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[Low back pain: from symptom to chronic disease].

In several prospective studies it has been demonstrated that psychological factors are better predictors of low back pain than biographical or medical factors. The most elaborate model for the development of chronic low back pain is the model of fear avoidance. The essential feature of this model is that exaggerated negative orientations towards pain ("pain catastrophizing") lead to fear of movements and the belief that movements will lead to more pain. The result is the perpetuation of avoidance behavior. This leads to inactivity, reduced mobility, increased disability, and increased anger, demoralization, anxiety, and depression. From fear avoidance models several principles for the therapeutic management of pain can be derived. Therapists have to be aware of the powerful effects of anticipating processes which can give rise to fear of pain, amplifying the intensity of pain, and consequently result in avoidance behavior. On the other hand, reduction of uncertainty via adequate information about the non-serious nature of back pain disorders may lead to an adequate confrontative pain behavior, less emotional arousal and more useful coping mechanisms. In particular, the uncritical use of widespread back schools has to be looked upon carefully for pronouncing avoidance learning. For chronic pain, therapy must include mechanisms from the treatment of phobias in which pain behavior is looked upon as the result of a phobic process.

Avoidance Learning↗

PubMed2001

Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters.

There is strong evidence supporting the deleterious effects of aging on learning and memory and behavioral parameters in normal mice. However, little is known about the Ames dwarf mouse, which has a Prop-1 gene mutation resulting in deficiencies in growth hormone, thyroid-stimulating hormone, and prolactin. These mice are much smaller and live significantly longer than their normal siblings. Using the elevated plus-maze, locomotor activity meters, and an inhibitory avoidance learning task, the present study compared Ames dwarf mice to their normal siblings. Results showed that Ames dwarf mice did not experience an age-related decline in locomotor activity when compared to their young counterparts. Furthermore, old dwarf mice did not differ from the young groups in inhibitory avoidance retention, while old normal animals performed more poorly than both young groups on this test. Elevated plus-maze behavior did not differ in the old normal versus dwarf groups, but the old groups did differ from the young. Results indicate that both old groups experienced a significant decline in anxiety with age. Taken together, these results indicate that multiple hormone deficiencies resulting from a lack of primary pituitary function have beneficial effects on cognitive function and locomotor behavior in advanced age. In fact, the Ames dwarf mouse may provide a model for studies of delayed mental as well as physical aging.

Aging↗

PubMed1991

Training-stage related neuronal plasticity in limbic thalamus and cingulate cortex during learning: a possible key to mnemonic retrieval.

This study is part of an ongoing project concerned with the analysis of the neural substrates of discriminative avoidance learning in rabbits. Multi-unit activity was recorded in 5 anterior and lateral thalamic nuclei and in 4 layers of 2 posterior cingulate cortical areas (29c/d and 29b) during learning. The rabbits learned to step in response to a warning tone to avoid a foot-shock, and to ignore a different tone not followed by shock. Excitatory training-induced unit activity (TIA, increased tone-elicited activity during training relative to a pretraining session with unpaired tone-shock presentations) and/or discriminative TIA (greater discharges to the warning than to the safe tone) developed during training in 11 of the 13 areas. Discriminative TIA in the thalamic nuclei increased monotonically as learning occurred. Anterodorsal (AD) thalamic excitatory TIA peaked in an early stage (the first session of training), laterodorsal thalamic and parvocellular anteroventral (AVp) excitatory TIA peaked in an intermediate stage (the session of the first behavioral discrimination), and magnocellular anteroventral (AVm) and anteromedial (AM) thalamic excitatory TIA peaked in a late stage (the session in which asymptotic behavioral discrimination first occurred). The excitatory TIA in these nuclei declined as training continued beyond the stage in which the peak occurred. Peaks of excitatory TIA developed in area 29c/d of posterior cingulate cortex in the early (layer IV), intermediate (layers I-III and V) and late (layer IV) training stages, as just defined. Only layer IV in area 29b of posterior cingulate cortex exhibited a peak of excitatory TIA, which occurred in the early and intermediate training stages. As in limbic thalamus, discriminative TIA increased monotonically over training stages in layers V and VI of areas 29c/d and in layer VI of area 29b. However, layers I-III and IV in area 29c exhibited peak discriminative TIA in the intermediate and late training stages, respectively. Lesion studies indicate that limbic thalamus and cingulate cortex are essential for learning. The peaks represent a unique topographic pattern of thalamic and cortical excitation elicited by the CS+. It is proposed that the peaks constitute a retrieval pattern, i.e. a unique topographic array of excitation. This pattern encodes the spatio-temporal context which defines the learning situation and is necessary for recall and output of the learned response.

Animals↗

PubMed2006

Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model.

To confirm the antidepressant-like activity of agomelatine (S 20098), a melatonin agonist and 5-hydroxytryptamine2C antagonist, already reported in the chronic mild stress and forced swimming tests, the effects of agomelatine were investigated in the learned helplessness test and compared with those of imipramine, melatonin and a selective 5-hydroxytryptamine2C antagonist, SB-242 084. Agomelatine was administered for 5 days either once a day or twice a day, and the effects of pretreatment by a melatonin receptor antagonist, S 22153 (20 mg/kg/day), were studied. A deficit in avoidance learning was observed in helpless control animals. Agomelatine (10 mg/kg/day) administered once a day significantly reduced this deficit with an effect similar to that of imipramine. Effects of agomelatine were abolished by S 22153 pretreatment. Melatonin or SB-242 084 did not reduce the deficit of helpless control animals. These results confirm the antidepressant-like activity of agomelatine and suggest a role of melatonin receptors in its mechanism of action.

Acetamides↗

PubMed2001

Intra-amygdala spermidine administration improves inhibitory avoidance performance in rats.

In the present study, we investigated the effect of immediate post-training bilateral infusion of spermidine, a polyamine agonist, into the amygdala on inhibitory avoidance learning of rats. Bilateral microinjection of spermidine (0.02--20 nmol) caused an increase in test step-down latencies at high concentrations. Administration of arcaine (0.002--0.2 nmol), an antagonist of the NMDA receptor polyamine binding site, decreased test step-down latencies. On the other hand, co-administration of arcaine and spermidine completely reversed the spermidine-induced increase of test step-down latencies. These results provide evidence that polyamines may be involved in learning and memory modulation in the amygdala.

Amygdala↗

PubMed2002

Facilitation of learning and modulation of frontal cortex acetylcholine by ventral pallidal injection of heparin glucosaminoglycan.

We examined the effects of heparin on learning and frontal cortex acetylcholine parameters following injection of the glucosaminoglycan into the ventral pallidum. In Experiment 1, possible mnemoactive effects of intrapallidal heparin injection were assessed. Rats with chronically implanted cannulae were administered heparin (0.1, 1.0, 10 ng) or vehicle (0.5 microl) and were tested on a one-trial step-through avoidance task. Two retention tests were carried out in each animal, one at 1.5 h after training to measure short-term memory and another at 24 h to measure long-term memory. Post-trial intrapallidal injection of 1.0 ng heparin improved both short- and long-term retention of the task, whereas the lower and the higher dose of the glucosaminoglycan had no effect. When the effective dose of heparin was injected 5 h, rather than immediately after training, it no longer facilitated long-term retention of the conditioned avoidance response. In Experiment 2, the effects of ventral pallidal heparin injection on frontal cortex acetylcholine and choline concentrations were investigated with in vivo microdialysis in anaesthetized rats. Heparin, administered in the dose of 1.0 ng, which was effective in facilitating avoidance performance, produced a delayed increase in cortical acetylcholine levels ipsi- and contralaterally to the side of intrabasalis injection, resembling the known neurochemical effects obtained for another glycosaminoglycan, chondroitin sulfate, which recently was shown to facilitate inhibitory avoidance learning and to increase frontal cortex acetylcholine. The present findings indicate that heparin, like other extracellular matrix proteoglycans, can exert beneficial effects on memory and strengthen the presumptive relationship between such promnestic effects of proteoglycans and basal forebrain cholinergic mechanisms. The data are discussed with respect to the presumed roles of matrix molecules in extrasynaptic volume transmission and in the 'cross-talk' between synapses.

Acetylcholine↗

PubMed2005

Role of circulating androgen levels in effects of apoE4 on cognitive function.

Compared with apoE2 and E3, apoE4 increases the risk of cognitive impairments and of developing Alzheimer's disease (AD). ApoE4 interacts with female sex, further increasing AD risk. Previously, we showed that female Apoe-/- mice are more susceptible to apoE4-induced cognitive deficits than male mice. Androgens protect against these deficits and apoE4 male mice are more sensitive to acute blockade of androgen receptors than apoE3 male mice. To determine the chronic effects of reduced circulating androgen levels on susceptibility to the effects of apoE4 on cognitive function in males, we castrated and sham-castrated apoE4, apoE3, and Apoe-/- male mice and behaviorally compared them 3 months later. Castration impaired novel location recognition in apoE4, but not apoE3 or Apoe-/-, mice. In contrast, castration impaired novel object recognition and spatial memory retention in the water maze in Apoe-/-, but not apoE3 or apoE4, mice. On the contrary, castrated, but not sham-castrated, apoE4 mice showed improved acquisition over the first two hidden platform sessions and spatial memory retention in the first probe trial. While apoE3 and Apoe-/- mice increased their exploratory times with the objects in the trial with the novel object, apoE4 mice did not. ApoE4 mice required more trials than apoE3 or Apoe-/- mice to reach criterion during passive avoidance training, but castration did not modulate passive avoidance learning or memory. Thus, androgens have differential roles in object recognition and spatial learning and memory in the water maze, depending on whether or not apoE4 is present.

Analysis of Variance↗

PubMed1998

Are glutamate receptors specifically implicated in some forms of memory processes?

Convergent data indicate that certain substances that interact with N-methyl-D-aspartate (NMDA) receptors or metabotropic glutamate receptors (mGluRs) do not affect acquisition processes per se, or retrieval, but interfere specifically with the formation of memory traces. This action differs widely in its amplitude and time-course according to the learning task used. We showed that systemic injection of the competitive NMDA receptor antagonists, gamma-L-glutamyl-L-aspartate (gamma-LGLA) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), or intracerebroventricular infusion of D-2-amino-5-phosphonovalerate (D-AP5), immediately following acquisition of a Y-maze avoidance learning task in mice, deeply impaired retention of the temporal component of the task (leaving the start alley within the first 5 s of a trial), which significantly improved in controls during the hours following acquisition. In contrast the same substances had no or only slight effects on retention of the discrimination component (choice of the correct alley), which did not improve over time in control animals. This retention deficit did not appear to be due to an action on acquisition, retrieval and/or forgetting processes, or to state-dependent effects. Moreover, gamma-LGLA, CPP or AP5, when administered immediately after partial acquisition of a food-reinforced bar-press task, suppressed the spontaneous improvement in post-training performance observed in control mice 24 h after the training session. (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG), an antagonist of mGluRs, also suppressed the post-training performance increment and its effects were antagonized by the co-administration of trans-ACPD, an agonist of mGluRs. Post-training improvement of performance over time is thought to reflect an active and dynamic process, leading to the organization of memory traces. According to this hypothesis, our results suggest that synaptic plasticity mediated by NMDA receptors and/or mGluRs activation is involved in mechanisms underlying long-term consolidation of memory traces.

Animals↗

PubMed2000

Impaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet.

Sparse-fur (spf) mice are a model for the congenital deficiency of ornithine transcarbamylase (OTC), the most common inborn error of urea synthesis in man. In this study, performance of clinically stable spf and control mice (8-10-weeks-old) on two learning tests was assessed under normal Arg(+) or arginine-free Arg(-) diet conditions. Used as an indicator of the metabolic status of the animals, plasma ammonia concentrations were significantly higher in spf than in controls on normal diet, and increased even more during the Arg(-) diet episode. Behaviourally, we found no difference in passive avoidance learning between control and spf mice on Arg(+) diet, whereas in spf mice receiving Arg(-) diet during training, retention performance was significantly reduced. In the hidden-platform water maze, spf mice on Arg(+) diet only showed decreased swimming velocity compared to controls. In mice on Arg(-) diet during the first week of acquisition training, performance on acquisition and retention (probe) trials showed that spf mice experienced more difficulties in actually locating the platform. Visible-platform control experiments only showed a reduction in swimming velocity in spf mice on either diet. We conclude that cognitive performance is impaired in spf mice as a consequence of Arg(-) diet-induced neurochemical alterations.

Ammonia↗

PubMed1990

Learning and retrieval are impaired after lesions of the ventral part of rat's nucleus reticularis pontis oralis.

Adult male hooded rats of the Long-Evans strain were investigated before and after lesions of the ventral nucleus reticularis pontis oralis (vRPO) in an open field test (OF) and in a Y-maze. The OF and the neurological findings were scarcely changed. Startle responses were strongly reduced and also horizontal head and body turning in the OF were significantly reduced. The retention of Y-maze avoidance tasks was reduced and relearning of the tasks relatively slow. Brightness discrimination remained unaffected by the lesion. The postoperative active avoidance learning of a new task in the jump test box was impossible. Postoperative learning of a thirst-motivated labyrinth task was significantly retarded compared with unoperated control rats. The vRPO lesion syndrome is quite different compared with 1 mm more dorsal (dRPO) and 1 mm more posterior (vRPC, dRPC) placed lesions and underlines the hypothesis of the functional heterogeneity of the pontine reticular formation.

Animals↗

PubMed1980

Facilitation of learning by post-trial injection of substance P into the medial septal nucleus.

The undeca-neuropeptide substance P (SP) was injected post-trial into the medial nucleus of the septum to test its influence on passive avoidance learning in rats. A facilitation of learning was attained in the alcove avoidance task with doses of 50 ng (37 pmol), 500 ng (370 pmol) and 6.7 microgram (5 nmol) SP and in the step-up avoidance task with 500 ng and 6.7 microgram SP. In the step-down avoidance task no influence of SP was discernible, probably as a consequence of the high retention shown by control animals, masking a possible SP-induced facilitation of learning (ceiling effect). Interestingly, in its effect on learning, SP applied in the septum imitates the effect of electrical septal stimulation, thus providing another example for the parallelism between post-trial SP and electrical brain stimulation which we have demonstrated previously in the substantia nigra, amygdala and lateral hypothalamus.

Animals↗

PubMed1988

Effects of an irreversible muscarinic agonist (BM123) on avoidance and spontaneous alternation performance.

The present study sought to assess whether the compound N-[4-(2-chloro-ethylmethylamine)-2-butynyl]-2-pyrrolidone (BM123), a potent muscarinic agonist that binds irreversibly to the muscarinic receptor (mAChR), has long-lasting functional effects which may be related to a reduction in functional mAChRs. Passive (inhibitory) avoidance performance, one-way active avoidance learning, and spontaneous alternation behavior were studied in rats. The results confirmed the acute muscarinic stimulating effects of BM123, including tremor, salivation, chromodacryorrhea and hypothermia. In addition, when measured 3-4 days after administration, rats treated with BM123 had disrupted spontaneous alternation performance and tended to have impaired performance for the inhibitory avoidance task with facilitated acquisition of active avoidance. This spectrum of effects is consistent with previous reports showing a 20-40% reduction in mAChRs at these times after BM123. The reversible muscarinic agonist, oxotremorine, was without significant effect. In a further experiment, it was found that pretreatment with methyl atropine did not prevent the disruption of spontaneous alternation behavior by BM123, whereas pretreatment with atropine did. Thus, these long-lasting behavioral effects of BM123 are related to its alkylation of and subsequent reduction in central mAChRs.

Animals↗

PubMed2003

Carbon monoxide neurotoxicity: transient inhibition of avoidance response and delayed microglia reaction in the absence of neuronal death.

Carbon monoxide exposure produces neurobehavioral effects associated with the level of carboxyhemoglobin (COHb) in the blood. A threshold has been proposed of approximately 35% COHb for the manifestation of disruption in neurobehavioral tasks. The effects of CO exposure producing 30-40% carboxyhemoglobin (COHb) levels in young adult male Fischer 344 rats were examined with regard to clinical signs of toxicity, performance on a previously learned avoidance procedure, and neuronal and glia histopathology. High levels of exposure (4000 ppm) for 15 min were imposed on either a background blood COHb level of 5% produced by a 2 h exposure to 50 ppm CO or a control background from conditioned-air exposure. Upon removal from the nose-only inhalation holder, signs of mild lethargy and decreased activity were evident for 2 min for conditioned-air controls and 50 ppm CO exposure groups and 3-4 min following 4000 ppm CO. Performance on a two-way shuttle box active avoidance task showed no differences between 50 ppm CO rats and conditioned-air controls while the 4000 ppm CO exposed groups showed a significant decrease in avoidance and escape responses. Histological examination showed no evidence of delayed neuronal death or astrocyte reactivity in the hippocampus or cerebellum; however, a distinct focal staining of reactive microglia in both regions was evident in animals exposed to 4000 ppm CO. While 50 ppm CO (5% COHb) alone produced no disruption in avoidance performance, microglia staining in the cerebellum was significantly increased over conditioned-air controls. This regional and focal response of microglia suggests the need for further study regarding such subtle cellular changes and their relationship with COHb levels.

Administration, Inhalation↗

PubMed2004

Benzimidazole derivatives. Part 5: design and synthesis of new benzimidazole-arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands.

A series of new mixed benzimidazole-arylpiperazine derivatives were designed by incorporating in general structure III the pharmacophoric elements of 5-HT(1A) and 5-HT(3) receptors. Compounds 1-11 were synthesized and evaluated for binding affinity at both serotoninergic receptors, all of them exhibiting high 5-HT(3)R affinity (K(i)=10-62nM), and derivatives with an o-alkoxy group in the arylpiperazine ring showing nanomolar affinity for the 5-HT(1A)R (K(i)=18-150nM). Additionally, all the synthesized compounds were selective over alpha(1)-adrenergic and dopamine D(2) receptors (K(i)>1000-10,000nM). Compound 3 was selected for further pharmacological characterization due to its interesting binding profile as mixed 5-HT(1A)/5-HT(3) ligand with high affinity for both receptors (5-HT(1A): K(i)=18.0nM, 5-HT(3): K(i)=27.2nM). In vitro and in vivo findings suggest that this compound acts as a partial agonist at 5-HT(1A)Rs and as a 5-HT(3)R antagonist. This novel mixed 5-HT(1A)/5-HT(3) ligand was also effective in preventing the cognitive deficits induced by muscarinic receptor blockade in a passive avoidance learning test, suggesting a potential interest in the treatment of cognitive dysfunction.

Animals↗

PubMed1997

The acoustic startle response in inbred Roman high- and low-avoidance rats.

To investigate the emotional reactions of two rat strains selectively bred for good and poor two-way avoidance acquisition (RHA/Verh and RLA/Verh), male animals of both strains were tested in an acoustic startle response test. They received 40 acoustic stimuli followed by 10 electric foot shocks and another 30 acoustic stimuli. RLA/Verh rats showed a significantly higher startle response compared to RHA/Verh animals, indicating a stronger emotional reaction to acoustic stimuli. In addition, the former showed a stronger response to foot shocks. Combined with earlier findings, we conclude that selection for two-way avoidance learning does not result in cognitive defects in the RLA/Verh strain but, rather, in stronger emotional reactions to fearful stimuli.

Acoustic Stimulation↗

PubMed1991

[Functional inactivation of the hippocampus by controlled neuroimmunization].

The method of immunization with hippocampal tissue cytosol was employed for functional disturbance of hippocampus in newborn and mature rats. This influence resulted in behavioral disorders resembling the hippocampectomy consequences. There were ++non-decremental motor activity and rearing in "open field" test and an improvement in acquisition of active avoidance response in adult rats (250-300 g). In young animals the decreased levels of motor and exploratory activity in "open field" and difficulties in active avoidance learning (in 40 days) were the main features of hippocampal disturbance. In case of immunization with neocortical cytosol no significant alterations in behavior were revealed.

Animals↗

PubMed1987

[Noradrenaline content of the brain of rats of various ages following adaptation to a new situation and to the development of a passive avoidance conditioned reflex].

Noradrenaline (NA) levels in cortico-striatal (including cerebral cortex, hippocamp, striatum) and hypothalamo-brainstem (including hypothalamus, thalamus, tectum + tegmentum) regions were determined by fluorometry in I- and 2-month-old male rats after 7-day adaptation to experimental conditions and passive avoidance learning by single electric foot shock. Neither the new environment nor a week's adaptation to it resulted in any significant alteration of NA content in both brain regions of 1- and 2-month-old rats. No considerable differences in NA levels were found in rats of both age groups with and without passive avoidance responses. But 24 hours after the exposure to foot shock NA basal levels markedly decreased in both brain regions of 1-month-old rats, while in 2-month-old ones NA basal levels markedly increased in hypothalamo-brainstem region.

Adaptation, Physiological↗

PubMed1981

Effects of neonatal pyridostigmine treatment on sexual maturation and adult behaviour in female rats subjected to maternal deprivation.

The present study deals with the effects on adult behaviour of early postnatal maternal, i.e. psychosocial and/or nutritional deprivation and of altering the brain levels and/or turnover rates of acetylcholine in preweaning deprived rats. The following data were obtained: 1. Female rats separated from their mothers and littermates for 16 hours each day during the first two weeks of life showed a significant delay of puberty onset in comparison with non-separated controls. Furthermore, these animals exhibited significantly reduced emotionality as well as learning capability and memory capacity in adulthood. 2. Administration of the acetylcholinesterase inhibitor pyridostigmine during the first two weeks of life to the deprived females did not compensate the puberty-delaying effect of separation. However, the neonatally pyridostigminized female rats exhibited an increased emotional reactivity in adult life. 3. Female rats deprived from their mothers and treated with pyridostigmine during the neonatal period displayed increased avoidance learning and memory capacity in adulthood as compared to neonatally deprived but untreated animals. It might be concluded from our results that defects of brain differentiation produced by early postnatal deprivation could be prevented, at least in part, by simultaneous administration of pyridostigmine.

Acoustic Stimulation↗