Lack of tolerance to the anxiolytic effect of diazepam and pentobarbital following chronic administration in perinatally undernourished rats.

Adult female rats, undernourished at perinatal age, were evaluated for anxiolytic action in the plus-maze test after acute and chronic administration of diazepam (DZP) and pentobarbital (PTB). Deprived (D) rats chronically treated with vehicle showed an increased anxiety as compared with control (C) animals. A single intraperitoneal (i.p.) administration of DZP (1 mg/kg) or PTB (7.5 mg/kg) produced similar anticonflict effect in both C and D rats. Tolerance to the anxiolytic effect of DZP and PBT developed in C rats after a 15-day administration schedule, whereas no tolerance was observed in D animals. Drug disposition was not altered after chronic treatment either in C or in D rats. Gamma-aminobutyric acid (GABA)-mediated chloride uptake in microsacs of cerebral cortex of naive D rats was decreased as compared with naive C rats. After chronic DZP administration (1 mg/kg/day i.p. for 15 days), GABA-mediated 36Cl- influx in brain cortex microsacs of C rats did not change; however, GABA efficacy was increased in microsacs of D animals. In addition, chronic DZP treatment induced GABA-benzodiazepine uncoupling in brain cortex of C rats, but not in D animals, as assessed by chloride uptake in microsacs. Chronic PTB treatment (7.5 or 30 mg/kg/day i.p. for 15 days) did not modify GABA stimulation or GABA-PTB interaction in cortical microsacs of C or D rats.

Chronic Diazepam Administration Failed to Induce Tolerance and Withdrawal Syndrome in Perinatally Undernourished Female Rats as Measured in the Open Field Drink Test.

Adult female rats, receiving a low protein diet at perinatal age and then recovered with balanced chow (D rats), were evaluated in the Open Field Drink Test (OFDT), after different acute and chronic treatments with benzodiazepines (BZD) ligands, as compared with control (C) female rats. Control and D rats showed similar reactivity to acute administration of diazepam (DZP, 1 mg/kg) and FG 7142 (2.5mg/kg), both BZD ligands with anxiolytic and anxiogenic effects, respectively. After chronic DZP treatment (3mg/kg/day i.p. for 3 weeks), C rats developed tolerance to the anxiolytic effect of DZP as well as withdrawal syndrome upon abrupt interruption of chronic treatment. On the contrary, D animals failed to develop tolerance to the anxiolytic effect of DZP, and did not show an increased anxiety upon withdrawal. The functionality of the GABAA receptor-complex, as measured by (36)Cl(-) uptake in cortical cerebral microsacs, was not altered in the DZP withdrawn rats. The lack of tolerance and withdrawal syndrome may be related to the incapacity of D rats to generate adaptive changes after chronic treatments. For instance, C rats showed a lower anxiety level in the OFDT after chronic vehicle administration, whereas D animals did not evidence such an adaptive response. Furthermore, D rats failed to respond to the anxiolytic effect of DZP after chronic vehicle treatment. These results reassert the deleterious effects of perinatal undernutrition on the capacity to develop adaptive responses to repeated drug administration or adequate stimuli.

Reduced tolerance to certain pharmacological effects of ethanol after chronic administration in perinatally undernourished rats.

We have previously reported that recovered adult rats undernourished at perinatal age failed to develop tolerance to the anticonflict effect of ethanol after chronic ethanol administration (1 g/kg/day during 30 days) (4). To further study the extent of this finding, we examined the effect of a similar chronic ethanol treatment on the hypothermic and anticonvulsant effects of ethanol in perinatally deprived rats. Hypoalgesic activity was assessed in ethanol treated rats during 15 days. After chronic ethanol treatment, a similar development of tolerance to the hypothermic effect of ethanol was observed in control and deprived rats. However, tolerance to the anticonvulsant and hypoalgesic effect of ethanol was significantly reduced in deprived as compared with control animals. Thus, early undernutrition differentially affects the development of tolerance elicited by chronic ethanol administration.

Perinatal undernutrition impairs spatial learning in recovered adult rats.

Learning ability of adult rats undernourished at perinatal age and nutritionally recovered (D-rats) was assayed in the Morris water maze test as compared with controls (C-rats). D-rats showed longer escape latencies to locate a hidden platform in absence of proximal cues during the acquisition period. Swimming pre-training experience did not improve this shortcoming. Retention scores obtained 1, 3, 10 and 30 days after training showed that spatial information was efficiently consolidated after acquisition since D-rats performed as well as C-rats on retention tests. A cue learning task revealed no significant differences between both groups. These results suggest that perinatal undernutrition induces, even after a long period of nutritional recovery, a deficit in efficient place navigation in adult rats.

Perinatal undernutrition impairs spatial learning in recovered adult rats.

Learning ability of adult rats undernourished at perinatal age and nutritionally recovered (D-rats) was assayed in the Morris water maze test as compared with controls (C-rats). D-rats showed longer escape latencies to locate a hidden platform in absence of proximal cues during the acquisition period. Swimming pre-training experience did not improve this shortcoming. Retention scores obtained 1, 3, 10 and 30 days after training showed that spatial information was efficiently consolidated after acquisition since D-rats performed as well as C-rats on retention tests. A cue learning task revealed no significant differences between both groups. These results suggest that perinatal undernutrition induces, even after a long period of nutritional recovery, a deficit in efficient place navigation in adult rats.

Perinatally protein-deprived rats and reactivity to anxiolytic drugs in the plus-maze test: an animal model for screening antipanic agents?

Adult rats submitted to a protein deprivation schedule at perinatal age (from 14th day of fetal life until 50 days of age) and then recovered on balanced chow (D rats) were assayed in the elevated plus-maze test for anticonflict effects of diazepam and drugs with therapeutic efficacy in panic disorders as compared with controls (C rats). Diazepam and alprazolam showed a similar anticonflict effect in D rats than in C rats. In contrast, buspirone, which was ineffective in C rats at a wide dosage range, showed a significant anticonflict effect on D rats at 0.3 mg/kg. Neither propranolol, desipramine, nor phenelzine treatment (10 mg/kg/day during 3-7 days) induced anticonflict effect in C rats. Conversely, these treatments fostered a significant and selective anxiolytic effect on D rats. Such results underscore long-lasting alterations caused by early undernutrition, namely, changes in reactivity to the drugs assayed. In addition, perinatally deprived rats may represent a useful animal model for studying potential antipanic agents.

Perinatal protein deprivation enhances the anticonflict effect measured after chronic ethanol administration in adult rats.

The anticonflict effects of ethanol, diazepam and pentobarbital were evaluated in adult rats fed a low protein diet during the perinatal period in the plus-maze test, after single injections and following chronic ethanol administration (1 g.kg-1.d-1 for 30 d). Reactivity to the anticonflict effect of these drugs was similar in control and protein-deprived rats after acute treatment. After chronic ethanol administration, control rats showed tolerance to ethanol and cross-tolerance (i.e., lower reactivity) to the anxiolytic effect of diazepam and pentobarbital. Conversely, protein-deprived rats showed greater reactivity to ethanol and lack of cross-tolerance to diazepam and pentobarbital following chronic ethanol treatment. A significantly greater density of cortical gamma-aminobutyric acid receptors subtype A (GABA-A) was detected in protein-deprived rats after chronic ethanol administration compared with the density after chronic saline treatment, whereas no differences were observed in nourished controls. This suggests that the greater anxiolytic activity detected in protein-deprived rats may correlate with higher GABA-A receptor density.

Acute prenatal experience with alcohol in the amniotic fluid: interactions with aversive and appetitive alcohol orosensory learning in the rat pup.

Prenatal alcohol acute contamination of the amniotic fluid and different postnatal manipulations with this drug alter subsequent responsiveness to EtOH's chemosensory cues. In this study, the interaction between prenatal and postnatal alcohol-related experiences was examined. Alcohol administered in the amniotic fluid during gestational Day 21 potentiated subsequent alcohol-odor conditioned preferences resulting from postnatal pairings between the odor and sucrose intraoral infusions. No interaction was attained when examining the impact of the in utero experience with postnatal aversive conditioning defined by alcohol odor-citric acid pairings (Exps. 1a & 1b). In Exp. 2, infantile alcohol aversions derived from a state of acute ethanol intoxication were inhibited by prior alcohol experience in utero. Examination of alcohol levels in fetal trunk blood and the amniotic fluid suggests that the antenatal experience is related to the chemosensory perception of the drug rather than its intoxicating properties (Exp. 3). These results strongly suggest that the alcohol-related memory generated proximal to birth can modulate subsequent learning with the drug.

Perinatal undernutrition reduced ethanol intake preference in adult recovered rats.

Adult female rats submitted to a protein deprivation schedule at perinatal age (from 14th day of fetal life until 50 days of age) were tested for alcohol intake in a preference test. When compared with control animals, experimental rats exhibited higher overall fluid intake. Nevertheless, in terms of ethanol preference these subjects evidenced lower preference to this drug. A test for assessing ethanol olfactory preference did not show any differences between control and experimental rats in basal conditions. However, after repeated exposure to alcohol, deprived rats showed an aversion to ethanol odor, while controls evidenced the opposite effect, i.e., heightened preference. Possible differences to the aversive effects of ethanol between control and experimental animals were assayed by means of two taste aversion tests, by associating alcohol to sucrose or NaCl. No differences were detected between both groups of rats. These results demonstrate that early undernutrition reduces ethanol preference in a free choice situation. Such an effect could be due, at least partially, to odor aversion developed by repeated exposure.

Gangliosides enhance the anti-immobility response elicited by several antidepressant treatments in mice.

Ganglioside pretreatment enhanced the anti-immobility effect induced in the forced swim test after a chronic treatment with desipramine, mianserin, clomipramine, nialamide or repeated electroconvulsive shock in mice. Gangliosides, which had no effect per se, showed a clear dose-response relationship in enhancing the anti-immobility effect of desipramine. These results suggest that, regardless of their mechanisms of action, gangliosides facilitate the behavioral response of several antidepressant treatments.

Perinatal undernutrition alters different pharmacological effects of ethanol in adult recovered rats.

Different effects of ethanol were assayed in adult rats submitted to a protein deprivation schedule at perinatal age. Hypothermic and hypnotic responses were higher than normal in experimental rats, while the anticonflict effect of ethanol was lower in deprived animals. No differences were detected in the ethanol clearance rate between control and undernourished rats. These results stressed that the deleterious effects of early undernutrition persist in adult recovered animals and induce an altered reactivity to different pharmacological treatments.

Perinatal undernutrition alters different pharmacological effects of ethanol in adult recovered rats.

Different effects of ethanol were assayed in adult rats submitted to a protein deprivation schedule at perinatal age. Hypothermic and hypnotic responses were higher than normal in experimental rats, while the anticonflict effect of ethanol was lower in deprived animals. No differences were detected in the ethanol clearance rate between control and undernourished rats. These results stressed that the deleterious effects of early undernutrition persist in adult recovered animals and induce an altered reactivity to different pharmacological treatments.