In vivo electrochemical studies of dopamine overflow and clearance in the striatum of normal and MPTP-treated rhesus monkeys

Translational recruitment of maternal mRNAs is an essential process in early metazoan development. To identify genes required for this regulatory pathway, we have examined a collection of Drosophila female-sterile mutants for defects in translation of maternal mRNAs. This strategy has revealed that maternal-effect mutations in the cortex and grauzone genes impair translational activation and cytoplasmic polyadenylation of bicoid and Toll mRNAs. Cortex embryos contain a bicoid mRNA indistinguishable in amount, localization, and structure from that in wild-type embryos. However, the bicoid mRNA in cortex embryos contains a shorter than normal polyadenosine (poly(A)) tail. Injection of polyadenylated bicoid mRNA into cortex embryos allows translation demonstrating that insufficient polyadenylation prevents endogenous bicoid mRNA translation. In contrast nanos mRNA, which is activated by a poly(A)-independent mechanism, is translated in cortex embryos, indicating that the block in maternal mRNA activation is specific to a class of mRNAs. Cortex embryos are fertilized, but arrest at the onset of embryogenesis. Characterization of grauzone mutations indicates that the phenotype of these embryos is similar to cortex. These results identify a fundamental pathway that serves a vital role in the initiation of development.     

Long-term engraftment following in utero T cell-depleted parental marrow transplantation into fetal rhesus monkeys

A major concern with allogeneic BMT for treating most inherited diseases is the need to overcome graft rejection with conditioning chemotherapy which is associated with a relatively high morbidity and mortality. This can be eliminated if the transplant is done in utero when the fetus is unable to reject donor hematopoietic stem cells (HSC). We studied the efficacy of T cell-depleted (TCD) parental bone marrow as a source of HSC for transplantation into early gestation non-defective fetal rhesus monkeys. Thirteen opposite sexed TCD transplants were done into 44 day fetal recipients and 12 into 61 day recipients (165 day total gestation). The procedure-related mortality was 8%, all in the earlier age group. The overall survival was 60% at birth with a projected survival of 44 +/- 10% at 1.5 years with no difference between the two age groups. We used a PCR assay for the rhesus Y chromosome to detect male donor cells in female recipients (six animals transplanted at 44 days and five at 63 days). The overall engraftment rate was 73% with no difference as a function of gestational age at transplant. In six long-term surviving engrafted females we detected donor cells in the peripheral blood and bone marrow up to 3 years of age. We found a delay in the appearance of donor cells in the peripheral blood in engrafted animals, in some cases for up to 6 months post-BMT. In vitro mixed lymphocyte reaction and cell-mediated lymphocytotoxicity studies between the recipient and donor cells indicate that tolerance was induced to donor cells. Individual and pooled erythroid and myeloid marrow colonies grown in methyl cellulose were collected and analyzed for donor origin by PCR. The amount of donor cells in marrows from long-term engrafted animals was < 0.1%. In a fetal recipient studied at 35 days post-BMT, donor cells were detected in bone marrow and liver in both erythroid and myeloid lineages. These results indicate that TCD parental marrow can durably engraft in utero. While the engraftment rate is similar to that seen with fetal liver as the source of HSC, the degree of peripheral blood engraftment (percent donor cells) in this non-defective primate model is low. It will require increasing the percent pre-or postnatally for this approach to be clinically relevant in those disorders in which there is no selective survival advantage for normal engrafted donor cells.     

Smoked heroin self-administration in rhesus monkeys

The Symphysis Pubis (SP) joint was investigated by X-ray in 96 adults without any history of disease of the joints. We evaluated the width of this joint by measuring the distance between the two articular surface at three points. We calculated the mean for the three interpubic distances and carried out statistical analysis so as to evaluate if there is a significative difference between the four age classes (< 50; 50-59; 60-69; > 70) and between males and females. We did not found statistically-significative differences between males and females, and between the age classes; nevertheless, it is to be noted that a slight widening of the SP joint can be seen in the elderly, which is thus not significant. We also noted that the medium part of the SP joint undergoes a larger widening in older people: this is probably due to degenerative changes in the fibrocartilagineous disc and the ligaments.     

Improving effects of huperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment

Our previous studies demonstrated that huperzine A, a reversible and selective acetylcholinesterase inhibitor, exerts beneficial effects on memory deficits in various rodent models of amnesia. To extend the antiamnesic action of huperzine A to nonhuman primates, huperzine A was evaluated for its ability to reverse the deficits in spatial memory produced by scopolamine in young adult monkeys or those that are naturally occurring in aged monkeys using a delayed-response task. Scopolamine, a muscarinic receptor antagonist, dose dependently impaired performance with the highest dose (0.03 mg/kg, i.m.) producing a significant reduction in choice accuracy in young adult monkeys. The delayed performance changed from an average of 26.8/30 trials correct on saline control to an average of 20.2/30 trials correct after scopolamine administration. Huperzine A (0.01-0. 1 mg/kg, i.m.) significantly reversed deficits induced by scopolamine in young adult monkeys on a delayed-response task; performance after an optimal dose (0.1 mg/kg) averaged 25.0/30 correct. In four aged monkeys, huperzine A (0.001-0.01 mg/kg, i.m.) significantly increased choice accuracy from 20.5/30 on saline control to 25.2/30 at the optimal dose (0.001 mg/kg for two monkeys and 0.01 mg/kg for the other two monkeys). The beneficial effects of huperzine A on delayed-response performance were long lasting; monkeys remained improved for about 24 h after a single injection of huperzine A. This study extended the findings that huperzine A improves the mnemonic performance requiring working memory in monkeys, and suggests that huperzine A may be a promising agent for clinical therapy of cognitive impairments in patients with Alzheimer's disease.     

Metabolic disturbances in Plasmodium coatneyi-infected rhesus monkeys

To investigate metabolic disturbances in an animal model of human malaria, four rhesus monkeys (Macaca mulatta) were infected with Plasmodium coatneyi, a parasite which induces cytoadherence of infected erythrocytes. When moribund or the parasitaemia had plateaued, the monkeys were sacrificed (3 animals) or treated with chloroquine (1 animal). Blood and cerebrospinal fluid (CSF) were sampled at intervals between inoculation and sacrifice or treatment. Arterial and CSF glucose and lactate rose during infection, indicating evolving insulin resistance. The arteriovenous difference in glucose concentration also increased, consistent with increased glucose consumption by parasitised tissues. Arterial plasma lactate rose but a positive arteriovenous concentration difference suggested tissue lactate uptake. The animal with the highest plasma lactate at sacrifice remained hyperglycaemic but also had the highest CSF lactate, the greatest cerebral sequestration and neurological depression, and biochemical and histological evidence of severe hepatic pathology. Serum cholesterol and corrected serum calcium fell consistently during infection; serum phosphate was also reduced in animals without renal impairment. These preliminary results indicate that lactic acidosis is a late complication of severe malaria and, by implication from this and other studies, hypoglycaemia occurs even later; other metabolic changes during P. coatneyi infection in rhesus monkeys also parallel those of severe falciparum malaria in humans. The model could be used in further studies of malaria-associated metabolic dysfunction and its management.     

Seasonal testicular function in male rhesus monkeys

Some studies report seasonal patterns of testicular function in male rhesus monkeys even when they are housed away from females, while others suggest that exposure to sexually active females is essential for male seasonality. We conducted the present experiment (1) to test claims that seasonal testicular activation occurs in the absence of females and (2) to determine whether regular exposure to and copulation with females enhances, or is without effect upon, seasonal increases in testicular function. We studied two groups of male monkeys housed in a colony room containing no females. Males in the Female Exposure group (n = 7) were paired twice weekly with estradiol-implanted females and copulated vigorously. Males in the second group (n = 7) were placed in the same test chamber (at least 16 h after it had been scrubbed with disinfectant) but were never exposed to females. Serum testosterone levels and testis volume were monitored for both groups. Each group displayed a seasonal pattern of testosterone and of testis volume comparable in timing and magnitude to seasonal increases previously reported in group-housed males, but the two groups did not differ from each other. Our findings confirm that seasonal changes in testosterone and testis size occur in the absence of sexual interaction and demonstrate that moderate levels of sexual activity do not enhance this response.     

Long-term studies of metopic synostosis: frequency of cognitive impairment and behavioral disturbances

The most evident immunosuppressive effect of cyclosporin A (CsA) on T cells is suppression of interleukin-2 (IL-2) production through the suppression of type-2B serine/threonine-specific phosphatase, calcineurin. To test whether suppression of IL-2 production is a major mechanism of CsA-mediated suppression of allograft rejection, we treated allogeneic skin-grafted mice with CsA and IL-2, and observed that IL-2 did not override the suppressive effect of CsA. Specific cytotoxic T lymphocyte (CTL) activity and natural killer (NK) activity of the spleens were increased by treatment with IL-2, and CsA significantly suppressed the killing activity. We also found that CsA-treatment decreased the expression of lck kinase of T cells and the production of IL-2 in response to concanavalin A (ConA), with minimum effect on IL-4 production. These results suggest that T cell dysfunctions other than decreased production of IL-2 are essential for suppressive effect of CsA on skin allograft rejection.     

Progressive neuropathologic lesions in vitamin E-deficient rhesus monkeys

A consistent group of progressive central and peripheral nervous system lesions developed in seven rhesus monkeys maintained on a vitamin E-deficient diet for 30 to 33 months. These lesions were absent from vitamin E-supplemented monkeys. The principal neuropathologic alteration was loss of sensory axons in the posterior columns, sensory roots, and peripheral nerves. Morphologic and morphometric studies indicated that the distal segments of the axons were affected most severely and large-caliber myelinated fibers are selectively involved. Swollen, dystrophic axons (spheroids) occurred infrequently. Degeneration and phagocytosis of small numbers of neuronal perikarya were observed in the dorsal root ganglia and the anterior horns. The number of affected neurons was not proportional to the number of affected axons. Accumulation of lipopigment was evident in neuronal perikarya and CNS endothelial cells. The nervous system lesion were usually accompanied by a chronic necrotizing myopathy. The neuropathologic lesions in vitamin E-deficient monkeys are compared with those in vitamin E-deficient rats and in humans with low serum vitamin E concentrations. A similar type of sensory axonopathy is associated with chronic deficiency of vitamin E in these three species.     

The development of stereoacuity in infant rhesus monkeys

The emergence of stereopsis at 3-4 months postnatal in human infants is striking and has led to speculation that its rapid onset and subsequent development must be due to a dramatic reorganization of the brain. Stereopsis has never been measured in infant monkeys, but previous studies have demonstrated that many other visual functions develop four times faster in infant monkeys than in humans. We made longitudinal assessments of stereoacuity in 11 infant rhesus monkeys. A forced-choice preferential-looking technique was used to present random-dot stereograms during testing. By 8 weeks after birth, all of the monkeys were responding to at least coarse levels of disparity (1760" [seconds]), and by 13 weeks of age, all were responding to the relatively fine level of 88" disparity. Age of onset for stereopsis in monkeys was at about one-quarter the age when it occurs in humans, as expected. However, subsequent development proceeded at a similar absolute rate in monkeys and humans. The findings are discussed relative to the neural mechanisms which might be responsible for the differing rates of development.     

Neuropathogenesis induced by rhesus cytomegalovirus in fetal rhesus monkeys (Macaca mulatta)

In a double-blind study, 655 sputum specimens were obtained from individuals suspected of having tuberculosis and were analyzed for the presence of Mycobacterium tuberculosis and rifampin susceptibility with use of a polymerase chain reaction (PCR)-based universal heteroduplex generator assay (PCR/UHG-Rif). Of the specimens containing viable M. tuberculosis, 100% of the smear-positive (n = 41) and 50% of the smear-negative (n = 6) specimens tested positive for the organism by PCR/UHG-Rif. Nineteen of 537 culture-negative specimens tested positive for M. tuberculosis by PCR/UHG-Rif and were from patients with confirmed tuberculosis who were receiving antituberculosis therapy at the time of specimen collection. Thirty-five specimens contained nontuberculous mycobacteria and were negative by PCR/UHG-Rif. Genotypic evidence of rifampin resistance in five of six culture-confirmed, rifampin-resistant isolates was obtained by PCR/UHG-Rif, yielding a sensitivity and specificity for the assay of 83% and 98.2%, respectively. These results demonstrate the feasibility of using a PCR-based assay directly on sputum specimens for simultaneous detection of M. tuberculosis and rifampin susceptibility, and they suggest that patients with smear-positive, untreated tuberculosis and those presenting with suspected drug-resistant tuberculosis are the most appropriate groups for testing by PCR/UHG-Rif.     

Music perception and octave generalization in rhesus monkeys.

Two rhesus monkeys were tested for octave generalization in 8 experiments by transposing 6- and 7-note musical passages by an octave and requiring same or different judgments. The monkeys showed no octave generalization to random-synthetic melodies, atonal melodies, or individual notes. They did show complete octave generalization to childhood songs (e.g., "Happy Birthday") and tonal melodies (from a tonality algorithm). Octave generalization was equally strong for 2-octave transpositions but not for 0.5 or 1.5-octave transpositions of childhood songs. These results combine to show that tonal melodies form musical gestalts for monkeys, as they do for humans, and retain their identity when transposed with whole octaves so that chroma (key) is preserved. This conclusion implicates similar transduction, storage, processing, and relational memory of musical passages in monkeys and humans and has implications for nature–nurture origins of music perception. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Observational conditioning of snake fear in rhesus monkeys.

Hypothesized that observational conditioning is involved in the origins of many human and nonhuman primates' fears and phobias. In Exp I, a new index of snake fear in 7 19–28 yr old wild-reared rhesus monkeys and 9 laboratory-reared offspring (aged 8 mo to 6 yrs) was tested. Results show the measure was useful and demonstrated that young Ss raised by parents who had a fear of snakes did not acquire the fear in the absence of any specific experience with snakes. In Exp II, using 5 of the wild-reared Ss and 6 of the laboratory-reared Ss from Exp I, 5 of 6 offspring acquired an intense and persistent fear of snakes as a result of observing their wild-reared parents behave fearfully in the presence of real, toy, or model snakes for a short period of time. The fear was not context specific and showed no significant signs of diminution at 3-mo follow-up. (49 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Frustration and self-aggression in social isolate rhesus monkeys.

Compared the frequency of self-aggressive behavior emitted by 6 partial social isolate and 6 socialized rhesus monkeys under baseline living conditions and a continuous reinforcement-extinction schedule of leverpressing. Under baseline conditions, male isolates showed higher levels of self-aggressive behavior than did the female isolates. Further, frustration produced by extinction of the leverpressing response produced a significant but transitory intensification of self-aggressive behavior. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Phentermine/fenfluramine decreases cocaine self-administration in rhesus monkeys

Dopaminergic agonists can decrease cocaine self-administration at doses that do not decrease food-maintained responding, a pre-clinical effect indicative of a potential treatment for human cocaine abuse. To assess whether similar effects could be obtained with medications currently used to treat substance abuse, phentermine and fenfluramine were given alone and in combination to rhesus monkeys responding under schedules of food and cocaine delivery. Phentermine decreased cocaine-maintained responding with no effect on food-maintained responding. Fenfluramine also selectively decreased cocaine-maintained responding, but only at the highest dose. Combining a lower dose of fenfluramine with phentermine selectively decreased cocaine-maintained responding, but not more than with phentermine alone. These results suggest that phentermine, as well as its combination with fenfluramine, may be useful in the treatment of cocaine abuse.     

Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease

Peripheral neuropathy is a recognized but poorly understood manifestation of Lyme disease. We performed serial electrophysiological studies on 8 rhesus monkeys chronically infected with the JD1 strain of Borrelia burgdorferi and compared the results with those of similar studies on 10 uninfected control monkeys. Four infected and 2 uninfected animals underwent sural nerve biopsy. Five of the infected and 1 of the uninfected animals also had postmortem neuropathological examinations. Altogether, 5 of the infected monkeys demonstrated primarily axonal-loss-variety multifocal neuropathies. Only one nerve lesion exhibited findings compatible with demyelination. Pathologically, peripheral nerve specimens showed multifocal axonal degeneration and regeneration and occasional perivascular inflammatory cellular infiltrates without vessel wall necrosis. Free spirochetal structures were not seen, but several macrophages exhibited positive immunostaining with a highly specific anti-B. burgdorferi, 7.5-kd lipoprotein monoclonal antibody. In the infected animals, serial analysis of serum antibodies to B. burgdorferi showed increasing numbers of IgG specificities and new IgM specificities, suggesting persistent infection. Thus, peripheral neuropathy in the form of a mononeuropathy multiplex develops frequently in rhesus monkeys chronically infected with B. burgdorferi. The pathogenesis of these nerve lesions is not yet known, but our studies suggest an immune-mediated process perhaps driven by persistent infection with B. burgdorferi.     

Factors influencing sexual performance in male rhesus monkeys.

Describes a 5-yr retrospective study of the sexual behavior of 8 adult rhesus monkeys showing that sexual vigor declined over the years but testosterone levels in peripheral vein plasma did not. Two prospective experiments were carried out on these males during the 6th yr: (a) The 4 poorest performers were injected daily for 28 days with testosterone propionate (1 mg/kg). There was no significant increase in level of performance, and behavior was not correlated with plasma levels of testosterone either before or 24 hrs after the last hormone injection. (b) All 8 males were exposed to novel nonspecific sensory stimulation during tests of sexual behavior. Eight different adult male rhesus strangers—present in the room but not in the test cage—were used as stimuli, one for each experimental test. Sexual behavior during experimental and control tests did not differ. (44 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticothalamic connections of extrastriate visual areas in rhesus monkeys

Corticothalamic connections of extrastriate visual areas were studied by using the autoradiographic anterograde tracing technique. The results show that the medial extrastriate region above the calcarine sulcus projects mainly to the lateral pulvinar (PL), medial pulvinar (PM), and lateral posterior (LP) nuclei. In addition, the dorsal portion of the medial region has connections to the lateral dorsal (LD) as well as to intralaminar nuclei. The dorsolateral extrastriate region projects strongly to the PL and LP nuclei, to the PM and inferior pulvinar (PI) nuclei, and to the LD and intralaminar nuclei. The lateral extrastriate region above the inferior occipital sulcus (IOS) has strong connections to both the PL and PI nuclei and has minor projections to the PM and oral pulvinar nuclei. The ventrolateral extrastriate region below the IOS projects mainly to the PI nucleus and to the caudal portion of the PL nucleus and has some projections to the PM nucleus. The ventromedial extrastriate region medial to the occipitotemporal sulcus has strong connections with the ventral and medial sectors of the PI nucleus. This region also projects to the caudal portion of the PL nucleus and has minor connections to the LP nucleus. Finally, the annectant gyrus projects to the PL nucleus and to the rostral portion of the PI nucleus and has minor connections to the PM nucleus. Thus, the medial and dorsolateral extrastriate regions are related mainly to the PL and LP nuclei as well as to intralaminar nuclei. In contrast, the ventrolateral and ventromedial regions are connected strongly with the PI nucleus. This connectional organization appears to reflect functional differentiation at the cortical level.     

Cognitive function in aged ovariectomized female rhesus monkeys.

To determine whether ovariectomy exacerbates age-related cognitive decline, the performance of 6 aged monkeys that had been ovariectomized early in life (OVX-Aged) was compared to that of 8 age-matched controls with intact ovaries (INT-Aged) and that of 5 young controls with intact ovaries (INT-Young) in tasks of visual recognition memory, object and spatial memory, and executive function. The OVX-Aged monkeys were marginally more impaired than the INT-Aged monkeys on the delayed nonmatching-to-sample with a 600-s delay. In contrast, they performed significantly better than the INT-Aged controls on the spatial condition of the delayed recognition span test. The hypothesis that prolonged estrogenic deprivation may exaggerate the age-related decline in visual recognition memory will require additional support. However, the findings suggest that long-term ovariectomy may protect against the development with aging of spatial memory deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delay discounting of cocaine by rhesus monkeys.

The present, subjective value of a reinforcer typically decreases as a function of the delay to its receipt, a phenomenon termed delay discounting. Delay discounting, which is assumed to reflect impulsivity, is hypothesized to play an important role in drug abuse. The present study examined delay discounting of cocaine injections by rhesus monkeys. Subjects were studied on a discrete-trials task in which they chose between 2 doses of cocaine: a smaller, immediate dose and a larger, delayed dose. The immediate dose varied between 0.012 and 0.4 mg/kg/injection, whereas the delayed dose was always 0.2 mg/kg/injection and was delivered after a delay that varied between 0 and 300 s in different conditions. At each delay, the point at which a monkey chose the immediate and delayed doses equally often (i.e., the ED50) provided a measure of the present, subjective value of the delayed dose. Dose-response functions for the immediate dose shifted to the left as delay increased. The amount of the immediate dose predicted to be equal in subjective value to the delayed dose decreased as a function of the delay, and hyperbolic discounting functions provided good fits to the data (median R2 = .86). The current approach may provide the basis for an animal model of the effect of delay on the subjective value of drugs of abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Abnormal social development of protein-malnourished rhesus monkeys.

Reports results of an experiment with 2 groups of 5 rhesus monkeys. Ss fed diets deficient in protein (3.5% casein) exhibited social behaviors qualitatively different from controls fed diets sufficient in protein (25% casein). In general, the protein-malnourished Ss showed a lack of reciprocal responsiveness to social initiations, aggression, and a predominance of nonsocially-directed behaviors when compared to controls. Results are discussed in terms of a nutritional-environmental interaction that produces abnormal and possibly long-term deficits in social development. (22 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)