine-induced biochemical adaptations in rodent models have advanced our knowledge; however, unbiased detailed assessments of intracellular alterations in the primate brain are scarce, yet essential, to develop a comprehensive understanding of cocaine addiction. To this end, two-dimensional difference in gel electrophoresis (2D-DIGE) was used to compare changes in cytosolic protein abundance in the NAc between rhesus monkeys self-administering cocaine and controls. Following image normalization, spots with significantly differential image intensities (P<0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser-desorption ionization time-of-flight time-of-flight (MALDI-TOF-TOF). In total, 1098 spots were subjected to statistical analysis with 22 spots found to be differentially abundant of which 18 proteins were positively identified by mass spectrometry. In addition, approximately 1000 protein spots were constitutively expressed of which 21 proteins were positively identified by mass spectrometry. Increased levels of proteins in the cocaine-exposed monkeys include glial fibrillary acidic protein, syntaxin-binding protein 3, protein kinase C isoform, adenylate kinase isoenzyme 5 and mitochondrial-related proteins, whereas decreased levels of proteins included beta-soluble N-ethylmaleimide-sensitive factor attachment protein and neural and non-neural enolase. Using a complimentary proteomics approach, the differential expression of phosphorylated proteins in the cytosolic fraction of these subjects was examined. Two-dimensional gel electrophoresis (2DGE) was followed by gel staining with Pro-Q Diamond phosphoprotein gel stain, enabling differentiation of approximately 150 phosphoprotein spots between the groups. Following excision and trypsin digestions, MALDI-TOF-TOF was used to confirm the identity of 15 cocaine-altered phosphoproteins. Significant increased levels were detected for gamma-aminobutyric acid type A receptor-associated protein 1, 14-3-3 gamma-protein, glutathione S-transferase and brain-type aldolase, whereas significant decreases were observed for beta-actin, Rab GDP-dissociation inhibitor, guanine deaminase, peroxiredoxin 2 isoform b and several mitochondrial proteins. Results from these studies indicate coordinated dysregulation of proteins related to cell structure, signaling, metabolism and mitochondrial function. These data extend and compliment previous studies of cocaine-induced biochemical alterations in human postmortem brain tissue, using an animal model that closely recapitulates the human condition and provide new insight into the molecular basis of the disease and potential targets for pharmacotherapeutic intervention.

Pharmacokinetics of fluoxetine in rhesus macaques following multiple routes of administration.

BACKGROUND/AIMS: Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor currently used to treat depression and mood disorders. It has been widely studied clinically and preclinically, yet there is limited knowledge of its pharmacokinetics in nonhuman primates. METHODS: The present study characterized the pharmacokinetics of fluoxetine and its active metabolite norfluoxetine in rhesus macaques following both acute (1, 3, 5.6 and 10 mg/kg) and chronic doses (5.6 and 10 mg/kg/day) via different routes of administration (intravenous, subcutaneous, intramuscular, and oral). Blood samples were collected at multiple time points following administration and analyzed using mass spectrometry. RESULTS: Fluoxetine had a half-life of 11-16 h and norfluoxetine had a half-life of 21-29 h. Potentially functionally significant serum concentrations of norfluoxetine were present at 24 h even after a single administration of fluoxetine. Similar to observations in humans under steady state conditions, norfluoxetine accounted for the greater percentage of active drug in the blood stream. CONCLUSION: A daily dose of 10 mg/kg administered orally maintained serum concentrations in the human clinical range over the course of 6 weeks. Given the long half-lives of fluoxetine and norfluoxetine observed in this study, precautions should be taken when designing preclinical studies to prevent accumulation of drug serum concentrations.

Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys.

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that elicits complex biological effects in humans. One plausible mechanism for this phenomenon is that racemic MDMA is composed of two stereoisomers that exhibit qualitatively different pharmacological effects. In support of this, studies have shown that R(-)-MDMA tends to have hallucinogen-like effects, whereas S(+)-MDMA tends to have psychomotor stimulant-like effects. However, relatively little is known about whether these stereoisomers engender different endocrine and neurochemical effects. In the present study, the endocrine and neurochemical effects of each stereoisomer and the racemate were assessed in four rhesus monkeys after intravenous delivery at doses (1-3 mg/kg) that approximated voluntary self-administration by rhesus monkeys and human recreational users. Specifically, fluorescence-based enzyme-linked immunosorbent assay was used to assess plasma prolactin concentrations, and in vivo microdialysis was used to assess extracellular dopamine and serotonin concentrations in the dorsal striatum. R(-)-MDMA, but not S(+)-MDMA, significantly increased plasma prolactin levels and the effects of S,R(+/-)-MDMA were intermediate to each of its component stereoisomers. Although S(+)-MDMA did not alter prolactin levels, it did significantly increase extracellular serotonin concentrations. In addition, S(+)-MDMA, but not R(-)-MDMA, significantly increased dopamine concentrations. Furthermore, as in the prolactin experiment, the effects of the racemate were intermediate to each of the stereoisomers. These studies demonstrate the stereoisomers of MDMA engender qualitatively different endocrine and neurochemical effects, strengthening the inference that differences in these stereoisomers might be the mechanism producing the complex biological effects of the racemic mixture of MDMA in humans.

Discriminative stimulus effects of psychostimulants and hallucinogens in S(+)-3,4-methylenedioxymethamphetamine (MDMA) and R(-)-MDMA trained mice.

3,4-Methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine more commonly known as the drug of abuse "ecstasy." The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted phenethylamines, R(-)-enantiomers tend to have hallucinogen-like effects, whereas S(+)-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S(+)- or R(-)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar phenethylamine dopamine/norepinephrine releaser S(+)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar phenethylamine 5-hydroxytryptamine (5-HT)(2A) agonist 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT(2A) agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(+)-amphetamine fully substituted in the S(+)-MDMA-treated animals but did not substitute for the R(-)-MDMA cue. 2C-T-7 fully substituted in the R(-)-MDMA-trained animals but did not substitute for the S(+)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(+)-MDMA-trained mice, DPT was more potent in R(-)-MDMA-trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.

Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys.

Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate "agonist" medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys (N=3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032-0.01 mg/kg/hr) and RTI-113 (0.01-0.056 mg/kg/h) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys.

Substrate preferences of wild and a mutant house fly acetylcholinesterase and a comparison with the bovine erythrocyte enzyme.

Comparisons were made of purified acetylcholinesterase from the heads of wild type house flies with a mutant form (which bound organophosphates and carbamates less tightly). Using 12 substrates and 6 quaternary inhibitors, the only substantial difference was that the Km for butyrylcholine was 25 times greater for the mutant enzyme, suggesting that butyrylcholine and the organophosphates and carbamates shared a common binding site. The pure enzyme from the wild type house fly was also compared with bovine erythrocyte acetylcholinesterase. The major difference was again with butyrylcholine as substrate: the ability to acylate or deacylate was 30 times greater in the fly enzyme (the Km values differed by a factor of 4).

Effect of dihydroergotamine on +Gz acceleration tolerance.

Dihydroergotamine is a potent vasoconstrictor of the venous capacitance vessels and has been shown to decrease blood pooling in patients with orthostatic hypotension. Acceleration acting on the long axis of the body (+Gz) pools blood into the lower body of the subject. Nine healthy men received an injection of 1 mg dihydroergotamine and 1 ml of saline intramuscularly in a randomised, double blind fashion, and had their Gz acceleration tolerances measured. Dihydroergotamine significantly increased Gz tolerance by 0.24 G and narrowed the difference between the maximum heart rate during the acceleration epoch and resting baseline by 10%. The drug had no effect on blood pressure and heart rate when the subjects changed from the supine to standing position. The increase in Gz tolerance was not sufficient for operational use.

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning.

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg(-1)) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 µg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.

Functional connectivity in frontal-striatal brain networks and cocaine self-administration in female rhesus monkeys.

RATIONALE: Cocaine addiction is characterized by alternating cycles of abstinence and relapse and loss of control of drug use despite severe negative life consequences associated with its abuse. OBJECTIVE: The objective of the present study was to elucidate critical neural circuits involved in individual vulnerabilities to resumption of cocaine self-administration following prolonged abstinence. METHODS: The subjects were three female rhesus monkeys in prolonged abstinence following a long history of cocaine self-administration. Initial experiments examined the effects of acute cocaine administration (0.3 mg/kg, IV) on functional brain connectivity across the whole brain and in specific brain networks related to behavioral control using functional magnetic resonance imaging in fully conscious subjects. Subsequently, these subjects were allowed to resume cocaine self-administration to determine whether loss of basal connectivity within specific brain networks predicted the magnitude of resumption of cocaine intake following prolonged abstinence. RESULTS: Acute cocaine administration robustly decreased global functional connectivity and selectively impaired top-down prefrontal circuits that control behavior, while sparing connectivity of striatal areas within limbic circuits. Importantly, impaired connectivity between prefrontal and striatal areas during abstinence predicted cocaine intake when these subjects were provided renewed access to cocaine. CONCLUSIONS: Based on these findings, loss of prefrontal to striatal functional connectivity may be a critical mechanism underlying the negative downward spiral of cycles of abstinence and relapse that characterizes cocaine addiction.

Behavioral effects of chronically administered cocaine in squirrel monkeys.

Cocaine (0.1 or 0.3 mg/kg/h) was infused continuously from osmotic minipumps during 14-day periods in three squirrel monkeys trained under a fixed-interval schedule of stimulus-shock termination. Chronic exposure to 0.1 mg/kg/h cocaine increased response rates during control sessions for two subjects, and rates returned to pre-infusion levels after the osmotic minipumps were removed. During chronic administration with 0.3 mg/kg/h cocaine, tolerance developed to the gross behavioral effects observed initially in all subjects and to the rate-suppressing effects observed in one subject. Using a cumulative-dosing procedure, cocaine was administered IV acutely once per week before, during and after each chronic administration with cocaine. The acute effects of cocaine on schedule-controlled responding before chronic administration and during chronic exposure to 0.1 and 0.3 mg/kg/h cocaine were similar, providing no evidence of sensitization or tolerance.

Pharmacological interactions between serotonin and dopamine on behavior in the squirrel monkey.

The behavioral effects of GBR 12909, a selective dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. Intermediate doses of GBR 12909 increased FI response rate markedly, and the highest dose decreased response rate below control values. The 5HT uptake inhibitors, alaproclate and fluoxetine, and the 5HT agonist, quipazine, attenuated the behavioral-stimulant effects of GBR 12909, whereas the 5HT2A/2C antagonist, ritanserin, enhanced the behavioral-stimulant effects of the lowest dose. GBR 12909 reliably maintained self-administration, and ritanserin increased response rate maintained by the highest dose. The dopamine agonist, quinpirole, increased FI response rate in only one of three subjects, and ritanserin enhanced the behavioral-stimulant effects of quinpirole in that subject. The dopamine agonist, apomorphine, only decreased FI response rate, and ritanserin did not alter its behavioral effects. The pharmacological profile of GBR 12909 administered alone and in combination with selective 5HT drugs in the present study was similar to that obtained previously with cocaine, further demonstrating that 5HT can reliably modulate the behavioral effects of psychomotor stimulants with prominent dopaminergic actions.

Cocaine-induced changes in extracellular dopamine determined by microdialysis in awake squirrel monkeys.

RATIONALE: The behavioral effects of cocaine have been linked to brain dopamine systems. Extending the findings to neurochemical studies in the squirrel monkey would enhance our understanding of the behavioral pharmacology of cocaine in nonhuman primates. OBJECTIVES: The present studies characterized the effects of cocaine and the selective dopamine uptake inhibitor GBR 12909 on extracellular dopamine in the caudate nucleus of awake squirrel monkeys through microdialysis experiments. METHODS: Guide cannulae were implanted in the caudate nucleus of four monkeys using a stereotaxic apparatus and coordinates obtained from a standard squirrel monkey brain atlas. Accurate probe placement was confirmed in all subjects with magnetic resonance imaging. RESULTS: Collectively, the results support the feasibility of a repeated-measures design. Stability of tissue integrity after repeated probe insertion was supported by measurement of consistent basal levels of dopamine and its metabolites across several experiments, observation of potassium-induced dopamine release and absence of significant glial proliferation as assessed by GFAP (glial fibrillary acidic protein) immunochemistry. Moreover, peak drug effects and time-course of action were similar when multiple probes were positioned in the same anatomical site over several experiments. Cocaine (1.0 mg/kg i.m.) and GBR 12909 (3.0 mg/kg i.m.) elevated extracellular dopamine to approximately 300% of basal levels, but GBR 12909 produced a slower, more sustained elevation than cocaine. CONCLUSIONS: The results validate the use of microdialysis in awake primates using repeated sampling of the same anatomical site and demonstrate orderly changes in extracellular dopamine following administration of dopamine uptake inhibitors.

Serotonergic modulation of the discriminative-stimulus effects of cocaine in squirrel monkeys.

In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever drug-discrimination procedure. Substitution of a range of cocaine doses (0.03-1.7 mg/kg) occasioned orderly, dose-dependent increases in cocaine-lever responding. When administered alone, the non-selective serotonin direct agonist, quipazine, also occasioned increases in cocaine-lever responding which were more pronounced in subjects trained with the lower cocaine dose. When quipazine was administered in combination with cocaine, there was an increase in cocaine-lever responding, indicating an additive effect. The serotonin uptake inhibitor, fluoxetine, occasioned saline-lever responding when administered alone. However, in combination with cocaine, fluoxetine enhanced the discriminative effects of cocaine in subjects trained at the lower cocaine dose. The 5-HT2-selective antagonists, ketanserin and ritanserin, did not occasion cocaine-lever responding when administered alone. In combination with cocaine, ketanserin attenuated the discriminative effects of cocaine in most subjects, and ritanserin attenuated the discriminative effects of cocaine in subjects trained at the higher dose. These results indicate that the discriminative-stimulus effects of cocaine may be increased by direct- and indirect-acting serotonin agonists and attenuated by serotonin antagonists in squirrel monkeys.

Behavioral and physiological effects of xanthines in nonhuman primates.

Caffeine and related xanthines can have significant behavioral effects on measures of locomotor activity, schedule-controlled behavior, drug self-administration, and learning and memory. Xanthines also produce numerous physiological effects including positive inotropic and chronotropic effects on the heart, decreased airway resistance in the lung, and respiratory stimulation. Due to the widespread use of xanthines as constituents of food and beverages and as therapeutic drugs, identification of mechanisms that mediate their pharmacological effects has considerable relevance for drug development and therapeutics. Two primary mechanisms involving the cyclic nucleotide system have been implicated as the bases for the effects of xanthines in the CNS. Many xanthines bind to specific adenosine recognition sites and block the actions of adenosine. Xanthines also inhibit cyclic nucleotide phosphodiesterases, the enzymes responsible for the hydrolytic inactivation of cyclic AMP and cyclic GMP. Recent research in nonhuman primates has characterized the behavioral, respiratory and cardiovascular effects of a number of xanthines and related drugs differing in affinity at different subtypes of adenosine receptors and in capacity to inhibit different molecular forms of PDE. The behavioral-stimulant effects of xanthines appear to be mediated principally by their adenosine-antagonist actions and may be limited by PDE inhibition. The respiratory-stimulant and cardiac effects of xanthines, on the other hand, appear to be linked more closely to their PDE-inhibiting actions than to adenosine antagonism. Converging lines of evidence suggest that adenosine A2 and cAMP-specific (possibly type IV) PDE mechanisms play especially prominent roles in mediating the behavioral and physiological effects of xanthines in nonhuman primates.

Hemodynamic effects of anti-G suit inflation in a 1-G environment.

This study evaluated effects of various anti-G inflation pressures on cardiac volumes and the relationship of these volume changes to mean arterial pressure changes. Ventricular volumes were calculated using two-dimensional echocardiography. An anti-G suit was inflated to 2, 4, and 6 psi in the standing and supine positions for 10 male subjects. In the supine position, mean arterial pressure increased from base line for all three inflation pressures (P = 0.05). The end-diastolic volume increased after 2-psi inflation (P = 0.03). Cardiac output or stroke volume did not change. After standing, mean arterial pressure (P = 0.002), end-diastolic volume (P = 0.002), and stroke volume (P = 0.05) fell after suit deflation. Peripheral vascular resistance fell in the 2- and 4-psi inflation profiles. In the standing protocol, mean arterial pressure, end-diastolic volume, stroke volume, and cardiac output rose with all three inflation pressures (P less than 0.05). After reclining, heart rate increased (P = 0.02) and mean arterial pressure fell (P less than 0.05) in the 4- and 6-psi inflation profiles after suit deflation. Increases in mean arterial pressure are caused by increases in cardiac preload and cardiac output after inflation of the anti-G suit while subjects were standing. Increased cardiac preload was not consistently seen after inflation while subjects were supine. Changes in end-diastolic volume and mean arterial pressure were dependent on the pressure used to inflate the anti-G suit.

Long-duration +Gz acceleration on cardiac volumes determined by two-dimensional echocardiography.

To enhance protection of humans exposed to long-duration low-gravity environments such as the Space Shuttle and National Aerospace Plane during re-entry or in the short-duration high(-)+Gz environment of fighter aircraft, the effects of +Gz acceleration on cardiovascular hemodynamics must be understood. This study reports the use of two-dimensional echocardiography in normal men during +Gz acceleration. The heart's position in relation to the chest did not change during acceleration up to +7 Gz. The success in maintaining high-quality images during exposures to G-forces of this magnitude may be attributed to the relatively low rate of G onset. End-diastolic volumes (EDV) and stroke volumes (SV) decreased during a +Gz acceleration ramp that increased until the subject experienced peripheral light loss (PLL) (P < .05). An inflated G-suit partially counteracted this effect. By 30 seconds of a +3 Gz acceleration plateau, the protective effects of the inflated G-suit to maintain EDV is lost and the EDV of the inflated G-suit was lower than the EDV of the uninflated G-suit (P < .05).

An apparatus and behavioral training protocol to conduct positron emission tomography (PET) neuroimaging in conscious rhesus monkeys.

Nonhuman primates offer a unique resource in neuroimaging research, providing the opportunity to manipulate appropriate biological and behavioral variables under well-controlled experimental conditions in an animal model that is closely related to humans, both functionally and neuroanatomically. The present report describes the development and standardization of PET neuroimaging protocols in conscious rhesus monkeys and their application to characterize the acute effects of cocaine on cerebral blood flow. Specific attention was devoted to the development of an effective and comfortable head restraint device to be used in the imaging of conscious monkeys. The restraint device was designed to attach to a standard primate chair to facilitate frequent immobilization. Subjects received extensive behavioral training prior to neuroimaging in order to ensure their comfort and minimize potential stress associated with the imaging protocols. Functional changes in cerebral blood flow were characterized in three subjects with the positron-emitting tracer 15O water following acute i.v. administration of cocaine. Regions of interest were defined on MRI scans with a high degree of accuracy. Cocaine caused pronounced increases in cerebral blood flow at 5 min postinjection that diminished markedly within 25 min. The results document the feasibility to conduct PET neuroimaging studies of cerebral blood flow in conscious nonhuman primates. Extension of the methodology to include brain activation during behavioral studies could contribute significantly to the growing discipline of behavioral neuroscience.

Behavioral effects of phencyclidine and ketamine alone and in combination with other drugs.

The behavioral effects of phencyclidine (PCP) and ketamine administered alone and in combination with naloxone, atropine, methyl atropine, chlorpromazine and d-amphetamine were studied in squirrel monkeys trained to press a response lever under a fixed-ratio 30 schedule maintained by the termination of a stimulus associated with electric shock presentation. Under non-drug conditions, a period of high-rate responding in the presence of the stimulus associated with shock presentation was followed by a period of no responding during a 40-s timeout scheduled between fixed-ratio components. Mean rates of responding during fixed-ratio components decreased monotonically as PCP dose increased from 0.1 to 0.56 mg/kg, and doses of 3.0 and 5.6 mg/kg ketamine produced decreases in mean response rate comparable to doses of 0.3 and 0.56 mg/kg PCP. The dose-effect functions revealed that ketamine was approximately one-tenth as potent as PCP. The present data also characterized the time-course effects of PCP and ketamine, with the former having effects that were slower in onset yet more persistent in time. None of the drugs studied in combination with PCP and ketamine provided evidence of a pharmacological antagonism of the behavioral effects of the latter two drugs. Rather, the data indicated an enhancement of behavioral effects when certain drug combinations were studied.