Aging and caloric restriction in nonhuman primates: behavioral and in vivo brain imaging studies.

In a long-term longitudinal study of aging in rhesus monkeys, a primary objective has been to determine the effects of aging and caloric restriction (CR) on behavioral and neural parameters. Through the use of automated devices, locomotor activity can be monitored in the home cages of the monkeys. Studies completed thus far indicate a clear age-related decline in activity consistent with such observations in many other species, including humans. However, no consistent effects of CR on activity have been observed. Selected groups of monkeys have also been involved in brain imaging studies, using magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI studies completed thus far reveal a clear age-related decline in the volumes of the basal ganglia, the putamen, and the caudate nucleus, with no change in total brain volume. PET analysis has revealed an age-related decline in the binding potential of dopamine D2 receptors in the same brain regions. These results are consistent with findings in humans. Although additional longitudinal analysis is needed to confirm the present results, it would appear that locomotor activity, volume of the basal ganglia, as well as dopamine D2 receptor binding potential provide reliable, noninvasive biomarkers of aging in rhesus monkeys.

Locomotor activity in female rhesus monkeys: assessment of age and calorie restriction effects.

As a component of a long-term, longitudinal study of aging in this primate model, the objective of the current experiment was to assess age and diet effects on locomotor activity in a cross-sectional analysis. By attaching a motion detection device to the home cage, locomotor activity was monitored over a week in a group (N = 47) of female rhesus monkeys (Macaca mulatta) 6-26 yrs of age. About half these monkeys composed a control group fed a nutritionally fortified diet near ad libitum levels, whereas an experimental group had been fed the same diet at levels 30% less than comparable control levels for approximately 5 yrs prior to testing. Among control monkeys, a marked age-related decline in activity was noted when total activity was considered and also when diurnal and nocturnal periods of activity were analyzed separately. When comparing activity levels between control and experimental groups, only one significant diet effect was noted, which was in the youngest group of monkeys (6-8 yrs of age) during the diurnal period. Monkeys in the experimental group exhibited reduced activity compared to controls. Body weight was not consistently correlated to activity levels. In some older groups, heavier monkeys tended to show greater activity, but in younger groups the opposite pattern was observed.

Subtype-selective antagonism of N-methyl-D-aspartate receptors by felbamate: insights into the mechanism of action.

Felbamate is an anticonvulsant used in the treatment of seizures associated with Lennox-Gastaut syndrome and complex partial seizures that are refractory to other medications. Its unique clinical profile is thought to be due to an interaction with N-methyl-D-aspartate (NMDA) receptors, resulting in decreased excitatory amino acid neurotransmission. To further characterize the interaction between felbamate and NMDA receptors, recombinant receptors expressed in Xenopus oocytes were used to investigate the subtype specificity and mechanism of action. Felbamate reduced NMDA- and glycine-induced currents most effectively at NMDA receptors composed of NR1 and NR2B subunits (IC50 = 0.93 mM), followed by NR1-2C (2.02 mM) and NR1-2A (8.56 mM) receptors. The NR1-2B-selective interaction was noncompetitive with respect to the coagonists NMDA and glycine and was not dependent on voltage. Felbamate enhanced the affinity of the NR1-2B receptor for the agonist NMDA by 3.5-fold, suggesting a similarity in mechanism to other noncompetitive antagonists such as ifenprodil. However, a point mutation at position 201 (E201R) of the epsilon2 (mouse NR2B) subunit that affects receptor sensitivity to ifenprodil, haloperidol, and protons reduced the affinity of NR1-epsilon2 receptors for felbamate by only 2-fold. Furthermore, pH had no effect on the affinity of NR1-2B receptors for felbamate. We suggest that felbamate interacts with a unique site on the NR2B subunit (or one formed by NR1 plus NR2B) that interacts allosterically with the NMDA/glutamate binding site. These results suggest that the unique clinical profile of felbamate is due in part to an interaction with the NR1-2B subtype of NMDA receptor.