Effect of lesions in the medial forebrain bundle on three measures of pain sensitivity and noise-elicited startle.

Subjected 137 male Holtzman albino rats to bilateral lesions of the medial forebrain bundle (MFB) or to surgical control procedures. Lesions produced equivalent decreases in paw-lick latency to heat and in jump and high-magnitude-response thresholds to footshock. Flinch and detection thresholds to footshock were also significantly decreased, though the lesion did not alter the magnitude or habituation of noise-elicited startle. Injection of 75 mg/kg serotonin into lesioned Ss returned the high-magnitude-response threshold to normal values but did not affect detection threshold. It is concluded that the increased sensitivity to painful stimuli resulted from the decrease in telencephalic content of serotonin following MFB lesions. Previous exposure of lesioned Ss to footshock resulted in a potentiation of the startle response to noise, further suggesting that the lesion had increased the aversiveness of footshock. (27 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of neurotoxic lesions of the ascending monoamine pathways in the rat brain.

Intracranial microinjections of 6-hydroxydopamine or 5,6-dihydroxytryptamine into 6 ascending monoamine pathways produced the expected patterns of depletion of telencephalic serotonin, dopamine (DA), and norepinephrine (NE). Serotonin level was specifically lowered after dorsal or median raphe lesions but not after mesolimbic or nigrostriatal system lesions which lowered both NE and DA. Lesions in the locus coeruleus (LC) or ventral noradrenergic bundle lowered only NE, and LC lesions elevated serotonin level. Behavior was examined in an open field, 1-way active avoidance, and 2 passive avoidance (PA) tasks, and measures were taken of water consumption and body weight. Dorsal raphe lesions had no effect on any of the measures; the other 5 lesion groups exhibited deficient acquisition of the 1-way active avoidance task. In the appetitive PA task, only the substantia nigra lesion group exhibited a deficiency. In the step-through PA task, both the substantia nigra and the median raphe groups exhibited a deficit, with the median raphe group exhibiting hyperactivity in the start box during testing. Water consumption was decreased by lesions in the ventral noradrenergic bundle during the 1st postoperative week and was increased in the median raphe group by the 4th postoperative week. Lastly, lesions in the LC dramatically decreased activity in the open field. Results are discussed in regard to the search for specificity of behavioral functions of the distinct ascending monoamine pathways. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disruption of passive avoidance learning in the rat by electrical stimulation of the hippocampus.

Five experiments, with 184 male albino rats, examined the effect of electrical stimulation to discrete regions of the dorsal hippocampus on passive avoidance. Ss stepped from a brightly lit, white compartment to a dark compartment. Following footshock in the dark compartment, step-through latencies were recorded 1 min, 24 hrs, and 48 hrs after footshock. When given 20 step-through trials prior to footshock, dentate-stimulated Ss exhibited lack of passive avoidance with particularly short latencies at 1 min, and CA1-stimulated Ss showed reduced latencies compared with latencies of cortical and nonoperated controls. In Exp II, Ss given stimulation in the same regions performed the avoidance task without prior step-through experience. All groups showed less passive avoidance than the control group in Exp I, and there were no significant differences between groups. With a single step-through trial before the footshock trial, longer avoidance latencies were recorded, but again groups did not differ significantly. Dentate-implanted Ss, given 20 prior exposure trials but with stimulation at different stages of the task sequence, demonstrated a passive avoidance deficit at 1 min after footshock. Results are discussed in terms of the generation of expectancy that the black compartment was a safe place and the effects of brain stimulation on the expectancy, with particular reference to O. S. Vinogradova's (1975) theory of hippocampal function. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functional organization of the rat amygdala with respect to avoidance behavior.

Conducted tests with approximately 100 adult female albino Holtzman Sprague-Dawley rats. Bilateral electrolytic lesions in the periamygdaloid piriform cortex of Ss produced marked disruptive effects on the acquisition of active avoidance responses in a 1-way as well as a 2-way test situation, significantly impaired passive avoidance behavior, and inhibited feeding in a novel environment. Lesions in each of the 6 major subdivisions of the amygdala (cortical, medial, central, intercalated, lateral, and basolateral nuclei) consistently produced facilitatory effects on active avoidance behavior in 1-way as well as 2-way situations. Passive avoidance behavior was impaired in Ss with lesions in the central, intercalated, and basolateral nuclei. Damage to the anterior amygdaloid area or the nuclei of the lateral olfactory tract did not reliably affect active or passive avoidance behavior. (34 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The pain ward follow-up analyses

The site of action of corticosteroids in avoidance learning was investigated in 110 rats. Injection of cycloheximide, 30 min before one-trial training on a passive avoidance task suppressed corticosteroid secretion in response to footshock, and produced an avoidance deficit in a test 6 days later. However, an additional injection of hydrocortisone, either subcutaneously or intra-hippocampally within 5 min of training, restored the avoidance response in the test. Septal and hypothalamic injections of the hormone were ineffective in reversing the cycloheximide effect, whereas the effect of hormone injection into the amygdala was equivocal because of an increased level of activity. Corticosteroids secreted following an aversive experience appear to act upon the steroid-sensitive neurons in the hippocampus to influence the animal's later performance of passive avoidance response.     

Stimulation and antagonism of opioid !d-receptors produce opposite effects on active avoidance conditioning in mice.

The effects of opioid δ-receptor activation on conditioning in a one-way active avoidance paradigm were investigated in mice. Peripheral administration of 30 and 100 μg/kg of [Leu–5] enkephalin (LE) and 11.6 μg/kg of [D-Pen–2,D-Pen–5]enkephalin ({dpdpe}), a synthetic enkephalin analog with high δ-selectivity, impaired acquisition of avoidance responding. The dose response functions for both peptides were U-shaped. Deficits in responding were also present 24 hours after training, which suggests that the impaired performance observed during training was not an impairment in the ability of the mice to perform. Also, neither LE nor {dpdpe} decreased footshock sensitivity or open-field activity, which rules out analgesia and decreased activity levels as likely explanations for the deficits in conditioning. Finally, antagonizing endogenous ligands with the δ-selective antagonist ICI 154,129 enhanced acquisition, an effect opposite that produced by LE and {dpdpe}. The results suggest that activation of δ-receptors is normally involved in the modulation of active avoidance learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A single pre-training glucose injection induces memory facilitation in rodents performing various tasks: contribution of acidic fibroblast growth factor

Effects of a pre-training intraperitoneal glucose injection on learning and memory were tested using two tasks: passive avoidance and Morris water maze. In the former task, mice that had received glucose 2 h prior (but not 1, 3, or 5 h prior) to a trial that combined acquisition with passive avoidance of foot shock showed a significantly increased retention latency when tested 24 h later. Thus, this effect was time-dependent, and it was also found to be dose-dependent by further experiment. In contrast, 2-deoxy-D-glucose and fructose had no such effect. In the Morris water maze task, glucose injection 2 or 3 h before a block of trials enhanced the spatial memory performance of mice. These glucose-induced memory-facilitation effects were abolished by an intracerebroventricular injection of anti-acidic fibroblast growth factor antibody 30 min before the glucose injection, suggesting a critical role for endogenous acidic fibroblast growth factor in this facilitatory effect. Furthermore, continuous intracerebroventricular infusion of acidic fibroblast growth factor in rats significantly increased retention latency (when tested repeatedly on successive days using a passive avoidance task). Our earlier studies demonstrated that brain acidic fibroblast growth factor is produced in the ependymal cells of the cerebroventricular system, and is released into the cerebrospinal fluid following either a meal or a (intraperitoneal or intracerebroventricular) glucose injection. This released acidic fibroblast growth factor also diffuses into the brain parenchyma, and is taken up by neurons in the hippocampus, hypothalamus, and elsewhere in the brain some 2 h after the meal or glucose injection. These and the present findings indicate (i) that pre-training glucose injection improves memory performance, and (ii) that acidic fibroblast growth factor, especially by its action within the hippocampus, is involved in this enhancement process.     

The synaptic release of dopamine in the striatum of rats during the acquisition of a passive avoidance conditioned reflex

To study the striatal synaptic dopamine release during passive avoidance behaviour the intracranial microdialysis technique combined with radioenzymatic assay method was used in Sprague-Dawley rats. It was shown that the acquisition of passive avoidance conditioning and an unescapable footshock led to delayed increases in striatal synaptic dopamine release.     

Altered sensitivity to footshock after selective serotonin depletion: Comparison of electrolytic lesions and neurotoxin injections in the medial forebrain bundle of the rat.

Compared the changes in 183 male albino rats' jump threshold with changes in monoamine content of the telencephalon after damage to the lateral hypothalamus produced either by electrolytic lesions or by 6-hydroxydopamine (6-OHDA) and 5,7-dihydroxytryptamine (DHT). Electrolytic lesions produced significant decreases in jump threshold and in telencephalic content of serotonin, norepinephrine, and dopamine. Infusions of DHT, with or without pretreatment with desipramine, always reduced both jump thresholds and serotonin content, even when there was no effect on norepinephrine or dopamine. In contrast, 6-OHDA had no effect on jump thresholds or serotonin content, even though both norepinephrine and dopamine were greatly reduced. Results suggest that the increased sensitivity to footshock was solely due to the interruption of ascending serotonergic pathways within the lateral hypothalamus and was not a result of damage either to norepinephrine and dopamine pathways or to some other neural system. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexually dimorphic responses to neonatal basal forebrain lesions in mice: I. Behavior and neurochemistry

The nucleus basalis magnocellularis (nBM) provides the primary source of cholinergic input to the cortex. Neonatal lesions of the nBM produce transient reductions in cholinergic markers, persistent abnormalities in cortical morphology, and spatial navigation impairments in adult mice. The present study examined sex differences in the effects of an electrolytic nBM lesion on postnatal day 1 (PND 1) in mice on behavior and neurochemistry in adulthood. Mice were lesioned on PND 1 and tested at 8 weeks of age on a battery of behavioral tests including passive avoidance, cued and spatial tasks in the Morris water maze, simple and delayed nonmatch to sample versions of an odor discrimination task, and locomotor activity measurements. Following behavioral testing, mice were sacrificed for either morphological assessment or neurochemical analysis of a cholinergic marker or catecholamines. There were no lesion or sex differences in acquisition or retention of passive avoidance, performance of the odor discrimination tasks, or activity levels. Control mice showed a robust sex difference in performance of the spatial water maze task. The lesion produced a slight cued but more dramatic spatial navigation deficit in the water maze which affected only the male mice. Neurochemical analyses revealed no lesion-induced changes in either choline acetyltransferase activity or levels of norepinephrine or serotonin at the time of testing. The subsequent report shows a sex difference in lesion-induced changes in cortical morphology which suggests that sexually dimorphic cholinergic influences on cortical development are responsible for the behavioral deficits seen in this study.     

Cortical cholinergic impairment and behavioral deficits produced by kainic acid lesions of rat magnocellular basal forebrain.

The rat magnocellular basal forebrain (MNBF) is homologous to the human nucleus basalis of Meynert, a structure implicated in the cholinergic hypothesis of cognitive impairment in Alzheimer's disease (AD). In the present study, 18 male Sprague-Dawley rats with kainic acid lesions in the MNBF were compared with 6 unoperated controls, 10 sham-operated controls, and 6 controls injected with kainic acid in the cortical area directly above the MNBF. MNBF lesions depleted choline acetyltransferase in cortex but not in striatum or hippocampus. Cortical dopamine levels were unchanged; serotonin levels were unchanged in hippocampus and parietal cortex but decreased in frontal cortex. Compared with controls, MNBF-lesioned Ss were impaired in 24-hr retention, but not acquisition, of a passive avoidance task with escapable footshock. The groups did not differ in mean number of daily avoidances on a barpress active avoidance task, although learning was slower in MNBF-lesioned Ss. In a serial spatial discrimination reversal test, MNBF-lesioned Ss performed significantly worse than controls. This model may be useful for studying the role of the cholinergic system in memory and possibly for developing treatment strategies to alleviate the cognitive dysfunction of AD. (63 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of pretraining compatible and incompatible responses on subsequent one-way and shuttle-avoidance performance in rats.

Conducted 6 experiments with male Holtzman rats. A single noncontingent footshock was found to facilitate subsequent one-way and shuttle avoidance if the CS in preshock and avoidance training was the same. If the to-be-established instrumental response was punished during preshock, or if Ss were required to run toward the CS paired with shock during pretraining, the facilitative effects of preshock were eliminated. Facilitation by a single preshock was not enhanced if shock was escapable, regardless of the CSs, task, or whether escape was immediate or delayed. If Ss received 10 one-way escape trials, the beneficial effects of preshock on one-way and shuttle avoidance were enhanced. In contrast, shuttle-escape training produced no such beneficial effects on avoidance performance. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Instrumental avoidance conditioning in the spinal rat

Spinal rats exposed to an instrumental avoidance routine in a counterbalanced Horridge paradigm were able to achieve successively higher criteria. Both experimental and yoked control animals were capable of instrumental avoidance conditioning to incremental criteria; experimental animals exhibited retention of the task when tested. During acquisition, naive experimental animals were superior in performance to previous control animals. Due to the use of a counterbalanced Horridge paradigm, the effectsof sensitization and response variability are probably not sufficient to explain all of the results of this experiment. The data suggest that both graded acquisition and retention occur at the spinal level.     

Exploration and avoidance in rats with lesions in amygdala and piriform cortex.

Lesions localized to specific areas of the amygdala and overlying cortex in 41 adult male M?ll-Wistar rats produced differential effects in several behavioral tasks. Three different types of lesions were tested: central, basolateral, and cortex lateral to the amygdala. Lesions restricted to the central nucleus produced increased activity on all parameters studied in an open-field test, but the other 2 groups were not changed. In 1-way active avoidance all 3 groups with lesions showed deficits. The most pronounced change was observed in the central group. All groups showed the same degree of retention loss, but in forced extinction of 1-way active avoidance after retraining, the cortical and basolateral groups were most defective. A fear-reduction hypothesis is proposed for the central lesion. The basolateral and cortical areas may be more specifically involved in passive avoidance behavior. (13 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic treatment of severe hemoglobinopathies: the combat against transgene variegation and transgene silencing

A multiple-trial passive avoidance paradigm was used to examine and compare the ability for estrogen replacement to attenuate learning and memory deficits produced by the muscarinic antagonist scopolamine and the benzodiazepine lorazepam. The multiple-trial paradigm was used in order to distinguish effects on acquisition from effects on retention. Estrogen replacement significantly attenuated a scopolamine-induced deficit on passive avoidance acquisition, but not retention. The ability for estrogen to attenuate the effect of scopolamine on acquisition was observed only when the analysis was limited to animals with serum levels of estradiol <200 pg/ml, suggesting that higher levels of estradiol were ineffective. This observation is consistent with at least one recent study showing dose-related effects of estrogen on ChAT-like immunoreactivity in the basal forebrain and supports the hypothesis that effects of estrogen on basal forebrain cholinergic neurons can help to reduce cognitive deficits associated with cholinergic impairment. Estrogen replacement was also observed to protect against a lorazepam-induced impairment on passive avoidance retention. This effect was observed specifically in animals that received estrogen prior to and during training and was not due to any effect of estrogen on serum levels of lorazepam following acute lorazepam administration. Collectively, these data demonstrate the ability for estrogen replacement to attenuate specific pharmacologically induced impairments in learning and retention and provide additional clues as to potential mechanisms by which estrogen replacement may help to reduce cognitive deficits associated with aging and Alzheimer's disease in postmenopausal women.     

Effects of 3,3'-iminodipropionitrile on acquisition and performance of spatial tasks in rats

3,3'-Iminodipropionitrile (IDPN) has been reported to disrupt learning and memory in rats (24). The present work addressed the effects of IDPN on tasks requiring the use of spatial information. Separate groups of male rats were dosed with IDPN (IP, in 1 ml/kg saline) for 3 consecutive days and tested in the following procedures: (a) step-through passive avoidance conditioning (0, 100, 150, and 200 mg/kg/day); (b) Morris water maze (MWM) acquisition and retention (0, 125, 150, 175, and 200 mg/kg/day); (c) radial arm maze (RAM) acquisition (0, 100, 200, and 400 mg/kg/day); (d) RAM steady-state performance (0, 200, and 400 mg/kg/day); (e) repeated acquisition in the RAM (0, and 200 mg/kg/day). The vestibular toxicity of IDPN resulted in alterations in spontaneous behavior or swimming deficits in 5 of 8 rats treated with 175 mg/kg/day and in all the animals dosed with 200 or 400 mg/kg/day. IDPN increased step-through PA latencies at 200 mg/kg/day but not at lower doses. In the MWM, no performance deficits were observed at the dose levels preserving the swimming ability of the animals. In both the acquisition and the steady-state RAM tasks, IDPN (400 mg/kg/day) induced an increase in both choice errors and perseverative errors. In the RAM repeated acquisition paradigm, IDPN (200 mg/kg/day) induced performance deficits that included a decreased rate of within-session reduction in errors. The present data show that IDPN disrupts performance of tasks requiring spatial learning and memory and indicate that these deficits can be in part caused by an acquisition deficit.     

Passive avoidance behavior in rats after electroconvulsive shock: Facilitative effect of response retardation.

In 3 experiments, a total of 178 male Wistar rats were trained in a one-trial passive avoidance task and then were submitted to electroconvulsive shock (ECS) or to sham ECS. 24 hrs later they were tested for retention, with the door opened either immediately or 30 sec after the beginning of the test. Ss initially forced to avoid for 30 sec continued to avoid for the entire test, but the others had the usual low step-through latencies seen with ECS-treated Ss. Activity measures for those Ss stepping through differentiated groups having received footshock from those not having footshock and ECS. A retest 5-10 min later showed "recovery" in the amnestic Ss and continued avoidance behavior for those that avoided on the first test. Results are taken as evidence that ECS effects are not on memory storage but on the capacity of the animal to organize information effectively and quickly in order to produce an adaptive response. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral responsiveness of adrenalectomized, hypophysectomized, and intact rats to electric shock.

Tested whether the altered rates of acquisition and extinction of avoidance behavior in adrenalectomized and hypophysectomized rats are associated with abnormal responsiveness to electric shock. The electrical threshold for flinch, jump, and vocalization behaviors in adrenalectomized and hypophysectomized Ss (N = 95) was measured in 2 experiments. Adrenalectomized Ss had higher thresholds for flinch and jump responses than hypophysectomized Ss, and also a higher flinch threshold than weight-matched controls. Hypophysectomized Ss had normal thresholds for all 3 behaviors. The difference in threshold for the flinch response between adrenalectomized and hypophysectomized or normal Ss was not explained by differences in body weight, although heavy Ss responded less to electric shock than light Ss. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The ethical problem of the health-environment relationship]

The effects of sustained stress on response rate and temporal patterning (quarter-life) of rats performing either a previously learned fixed-interval schedule (FI 60) or learning an FI 60 simultaneously with stress onset were determined. Rats lived 24 h/day in operant cages, where they earned all of their food via lever-pressing. During the stress portion of each experiment, one group of rats was able to avoid or escape signalled intermittent footshock (Avoidance/ Escape Group), a second group (Yoked) did not have control over shock termination, a third group never received shock (Control). Shock trials were presented around the clock at approximately 5-min intervals and the stress portion of each study lasted 1-2 weeks. We have previously reported that rats tolerate this paradigm well and avoid/escape 99% of the shock trials. In rats previously trained on the FI task, both rate of responding and quarter-life values were significantly decreased on the first day of stress for both the Avoidance/Escape and Yoked Groups. Food intakes and quarter-life values were not significantly different from the controls by stress Days 3 and 2, respectively. In the acquisition study, controls learned the F1 task by Day 4 as judged by quarter-life of responding. FI task acquisition was significantly impaired in stressed rats compared to controls, not reaching asymptotic performance until Day 9 of stress. There were no major differences between the 2 stress groups in either study. These data demonstrate that stress may impair both the rate and patterning of behavior, and suggest that this rodent paradigm may usefully model some aspects of the effects of stress in humans.     

Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval). Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-microliter infusion containing 5.0 microgram of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5) or vehicle (phosphate-buffered saline, pH 7.4). Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean +/- SEM number of conditioned responses (CRs) during retention test session was 16.47 +/- 1.78 in the vehicle group and 9.93 +/- 1.59 in the AP5 group; P < 0.05). Post-training infusion of AP5 did not affect retention (mean +/- SEM number of conditioned responses during retention test session was 18.46 +/- 1.94 in the vehicle group and 20.42 +/- 2.38 in the AP5 group; P > 0.10). This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.