Elizabeth A. Keller

The learning capacity of high or low performance rats is related to the hippocampus NMDA receptors

The hippocampal synaptic plasticity of rats with an inborn high (HP) or low (LP) learning capacity to perform in a shuttle box is closely related to their percentage of conditioned responses (Crs). HP rats show less sensitivity to the blocking effect of 2-aminophosphonopentanoic acid (AP5) on the generation of long-term potentiation (LTP) than do LP rats. Results described in the present report are indicative of an increased density of N-methyl-D-aspartate (NMDA) receptors in HP rats compared to control and LP rats. We postulate that the differential pharmacological sensitivity of LTP in these rats is a reflection of this biochemical difference. Also, from these results we suggest that the learning capacity may be related to the density of glutamate NMDA receptors of HP, LP and control rats.

Opiate agonist-induced changes in behavioral sensitivity to clonidine are observed in perinatally malnourished rats exposed to chronic stress

Sensitivity of alpha2-adrenoceptors following repeated immobilization sessions plus morphine (MOR) or beta-endorphin (BETA) was assayed by examining clonidine (CLO)-induced hypoactivity in adult malnourished rats at perinatal age. As previously described, chronic restraint did not attenuate the hypoactivity elicited by CLO in malnourished rats, although chronic restraint did have such an effect on motor activity in control animals. MOR and BETA administration prior to each restraint session induced subsensitivity of alpha2-adrenoceptors in malnourished rats as determined by a blunted response to clonidine challenge. An injection of naloxone (NAL) prior to BETA before each stress session fully antagonized the subsensitivity to clonidine observed in malnourished animals. A possible deficiency in the functional role of the opiate system in the process of adaptation to chronic stress in perinatal malnourished rats is suggested.

Lack of adaptive changes in 5-HT sites in perinatally undernourished rats after chronic stress: Opioid influence

The reactivity of 5-HT receptors following repeated immobilization sessions or after immobilization plus morphine was measured through 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) or 8-hydroxy-2-(dipropyl-amino)tetralin (8-OH-DPAT)-induced serotonergic syndrome in adult rats undernourished at perinatal age. Repeated stress enhanced the scores of forepaw treading and hindlimb abduction elicited by 5-MeODMT in control animals. In a similar way, forepaw treading induced by 8-OH-DPAT was enhanced in chronically stressed control rats. These results indicate the development of supersensitivity in 5-HT1 receptors. Conversely, this effect was not observed in undernourished animals. Morphine injections before each stress session instaured the increased reactivity to 5-HT1 sites in malnourished animals. An injection of naloxone prior to morphine before each stress session fully antagonized the increased behavioral reactivity to 5-MeODMT observed in deprived animals. A possible deficiency in the functional role of the opiate system involved in the process of adaptation to chronic stress in early undernourished rats is suggested.

Lack of neuronal adaptive changes following chronic treatments in perinatally undernourished rats

Reactivity of presynaptic dopaminergic and alpha 2-adrenoceptors following repeated stress or desipramine treatment was investigated by means of apomorphine (APO)- or clonidine (CLO)-induced hypoactivity, respectively, in adult rats undernourished at perinatal age. Under basal conditions, a comparable hypoactive response was observed in control and experimental animals following either APO or CLO administration. Chronic DMI or repeated immobilization sessions attenuated the hypoactivity elicited by APO or CLO in control animals; however, this effect was not observed in experimental rats. These findings demonstrate that deprived animals show impairment to produce neuronal adaptive changes in response to appropriate stimuli, which may account for the behavioral alterations attributed to early undernutrition.

Vascular reactivity in perinatally undernourished rats

Adult rats submitted to perinatal protein deprivation (from day 14 of fetal life till 50 days of age) followed by a longer phase of nutritional recovery on balanced laboratory chow, showed a significant decrease of the pressor response elicited by noradrenaline and adrenaline, an effect that persisted after ganglionic blockade by hexamethonium. However, the effects of serotonin, acetylcholine, angiotensin II and vasopressin on blood pressure did not differ from those in the controls. Cumulative dose-response curves to noradrenaline and methoxamine on the circular contraction of isolated iliac arteries showed a significant shift to the right, together with a reduction in the maximal contraction. No significant difference in the maximal contraction elicited by Ba2+ was observed in experimental preparations as compared with controls. These results suggest the development of a specific subsensitivity to sympathetic drugs in the vascular bed as a consequence on undernutrition during perinatal life.

Gangliosides enhance behavioral and neurochemical effects induced by chronic desipramine (DMI) treatment

Rats pretreated with gangliosides showed a significant enhancement of the anti-immobility effect of desipramine (DMI) in the forced swimming test. Accordingly, an associated treatment of gangliosides and DMI for 7 days significantly enhanced beta-adrenergic down-regulation in the frontal cortex as compared with the effect of DMI alone. Gangliosides exerted an accelerating effect on the decrease of beta-adrenoceptor density induced by DMI, since the down-regulation phenomenon appeared after 3 days of treatment. Gangliosides did not affect the pharmacokinetics of DMI, since associated acute or prolonged treatments did not modify the brain levels of DMI as compared to the levels of animals that had received DMI alone. These results evidence a stimulating effect of gangliosides on the development of adaptative receptor changes induced by chronic DMI treatment.

Prenatal amphetamine reduces alpha but not beta adrenergic receptor binding in brain of adult rats

Adult offspring of rats treated with daily injection of d, 1-amphetamine sulfate (0.5 mg/kg s.c.) during pregnancy showed a significant decrease in brain alpha but not beta adrenergic receptor binding, without apparent changes in receptor affinity. This change may be a consequence of long lasting alterations in the metabolism of brain catecholamines produced by amphetamine administration at fetal age, and may account for the behavioral alterations described in these animals.

Reduced cyclic AMP response to adrenergic stimulation in brain slices from perinatally undernourished rats

Abstract Cyclic AMP generation response to adrenergic stimulation was assayed in cortical brain slices from adult rats submitted to a protein deprivation schedule in perinatal age and then recovered on balanced chow. Basal cAMP content was similar in deprived and control rats. Higher concentrations of NA (50 to 100 μM) induced a lower cAMP response in deprived animals. Selective alpha adrenergic stimulation (NA + timolol) induces the same cAMP response in both control and deprived rats, but potentiation of the beta response was higher in the latter group. On the other hand, selective beta adrenergic stimulation (NA + phentolamine or Isoproterenol) provoked a lower response in deprived animals. Prolonged desipramine treatment reduced response to beta stimulation in control rats but was unable to modify cAMP response in deprived animals, as compared with saline-treated ones. These results stressed long-lasting effects induced by early undernutrition, characterized in this case by the inability to induce neuronal changes to appropriate stimuli. ( J. Nutr. Biochem. 5:338–341, 1994 .)

Gangliosides facilitate the recovery of behavioral response mediated by dopaminergic sites following their irreversible blockade

The effect of acute and chronic exogenous ganglioside (G) administration on the functional recovery of dopaminergic receptors following their blockade by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was investigated by means of apomorphine (APO)-induced stereotyped behavior. Animals previously treated with EEDQ exhibited a lack of behavioral response to APO 6 or 24 h later. A progressive behavioral recovery was already evident at day 3 and reached control values at day 7. G pretreatment accelerated the behavioral recovery after EEDQ administration, because a higher behavioral response to APO in these animals as compared with rats treated with EEDQ alone at the same time was observed. These findings indicate that G accelerates the functional recovery of dopaminergic sites following their irreversible blockade.

Reduced anti-immobility effect of repeated desipramine (DMI) treatment in adult rats undernourished at perinatal age ☆

Adult rats submitted to a protein deprivation schedule at perinatal age showed a reduced anti-immobility effect following seven days of DMI treatment (20 mg/kg/day) in the forced swimming test. The ineffectiveness of DMI treatment is attributed to the inability of deprived animals to produce neuronal adaptative changes in central monoaminergic pathways.