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PubMed1976

Variable interval responding maintained by intravenous codeine and ethanol injections in the rhesus monkey.

Rhesus monkeys were trained to respond under a variable interval 2 min schedule for codeine or ethanol injections. Both codeine and ethanol were effective in the initiation of variable-interval responding; responding was maintained over a range of codeine (0.003-1.0 mg/kg/injection) and ethanol doses (32.0-560 mg/kg/injection). Maximum rates of responding were obtained at the 0.01 mg/kg/injection codeine dose (0.14 responses/sec) and at the 180 mg/kg/injection codeine dose (0.19 responses/sec). Rates of responsing were bitonic functions of the reinforcer dose for both codeine and ethanol; maximum rates were obtained at intermediate doses and lower rates occurred at the extremes of the dose range. Both codeine and ethanol showed within-session decreases in responding across the range of reinforcer doses. Codeine-reinforced responding declined in rate within the one-hour session without a similar change in the frequency of drug injection; in contrast, both ethanol-reinforced responding and the frequency of ethanol injections declined within each session across a range of doses. Increasing or decreasing the codeine dose half-way through the one-hour session resulted in increases or decreases in codeine responding compared to controls. These data indicate that the progressive decline in codeine-reinforced responding is not the result of a generalized disruption of responding.

Animals↗
PubMed1979

Rapid substitution procedure for intravenous drug self-administration studies in rhesus monkeys.

Rhesus monkeys were trained to press a lever one hundred times (FR 100) to obtain either a food pellet or an intravenous drug injection. Two daily experimental sessions, one in the morning and one in the afternoon, were divided into three 15 minute periods each. In Periods 1 and 3 lever pressing behavior was maintained by the delivery of food. Period 2 lever pressing was maintained by the intravenous injection of a drug solution. The drug available each day followed a four day sequence of cocaine (30 microgram/kg/injection), saline (1.0 ml/injection), cocaine, and test compound. This four day sequence was repeated to test a series of 16 psychoactive compounds at two doses each. These drugs were compared to saline for their ability to maintain Period 2 responding during the afternoon session. Morphine, oxymorphone, codeine, pentazocine, d-amphetamine and methylphenidate all maintained responding at rates significantly greater than for saline. Cyclazocine, naloxone, levallorphan, scopolamine, chlorpromazine, fenfluramine, and (+/-)-9-nor-9-alpha-hydroxy-hexahydrocannabinol (alpha-HHC) did not maintain responding during Period 2. The results with procaine, beta-HHC and nalorphine were considered equivocal. The authors suggest the use of a rapid substitution procedure as a method of initial screening of drugs with potential reinforcement efficacy.

Animals↗
PubMed1986

Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and piribedil by rhesus monkeys.

Rhesus monkeys were surgically prepared with chronic intravenous catheters and allowed to self-administer the indirect dopamine (DA) agonist cocaine (0.03 or 0.1 mg/kg/inj) or the direct D2 agonist piribedil (0.1 or 0.2 mg/kg/inj) on a fixed-ratio 10 schedule of drug delivery during daily 2 hour experimental sessions. When responding was stable, they were injected IV with SCH 23390, a selective D1 antagonist (0.003-0.3 mg/kg, 30 min pre-session) or pimozide, a selective D2 antagonist (0.003-0.3 mg/kg, 2 hours pre-session). Intermediate doses of pimozide generally increased self-administration of cocaine or piribedil, though increases in piribedil self-administration were more reliable. In contrast, intermediate doses of SCH 23390 either did not affect or decreased cocaine and piribedil self-administration. High doses of each antagonist decreased the rate of self-administration of each compound and produced catalepsy. The selective increase in responding maintained by cocaine or piribedil following pimozide pretreatment suggests a role for a D2-like receptor in psychomotor stimulant self-administration.

Animals↗
PubMed1987

Evaluation of the role of norepinephrine in the reinforcing effects of psychomotor stimulants in rhesus monkeys.

Rhesus monkeys were surgically prepared with intravenous catheters and allowed to self-administer cocaine (0.03-0.1 mg/kg/injection) under a fixed-ratio 10 schedule of drug delivery during daily 2-hour experimental sessions. When responding was stable for cocaine, saline or various doses of nisoxetine, a selective norepinephrine (NE) reuptake blocker, was substituted for cocaine for 5-7 consecutive sessions. Nisoxetine failed to maintain self-administration responding at any dose in 3 of 4 monkeys tested. Pre-session administration of the selective alpha 1 NE receptor blocker prazosin (0.2-1.6 mg/kg, IV, 15 minutes pre-session) did not systematically alter cocaine self-administration in any monkey. The results are in contrast to what has been found with DA agonists and antagonists and are consistent with the belief that NE does not play a primary role in the reinforcing properties of psychomotor stimulants.

Animals↗
PubMed1986

A tail withdrawal procedure for assessing analgesic activity in rhesus monkeys.

Rhesus monkeys were restrained in chairs from which their tails hung free so that their tails could be immersed into a thermos of water. Monkeys consistently kept their tails in 38-40 degrees C water for at least 20 sec, but withdrew them from 55 degrees C water in 1-4 sec. Tail withdrawal latencies from 55 degrees C water remained consistent over a period of 3 hr. Morphine produced dose-dependent increases in tail withdrawal latencies from 55 degrees C water, whereas pentobarbital, haloperidol, and phencyclidine did not increase tail withdrawal latencies except at doses that produced marked sedation.

Analgesics↗
PubMed1982

The role of frontal eye-fields and superior colliculi in visual search and non-visual search in rhesus monkeys.

Rhesus monkeys were tested on a visual search task in which they had to find and retrieve a peanut from a display of visually similar but inedible objects. The speed with which they did so was measured. Animals in which the superior colliculi or frontal eye-fields had been removed took longer to find the peanut than two operated control groups. Animals with collicular lesions had longer latencies than those with frontal eye-fields removed. These two groups were also tested on a second task, non-visual search, in which a peanut was concealed in each of 25 identical holes. The animals' task was to retrieve all 25 peanuts as quickly as possible. The group with frontal eye-fields removed made significantly more return errors, i.e. returning to a hole already sampled, than the control group but, in contrast to the first task, the animals with collicular lesions were not impaired. The results are related to the physiological properties of frontal eye-fields and superior colliculi and to the effects of frontal cortical brain damage in man. It is suggested that the frontal eye-fields are concerned with internally organized, i.e. voluntary, eye scanning whereas the superior colliculi are concerned with the detection and location of targets which are then fixated involuntarily.

Animals↗
PubMed1988

Effects of ethanol withdrawal on ethanol-reinforced responding in rhesus monkeys.

Rhesus monkeys self-administered ethanol intravenously during daily, 3-h sessions. When ethanol-reinforced responding was stable and ethanol intake was in the range of 2.6-3.6 g/kg/3 h, physiological dependence to ethanol was induced by daily passive infusions of additional ethanol. In less than 1 week, mild to moderate withdrawal signs were observed prior to daily sessions. Ethanol intake was suppressed in the presence of these withdrawal signs and returned to normal only after withdrawal signs had subsided.

Animals↗
PubMed1992

The intravenous self-administration of antihistamines by rhesus monkeys.

Rhesus monkeys were trained to lever press for infusions of cocaine during daily, 1-h experimental sessions. Following stabilization of the cocaine-maintained baselines, various antihistamines were substituted for cocaine to determine whether they would be self-administered. The results indicated that all monkeys tested self-administered tripelennamine and chlorpheniramine. One monkey out of the four self-administered pyrilamine, but only at a single (300 microgram/kg) high dose. Phenyltoloxamine, cimetidine and hydroxyzine were not self-administered. These results further illuminate differences amongst H1 antagonists in their potential for self-administration and, when examined in context with other reports, suggest that stimulant-like properties may help mediate their reinforcing effects when present.

Animals↗
PubMed1993

Effects of three monoamine uptake inhibitors on behavior maintained by cocaine or food presentation in rhesus monkeys.

Rhesus monkeys (n = 6) were surgically prepared with double lumen i.v. catheters and the effects of continuous infusion of the monoamine reuptake blockers mazindol, sertraline and fluoxetine were examined on behavior maintained by food presentation or i.v. cocaine injections. Under baseline conditions, lever pressing was maintained under a three-component multiple schedule of reinforcement in which food (1-g banana-flavored pellets) was available for 600 s under a fixed-ratio 30 schedule in the first and third components. In the second component, the dose of cocaine that maintained maximum rates of responding (0.03 or 0.05 mg/kg per injection) was available for 1800 s under a fixed-ratio 30 schedule. There was a brief time-out after each reinforcer. When behavior was stable, mazindol (0.4-3.2 mg/kg per 24 h), sertraline (0.1-8.0 mg/kg per 24 h) or fluoxetine (0.4-3.2 mg/kg per 24 h) was administered continuously via the second lumen of the double lumen catheter. Mazindol was administered for the same number of sessions that were required for responding to decline to low levels when the monkeys were allowed to self-administer saline [5-13] while sertraline and fluoxetine were administered for a minimum of 21 days. Baseline conditions were reinstated between doses of each drug. Each drug decreased cocaine-maintained responding in a dose-related manner. In most cases, food-maintained responding was disrupted at doses equal to or lower than those that decreased cocaine-maintained responding. Additionally, the higher doses of each drug decreased food intake outside the daily sessions. These results suggest that monoamine uptake blockers with prominent effects on either dopamine or serotonin neurotransmission can decrease cocaine self-administration but only at doses that also affect behavior maintained by other reinforcers.

1-Naphthylamine↗
PubMed1994

Discriminative stimulus effects of combinations of pentobarbital and ethanol in rhesus monkeys.

Rhesus monkeys (N = 3) were trained in a 2-lever drug discrimination paradigm to discriminate pentobarbital (PB; 10 mg/kg, i.g., 60 min pre-session) from saline. Lever pressing was maintained under a discrete-trials shock avoidance schedule of reinforcement (30 trials/day, 30-s ITI, FR1). Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with PB and ethanol (EtOH), alone or in combination. Administration of PB alone resulted in a dose-related increase (0-100%) in the percentage of responses emitted on the drug-appropriate lever. The mean ED50 for PB was 7.0 mg/kg (95% C.L. = 6.3-7.7 mg/kg). When administered 60 min pre-session, EtOH engendered a dose-related increase in PB appropriate trials and substituted completely for PB at 3.0 g/kg in two monkeys. In the third monkey, EtOH engendered a maximum of 65% PB-appropriate responding at 1.7 g/kg given 30 min pre-session and predominantly saline-appropriate responding at other pretreatment times. The group ED50 for EtOH at the time of maximum effect was 1.9 g/kg (95% C.L. = 1.4-2.5 g/kg). Administration of 0.3 g/kg EtOH in combination with PB had little or no effect on the PB dose effect function (PB ED50 = 6.7 mg/kg) while 1.0 g/kg EtOH shifted the PB dose-effect function to the left in all monkeys, an average of approximately 3-fold (PB ED50 = 2.1 mg/kg). Isobolographic analysis of the effects of the combination revealed that EtOH and PB were dose additive.

Animals↗
PubMed2006

The human CMV-UL86 peptide 981-1003 shares a crossreactive T-cell epitope with the encephalitogenic MOG peptide 34-56, but lacks the capacity to induce EAE in rhesus monkeys.

Rhesus monkeys immunized with MOG(34-56), a dominant T-cell epitope from myelin/oligodendrocyte glycoprotein, develop an acute neurological disease resembling acute disseminated encephalomyelitis (ADEM) in humans. The typical large demyelinated lesions and mononuclear infiltrates in the monkey brains are caused by MOG(34-56) T-cells. We show that MOG(34-56)-reactive CD4+ and CD8+ T-cells are induced in monkeys immunized with a peptide from the human CMV major capsid protein (UL86; 981-1003), that shares sequence similarity with MOG(34-56). Monkeys sensitized against the viral peptide and subsequently challenged with MOG(34-56) display histological signs of encephalitis, but do not show overt neurological signs.

Animals↗
PubMed1983

Contraceptive efficacy of testosterone-estradiol implants in male rhesus monkeys.

Rhesus monkeys (Macaca mulatta) were treated with testosterone (100 micrograms/kg/day) plus estradiol (0.5 micrograms/kg/day) via subcutaneous polydimethylsiloxane (PDS, Silastic) implants. This treatment caused a striking reversible sterility. No pregnancies were observed in females bred to the steroid-treated males. In contrast, there was no difference in pregnancy rate of females bred to control and steroid-treated monkeys for 14 weeks, beginning 17 weeks after removal of the steroid-filled implants.

Animals↗
PubMed2000

Cellular phenotypes of age-associated skeletal muscle mitochondrial abnormalities in rhesus monkeys.

Rhesus monkey vastus lateralis muscle was examined histologically for age-associated electron transport system (ETS) abnormalities: fibers lacking cytochrome c oxidase activity (COX(-)) and/or exhibiting succinate dehydrogenase hyperreactivity (SDH(++)). Two hundred serial cross-sections (spanning 1600 microm) were obtained and analyzed for ETS abnormalities at regular intervals. The abundance and length of ETS abnormal regions increased with age. Extrapolating the data to the entire length of the fiber, up to 60% of the fibers were estimated to display ETS abnormalities in the oldest animal studied (34 years) compared to 4% in a young adult animal (11 years). ETS abnormal phenotypes varied with age and fiber type. Middle-aged animals primarily exhibited the COX(-) phenotype, while COX(-)/SDH(++) abnormalities were more common in old animals. Transition region phenotype was affected by fiber type with type 2 fibers first displaying COX(-) and then COX(-)/SDH(++) while type 1 fibers progressed from normal to SDH(++) and then to COX(-)/SDH(++). In situ hybridizations studies revealed an association of ETS abnormalities with deletions of the mitochondrial genome. By measuring cross-sectional area along the length of ETS abnormal fibers, we demonstrated that some of these fibers exhibit atrophy. Our data suggest mitochondrial (mtDNA) deletions and associated ETS abnormalities are contributors to age-associated fiber atrophy.

Aging↗
PubMed1999

Immunization with recombinant Helicobacter pylori urease decreases colonization levels following experimental infection of rhesus monkeys.

Rhesus monkeys, naturally colonized with H. pylori as indicated by culture and histology were immunized with either 40 mg recombinant H. pylori urease administered orally together with 25 microg Escherichia coli heat-labile enterotoxin (LT) or immunized with LT alone. An initial 6 doses were administered over an 8 week period. All five vaccinated monkeys had a greater than two-fold rise in urease-specific serum IgG and IgA level and urease-specific salivary IgA was induced in 3 of 5 vaccinated animals after 6 or 7 doses of vaccine. Vaccination had no measurable therapeutic effect on H. pylori colonization. H. pylori was eradicated from these monkeys with a course of antimicrobials plus omeprazole, a 7th vaccine dose was given (10 months after the 6th dose) and they were rechallenged with H. pylori. Necropsy was performed 23 weeks after rechallenge and H. pylori colonization was determined by histological examination of 12 individual gastric sites. A significant reduction in colonization (p < or = 0.0001; Friedman's analysis of variance) was found in the vaccinated animals. Histopathologic examination of necropsy tissues also revealed a trend towards reduced gastritis and epithelial alterations in the vaccinated group compared to animals receiving LT alone. This study provides the first evidence for effective vaccination of nonhuman primates against H. pylori, and preliminary evidence that a reduction in bacterial density attributable to immunization may lessen gastric inflammation.

Adjuvants, Immunologic↗
PubMed1996

Role of the hippocampus plus subjacent cortex but not amygdala in visuomotor conditional learning in rhesus monkeys.

Rhesus monkeys were trained to learn a large series of visuomotor conditional associations, each involving the arbitrary coupling of a visual stimulus with 1 of 3 potentially correct forelimb movements. The monkeys then received bilateral aspiration lesions of either the amygdala plus subjacent cortex or the hippocampus plus subjacent cortex. Hippocampal but not amygdala removals significantly retarded the learning of new visuomotor associations. Neither lesion affected retention. The findings argue against a general role for the amygdala in associating information across modalities, construed broadly to include motor information. By contrast, the finding that the hippocampal formation and its subjacent cortex play a role in learning new sensorimotor associations supports the view that this region participates in the long-term storage of associative information or in the recall of recently acquired information.

Amygdala↗
PubMed1979

Contrasting effects of lateral striate and superior colliculus lesions on visual discrimination performance in rhesus monkeys.

Rhesus monkeys with lesions of lateral striate cortex, monkeys with superior colliculus lesions, and unoperated monkeys were tested for retention of a preoperatively acquired pattern discrimination. The three groups of monkeys were then tested in two-choice, color, color discrimination tests, one involving varying degrees of stimulus-response (S-R) separation and the other, administered several months later, involving various directions of S-R separations. The monkeys were also tested in a series of two-choice pattern discriminations, following each of which they were tested for relearning when the patterns were masked with bars or circles. The monkeys with lateral striate lesions were moderately retarded in retention of the pattern discrimination, whereas those with superior colliculus lesions were not. The monkeys with colliculus lesions, but not those with lateral striate lesions, were impaired in both S-R separation tests, which demonstrates that their deficit was not transient or solely due to a difficulty in shifting the gaze in one direction. The lateral striate monkeys, unlike those with colliculus lesions, were dificient in relearning discriminations between masked patterns. These findings suggest that superior colliculus and striate cortex may be involved in two different aspects of attention: respectively, shifting attention (and orientation) from one spatial locus to another and maintaining attention on fixated stimuli. Alternative interpretations of the effects of the lesions, based on their retinotopic loci, are discussed.

Animals↗
PubMed1995

Distribution of SIV in lymph nodes of serially sacrificed rhesus monkeys.

Rhesus monkeys were inoculated with SIVDeltaB670 and sacrificed 2, 4, 8, and 24 weeks after inoculation or when moribund. Two monkeys predicted to have a rapid disease course and two predicted to have a slower disease course were sacrificed at each time point. Lymph nodes were studied by histopathology, immunohistochemistry, in situ hybridization, electron microscopy, flow cytometry for lymphocyte subsets, and mitogen responsiveness. A greater selective decrease in peripheral CD4+CD29+ (helper-inducer/memory) T cells occurred in monkeys with high antigenemia. Although the percentage of CD8+ lymphocytes was increased and the CD4+/CD8+ ratio decreased in all infected groups, there were no consistent differences between monkeys with high or low antigenemia in lymph node lymphocyte subsets. Blastogenic responses of lymph node lymphocytes to PHA, ConA, or PWM were not significantly altered in infected monkeys. A reticular pattern typical of antigen deposition within germinal center follicular dendritic cells was seen in three monkeys with atrophic lymph nodes, high serum antigenemia, and a low percentage of circulating CD4+/CD29+ cells. More individually stained cells were in monkeys with high serum antigen and in moribund animals. By in situ hybridization, most monkeys had signal in a reticular pattern of germinal centers. Animals with higher levels of serum antigenemia tended to have more infected cells and a more intense signal. Extracellular virions were found between the FDC foot processes in the germinal centers of lymph nodes. Disease course was already established 2 weeks after inoculation.

Animals↗
PubMed1987

Effects of maternal and long-term postnatal protein malnutrition on brain size and composition in rhesus monkeys.

Rhesus monkeys consumed purified diets that supplied either low or adequate levels of protein (3.8 vs. 13.9% of energy as casein) from birth until approximately 10 yr of age. A subgroup (PN) was born of mothers that also received low or control levels of protein throughout pregnancy. The deprived groups weighed significantly less than corresponding control groups. Weights of the total brain, cerebellum and brain stem were significantly reduced in the PN deprived group. Analysis of variance also indicated that low protein diets produced a significant reduction in cerebral weight. The concentrations of DNA, protein and eight different lipids from seven different sites in the central and peripheral nervous system were not greatly affected by diet. The total content of lecithin and phosphatidylethanolamine was significantly depressed in some parts of the deprived monkey brains. The deficits in brain weight of the PN group (10% for the cerebrum, 13% for the cerebellum and 18% for the brain stem) were very similar to those observed previously in 1-mo-old monkeys born of protein-deprived mothers and fed low protein diets postnatally. On the other hand, monkeys born of adequately nourished mothers and then fed low protein diets from birth up to 12 yr showed no deficit in brain weight despite reduction in body weight to less than half of control values.

Animals↗