Barbara W. Adams

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.

Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex

BACKGROUND The increase in glutamate efflux in the prefrontal cortex by the psychotomimetic drugs phencyclidine (PCP) and ketamine may produce the dopaminergic and some of the behavioral effects of these drugs. Here, we examined whether antipsychotic drugs influence this increase. METHODS The effect of haloperidol, clozapine or the 5-HT(2A) antagonist, M100907, on PCP-induced increase in cortical glutamate efflux was examined by microdialysis. Because previous studies had suggested that M100907 attenuates some behavioral effects of PCP, we also examined the effect of M100907 on PCP-induced cortical and accumbal dopamine activation while making concomitant measures of locomotion and stereotypy. RESULTS Haloperidol, clozapine or M100907 did not significantly block hyperglutamatergic effects of PCP. M100907 was ineffective in inhibiting the dopaminergic and motoric effects of PCP. CONCLUSIONS These results contrast previous findings with glutamatergic drugs, such as AMPA antagonists or group II metabotropic glutamate agonists, that blocked glutamatergic and motoric effects of PCP. Thus, the PCP glutamate activation model lacks predictive validity for conventional antipsychotics; however, this model may be useful for design of novel classes of drugs that target those symptoms of schizophrenia that are not generally treated with monoamine-based antipsychotics.

Tactile stimulation activates dopamine release in the lateral septum.

Little is known about the functional properties of the dopamine innervation of the lateral septum. In this study, the feasibility of using microdialysis to assess action-potential mediated release of dopamine in the lateral septum was established. A mild stressor, in the form of handling, significantly increased septal dopamine levels, implicating a role for dopamine in sensory-related processing associated with the septal complex.

Behavioral thermoregulation in the squirrel monkey: Adaptation processes during prolonged microwave exposure.

During 10-min exposures to 2450-MHz microwaves at a power density of 6-8 m W/cm2, squirrel monkeys reliably select a cooler environment. Exposure duration, at power densities above and below this threshold, was the parameter investigated in these experiments. Monkeys were restrained in the far field of a horn antenna inside a 1.8 x 1.8 x 2.5 m anechoic chamber which was heated and cooled by forced convection. The animals learned to control the temperature of the circulating chamber air by selecting between cold (10-15 degrees C) and warm (50-55 degrees C) air sources. During the experiments, they were exposed to 12.4-cm (2450-MHz) continuous-wave microwaves for periods from 5 to 150 min. Microwave power densities explored were 4, 10, and 20 mW/cm2 which represent rates of whole-body energy absorption that range from approximately, .6 to 3.0 W/kg. No microwaves were present during 4-hr control experiments. The 4 mW/cm2 microwave exposure did not modify thermoregulatory behavior, no matter how long it lasted. The 10 and 20 mW/cm2 exposures stimulated the monkeys to select ambient temperatures 1.5 and 3.0 degrees C cooler than control levels, respectively. Except during the first microwave presentation of a series, or during the early minutes of a single long exposure, duration had no significant effect on selection of air temperature or on the body temperatures achieved thereby.

Autonomic thermoregulatory responses of febrile monkeys during microwave exposure

Adult male squirrel monkeys were stereotaxically implanted with Delrin injection cannulas and reentrant tubes in the medial preoptic nucleus of the hypothalamus (PO/AH). An injection into the PO/AH of 250 ng prostaglandin E/sub 1/ (PGE/sub 1/) in 1 /spl mu/l sterile saline generated a controlled fever of 1.4/spl plusmn/0.3/spl deg/C. Autonomic mechanisms of heat production and heat loss were measured in febrile monkeys during 30 min exposures to 450 or 2450 MHz CW microwave (MW) fields at different phases of the fever cycle (induction, plateau, defervescence). Heat production was spared when MW exposure occurred early in the fever cycle; heat loss (vasodilation, sweating) was stimulated when MW exposure occurred during defervescence. The magnitude and pattern of autonomic response change was frequency dependent.