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PubMed2001

Involvement of 5-HT(2C) receptors in the anti-immobility effects of antidepressants in the forced swimming test in mice.

Several recent studies have demonstrated that 5-HT(1A), 5-HT(1B) and 5-HT(3) receptors were implicated in the mechanism of action of antidepressants in the mouse forced swimming test. Despite extensive evidence for a role of 5-HT(2C) receptors in depression, the precise role of these receptors in the effects of clinically established antidepressants was not directly investigated in the mouse forced swimming test. This work was aimed at exploring interactions between several doses of Ro 60-0175, a recently available, full and selective 5-HT(2C) agonist, and antidepressant drugs in the mouse forced swimming test. Spontaneous locomotor activity was measured as an index of intact sensorimotor functions and the dose-effect of Ro 60-0175 alone, as well as interactions with several antidepressants, such as tricyclic antidepressants (imipramine, desipramine and maprotiline) and selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, fluvoxamine and sertraline), were studied in the mouse forced swimming test. There was no intrinsic antidepressant-like effect of Ro 60-0175, but an impairment in locomotor function was detected when using doses higher than 4 mg/kg in the mouse. There was a synergistic effect of low doses of Ro 60-0175 with sub-active doses of imipramine, paroxetine, citalopram and fluvoxamine; an antagonism between the highest dose of Ro 60-0175 and the active doses of paroxetine and fluoxetine was also detected. There is evidence that 5-HT(2C) receptors may be involved in the action of antidepressants which are able to boost the concentration of serotonin in the synapse, i.e. SSRIs and imipramine

Animals↗

PubMed1996

Reliability of the Modified Ordinal Scales of Psychological Development: a cognitive assessment battery for severe dementia.

Two reliability studies were performed on a recently developed cognitive assessment battery for severe dementia. The method, the Modified Ordinal Scales of Psychological Development (M-OSPD), is based on the Piagetian developmental model of sensorimotor functions. Procedures have been adapted from this test battery, which was originally applied to infants and small children, for the assessment of remaining cognitive capacity in severe dementia. Two independent interrater reliability studies were conducted. In these studies, two different raters simultaneously evaluated patients with severe dementia. One interrater reliability study was performed in a nursing home setting (Study 1), and the other reliability study consisted of a sample of community-residing patients (Study 2). The Global Deterioration Scale and the Mini-Mental State Examination were used to assess dementia severity. Study 1 (N = 22) resulted in an intraclass correlation coefficient (ICC) of .99 (p < .01) for the M-OSPD total score. Study 2 (N = 19) resulted in an ICC of .96 (p < .01) for the M-OSPD total score. The M-OSPD proved to be a reliable instrument in these studies. This cognitive assessment measure can provide meaningful information regarding the cognitive abilities of late-stage dementia patients. Until recently, these late-stage dementia patients had been considered untestable in studies that utilized conventional psychometric and mental status evaluation measures.

Aged↗

PubMed1986

Dopamine in the lateral caudate-putamen of the rat is essential for somatosensory orientation.

The present study examined the possible localization of somatosensory orientation in the caudate-putamen (CP) of the rat. In the first experiment, 6-hydroxydopamine (6-OHDA) was injected into either the anterodorsal (AD), anteroventral (AV), posterodorsal (PD), or posteroventral (PV) CP. Only rats with PV-CP 6-OHDA injections showed impaired orientation scores. However, these PV injections often caused widespread CP dopamine (DA) depletions, and no specific CP region appeared to be particularly associated with somatosensory orientation. In the second experiment, multiple injections of 6-OHDA were directed toward the medial or lateral halves of the CP to assess their relative contributions directly. DA depletions confined to the lateral (but not medial) CP resulted in orientation deficits; these deficits were greater than would be predicted from the volume of CP/DA loss. Furthermore, the magnitude of the DA fluorescence loss in the lateral CP was more highly correlated with the orientation impairment than was the medial CP fluorescence loss. Thus the lateral CP contributes to sensorimotor functions to a greater extent than does the medial CP, but the volume of CP/DA depletion also appears important.

Animals↗

PubMed1991

Response-related deficits following unilateral lesions of the medial agranular cortex of the rat.

Rats with lesions of the medial agranular frontal cortex (AGm) were tested for sensorimotor function. Spatial response bias and reaction time to lateralized visual targets were recorded in an automated test of visual reaction time. The same rats were also tested for somatosensory capacity and on a skilled reaching task. In all tasks, there was an ipsilateral response bias but no evidence of sensory neglect. In the visual reaction time task, initiation time was lengthened bilaterally. These deficits may parallel the effects on motor function after unilateral frontal cortical lesioning in primates. The results support the hypothesis that rat AGm contains a homologue of primate secondary motor cortex.

Afferent Pathways↗

PubMed1997

Mutations that prevent associative learning in C. elegans.

The nematode Caenorhabditis elegans offers a promising system for the reductionist study of learning and memory. In this article, classical conditioning in C. elegans is demonstrated with a variety of associative learning assays. These assays allowed for the isolation and behavioral characterization of 2 mutant C. elegans lines impaired in associative learning. Both lines show no short-term or long-term associative conditioning; however, they appear relatively normal in tests of nonassociative learning and sensorimotor function. In combination with the well-described genetics and neuroanatomy of C. elegans, the isolation of mutants selectively, yet completely, blocked in associative learning provides the basis for an effective characterization of the cellular and molecular aspects of associative learning.

Animals↗

PubMed1997

Assessment of sensorimotor neglect after occlusion of the middle cerebral artery in the rat.

Evaluating the efficacy of neuroprotective drugs in rat models of focal cerebral ischemia has involved histological and behavioral batteries to examine treatment outcome. However, the behavioral tests used to date provide little insight into the nature of the neurological impairments. To provide an analysis of a possible "neglect" syndrome after occlusion of the middle cerebral artery, M. I. Posner's (1980) visual attentional paradigm was adapted for use in the rat. A paw-reaching task and a test of somatosensory "neglect" also were used to assess forelimb sensorimotor function. The lesion group displayed unilateral deficits; however, there was no evidence of attentional dysfunction. Results are consistent with the conclusion that the behavioral deficits identified arise from a somatosensory deficit rather than hemineglect due to dysfunctional spatial attention.

Animals↗

PubMed1998

Reversible inactivation of the medial septum or nucleus basalis impairs working memory in rats: a dissociation of memory and performance.

Lidocaine-induced inactivation of the medial septum immediately after training or prior to testing in a delay radial-arm maze task produced deficits in spatial working memory that reflected impaired acquisition of the task. Injection of lidocaine into the nucleus basalis magnocellularis produced a profile of behavioral changes that indicated that temporary inactivation of this structure impaired the behavioral expression of information already stored in working memory. This appears to reflect an impairment in processes that are required for performance (i.e., attention, motivation, sensorimotor function) of the task but not for retrieval of stored information. Site-specific inactivation of the basal forebrain should help to reveal the involvement of its component structures in different aspects of cognitive function.

Analysis of Variance↗

PubMed1984

Effect of dopamine-depleting brain lesions on suckling and weaning in rats.

Rats given large dopamine-depleting brain lesions as adults exhibit severe impairments in ingestive behavior and sensorimotor function. In contrast to these well-known effects, virtually complete destruction of central dopaminergic neurons produced no such dysfunctions when it occurred in neonates. Indeed, rats continued to suckle and grow, albeit somewhat more slowly, and they could be weaned readily when they were 27 days old. Although most brain-damaged animals did not survive weaning when they were 18 days old, whereas controls exhibited no difficulty, this failure appears to be the consequence of their reduced body weight and related inability to maintain body temperature in a relatively cool environment (22 degrees C). Such premature weaning occurred more successfully when growth was stimulated by rearing brain-damaged pups in small litters or when ambient temperatures were raised to 31 degrees C so as to minimize heat loss. These results demonstrate that the effects of near-total dopamine-depleting brain lesions are considerably less severe when they occur in infants than when they occur in adults, and, consequently, they reveal a capacity for neural plasticity during development that is no longer present at maturity.

Animals↗

PubMed1984

Bilateral cutaneous stimulation of the somatosensory system in hemidecorticate rats.

An enduring somatosensory consequence of extensive neocortex injury in people is "simultaneous extinction," which is an interhemispheric perceptual interaction that is operationally distinguishable from neglect. A cutaneous stimulus presented on the contralateral side of the body is readily detected when presented singly but is actively masked during bilateral stimulation. In hemidecorticate rats, small adhesive stimuli were attached to the radial surface of each forelimb simultaneously, and the latencies to contact and to remove each stimulus were recorded. Neglect of the contralateral stimulus lasted 2-3 days. Thereafter the ipsilateral stimulus was removed first, followed immediately by the contralateral stimulus. This ipsilateral sensorimotor bias lasted several months. Further analysis with unremovable tactile stimuli provided evidence for true extinction. For a limited period (during the first 2 postoperative weeks), the contralateral stimulus did not appear to be detected in the presence of the ipsilateral stimulus. Rather than switching back and forth between the two stimuli, the animals ignored the stimulus on the contralateral limb and persisted in their attempts to remove the ipsilateral stimulus. A key feature of the "extinction" was its complete reversibility. Simply by adjusting the sensory fields occupied by the contralateral (C) and ipsilateral (I) stimuli (specifically, by increasing the C/I ratio), the sensorimotor bias was totally shifted to contralateral. During recovery, the size of the C/I ratio necessary to reverse sensorimotor asymmetry gradually decreased. Asymmetrical sensorimotor behavior and amphetamine-induced circling were examined in three additional groups of hemidecorticate rats, which were given their initial behavioral tests at 2, 12, or 52 postoperative weeks. This experiment confirmed the above findings and controlled for practice. Over the course of a year, apparently complete recovery occurred; however, there were residual effects. At each period, previously recovered symptoms were reinstated simply by turning on the room lights and opening the home cage slightly. These data underscore the importance of detailed behavioral analysis and the value of the rat as a model in studies of recovery of sensorimotor function.

Afferent Pathways↗

PubMed1976

Roles of anoxia and noise-induced hearing loss in the postictal refractory period for audiogenic seizures in mice.

The present series of experiments demonstrated a postictal refractory period for audiogenic seizures in DBA/2J mice, which was not related to hearing loss but apparently was related to anoxia. Unlike many previous studies, Experiment 1 controlled for the effects of noise exposure upon hearing sensitivity and demonstrated reduced susceptibility to subsequent audiogenic seizures for at least 1 hr after initial clonic-tonic convulsions. The postictal refractory period was shown to result from the occurrence of seizures per se, not from noise exposure alone. Experiment 2 demonstrated deficiencies of sensorimotor functions that accompanied reduced postictal seizure susceptibility. The two phenomena had similar time courses of recovery, which suggested a common mechanism, probably anoxia, associated with the initial convulsions. In support of this view, Experiment 3 showed that recovery from both phenomena was expedited by allowing subjects to breathe increased O2. The role of anoxia in fatal convulsions was suggested by the finding that subjects experiencing clonic-tonic convulsions in a high-O2 environment survived without exception. In contrast, seizures of air-breathing controls were almost always fatal. Taken together, the data indicate that the postictal reduced susceptibility to audiogenic seizures was closely related to metabolic depletion (in particular, anoxia). The pattern of recovery of susceptibility further suggests that the effects of anoxia impair the spread of seizure activity through the central nervous system, although the initiation of seizures is also affected for a short time.

Anesthesia, Inhalation↗

PubMed2000

Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors.

ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.

Adenosine Triphosphate↗

PubMed2000

Dopamine is required for hyperphagia in Lep(ob/ob) mice.

Feeding is a complex process responsive to sensory information related to sight and smell of food, previous feeding experiences, satiety signals elicited by ingestion and hormonal signals related to energy balance. Dopamine released in specific brain regions is associated with pleasurable and rewarding events and may reinforce positive aspects of feeding. Dopamine also influences initiation and coordination of motor activity and is required for sensorimotor functions. Thus, dopamine may facilitate integration of sensory cues related to hunger, initiating the search for food and its consumption. Dopaminergic neurons in the substantia nigra and ventral tegmental area project to the caudate putamen and nucleus accumbens, where they modulate movement and reward. There are projections from the nucleus accumbens to the lateral hypothalamus that regulate feeding. Dopamine-deficient mice (Dbh(Th/+), Th-/-; hereafter DD mice) cannot synthesize dopamine in dopaminergic neurons. They gradually become aphagic and die of starvation. Daily treatment of DD mice with L-3,4-dihydroxyphenylalanine (L-DOPA) transiently restores brain dopamine, locomotion and feeding. Leptin-null (Lep(ob/ob)) mice exhibit obesity, decreased energy expenditure and hyperphagia. As the hypothalamic leptin-melanocortin pathway appears to regulate appetite and metabolism, we generated mice lacking both dopamine and leptin (DD x Lep(ob/ob)) to determine if leptin deficiency overcomes the aphagia of DD mice. DD x Lep(ob/ob) mice became obese when treated daily with L-DOPA, but when L-DOPA treatment was terminated the double mutants were capable of movement, but did not feed. Our data show that dopamine is required for feeding in leptin-null mice.

Animals↗

PubMed1990

The relationship between global and local changes in PET scans.

In order to localize cerebral cognitive or sensorimotor function, activation paradigms are being used in conjunction with PET measures of cerebral activity (e.g., rCBF). The changes in local cerebral activity have two components: a global, region independent change and a local or regional change. As the first step in localizing the regional effects of an activation, global variance must be removed by a normalization procedure. A simple normalization procedure is division of regional values by the whole brain mean. This requires the dependence of local activity on global activity to be one of simple proportionality. This is shown not to be the case. Furthermore, a systematic deviation from a proportional relationship across brain regions is demonstrated. Consequently, any normalization must be approached on a pixel-by-pixel basis by measuring the change in local activity and change in global activity. The changes associated with an activation can be partitioned into global and local effects according to two models: one assumes that the increase in local activity depends on global values and the other assumes independence. It is shown that the increase in activity due to a cognitive activation is independent of global activity. This independence of the (activation) condition effect and the confounding linear effect of global activity on observed local activity meet the requirements for an analysis of covariance, with the "nuisance" variable as global activity and the activation condition as the categorical independent variable. These conclusions are based on analysis of data from 24 scans: six conditions over four normal subjects using a verbal fluency paradigm.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1997

Motor cortical mapping of proximal upper extremity muscles following spinal cord injury.

Focal transcranial magnetic stimulation was used to map the motor cortical representations of the relaxed and gently contracted biceps brachii, deltoid and triceps muscles in 22 subjects comprised of 12 controls, five subjects with complete and five with incomplete cervical spinal cord lesions (SCI). Motor evoked potentials (MEPs) were rarely observed during the resting condition (3/30 muscles tested; SCI group) which precluded detailed analysis of these data. With background facilitation, the mean number of scalp stimulation sites producing MEPs varied according to muscle (P < 0.001); biceps yielded the largest maps and triceps the smallest. The cortical representations of proximal upper extremity muscles were largest for the control group and smallest for the incomplete SCI group although differences were not significant (P > 0.09). The optimal site of stimulation (that which produced the largest MEP) was always surrounded by an area producing submaximal MEPs, but was variable across subjects and groups. There was extensive overlap in the motor cortical representation areas corresponding to the three muscles of interest. Following maximal intensity stimulation at the optimal site, the mean MEP amplitudes (normalized) were largest for the biceps muscle and smallest or absent in triceps (P < 0.02). No differences were detected between groups (P > 0.50). The threshold stimulus intensity was highest for those with incomplete SCI and lowest amongst control subjects (P < 0.05), with biceps then deltoid muscles generally having lower thresholds than triceps (P < 0.001). The findings suggest that cortical map areas and MEP characteristics are not significantly altered in gently contracting muscles innervated by nerve roots rostral to the lesion. Only activation thresholds are higher following SCI, particularly incomplete lesions, although there is no apparent association with sensorimotor function. The inability to elicit MEPs in the relaxed muscles of patients with SCI fail to support previous reports of expanded motor cortical representations associated with muscles innervated by roots rostral to the lesion.

Adult↗

PubMed2000

Intravenous infusion of 4-AP in chronic spinal cord injured subjects.

STUDY DESIGN: A prospective double blind cross over trial of intravenous 4-Aminopyridine (4-AP). OBJECTIVE: To determine the efficacy of this drug in the treatment of spinal cord injured (SCI) patients for neurologic impairment, pain and spasticity. SETTING: The post anesthesia care unit (PACU) of a tertiary care acute hospital. METHODS: Twelve paraplegic patients were enrolled in a double blind cross over intravenous trial of 4-Aminopyridine (4-AP). Thirty milligrams of 4-AP or placebo were administered over a 2 h period. Patients were serially examined during and after the infusion clinically for pain, sensorimotor function, hypertonicity and motor control using electromyography (EMG). Samples of blood and cerebrospinal fluid (CSF) were also analyzed at similar intervals. RESULTS: Despite penetration of 4-AP into the CSF, no significant differences were noted in the clinical and EMG parameters at the times measured. Individual changes in sensory function were reported by some patients in both the placebo and 4-AP trials, however mean values were not robust. Frequently, patients complained of unpleasant symptoms during the 4-AP infusion. CONCLUSION: The intravenous route may not be the best way to administer this drug as no short term benefits were observed.

4-Aminopyridine↗

PubMed1991

Mirror-reversal phenomena in the cutaneous perception and writing of children.

When a letter is drawn on the forehead, it is perceived cutaneously as a mirror reversal of the experimenter-defined stimulus. An analogous mirror-reversal phenomenon is found in motor behaviour; eg, writing on the downward-facing horizontal surface of a table. We examined these mirror-reversal phenomena in tasks, performed by 4-year-old and 8-year-old children, involving cutaneous perception and motor-production. The children's tendencies toward mirror reversal in the two tasks varied with the orientation and position of the surface, but were similar to those of sighted and blind adult subjects. In addition, mirror reversal was independent of the left-right indifference often observed in young children in writing or visual-matching tasks. The implications of these findings are discussed in the context of a body schema used to guide sensorimotor functions.

Attention↗

PubMed1986

Construct validity of the Kendrick Battery with institutionalized aged.

In this study, we attempted to explore the construct validity of the Kendrick Battery by using an American sample and psychometric tests as indexes of diffuse organicity, depression, and normality. Institutionalized residents (N = 53) were tested twice (6-week interval). When organicity was defined by disorientation and memory deficits, then both the Object Learning test and the Digit Copying test were accurate in differentiating preestablished criterion groups. When organicity was defined more broadly, including sensorimotor function, the Digit Copying test alone was more accurate when depression was defined in terms of irritability, restlessness, and despair. These data suggest that although the Kendrick scales appeared to be sensitive to organicity and depression in this sample, their validity varied with the criteria for each when such were defined psychometrically.

Aged↗

PubMed2000

Cortical-organization in moles: evidence of new areas and a specialized S2.

The somatosensory cortex of several mole species (family Talpidae), with different peripheral sensory adaptations, was investigated and compared to determine common and specialized features of cortical organization. Previously unidentified medial representations of the trunk and limbs were found in all species, indicating that S1 in moles occupies a medial to lateral strip of cortex as in most other mammals. This finding suggests a large lateral forelimb representation, previously attributed to S1, is actually part of S2. In the face representation, evidence was found for three representations of the unusual nose of the star-nosed mole (Condylura cristata). Each of these areas was divided into a series of modules (visible in cytochrome oxidase processed tissue) representing individual nasal appendages on the star. In the closely related but less specialized eastern mole (Scalopus aquaticus) and coast mole (Scapanus orarius), only two nose representations were identified in an area of cortex with a more uniform histological appearance. The results indicate that moles have enlarged somatosensory representations of the glabrous nose as compared to shrews and rats that instead have large vibrissal representations. In addition moles have a very large and specialized representation of the digging forepaw in S2. Since this part of S2 projects directly to the cervical spinal cord, the specialization may provide adaptive sensorimotor functions related to digging.

Animals↗