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PubMed1975

Metabolic reduction of benzidine azo dyes to benzidine in the rhesus monkey.

Rhesus monkeys were fed azo dyes derived from benzidine (a known human bladder carcinogen). The urinary excretion of free benzidine was assayed and compared to the amount excreted when benzidine itself was fed. A substantial amount of the dye fed was converted to free benzidine. Results indicate that the simple precaution in the use of only azo dyes manufactured from noncarcinogenic aromatic amines, e.g., aniline, for all consumer products appears prudent.

Aminobiphenyl Compounds↗
PubMed1990

Effects of continuous infusions of SCH 23390 on cocaine- or food-maintained behavior in rhesus monkeys.

Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025-0.10 mg/kg/injection, i.v.) was available under a FR 30 schedule. There was a brief time-out period after each reinforcer was delivered. When responding was stable, monkeys received continuous (24 h/day) i.v. infusions of several doses of SCH 23390 (0.8-6.4 mg/kg/day) for at least the same number of sessions as was required for responding to decline to low levels when saline was available for self-administration. In two of four monkeys, SCH 23390 produced larger decreases in responding maintained by cocaine than in responding maintained by food. The effects of SCH 23390 on drug- and/or food-maintained responding progressively diminished over several days of continuous infusion such that, at the end of the infusion period, responding approximated control rates. Termination of daily infusions of SCH 23390 caused minimal effects on food-maintained responding, whereas in three of four monkeys decreases in responding maintained by cocaine were observed. These latter effects were greater following exposure to the higher doses. Following recovery from these effects, consistently higher rates of responding were maintained by doses of cocaine on the ascending limb of the dose-response function. These results suggest that a D(1) antagonist may decrease the reinforcing effects of cocaine. However, these effects diminish over time and exposure to SCH 23390 may result in long-lasting enhancement of sensitization to the reinforcing effects of cocaine.

Journal Article↗
PubMed1980

Antisera recognising HLA-A, -B and DRW antigens raised in rhesus monkeys.

Rhesus monkeys were immunized with partially purified HLA-A, -B, -C and DR antigens. The resulting sera were shown to have activity against species-specific determinants on both HLA-A, -B, -C chains and beta 2 microglobulin by the use of somatic cell hybrids. When this was removed by absorption, the sera showed activity against three of the four HLA-A and -B antigens in the immunogen when tested on a panel of peripheral blood lymphocytes and T cells. Antibodies recognizing HLA-DR antigens were detected by testing platelet absorbed sera on a panel of typed lymphoblastoid cell lines. After absorption to remove activity against species-specific determinants on the HLA-DR antigens, two cross reacting specificities were defined. One consisted of a determinant in common between HLA-DRw1, 2 and 6 and the other a putative determinant in common between HLA-DRw4, and 5. The nature and significance of these cross-reacting groups of HLA-DR antigens is discussed in the light of current HLA-DR serology and the nature of HLA antigens in general.

Animals↗
PubMed1992

Amnesia for Complex Naturalistic Scenes and for Objects Following Fornix Transection in the Rhesus Monkey.

Rhesus monkeys (Macaca mulatta) were trained to discriminate among many complex naturalistic scenes. The scenes were still frames from a cinema film. They were presented as the discriminative stimuli in a concurrent discrimination learning task in which each discriminative stimulus was presented on one trial each day. Learning of this task was severely impaired by fornix transection. The same animals were also deficient in a similar concurrent discrimination learning task, with each discriminative stimulus presented on one trial each day, but with objects, not complex scenes, as the stimulus material. The impairment in object discrimination learning in the present experiment is attributable to an interaction of object discrimination learning with scene discrimination learning, and can be understood as an effect of interference in long-term memory. In contrast to these impairments in long-term memory, a test of within-session learning of complex scenes, in which the average interval between successive presentations of the same stimulus was < 3 min, was performed without significant impairment by the fornix-transected animals. These results show that long-term memory for complex naturalistic scenes reveals analogues in the monkey of human episodic memory and its impairment in amnesia.

Journal Article↗
PubMed1971

Recovery of function after serial ablation of prefrontal cortex in the rhesus monkey.

Rhesus monkeys with one-stage or serial ablation of sulcus principalis (prefrontal association cortex) were compared on three spatial tasks. On all tests, the serial monkeys made fewer errors than did the monkeys with onestage lesions. These results indicate that partial recovery of function can occur after extensive destruction of association cortex in the mature primate brain if the damage is distributed over a number of operations.

Animals↗
PubMed1999

Identification of the R1 oncogene and its protein product from the rhadinovirus of rhesus monkeys.

Rhesus monkey rhadinovirus (RRV) is a gamma-2 herpesvirus that is most closely related to the human Kaposi's sarcoma-associated herpesvirus (KSHV). We have identified a distinct open reading frame at the left end of RRV and designated it R1. The position of the R1 gene is equivalent to that of the saimiri transforming protein (STP) of herpesvirus saimiri (HVS) and of K1 of KSHV, other members of the gamma-2 or rhadinovirus subgroup of herpesviruses. The R1 sequence revealed an open reading frame encoding a product of 423 amino acids that was predicted to contain an extracellular domain, a transmembrane domain, and a C-terminal cytoplasmic tail reflective of a type I membrane-bound protein. The predicted structural motifs of R1, including the presence of immunoreceptor tyrosine-based activation motifs, resembled those in K1 of KSHV but were distinct from those of STP. R1 sequences from four independent isolates from three different macaque species revealed 0.95 to 7.3% divergence over the 423 amino acids. Variation was located predominantly within the predicted extracellular domain. The R1 protein migrated at 70 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was extensively glycosylated. Tagged R1 protein was localized to the cytoplasmic and plasma membranes of transfected cells. Expression of the R1 gene in Rat-1 fibroblasts induced morphologic changes and focus formation, and injection of R1-expressing cells into nude mice induced the formation of multifocal tumors. A recombinant herpesvirus in which the STP oncogene of HVS was replaced by R1 immortalized T lymphocytes to interleukin-2-independent growth. These results indicate that R1 is an oncogene of RRV.

Amino Acid Sequence↗
PubMed1993

Primary open angle glaucomas in the rhesus monkey.

Rhesus monkeys from the closed Cayo Santiago colony of the University of Puerto Rico demonstrate elevated (> or = 22 mm Hg) intraocular pressure in a pattern which significantly favours certain maternal lineage groupings. The colony had remained genetically pure since 1938. Of nine matriarchal lineages (matrilines) examined, two had an incidence of ocular hypertension of more than 40% and six of more than 10%. Information on 18 matrilines is currently located in the colony data base which identifies each individual and its vital statistics. In 1990, six animals were moved to the laboratory in Florida. Among those from a low incidence matriline, we found abnormal optic nerve cups, pallor, reduced function of (mainly peripheral) fields, progression and loss of optic nerve axons in the presence of ocular hypertension. In another individual where the cup/disc ratio for the right eye was 0.7 and left eye 0.4 and outflow facility was normal, we excluded all other causes of optic nerve atrophy, and low tension glaucoma was diagnosed. This female was from a matriline with a low incidence of ocular hypertension. Relatively rapid aging (3-4 years/human year) monkeys with ocular hypertension and familial clustering produce a near ideal glaucoma research model.

Animals↗
PubMed1987

The effect of frontal eye field and superior colliculus lesions on saccadic latencies in the rhesus monkey.

Rhesus monkeys were trained to make saccadic eye movements to visual targets using detection and discrimination paradigms in which they were required to make a saccade either to a solitary stimulus (detection) or to that same stimulus when it appeared simultaneously with several other stimuli (discrimination). The detection paradigm yielded a bimodal distribution of saccadic latencies with the faster mode peaking around 100 ms (express saccades); the introduction of a pause between the termination of the fixation spot and the onset of the target (gap) increased the frequency of express saccades. The discrimination paradigm, on the other hand, yielded only a unimodal distribution of latencies even when a gap was introduced, and there was no evidence for short-latency "express" saccades. In three monkeys either the frontal eye field or the superior colliculus was ablated unilaterally. Frontal eye field ablation had no discernible long-term effects on the distribution of saccadic latencies in either the detection or discrimination tasks. After unilateral collicular ablation, on the other hand, express saccades obtained in the detection paradigm were eliminated for eye movements contralateral to the lesion, leaving only a unimodal distribution of latencies. This deficit persisted throughout testing, which in one monkey continued for 9 mo. Express saccades were not observed again for saccades contralateral to the lesion, and the mean latency of the contralateral saccades was longer than the mean latency of the second peak for the ipsiversive saccades. The latency distribution of saccades ipsiversive to the collicular lesion was unaffected except for a few days after surgery, during which time an increase in the proportion of express saccades was evident. Saccades obtained with the discrimination paradigm yielded a small but reliable increase in saccadic latencies following collicular lesions, without altering the shape of the distribution. Unilateral muscimol injections into the superior colliculus produced results similar to those obtained immediately after collicular lesions: saccades contralateral to the injection site were strongly inhibited and showed increased saccadic latencies. This was accompanied by a decrease of ipsilateral saccadic latencies and an increase in the number of saccades falling into the express range. The results suggest that the superior colliculus is essential for the generation of short-latency (express) saccades and that the frontal eye fields do not play a significant role in shaping the distribution of saccadic latencies in the paradigms used in this study.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Effect of dietary fat saturation on plasma lipoproteins and high density lipoprotein metabolism of the rhesus monkey.

Rhesus monkeys were fed corn or coconut oil-based diets for 3-6 mo to determine effects on the composition of all lipoprotein classes and on the metabolism of high density lipoproteins (HDL). Major findings included the following. Coconut oil feeding increased concentrations of all classes of plasma lipoproteins without altering lipoprotein size, suggesting an increase in particle number. The percentage of saturated fatty acids in the cholesteryl esters (CE) of low density lipoproteins (LDL) and HDL reached 40% with coconut oil feeding. This value probably constitutes a minimum estimate of the CE which were of intracellular rather than intraplasmic origin. The CE in LDL and HDL were nearly identical suggesting virtually complete equilibration by the core lipid transfer reaction. The CE in very low density lipoproteins, in contrast, were significantly more saturated than those in LDL and HDL irrespective of diet. Lower HDL levels on the corn oil diet were associated with higher fractional catabolic rates for both apolipoprotein A-I (0.42 vs. 0.31 d-1) and apolipoprotein A-II (0.45 vs. 0.30 d-1).

Animals↗
PubMed1976

Pathology of experimental Rocky Mountain spotted fever in rhesus monkeys.

Rhesus monkeys were inoculated intravenously or intraperitoneally with various numbers of Rickettsia rickettsii. Monkeys that were given more than 10(4) organisms intravenously died on days 3-6 after inoculation, whereas those given less than 10(3) intravenously or more than 10(4) intraperitoneally died on day 7 or later. There was no significant difference in incidence of lesions between the early- and late-death groups. Vasculitis and thrombosis occurred most frequently in the nares, pinna of the ear, scrotal skin, and testicle. Adrenal cortical necrosis was caused by capillary thrombosis. Rickettsiae, estimated by plaque formation in culture, were most numerous in the lung and spleen.

Adrenal Cortex↗
PubMed2001

Dietary caloric restriction prevents the age-related decline in plasma melatonin levels of rhesus monkeys.

Rhesus monkeys exhibit an age-associated decrease in peak plasma melatonin levels analogous to that reported for humans. This decrease is essentially abolished in monkeys subjected to a 30% reduction in caloric intake over a 12-yr period. The caloric restriction (CR) effect does not seem to be a reversal, but rather a long-term prevention, of the age-related decline in hormone concentrations. The age effect does not seem to be due to a phase shift in the peak of melatonin secretions, as has been observed in some populations of aged humans. It is also extremely unlikely that the CR effect simply reflects a phase shift, since old monkeys on the diet have nocturnal melatonin levels equal to or greater than adult fully fed controls. Thus, if peak times (approximately 0200 h) were actually shifted, maximal levels in old CR monkeys would be even higher. These findings, coupled with previous observations in humans, suggest that peak plasma melatonin levels may represent a possible candidate "biomarker of aging" in primates. Moreover, this index of age-associated physiological decrement seems to be inhibited by dietary CR.

Aging↗
PubMed1992

Effects of buprenorphine and other opioid agonists and antagonists on alfentanil- and cocaine-reinforced responding in rhesus monkeys.

Rhesus monkeys self-administered a range of doses of either cocaine or alfentanil under a fixed-ratio 30, time out 45 sec schedule of i.v. drug delivery. Buprenorphine suppressed responding maintained by both cocaine and alfentanil; however, much larger doses of buprenorphine were required to suppress cocaine-reinforced as opposed to alfentanil-reinforced responding. Neither cocaine nor alfentanil dose-effect curves were shifted to the right by buprenorphine, but were simply shifted downward. Opioid agonists heroin and nalbuphine produced similar downward shifts in both alfentanil and cocaine dose-effect curves; unlike buprenorphine, similar doses of heroin and nalbuphine suppressed behavior maintained by both cocaine and alfentanil. Increasing doses of the pure opioid antagonist quadazocine produced shifts to the right in the alfentanil rate-maintaining dose-effect curves but had no dose-related effect on behavior maintained by cocaine. The data suggest that buprenorphine suppresses drug-maintained responding through an agonist action but that alfentanil-maintained responding is uniquely sensitive to buprenorphine's effects.

Alfentanil↗
PubMed1991

[Morphological alterations of lymph nodes and thymus during the early course of SIV infection of rhesus monkeys].

Rhesus monkeys (M. mulatta) were i.v. infected with SIV mac251. Three phases of lymph node changes were observed. 1: physiological follicular hyperplasia (3 and 6 weeks p.i.). 2: Alterations of germinal centers: loss of follicular mantle zone, fragmentation or sclerosis (12 and 24 weeks p.i.). 3: Partial depletion of T-lymphocytes, accumulation of plasma cells, increased numbers of syncytial giant cells, hemophgocytosis in the sinuses (about 1 year p.i.). The thymus of the juvenile animals showed first changes 12 and 24 weeks after infection with focal loss of immature (and Ki-67 positive) cortical thymocytes, leading to severe accidental involution of the thymuses one year after infection and reduced numbers of Hassalls corpuscles. These investigations show the value of this animal model for the study of morphology and pathogenesis of AIDS.

Animals↗
PubMed1977

Immune responses during measles infection in immunosuppressed Rhesus monkeys.

Rhesus monkeys immunosuppressed with horse anti-human thymocyte gamma-globulin (ATG) were infected with measles and simultaneously inoculated with sheep erythrocytes (SRBC), a thymus-dependent antigen, and with pneumococcal polysaccaride type III (SSS-III), a thymus-independent antigen. ATG treatment alone suppressed SRBC antibody production, had no effect on SSS-III antibody production, and effectively eliminated circulating T cells compared to nonsuppressed monkeys. ATG treatment of measles-infected monkeys resulted in delayed virus clearance and delayed antibody production compared to nonsuppressed infected monkeys. After cessation of ATG treatment, measles antibodies and T cells reached normal levels, and measles virus was eliminated. Thus, immune clearance of measles virus is T cell-dependent, but the relative roles of cellular- and humoral-mediated immunity in vivo could not be clearly separated. Also, measles infection was associated with a decreased T cell mitogen responsiveness of circulating lymphocytes but not of lymph node lymphocytes, suggesting an altered circulating pattern of the cells responsible for delayed hypersensitivity. Also, measles infection had no effect on T-dependent antibody production to SRBC.

Animals↗
PubMed1990

Pharmacological characterization of the discriminative stimulus effects of cocaine in rhesus monkeys.

Rhesus monkeys (n = 6), trained in a two-lever, food-reinforced paradigm to discriminate cocaine (0.2 or 0.4 mg/kg, i.m.) from saline, received injections of cocaine (0.025-0.40 mg/kg, i.v. or i.m.) or various direct and indirect acting agonists (i.v.). Administration of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. The indirect dopamine agonists GBR 12909 (0.2-1.6 mg/kg), mazindol (0.025-0.4 mg/kg), nomifensine (0.025-0.2 mg/kg) and bupropion (0.1-1.6 mg/kg) each produced dose-related increases in cocaine-appropriate responding, with complete substitution for cocaine achieved at the highest doses of each drug. In contrast, the norepinephrine re-uptake blockers tomoxetine (0.8-6.4 mg/kg) and nisoxetine (0.4-1.6 mg/kg), the serotonin re-uptake blocker fluoxetine (1.6-12.8 mg/kg), the D1 agonist SKF 38393 (3.2-12.8 mg/kg) and the D2 agonist quinpirole (0.05-0.2 mg/kg) failed to engender cocaine-appropriate responding. Administration of the D1 antagonist SCH 23390 (0.05-0.2 mg/kg, i.m.) 20 min before cocaine resulted in a 4- to 8-fold parallel shift to the right in the cocaine dose-response function. Similarly, the D2 antagonist haloperidol (0.003-0.012 mg/kg, i.m.) produced at least a 2-fold shift to the right in the cocaine dose-response function. The results indicate that blockade of dopamine re-uptake is sufficient to mimic the cocaine discriminative stimulus and suggest that stimulation of either D1 or D2 receptors is necessary but not sufficient for the expression of the discriminative stimulus effects of cocaine.

Animals↗
PubMed1989

A pharmacological analysis of the discriminative stimulus properties of d-amphetamine in rhesus monkeys.

Rhesus monkeys (n = 4) were trained to discriminate d-amphetamine (AMPH; 0.67 or 1.33 mumol/kg i.v.) from saline in a two lever, food-reinforced drug discrimination paradigm. After acquisition of the discrimination (average, 127 sessions), the monkeys were tested with a series of compounds selected to characterize the neuronal mechanism(s) of the discrimination. AMPH (0.08-2.6 mumol/kg), cocaine (0.06-1.0 mumol/kg; n = 4), the dopamine (DA) uptake inhibitor bupropion (0.25-2.0 mumol/kg; n = 2) and the norepinephrine (NE) uptake inhibitor nisoxetine (1.0-16 mumol/kg; n = 4) produced dose-related increases in the percentage of responses that occurred on the AMPH-appropriate lever during test sessions in all monkeys tested. For all other drugs tested, individual differences in effects were noted. Compounds with primarily D2 DA receptor activity, including apomorphine (0.06-1.0 mumol/kg; n = 4), piribedil (0.25-8.0 mumol/kg; n = 4), bromocriptine (0.12-1.0 mumol/kg; n = 4) and propylbutyldopamine (0.25-4.0 mumol/kg; n = 3) occasioned AMPH-appropriate responding in one or two monkeys. The D1 agonist SKF 38393 (0.5-64 mumol/kg; n = 4) and pentobarbital (4.0-32 mumol/kg; n = 4) substituted for AMPH in only one monkey. In tests for antagonism, the D1 antagonist SCH 23390 (0.015-0.03 mumol/kg; n = 2) blocked completely the discriminative stimulus effects of AMPH in a dose-related manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Discriminative stimulus properties of intragastrically administered d-amphetamine and pentobarbital in rhesus monkeys.

Rhesus monkeys were trained to discriminate intragastrically administered d-amphetamine (AMPH) or pentobarbital (PENTO) from saline using a signaled shock-avoidance trail procedure. All monkeys maintained criterion levels (greater than 90% drug-appropriate responding) throughout the duration of the study during training sessions. In the AMPH experiment, the anorectics diethylpropion, mazindol, phendimetrazine, phenmetrazine and phentermine completely substituted for the training dose of AMPH. The atypical antidepressant bupropion and the psychomotor stimulant methylphenidate also completely substituted for AMPH. Other anorectics including benzphetamine, clortermine, fenetylline, mefenorex and the psychomotor stimulant pemoline that share some pharmacological properties with AMPH substituted for AMPH in some, but not all, of the monkeys tested. The anorectics fenfluramine and chlorphentermine failed to substitute for AMPH. Drugs from other pharmacological classes such as morphine, diazepam, nortripyline and PENTO also failed to substitute for AMPH, indicating pharmacological specificity. In the PENTO experiment, the benzodiazepines alprazolam, bromazepam, diazepam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, temazepam and triazolam and the sedatives methaqualone and phenobarbital completely substituted for the training dose of PENTO. The nonbenzodiazepine anxiolytic CL 218,872 only partially substituted for PENTO. In addition, morphine and AMPH failed to substitute for PENTO, indicating pharmacological specificity. In summary, drugs delivered intragastrically functioned as discriminative stimuli in a drug-class specific manner. The ability to use drugs delivered by this route as discriminative stimuli provides a way to compare anorectic drugs to AMPH or sedative drugs to PENTO under conditions that resemble the mode of human consumption to determine whether these drugs are likely to be associated with AMPH-like or PENTO-like drug dependence.

Animals↗
PubMed1978

Continuous intravenous naltrexone effects on morphine self-administration in rhesus monkeys.

Rhesus monkeys, surgically prepared with intravenous catheters, were given opportunities to self-administer morphine for 3 days, methamphetamine for 2 days and saline for 2 days in a constantly repeating cycle. Access to drugs was limited to a 15-minute period every 4 hours. After stable base-line self-administration rates, saline or various concentrations of naltrexone were infused continuously through the catheter. In the first phase of the study each concentration of naltrexone was infused for 4 weeks (separated by 3 weeks of saline) while the dose of morphine available for self-administration was held constant at 8 microgram/kg/injection. Stable naltrexone dose-related suppression of morphine self-administration occurred throughout each 4-week infusion. In the second phase of the study, various doses of morphine were made available for self-administration during 6- to 8-week continuous infusions of saline or various concentrations of naltrexone. The dose-effect curve relating self-administration rate to morphine dose per injection shifted to the right and decreased in maximum as the rate of infusion of naltrexone increased. Methamphetamine and saline self-administration rates were unaffected by naltrexone.

Animals↗