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Effects of prenatal alcohol exposure on birth weight in rats: is there an inverted U-shaped function?

Decreases in birth weight are among the most commonly reported effects of prenatal alcohol exposure in animals. However, these decreases are typically associated with relatively high doses of alcohol. Two studies were conducted. The first evaluated the effects of low doses of alcohol (0.15 and 0.30 g/kg) on birth weight and other measures. A second study examined the effects of a relatively high dose of alcohol (3.0 g/kg). The two low doses of alcohol produced a slight, but not significant, increase in birth weight relative to vehicle controls whereas the high dose of alcohol produced a significant decrease in birth weight relative to its controls. When the data for the two studies were combined, the relationship between alcohol and birth weight assumed an inverted U-shaped function. There was no effect of prenatal alcohol exposure on weights at weaning, passive avoidance learning, or ambulation. In the context of birth weight, slight increases may be related to increased protein synthesis associated with low doses of alcohol.

Animals↗

PubMed1994

Involvement of corticosteroids in the processing of stressful life-events. A possible implication for the development of depression.

In a sub-population of endogenously depressed patients, disturbances of the hypothalamic-pituitary-adrenal axis can be observed. Increased cortisol and CRH levels combined with normal ACTH concentrations have often been reported. Corticosteroids appear to play a role in the mood changes, in depressed subjects. However, their mechanism of action is unknown. In animal experiments, the involvement of corticosteroids in stressor-induced learning was investigated. Three paradigms were used. In the Porsolt swimtest an animal had to learn to adapt to an inescapable situation. In the lithium chloride conditioned taste aversion an animal learned to avoid sugar water. In the amphetamine sensitization a second injection of amphetamine caused a potentiated response, because of conditioning. All three conditions appeared to be stressful because they induced a corticosterone release. When adrenalectomized (ADX) mice were compared to control animals it appeared that, in all three paradigms, their memory function was disturbed. The data indicated that this was a specific glucocorticoid-mediated effect since corticosterone and dexamethasone injections were able to reverse the ADX-induced deficit. The ADX-induced disturbances were only observable at moderate stress levels. More severe stressors (lower water temperature in the Porsolt swimtest, higher lithium chloride and amphetamine doses) also made ADX mice remember their previous experiences. The results suggest that corticosteroids are involved in the consolidation of stressful events and the corresponding coping responses. They play, however, only a role in the case of moderate stressors. In ADX animals no stressor-induced corticosterone increase can occur and therefore these animals only remember severe stressors. In a depressed patient basal steroid levels are increased and consequently very mild stressors, which induce only a small extra steroid release, will be remembered. The remembering of all these negative experiences might be of importance for the development and maintenance of the depression.

Adrenal Cortex Hormones↗

PubMed2006

Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.

OBJECTIVE: The study objective was to determine the eventual consequences (falls, unsteadiness, and cognitive impairment) of mild chronic hyponatremia, which is generally considered as asymptomatic. METHODS: In a case-control study, we focused on the incidence of falls among 122 patients (mean age 72+/-13 years) with asymptomatic chronic hyponatremia (mean serum sodium concentration [SNa] 126+/-5 mEq/L), who were admitted to the medical emergency department, compared with 244 matched controls. To explore the mechanisms of the excess of falls, we prospectively asked 16 comparable patients (mean age 63+/-15 years; SNa+/-2 mEq/L) to perform 8 attention tests and a gait test consisting of 3 steps "in tandem," in which we measured the "total traveled way" by the center of pressure or total traveled way. Thereafter, the patients were treated and tested again (50% of the patients were tested first with normal SNa to avoid learning biases). RESULTS: Epidemiology of falls: Twenty-six patients (21.3%) of 122 were admitted for falls, compared with only 5.3% of the control patients (adjusted odds ratio: 67; 95% confidence: 7.5-607; P <.001). The frequency of falls was the same regardless of the level of hyponatremia. Gait: The total traveled way by the center of pressure significantly increased in hyponatremia (1336+/-320 mm vs 1047+/-172 mm with normal SNa; P=.003). Attention tests: The mean response time was 673+/-182 milliseconds in hyponatremia and 615+/-184 milliseconds in patients with normal SNa (difference: 58 milliseconds, P <.001). The total error number in hyponatremia increased 1.2-fold (P=.001). These modifications were comparable to those observed after alcohol intake in 10 volunteers. CONCLUSIONS: Mild chronic hyponatremia induces a high incidence of falls possibly as the result of marked gait and attention impairments. Treating these patients might prevent a considerable number of hospitalizations.

Accidental Falls↗

PubMed2004

Susceptibility to subchronic unpredictable stress is related to individual reactivity to threat stimuli in mice.

As in many complex behavioral responses, inter-individual variability can be observed in the responses to a chronic mild stress. While some subjects exhibit more resilient behaviours, others appear more susceptible to stress. This study hypothesizes that this variability relies on the individual appraisal of the stressful event. To study this assumption, mice were first subjected to a conditioned task occurring in a circular arena. In this task, a mild air-puff (i.e. stressor) in a given quadrant of the arena was coupled with the presence or the absence of a light in the same quadrant. Half of mice were then submitted to a 15-day subchronic stress consisting in various environmental and social mild stressors randomly applied two or three times a day. At the end of this procedure, the occurrence of depressive-like behaviours in stressed mice was assessed using measures of the stress regime (i.e. physical state, choice test, grooming test). The physical state assessed the physical appearance of mice. The grooming test consisted in measuring the time spent in grooming after mice were sprayed upon with a viscous solution. The choice test consisted in measuring the time spent in an uncomfortable place (i.e. whose floor was covered with damp sawdust) versus a more comfortable one (i.e. with dry sawdust) to evaluate the reactivity to a negative stimulus previously encountered during the subchronic stress. Multiple regression analyses revealed a relationship between attention toward salient stressful stimuli in the conditioned task and susceptibility to the subchronic stress procedure. These results are discussed regarding their relevance for the understanding of aetiologies of depressive illnesses.

Adaptation, Psychological↗

PubMed2005

Electrolytic lesions to nucleus accumbens core and shell have dissociable effects on conditioning to discrete and contextual cues in aversive and appetitive procedures respectively.

The nucleus accumbens (n. acc.) has been implicated in conditioning to both discrete and contextual cues but its precise role is as yet controversial because conflicting patterns of effect have been reported. These inconsistencies may relate to the extent to which the lesions used encroach on different subfields of n. acc. and the use of different task variants. The present study compared the effects of selective lesions of shell and core subfields of nucleus accumbens (n. acc.) across aversive and appetitive trace conditioning variants. In both experiments, an auditory stimulus was contiguous with footshock or food, or presented at a trace interval. A continuous flashing light in each case provided an experimental background stimulus. Conditioning to the cues provided by the experimental chambers was also assessed. Rats with electrolytic lesions to the n. acc. shell and core showed different patterns of effect in aversive (Experiment 1) and appetitive (Experiment 2) variants of this procedure. In Experiment 1, the core lesion reduced the difference between trace and contiguously conditioned groups, in responding to the discrete noise stimulus. However, neither lesion had any detectable effect on contextual conditioning. In Experiment 2, the shell lesion clearly increased contextual conditioning, selectively in the trace conditioned group, but neither lesion had any detectable effect on discrete cue conditioning. Thus, whilst the shell and core lesions produced dissociable effects on discrete cue and contextual conditioning, the conclusions to be drawn depend on the procedural variant in use.

Animals↗

PubMed2006

Conditioning method determines patterns of c-fos expression following novel taste-illness pairing.

Conditioned taste aversions (CTAs) can be established by exposing rats to a novel taste CS through a bottle or through intra-oral (IO) infusion. Lesion studies suggest differences between the two methods in their engagement of brain circuits, as excitotoxic amygdala lesions have no effect on bottle-conditioned CTAs, but eliminate CTAs produced using IO infusion. Fos-like immunoreactivity (FLI) was used to compare patterns of brain activation after pairing CS taste and US drug using bottle and IO methods. Conditioning rats using the bottle method was associated with widespread elevations in FLI throughout the putative CTA circuit (basolateral and central nuclei of amygdala, insular cortex and nucleus of the solitary tract). In contrast, IO conditioning led to activation only in the central nucleus of amygdala. This supports the suggestion of differences in aversion processing as a function of conditioning method and may explain the greater reliance on amygdala of IO-conditioned CTAs due to engagement of a less distributed neural network.

Administration, Oral↗

PubMed2006

Appetitive sensitization by amphetamine does not reduce its ability to produce conditioned taste aversion to saccharin.

Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA). Because amphetamine, unlike emetic agents like LiCl, possesses appetitive properties that sensitize when it is administered repeatedly, the present study assessed the contribution of sensitization to this US-pre-exposure effect (US-PEE). It was found that not all sensitizing regimens of systemic amphetamine injections produce a US-PEE. In addition, previous exposure to amphetamine in the VTA, where it acts to induce sensitization but not CTA, did not produce a US-PEE. It is concluded that amphetamine sensitization alone does not modulate this drug's ability to produce CTA. Implications of these findings for anatomically based associative and non-associative models of CTA and the US-PEE are discussed.

Amphetamine↗

PubMed2007

Preventive effect of kami-untan-to on performance in the forced swimming test in thiamine-deficient mice: relationship to functions of catecholaminergic neurons.

The kampo (Japanese herbal) medicine "kami-untan-to" (KUT) has been used for a long time in the treatment of neuropsychiatric disorders. We have recently reported that mice put on a thiamine-deficient (TD) diet exhibit a depressive behavior and impairment in avoidance learning after 20 days, and that this impairment was reversed by the chronic administration of KUT. In the present study, we investigated the effect of KUT on the depressive behavior observed in TD mice by using the forced swimming test. Our results show that oral administration of KUT from the 1st day of TD feeding prevented the increased duration of immobility in TD mice. Administration of KUT from the 10th day of TD feeding also had a beneficial effect on depressive behavior. To examine the relationship between the potential effects of KUT on monoaminergic neuronal functions and the depressive behavior observed in TD mice, we measured the immunohistochemical distribution of tyrosine hydroxylase (TH) in the brain using microphotometry. The fluorescence intensity of TH decreased in the limbic cortex and brainstem in TD mice compared with pair-fed mice as the control group, while KUT treatment protected against these decreases. These results suggest that KUT treatment may prevent a sign of depressive behavior, the animal immobility time, induced by TD feeding through a mechanism that involves the decrease of TH in some brain areas of TD mice.

Analysis of Variance↗

PubMed2006

Effects of copper metabolism on neurological functions in Wistar and Wilson's disease model rats.

Behavioral functions of Wistar and Long-Evans Cinnamon (LEC) rats, Wilson's disease animal model, were compared by measuring the open-field, acoustic startle reflex and prepulse inhibition (PPI), and shuttle-box avoidance learning tests with or without oral supplementation with copper or D-penicillamine, copper chelator. All of the LEC rats, irrespective of the treatment, exhibited higher locomotor activity, a decreased habituation to startle response or a lower PPI, compared with Wistar rats. The copper content of all brain regions examined, except for the medulla oblongata of LEC rats, was significantly lower than those in Wistar rats. Besides, in the region of the striatum and the nucleus accumbens of the LEC rats, lower content of norepinephrine, and higher content of dopamine and serotonin were observed compared with Wistar rats. Although copper supplementation did not affect the brain copper content, it reduced the PPI in both Wistar and LEC rats. In contrast, D-penicillamine supplementation decreased both the brain copper content and locomotor activity, and enhanced the startle amplitude only in Wistar rats. These findings suggest that an imbalance in copper homeostasis affects monoamine metabolism and behavioral functions.

Amines↗

PubMed2006

Passage of time leaves response-outcome associations intact.

The effect of the passage of time on the association between an instrumental response and its outcome was examined in three experiments with rats using outcome devaluation. In Experiments 1 and 2, rats were initially trained to make one pair of instrumental responses for different outcomes (e.g., lever press-->pellets and chain pull-->sucrose). Then, after a delay of several weeks, a second pair of responses for those different outcomes (e.g., nose poke-->pellets and handle pull-->sucrose) was trained in Experiment 1 but not in Experiment 2. One of the outcomes was then devalued and the responses were tested in extinction. There was no evidence that the passage of time eliminated the sensitivity of a response to a change in the value of its outcome. Experiment 3 used the same design as Experiment 1 to examine the effect of the passage of time on extinguished instrumental responses. First, one pair of responses was trained with different outcomes and then extinguished prior to the training and subsequent extinction of a second pair of responses. After retraining both pairs of responses with a polycose outcome, one of the original outcomes was devalued. Each pair of responses was then tested in extinction. The results of the extinction tests revealed no evidence that the passage of time removed the sensitivity of an extinguished response to devaluation of its original outcome. These findings are consistent with other reports that the response-outcome association survives various response elimination techniques.

Animals↗

PubMed2006

Within-compound associations are not sufficient to produce taste-mediated odor potentiation.

Rats were used in two flavor-aversion experiments to determine if within-compound associations could be detected with a taste+odor compound that would not support taste-mediated odor potentation. In Experiment 1, following taste+odor compound conditioning, postconditioning taste extinction significantly weakened the odor aversion. In Experiment 2, following taste+odor compound conditioning, postconditioning taste inflation significantly strengthened the odor aversion. There was no evidence that taste potentiated the odor aversion in either Experiment 1 or 2. Thus, the results demonstrate that the presence of within-compound associations is not sufficient to produce taste-mediated odor potentiation. We offer a mediated conditioning explanation to account for the results of these two experiments.

Animals↗

PubMed2006

Generalization of conditioned food aversions in grazing sheep and its implications for food categorization.

When grazing on heterogeneous pastures, herbivores may rely on food item generalization and categorization processes for reducing information processing while selecting their diet. The objective of this study was to assess the generalization of an aversion by grazing sheep for items differing by one or two criteria from an item against which they were negatively conditioned. Four items cultivated in pots were offered to the animals, resulting from the combination of an intrinsic criterion, i.e. grass species (ryegrass and fescue) and a transitory criterion, i.e. sward height (tall and short). We assessed the generalization process by comparing binary choices between the initially preferred tall ryegrass and the three other items, before and after animals had been partially conditioned against tall ryegrass. This method proved useful in assessing the generalization of an aversion. Sheep did not generalize their aversion on the basis of sward height but rather on species: they increased their preference for tall fescue and decreased their instantaneous preference for short ryegrass after having been conditioned against tall ryegrass. The generalization of an aversion through different states of a same species could indicate the possibility of a species-based categorization by grazing herbivores.

Animal Feed↗

PubMed2006

Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects.

BACKGROUND: Anticipation is a critical component of affective processing in general and for anxiety in particular. Prior research suggests that the right insula plays an important role in anticipation of affective processing during aversive images. This study aimed to test the hypothesis that individuals with increased anxiety-related temperamental traits (anxiety-prone [AP]) relative to anxiety-normative (AN) subjects would show an exaggerated insula response during anticipation of an aversive image. METHODS: 16 AP and 16 AN individuals performed a task in the functional magnetic resonance imaging scanner, during which they viewed pictures of spiders and snakes. Subjects were prompted 4-6 sec before the onset of each aversive image. Blood oxygenation level-dependent signal was contrasted during cued anticipation of images versus non-anticipatory task performance as well as viewing images. RESULTS: As hypothesized, AP subjects showed greater response than AN subjects in the bilateral insula during anticipation. In addition, these individuals had lower activity within the superior/medial frontal gyrus. During the image presentation phase, AN subjects showed greater activation than AP subjects in the bilateral temporal lobes and left superior frontal gyrus. Moreover, bilateral temporal lobe activation during image presentation was inversely correlated with bilateral insula activation during anticipation both within groups and in the combined group. CONCLUSIONS: These data suggest that greater activation of the insula during visual anticipation is associated with visual processing of aversive stimuli in AP individuals. Insula hyperactivity might be a common feature in persons with elevated trait anxiety and, as such, might be a neuroimaging marker for anxiety proneness.

Adolescent↗

PubMed2004

Pharmacological characterization of SIB-1663, a conformationally rigid analog of nicotine.

SIB-1663 ([+/-]-7-methoxy-2,3,3a,4,5,6,9b-hexahydro-1H-pyrrolo-[3,2h]-isoquinoline) is a conformationally restricted analog of nicotine (NIC). SIB-1663 exhibited modest affinities to cholinergic receptors (K(i) values displacing the binding of [(3)H]-nicotine (NIC) and [(3)H]-quinuclinidylbenzilate (QNB) binding were 1.0+/-0.3 and 2.6+/-0.3 microM, respectively) with no appreciable affinity to nearly 40 other receptors. SIB-1663 selectively activated alpha2beta4 and alpha4beta4 human recombinant neuronal nicotinic acetylcholine receptors (nAChRs) with no appreciable activation of alpha4beta2 nAChRs, the presumed high-affinity nAChRs in rodent brain. These properties led us to examine profile of SIB-1663 in native preparations. SIB-1663 increased DA release from the rat striatum (STR) and olfactory tubercles and NE release from hippocampus, thalamus and prefrontal cortex (PFC). SIB-1663 was equiefficacious to NIC in STR-DA and PFC-NE release assays and less efficacious than NIC in other release assays. SIB-1663 appeared to be partial agonist in the hippocampal NE release assay. SIB-1663-induced neurotransmitter release in vitro was relatively insensitive to the nAChR antagonists, mecamylamine (MEC) or dihydro-beta-erythroidine (DHbetaE) providing equivocal evidence for nAChR activity. SIB-1663 (3-30 mg/kg, s.c.) increased locomotor activity in naive rats in a novel environment, increased ipsilateral turning in rats with unilateral 6-OHDA nigrostriatal lesion and increased withdrawal latencies in the tail-flick assay. The in vivo effects of SIB-1663 in these assays showed varying degrees of sensitivity to nAChR antagonists in that the locomotor activity and turning behavior of SIB-1663 were partially sensitive to MEC, whereas the antinociceptive activity was completely sensitive to MEC. In addition, SIB-1663 (s.c. or i.c.v.) attenuated antinociceptive activity NIC given by the same route suggesting a partial agonist activity. SIB-1663 also increased the retention of avoidance learning in normal rats when administered immediately after the acquisition session. These data indicate that SIB-1663, a conformationally restricted analog of NIC, with distinct nAChR subtype selectivity from NIC exhibits contrasting pharmacology with some of its in vivo actions involving nAChRs.

Analgesics↗

PubMed2004

NMDA receptor function within the anterior piriform cortex and lateral hypothalamus in rats on the control of intake of amino acid-deficient diets.

Animals decrease intake of an indispensable amino acid (AA)-deficient or devoid diet, due in part to decreased dietary limiting AA (DLAA) concentrations within the anterior piriform cortex (APC), and to a recognition process that occurs as early as 20 min following exposure to AA deficiencies. Glutamate levels within the APC change in response to AA deficiencies. The APC projects to the lateral hypothalamus (LH), where glutamate acts to stimulate food intake. We hypothesize that the APC, through glutamatergic projections to the LH, inhibits the LH, which signals to reject the AA-deficient or devoid diet, and trigger aversions to the AA-deficient or devoid diet via an ascending pathway to the APC. We examined the effects of (1) bilateral APC and LH blockade of glutamate's NMDA receptors with the antagonist, D-AP5, (2) APC blockade of AMPA receptors with the antagonist, NBQX, to block glutamate transmission from the APC, and (3) direct injection of the agonist, NMDA, into the LH on intake of the AA-deficient, devoid, or corrected diet. Administration of D-AP5 into the APC increased intake of AA-deficient diet by 6 h, but D-AP5 in the LH decreased AA-devoid diet preferentially over AA corrected intake sooner. NBQX in the APC increased AA-deficient diet intake, also at 6 h. NMDA injection into the LH-stimulated intake of the AA corrected diet by 3 h, but did not affect AA-devoid diet intake. Thus, the glutamate receptors in the APC and LH are involved in the feeding responses to AA-deficient diet, albeit with regional differences. We suggest that glutamate mediates the anorectic responses to AA-deficient diets through recognition of AA-devoid diet with the glutamatergic output cells of the APC sending glutamate-based signals for changes in food intake within the LH and through learned avoidance of AA-deficient diet within the APC, as indicated through the more immediate and prolonged periods of activation within the LH and APC, respectively.

Amino Acids↗

PubMed2005

Effects of midazolam on the expression of conditioned taste aversion in rats.

In conditioned taste aversion (CTA), the animals learn to avoid a taste substance (conditioned stimulus, CS) which was previously associated with visceral distress (unconditioned stimulus, US). The present study examined the effects of administration of midazolam (MDZ), a benzodiazepine agonist, after the acquisition of CTA on the expression of CTA. After ingestion of 0.5 M sucrose (CS) was paired with an intraperitoneal (i.p.) injection of 0.15 M LiCl (US), control rats showed strong CTA to the CS. However, a systemic injection of MDZ (1.5 mg/kg, i.p.) before the retention test prevented conditioned animals from rejecting the CS, but in the subsequent retention tests where the drug was not administrated, those animals again showed strong aversions to the CS. Aversive taste reactivity patterns to the intraorally infused sucrose and 0.3 M dl-alanine in the conditioned animals were also diminished by the similar injection of MDZ, but not by a serotonergic anxiolytic agent, buspirone (2.5 or 5.0 mg/kg, i.p.). General taste sensory deficit might not be induced by MDZ because the drug injection did not impair conditioned aversions to 0.2 M NaCl and 0.01 M HCl. Infusion of MDZ into the basolateral nucleus of the amygdala (BLA) also attenuated conditioned aversions to sucrose. These results suggest that systemic or intra-BLA administrations of MDZ impair the expression of CTA selectively to sweet-tasting substances, implying that a transient MDZ-induced CTA expression deficit is due to the enhancement of palatability of CSs with preferable tastes rather than general anxiolytic or amnesic effects of MDZ.

Amygdala↗

PubMed2004

Evolution of nociception in vertebrates: comparative analysis of lower vertebrates.

Nociception is an important sensory system of major fundamental and clinical relevance. The nociceptive system of higher vertebrates is well studied with a wealth of information about nociceptor properties, involvement of the central nervous system and the in vivo responses to a noxious experience are already characterised. However, relatively little is known about nociception in lower vertebrates and this review brings together a variety of studies to understand how this information can inform the evolution of nociception in vertebrates. It has been demonstrated that teleost fish possess nociceptors innervated by the trigeminal nerve and that these are physiologically similar to those found in higher vertebrates. Opioid receptors and endogenous opioids are found in the brain and spinal cord of the fishes and morphine blocks avoidance learning using electric shock as well as reducing nociceptive behavioural and physiological responses to noxious stimulation. Comparative analysis of the fishes and higher vertebrates show that fish possess less C fibres than higher vertebrates. The electrophysiological properties of fish nociceptors are almost identical to those found in higher vertebrates suggesting the evolution of these properties occurred before the emergence of the fish groups.

Afferent Pathways↗

PubMed2005

Effect of vitamin E on memory retention in rats: possible involvement of cholinergic system.

This study concerned effects of vitamin E and the cholinergic system on memory retention of passive avoidance learning in rats. Post-training intracerebroventricular (i.c.v.) injections were carried out in all experiments. Administrations of vitamin E (10, 25 and 50 microg/rat), nicotine (0.1 microg/rat) and pilocarpine (0.5 microg/rat), the muscarinic receptor agonist increased memory retention, while mecamylamine (0.01, 0.1 and 0.5 microg/rat), the nicotinic receptor antagonist and scopolamine (0.1, 1 and 5 microg/rat), the muscarinic receptor antagonist decreased memory retention. The combination of vitamin E with nicotine or pilocarpine showed potentiation. Effects of mecamylamine or scopolamine were attenuated by vitamin E. It is concluded that vitamin E has a close interaction with cholinergic system in memory retention process.

Animals↗