Action of adenosine receptor antagonists on hypoxia-induced effects in the rat hippocampus in vitro

1. We have studied three hypoxia-induced phenomena in the CA1 stratum pyramidale of the rat hippocampal slice: (a) the increase in extracellular potassium ion concentration ([K+]e) measured with ion-sensitive microelectrodes, (b) the intracellularly-recorded pyramidal cell hyperpolarization and (c) the extracellularly-recorded depression of the synaptically-evoked field potential recorded in stratum pyramidale. 2. The extracellular potassium ion concentration ([K+]e) rose from 3 mM to 4.1-4.4 mM at a time when the pyramidal cells hyperpolarized by about 6 mV and neurotransmission was virtually abolished. 3. Presumed glial cells depolarized in response to hypoxia. The shape and time course of this response was remarkably similar to the rise in [K+]e so induced. This is consistent with findings that glial cell membrane potential is dependent on transmembrane K+ gradient. 4. We investigated the effects of theophylline (100 microM) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.1 microM) on these effects. We have found that these compounds attenuated by about half the hypoxia-induced increase in [K+]e; however, they did not reduce the hypoxia-induced hyperpolarization. We have confirmed that they dramatically reduced the suppression of excitatory transmission caused by the hypoxia. We conclude that adenosine A1 receptors may be involved in the alteration of K+ homeostasis in the hippocampal slice during hypoxia.     

A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.     

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.     

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)     

Prenatal exposure of female rhesus monkeys to testosterone propionate increases serum luteinizing hormone levels in adulthood

Monocyte chemotactic peptide-1 (MCP-1) belongs to a large family of cytokines known as chemokines. It is a potent mediator of inflammatory response and is thought to play a major role in recruiting monocytes into the site of inflammation. Mixed cryoglobulinemia is a systemic vasculitis characterized in 10 to 30% of the cases by renal involvement. Monocyte infiltration into the glomerulus, and in the periglomerular and perivascular areas is a common histopathological feature of this form of glomerulonephritis. We sought to determine, by in situ hybridization and immunohistochemistry, the renal gene and protein expression of MCP-1 in cryoglobulinemic glomerulonephritis compared to normal kidney, and to correlate it with macrophage infiltration. Kidney biopsy specimens were obtained from 9 patients with cryoglobulinemic glomerulonephritis and 9 control kidneys. The distribution and intensity of MCP-1 gene and protein expression, and the macrophage infiltration (CD68 positive cells) were evaluated and quantitated by a computerized image analysis system. In normal kidneys, MCP-1 was weakly expressed, both at the gene as well as at the protein level. In diseased kidneys, a statistically significant (P < 0.001) up-regulation of MCP-1 gene and protein expression was found, particularly within the areas of tubulointerstitial damage and the glomeruli. By means of CD68 positive cells, a significant correlation (P < 0.001) was found between glomerular, tubulointerstitial macrophage infiltration and MCP-1 expression. Moreover, by combining immunohistochemistry and in situ hybridization, we observed the presence of CD68 positive cells mainly, if not exclusively, around the cells expressing MCP-1 mRNA. Interestingly, a striking increase in MCP-1 urinary concentration was found in cryoglobulinemic patients. In conclusion, our data suggest that MCP-1 may play a major role in modulating the inflammatory process observed in cryoglobulinemic glomerulonephritis.     

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.     

Myocardial lesions induced by prolonged alcohol feeding in rhesus monkeys

To elucidate the effects of chronic alcohol ingestion in monkeys a synthetic, adequately balanced, fluid diet providing 40% of total calories from ethanol was gavaged through a stomach tube daily over a period of three months. Clinical, biochemical, radioisotope, and histopathological studies were performed at the beginning and end of the experiment. It was observed that chronic alcohol feeding at this dose level caused maked accumulation of triglycerides, cholesterol, and phospholipids in the serum and the liver. In the heart triglycerides and cholesterol ester were increased. Incorporation studies showed increased synthesis of triglycerides in the heart muscle and liver. Histologically the heart showed fatty change of the myocardium and evidence of focal myocytolysis, atrophy of muscle bundles, and early fibrosis. The liver showed generalized fatty change but no cirrhosis.     

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.     

Long-term cognitive impairment in MPTP-treated rhesus monkeys

Following MPTP administration, monkeys manifest cognitive deficits on tasks known to assess the fronto-striatal system; there are, however, no data regarding long-term cognitive effects. In this study, we examined the cognitive abilities of monkeys 10 years after MPTP administration. MPTP-treated monkeys and age-matched controls performed a spatial delayed response task with fixed and random delays. The MPTP-treated monkeys were impaired in both versions of the task. Both groups performed at the same level at very short delays suggesting that the nature of the impairment is related to a spatial memory deficit that is still apparent 10 years after treatment. These results suggest that, like Parkinson's patients, the MPTP-treated primates display spatial deficits.     

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.     

Attenuation of morphine withdrawal symptoms by subtype-selective metabotropic glutamate receptor antagonists

1. We have previously shown that chronic antagonism of group I metabotropic glutamate receptors (mGluRs), in the brain, attenuates the precipitated morphine withdrawal syndrome in rats. In the present investigation we assessed the effects of chronic antagonism of group II and III mGluRs on the severity of withdrawal symptoms in rats treated chronically with subcutaneous (s.c.) morphine. 2. Concurrently with s.c. morphine we infused intracerebroventricularly (i.c.v.) one of a series of phenylglycine derivatives selective for specific mGluR subtypes. Group II mGluRs (mGluR2,3), which are negatively coupled to adenosine 3':5'-cyclic monophosphate (cyclic AMP) production, were selectively antagonized with 2s, 1's, 2's-2-methyl-2-(2'-carboxycyclopropyl) glycine (MCCG). Group III mGluRs (mGluR4,6,7 and 8), which are also negatively linked to cyclic AMP production, were selectively antagonized with alpha-methyl-L-amino-4-phosphonobutanoate (MAP4). The effects of MCCG and MAP4 were compared with alpha-methyl-4-carboxyphenylglycine (MCPG), which non-selectively antagonizes group II mGluRs, as well as group I mGluRs (mGluR1,5) which are positively coupled to phosphatidylinositol (PI) hydrolysis. 3. Chronic i.c.v. administration of both MCCG and MAP4 significantly decreased the time spent in withdrawal, MCPG and MCCG reduced the frequency of jumps and wet dog shakes and attenuated the severity of agitation. 4. Acute i.c.v. injection of mGluR antagonists just before the precipitation of withdrawal failed to decrease the severity of abstinence symptoms. Rather, acute i.c.v. injection of MCCG significantly increased the time spent in withdrawal. 5. Our results suggest that the development of opioid dependence is affected by mGluR-mediated PI hydrolysis and mGluR-regulated cyclic AMP production.     

Perception of novel changes in a familiar environment by socially-housed rhesus monkeys

Many animals appear to have a sophisticated spatial representation of their environment. The development of these representations depends on the joint abilities of discriminating novel objects and remembering their locations. Variations of a detection of novelty paradigm were used to determine the nature and limitations of these abilities in rhesus monkeys. Socially-housed monkeys at two facilities (UMASS Primate Laboratory and the New England Regional Primate Research Center) were exposed to novelty detection tasks using a vertical object grid arranged on a mesh wall of the animals' pens. Monkeys rapidly responded with increased exploration to the replacement of one familiar object with a novel object, to the movement of a familiar object to a novel location, and to the swapping of two familiar objects. However, novelty of object was more salient than novelty of place. In these initial studies, monkeys were given continuous access to the grid, and only one or two changes occurred on a given day. In subsequent studies, the task difficulty was varied either by reducing the length of grid exposure or increasing the number of changed objects/session. Surprisingly, only a reduction in length of exposure markedly affected novelty detecting abilities. Rhesus monkeys clearly possessed the dual novelty detecting abilities. These skills were negatively affected only when monkeys' access to the grid was limited. The procedure employed here provided a convenient way to assess complex cognitive abilities in a group setting. It also relied on rhesus monkeys' inherent attraction to novelty and required only their species-typical behavior for assessment.     

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.     

Consort bonding and operant behavior by female rhesus monkeys.

An operant conditioning situation was used to relate the leverpressing performance of female rhesus monkeys to different measures of social, sexual, and agonistic behavior that underlie the formation and dissolution of consort bonds. Nine females were trained to press a lever 250 times to gain access to a male partner. After access, a standard 60-min behavioral test took place (1,440 tests). Data were analyzed independently of the stage of the menstrual cycle. Eight females were tested with 2 males, and every female gained access faster with 1 male (i.e, preferred partner). For all 8 females, the preferred male was the one that spent more time grooming the female. For 5 females, the preferred partner was also the one that ejaculated more frequently. For 4 females, where agonistic interactions with males could be evaluated, the preferred male was the one that elicited fewer submissive behavioral patterns. These results indicate that the operant behavior of female rhesus monkeys is positively reinforced by social and sexual factors and negatively reinforced by agonistic interactions and may thus provide a measure of the strength of consort bonds. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Visual observing by rhesus monkeys: influence of potentially threatening stimuli

7 rhesus monkeys were afforded the opportunity to observe a series of projected color slides of other monkeys exhibiting five content categories of social-communicative behavior (submission, intense threat, mild threat, grooming, and neutral behavior) combined with two levels of familiarity (familiar vs unfamiliar) with reference to the animals depicted in the slides. Mean duration of observing was significantly influenced by the social-communicative content categories, while mean frequency of observing was significantly affected by the familiarity dimension. The data were discussed in terms of the threat potential or fear-arousing capacity of social stimuli in relation to visual obsrving.     

Dissociated learning and state-dependent retention induced by pentobarbital in rhesus monkeys.

Demonstrated that 8 rhesus monkeys were subject to drug-dissociated learning and state-dependent retention in training situations involving color choices when alternate pharmacological states were produced by intraperitoneal injections of sodium pentobarbital or saline. Learning of a position discrimination was only moderately dissociated between states. Overtraining of color discrimination problems reduced dissociation between states and made subsequent cue reversal learning more difficult. A simple motor response did not dissociate between states. (24 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Insulin increases liver protein phosphatase-1 and protein phosphatase-2C activities in lean, young adult rhesus monkeys

Liver glycogen synthase activity is increased, and glycogen phosphorylase activity and glucose 6-phosphate content reduced by in vivo insulin during a euglycemic hyperinsulinemic clamp in lean young adult rhesus monkeys. To examine the mechanism of dephosphorylation of liver glycogen synthase and glycogen phosphorylase, the enzyme activities of protein phosphatase-1, protein phosphatase-2C, cAMP-dependent protein kinase, glycogen synthase kinase-3, protein kinase C and protein tyrosine kinase were determined before and after three hours of in vivo insulin in these same monkeys. The bioactivity of an inositol phosphoglycan insulin mediator (pH 2.0) and cAMP concentrations were also measured in the liver before and after insulin administration. Insulin caused significant increases in protein phosphatase-1 (p = 0.005) and in protein phosphatase-2C activities (p = 0.001). Insulin-stimulated minus basal bioactivity of the pH 2.0 insulin mediator was strongly inversely related to the insulin-stimulated minus basal glucose 6-phosphate content (r = -0.93, p < 0.0001). These findings suggest that protein phosphatase-1 and protein phosphatase-2C may be involved in the mechanism of in vivo insulin activation of liver glycogen synthase and inactivation of liver glycogen phosphorylase.     

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)