dizocilpine-maleate and Nutrition-Disorders

A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and cholinergic systems has previously been identified in predominantly male malnourished animals. The present study sought to compare the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on responding maintained by a differential reinforcement of low rates (DRL-18s) operant schedule in two groups of rats with different prenatal nutritional histories (well-nourished and protein restricted). The schedule required that the rats space their responses at least 18 s apart in order to obtain food reinforcement (timing behavior). After training to a stable high proficiency, MK-801 was administered to female rats (Experiment 1) at doses of 0 (saline), 0.004, 0.008, 0.016, 0.024 or 0.032 mg/kg (doses expressed as the free-base). MK-801 produced dose-dependent decreases in the percentage efficiency of responding and the number of rewarded responses, with dose-dependent increases in the number of responses emitted. Prenatal malnutrition significantly shifted the inter-response time (IRT) curve to the left, relative to that of the well-nourished controls, leading to a significantly lower efficiency and a lower number of reinforcers, at an MK-801 dose of 0.016 mg/kg. In Experiment 2, the effect of MK-801 on DRL performance was compared between male and female rats after prenatal malnutrition. In general, females proved more sensitive to MK-801 than males. Consistent with Experiment 1, a significantly greater drug impairment was observed in prenatally malnourished females compared with well-nourished females, albeit at a slightly higher dose (0.032 mg/kg). Prenatal malnutrition did not alter the drug response in male rats. These findings suggest that the behavioral response to NMDA blockade is augmented in adult female, but not male, rats after prenatal malnutrition.

Topics: Animals; Body Weight; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Male; Nutrition Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Sex Characteristics

A competitive antagonist of the N-methyl-D-aspartate receptor, CGP 39551, was administered daily to neonatal rats with increasing doses from postnatal day 1 to 22. These animals displayed approximately 50% decrease of body weight at the end of treatment and, therefore, both normal and neonatally undernourished rats were used as controls. At a young adult stage (55-75 days of age) CGP 39551-treated rats showed a much higher spontaneous locomotor activity as compared to control groups. This hypermotility was counteracted by D1 and D2 dopamine antagonists while administration of methamphetamine increased, to the same extent, the differential basal locomotor activity of treated and control groups. The locomotor activity response to the N-methyl-D-aspartate channel blocker, dizocilpine maleate, was significantly shifted to the right for treated rats so that an equivalent increase of motility was obtained by doubling the dose effective for control animals. In in vivo microdialysis experiments, similar amounts of dopamine were collected from the striatum of treated and control rats after high K+ or methamphetamine stimulation, the only difference being a greater Ca2+ dependency of the depolarization-induced dopamine release in treated rats. Assays for different neurochemical parameters, carried out at 80-90 days of age, suggested some alteration of the balance between excitatory and inhibitory circuits in the basal ganglia of CGP 39551-treated rats. Tyrosine hydroxylase and calbindin immunostaining, as well as acetylcholinesterase histochemistry, revealed a similar picture in the striatum of treated and control rats. However, 5'-nucleotidase histochemistry showed a stronger and evenly distributed reactivity in the striatum of treated rats, opposite to the weaker and patchy localization of normal or undernourished controls. From the present results it is possible to conclude that chronic blockade of the N-methyl-D-aspartate receptor during neonatal brain maturation results in long-lasting alteration of locomotor activity which appears related to functional changes of the dopamine receptors as well as to an altered balance between various excitatory and inhibitory neurotransmitter and neuromodulatory systems.

Topics: 2-Amino-5-phosphonovalerate; 2',3'-Cyclic-Nucleotide Phosphodiesterases; Aging; Animals; Animals, Newborn; Aspartic Acid; Benzamides; Benzazepines; Choline O-Acetyltransferase; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Glutamate Decarboxylase; Glutamate-Ammonia Ligase; Motor Activity; Nutrition Disorders; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate

Administration of non-competitive N-methyl-D-aspartate (NMDA) antagonists in rodents leads to a characteristic motor syndrome which has been related to changes in monoamine metabolism in a variety of brain regions. We examined the question whether chronic MK-801 treatment in neonatal rats from postnatal day 8 through 19, which has been shown previously to alter NMDA receptor function, would also affect monoamine metabolism in striatum and frontal cortex of adult rats. Monoamines and their metabolites were determined 5 months after the treatment using high-performance liquid chromatography with electrochemical detection. Dihydroxyphenylacetic acid (DOPAC) concentration was elevated (greater than 40%) in both regions tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19%), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47%). These results demonstrate that the long-lasting effects of chronic neonatal MK-801 treatment are not restricted to glutamate transmission, but include monoamine transmission as well.

Topics: Age Factors; Animals; Animals, Newborn; Ataxia; Biogenic Amines; Body Weight; Corpus Striatum; Dizocilpine Maleate; Dopamine; Frontal Lobe; Growth Disorders; Male; Motor Activity; Norepinephrine; Nutrition Disorders; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Serotonin; Synaptic Transmission