Body Tremor Research Articles

Treatment for a 14-Year-Old Girl With Lyme Disease Using Therapeutic Exercise and Gait Training

Lyme disease is well documented in the literature; however, specific physical therapy interventions for the pediatric population with residual effects of Lyme disease have not been addressed. The purposes of this retrospective case report are: (1) to present an example of a therapeutic intervention for a pediatric patient in the late stages of Lyme disease with related musculoskeletal dysfunction and severely impaired quality of life, (2) to report the patient's functional outcomes from treatment, and (3) to discuss implications for treatment of patients with musculoskeletal dysfunction in the late stages of Lyme disease. The patient was a 14-year old girl who had contracted Lyme disease 1 year prior to initiation of physical therapy. She was unable to participate with her peers in school, church, and sporting events due to significant impairments in strength (force-generating capacity), endurance, and gait; fatigue; pain; and total body tremor. Therapeutic exercise and gait training were used for treatment. The patient actively participated in managing her care by providing feedback during interventions and setting goals. After 18 weeks of treatment, the patient achieved 96.7% of her predicted distance on the Six-Minute Walk Test with normal gait mechanics and returned to playing high school sports. She had a manual muscle test grade of 4/5 or greater in major extremity muscle groups. She returned to school and church participation with minimal total body tremor when fatigued and daily pain rated 0 to 3/10. Therapeutic exercise and gait training may facilitate return to function in an adolescent patient with late effects of Lyme disease. Further investigation is advised to establish treatment effects in a broader population.

Time-course of the effects of chronic delta 9-tetrahydrocannabinol on behaviour, body temperature, brain amines and withdrawal-like behaviour in the rat.

The effects of clomipramine HCl (15 mg kg-1 i.p.) on behaviour, body temperature and brain amines were investigated in rats that had been chronically treated twice daily with increasing doses of delta 9-tetrahydrocannabinol (delta 9-THC, 2-6 mg kg-1 i.v.). delta 9-THC produced a biphasic change in behaviour, stimulation followed by depression, and a pronounced hypothermia. Tolerance developed rapidly to these effects of delta 9-THC. Chronic treatment with delta 9-THC reduced the levels of homovanillic acid, 5-hydroxytryptamine and noradrenaline. The level of dopamine was not altered with chronic treatment and tolerance appeared to develop to the increased levels of 5-hydroxyindoleacetic acid induced by delta 9-THC. Injection of clomipramine, 12-14 h after 2, 5 or 10 days of delta 9-THC treatment induced characteristic changes in the rats behaviour which consisted of writhes, backward kicking, wet shakes, jumps ataxia and front paw and whole body tremor. The severity of the behavioural changes appeared to be dependent on the period of delta 9-THC administration and they were not accompanied by a change in body temperature or consistent changes in brain amines or metabolites. The results indicate that physical dependence on delta 9-THC may occur since clomipramine is able to precipitate changes in behaviour, indicative on an abstinence syndrome, in rats chronically treated with delta 9-THC. It is suggested that tryptaminergic mechanisms are altered during chronic delta 9-THC treatment and that clomipramine induces the behavioural changes by interacting with an altered tryptaminergic system.

Comparison of intracisternally and intraperitoneally injected harmaline on body temperature and tremor in the rat

Abstract Low doses of harmaline (1–10 mg/kg) injected intraperitoneally into rats caused hypothermia, while higher doses (10–30 mg/kg) induced tremor in addition to hypothermia. Harmaline injected intracisternally decreased body temperature without inducing tremor. To induce a maximal fall in body temperature following intraperitoneal injection of harmaline, 1000 times more harmaline was needed than after intracisternal administration. Harmaline by this route induced hypothermia much faster than by intraperitoneal injection. It is concluded that harmaline-induced hypothermia is at least partly localized in the central nervous system and is not associated with the tremor.

A study of the effects of lamotrigine on mice using two convulsive tests

The AIM was to study the effects of lamotrigine on bicuculline and pentylenetetrazol models of epilepsy. Mice divided in 8 groups (n = 6) were pretreated intraperitoneally 30 min before pentylenetetrazol (50 mg/kg) or bicuculline (1 mg/kg) with saline 0.1 ml/10 g body weight or lamotrigine 10 mg/kg, 15 mg/kg or 20 mg/kg, respectively. The seizure intensity and latency to the seizures 60 min after bicuculline or pentylenetetrazol injection were observed. The following scale for seizure intensity was used: 1 - excitation; 2 - body tremor; 3 - clonic seizures of forelimbs; 4 - heavy clonic seizures with rotations; 5 - tonic seizures of forelimbs; 6 - tonic seizures of limbs. The controls showed bicuculline-induced seizure intensity up to 5. Lamotrigine in the higher doses used decreased the seizure intensity (p <0.05). Lamotrigine in all doses studied did not change the latency period of the first bicuculline seizure compared with the control. Controls treated with pentylenetetrazol showed seizure intensity up to 4. Lamotrigine in the highest dose decreased the pentylenetetrazol-induced seizure intensity (p < 0.05). Lamotrigine in all studied doses increased the latency to the first pentylenetetrazol-induced seizure compared with the controls (p < 0.05). Both convulsing drugs influence the brain GABA-ergic transmitter system by competitively blocking GABAA receptors. Lamotrigine inhibits glutamate transmission and sodium channels. Both neurotransmissions - glutamate and GABA are closely related in seizure control. The CONCLUSION is that lamotrigine has an anticonvulsive effect on both bicuculline and pentylenetetrazol seizure models, suppressing seizure intensity and influencing the latency to the first seizure.

Acute oral toxicity and neurobehavioural toxicological effects of hydroethanolic extract of Boophone disticha in rats

Boophone disticha (B. disticha) has been used systemically in traditional medical practice in Zimbabwe and neighbouring countries for the management of various central nervous system conditions including hysteria. Abuse of the plant by teenagers in Zimbabwe for its claimed hallucinogenic effects has also been reported, with the advent of serious toxicity in some cases. In the present work, we describe the acute toxicity and neurotoxicological effects of a freeze dried hydro-ethanolic plant extract of the bulb of B. disticha. Thirty-three adult (6-12 weeks old), non-pregnant female Sprague Dawley rats were used for the oral LD(50) estimation. Animals were given doses of 50, 120, 240, 360, 500 and 700 mg/kg and were observed using a modified Functional Observation Battery (FOB) for behavioural toxicity. The estimated oral LD(50) of the plant extract was between 120 and 240 mg/kg. For doses of 240 mg/kg and less, signs of toxicity began approximately 10 minutes after gavage, and the most prominent initial signs were head tremors (at 50 mg/kg) and body tremors, severe body tremors(>360 mg/kg) followed by convulsions. Generally, symptoms of toxicity lasted approximately 2 hours for doses of 240 mg/kg and less; and 3 hours for doses over 240 mg/kg for animals that survived. These results point to a rapid gastrointestinal absorption of the active principles in the plant extract. The most prominent neurotoxicological effects were increased flaccid limb paralysis and spastic hind-limb paralysis. Tachypnoea was noted at low doses and higher doses produced laboured breathing. The retropulsion observed with higher doses could indicate the reported hallucinogenic effects of the plant extract.

Evaluation of Rhodiola rosea L. extract on affective and physical signs of nicotine withdrawal in mice

The aim of the present study was to investigate the effects of a Rhodiola rosea L. extract on the prevention of the development of nicotine dependence and for the reduction of abstinence suffering following nicotine cessation in mice. Dependence was induced in mice by subcutaneous injections of nicotine (2 mg/kg, 4 times/day) for eight days. Spontaneous abstinence syndrome was evaluated 20 h after the last nicotine administration, by analysis of withdrawal signs, as affective (anxiety-like behaviour) and physical (somatic signs and locomotor activity). Rhodiola rosea L. extract was administered orally during nicotine treatment (10, 15 and 20 mg/kg) or during nicotine withdrawal (20 mg/kg). Results show that both affective and somatic signs (head shaking, paw tremors, body tremors, ptosis, jumping, piloerection and chewing) induced by nicotine withdrawal are abolished by administration of Rhodiola rosea L. extract in a dose-dependent fashion, during both nicotine exposure and nicotine cessation. In conclusion, our data encourage additional studies to define the use of R. rosea L. as a therapeutic approach in the treatment of smoking cessation.

Inhalation of the nerve gas sarin impairs ventilatory responses to hypercapnia and hypoxia in rats

Sarin, a highly toxic nerve gas, is believed to cause bronchoconstriction and even death primarily through respiratory failure; however, the mechanism underlying the respiratory failure is not fully understood. The goals of this study were to ascertain whether sarin affects baseline ventilation ( V E) and V E chemoreflexes as well as airway resistance and, if so, whether these changes are reversible. Four groups of F344 rats were exposed to vehicle (VEH) or sarin at 2.5, 3.5, and 4.0 mg h m − 3 (SL, SM, and SH, respectively). V E and V E responses to hypercapnia (7% CO 2) or hypoxia (10% O 2) were measured by plethysmography at 2 h and 1, 2, and 5 days after VEH or sarin exposure. Total pulmonary resistance ( R L) also was measured in anesthetized VEH- and SH-exposed animals 2 h after exposure. Our results showed that within 2 h after exposure 11% of the SM- and 52% of the SH- exposed groups died. Although the SM and SH significantly decreased hypercapnic and hypoxic V E to similar levels (64 and 69%), SH induced greater respiratory impairment, characterized by lower baseline V E (30%; P < 0.05), and total loss of the respiratory frequency response to hypercapnia and hypoxia. V E impairment recovered within 1–2 days after sarin exposure; interestingly, SH did not significantly affect baseline R L. Moreover, sarin induced body tremors that were unrelated to the changes in the V E responses. Thus, LC 50 sarin causes a reversible impairment of V E that is not dependent on the sarin-induced body tremors and not associated with changes in R L.

Autoantibodies against opioid or glutamate receptors are associated with changes in morphine reward and physical dependence in mice

Possible interactions between nervous and immune systems during opioid addiction remain elusive. Recombinant mu-delta opioid receptors (MDOR) and the glutamate receptor 1 (GluR1) subunit of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors are involved in acute and chronic effects of morphine. Elevated levels of autoantibodies (aAbs) to these receptors were demonstrated in heroin human addicts and in animal models. This study characterized the role of aAbs to these receptors in behavioral modulations recruited during opioid tolerance and sensitization. Male CD-1 mice, immunized with either MDOR or GluR1 peptide fragments (80 microg intraperitoneal (i.p.)), were examined for spontaneous behavior and response to morphine (5 mg/kg i.p.). Spontaneous home-cage activity, novelty-induced self-grooming and morphine-induced hyperactivity were higher in GluR1 mice compared to Vehicle subjects, whereas MDOR immunization was associated with an increased morphine-induced conditioned place preference. In response to escalating doses of morphine (from 10 to 60 mg/kg i.p., twice daily) and naloxone-precipitated withdrawal (1 mg/kg subcutaneous), GluR1 mice exhibited a more marked stereotyped sniffing behavior and less body tremors compared to Vehicle subjects, whereas less sniffing and teeth chattering were found in MDOR mice. The expected downregulation of mu receptor binding sites, induced by chronic morphine in vehicle subjects, was completely absent following MDOR immunization. These findings indicate an altered response to morphine-related reinforcing and aversive effects in MDOR mice and altered coping with the environment in GluR1 mice. Circulating aAbs to specific neuroreceptors may alter the response to opiates and play a role as determinants of vulnerability to opiate addiction.

Hipomielinização em cães Weimaraner: relato de caso

Três cães, fêmeas, da raça Weimaraner apresentaram tremores corporais rítmicos generalizados a partir da primeira semana de vida. Outros dois cães, machos, da mesma ninhada não apresentaram alterações. Uma fêmea com quatro semanas de idade foi submetida à eutanásia e necropsiada. Macroscopicamente, observou-se no encéfalo pouca demarcação da substância branca em relação à cinzenta. Histologicamente havia acentuada vacuolização de toda a substância branca subcortical. A mielinização no sistema nervoso periférico estava normal. Os sinais clínicos, a idade de ocorrência e as lesões histológicas são compatíveis com a hipomielinogênese congênita descrita em cães.

A “Dizzying” Diagnosis

Case Description: A 55 year old man gradually developed the inability to focus his gaze, whole body tremors, persistent nausea, vomiting and weight loss. Despite multiple ER visits, CT and MRI of his brain, the etiology of his symptoms were unknown. On physical examination he had horizontal nystagmus when fixing on objects. Myoclonus was noted on the left arm, head and trunk. His plantar reflex was withdrawn. Cerebrospinal fluid was negative for infection and no malignant cells were identified. Due to concerns for a paraneoplastic syndrome a CT of the chest and abdomen were performed and revealed asymmetric thickening of the distal esophagus, and several enlarged and potentially necrotic lymph nodes in the paraesophageal and retroperitoneal abdomen. All laboratory tests were normal. Esophagogastroduodenoscopy revealed a 4 cm necrotic mass in the distal esophagus, located within a long segment of Barrett's esophagus. Biopsies of the mass showed poorly differentiated adenocarcinoma, and surrounding biopsies confirmed Barrett's metaplasia with mild dysplasia. An increased fluorodeoxyglucose activity within the distal esophagus and a cluster of metabolically active lymph nodes at the celiac axis consistent with metastatic disease was discovered on PET scan. The patient was treated with intravenous and oral steroids which resulted in resolution of his nystagmus and improvement of his myoclonus. The patient is currently being evaluated for chemotherapy. Discussion: The most common presentation of esophageal adenocarcinoma is dysphagia, however it has been associated with a number of paraneoplastic syndromes including acrokeratosis paraneoplastica, hyperparathyroidism, vasculitis and cerebellar degeneration. This is the first case report of opsoclonus-myoclonus associated with an esophageal adenocarcinoma. Opsoclonus-myoclonus syndrome is most commonly found in pediatric patients with neuroblastomas, but it has also been described in patients with advanced breast and lung cancers. There have also been case reports of association with pancreatic and gastric cancer. The etiology is unknown but is believed to be immune-mediated due to the occasional presence of anti-neuronal antibodies and improvement with immunosuppressants. Esophageal adenocarcinoma should be added to the list of malignancies associated with opsoclonus-mycoclonus syndrome, and a thorough evaluation of the gastrointestinal tract should be considered in patients who present with this syndrome.

Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia

The quaking viable mouse mutation (qk(v)) is a deletion including the 5' regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNA-binding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68-96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing.

Sexual characteristics of domestic queens kept in a natural equatorial photoperiod

The objective of this study was to describe the sexual characteristics of domestic queens kept under natural equatorial photoperiod conditions without mating. Estrous signs were detected in 25 pubertal queens by manual stimulation and by exposure to a tomcat twice daily for 6 months (January to June). The signs observed were tail deflection, spinal flexion, rubbing or rolling, vaginal discharge, vocalization, treading of the hind legs, body or tail tremor and rigidity, blow or scratches, and discomfort on manipulation. The queen was considered in estrous when neck grip, tail deflection and attempted penile intromission by the male were allowed after mounting. From 187 cycles, there were (mean ± S.E.M.) 7.5 ± 0.7 cycles detected per queen; the duration of the cycle, estrus and non-acceptance were 18.1 ± 0.9, 7.9 ± 0.5, and 10.3 ± 0.9 d, respectively. Queens always maintained some signs of sexual behaviour; they remained ambivalent for no more than 24 h at a time. It was noted that 85.3% of the observations of body or tail tremor and rigidity were made during estrus; therefore, these signs were considered characteristic of sexual receptivity. There was no evidence of prolonged anestrus or of a circannual pattern to estrus cyclicity.

Dementia due to neurosyphilis with persistently negative CSF VDRL

A 44-year-old right-handed homosexual man was referred for gradual deterioration of skills as a chef, impairment of memory, and decreased fluency and comprehension of speech. He had prominent personality change from an easygoing nature to irritability and anxiety. Over a year, his mental abilities deteriorated such that he was unable to drive a car, maintain a job, or live independently. He had no prior neurologic, psychiatric, or systemic illness. Episodes of agitation, confusion, and body tremors appeared 1.5 years after onset. Evaluation by a neurologist at that time at another hospital revealed disorientation, disinhibition, poor attention and recall, tremors during handwriting, and motor impersistence. Mini-Mental State Examination score was 23 out of 30. There was diffuse cerebral atrophy on MRI (figure, A), and the EEG was normal. CSF had protein of 97 mg/dL, 1 WBC/mm3, and many oligoclonal bands. CSF Venereal Disease Research Laboratory test (VDRL), CSF 14-3-3 level, serum HIV and Lyme antibody, toxicology screen, thyroid and liver functions, …

MOVING WITHOUT DOPAMINE

Parkinson's disease (PD), a condition characterized by muscle stiffness and uncontrollable shaking, is caused by the progressive degeneration of midbrain neurons that control motor function. These neurons produce the neurotransmitter dopamine (DA), which has long been associated with motor function. As the neurons deteriorate, dopamine levels plummet, eventually leading to the symptoms of this debilitating disease. To understand the pathological processes leading to PD, researchers have developed rodent models that either recapitulate the loss of DA or recapitulate the neurodegenerative process. But many of these models only achieve incomplete DA depletion, often precluding an accurate recapitulation of the neurological manifestations of PD. Now, Tatyana Sotnikova and colleagues have successfully induced a reliable but transient recapitulation of PD symptoms in mice.Normally, neurons have a large intracellular storage pool of DA. After its release, DA is rapidly recycled back into neurons' dopaminergic terminals by the dopamine transporter (DAT). To create their new PD model, the team knocked out the dopamine transporter in a group of mice, creating DAT-KO mice that have virtually no intracellular DA stores. Unlike normal mice, which have plenty of dopamine in storage, DAT-KO mice depend upon the DA produced by ongoing synthesis. So, by blocking DA synthesis in these mice, the team could now eliminate all DA in these animals. When they administered the DA synthesis inhibitor αMT to the DAT-KO mice, the animals immediately showed reliable symptoms of PD; they became immobile and displayed extreme rigidity,body tremors and droopy eyelids. Now that the team had successfully created a mouse model of PD, they set out to identify drugs that could relieve the symptoms of PD. They first tested the effects of administering l-DOPA, a DA precursor that is commonly given to PD patients, to DAT-KO mice. They discovered that l-DOPA is just as effective in mice as it is in humans in the early stages of PD; the drug successfully restored locomotion in DAT-KO mice. Testing several amphetamine derivatives,the authors discovered that MDMA (better known as ecstasy) also restored movement control sufficiently to allow the mice to move forwards. Since amphetamines are thought to act through the dopamine system to affect movement, this was a surprising result, because the team was unable to detect measurable DA levels in the midbrain neurons of these mice. They conclude that ecstasy must be acting through an unknown DA-independent mechanism. When the team paired a lower dose of ecstasy with a minimally effective l-DOPA dose, a synergistic effect occurred: it caused the same effect as a higher dose of either ecstasy or l-DOPA alone. Thus,the DA-independent locomotor effect of ecstasy can be markedly enhanced with additional DA stimulation.It is currently unclear how this synergistic effect occurs, but amphetamines can clearly affect neuronal systems involved in motor control through mechanisms independent of dopamine. Amphetamines interact with proteins called trace amine receptors, and the authors suggest this interaction as a possible mechanism. Since very little is known about the physiological role of these receptors, more research is needed to delineate the DA-independent mechanism of amphetamines in locomotion. But in the search for new treatments for Parkinson's disease, this study certainly offers a glimmer of hope.

Oral Acute Toxicity of Polyenylphosphatidylcholine (PPC) in Rats

Endogen phospholipids play a major role in determining the structure and nature of cell membranes. A deficiency of phospholipids in cellular membranes makes it almost impossible for the cell membrane to perform its function as a selective barrier between what passes in and out of the cell. Polyenylphosphatidylcholine chemical structure corresponds to that of endogen phospholipids, but it possesses functional superiority because of its content of unsaturated fatty acids. Polyenylphosphatidylcholine integrates in the cell membrane and organelle systems while becoming their constitutive elements. A healthy cell membrane leads to healthy cells and then healthy tissue and then to healthy organs or body systems and finally, healthy bodies and minds. For a long time, polyenylphosphatidylcholine in combination with vitamins has been used in the treatment of numerous health problems such as liver diseases, dyslipoproteinaemias and different intoxications with consequent liver failure. The main aim of toxicology studies is evaluation of the toxic potential and risks of human exposition to the substance. According to the Organization for Economic Cooperation and Development (OECD) acute oral toxicity refers to those adverse effects occurring following oral administration of a single dose of a substance or multiple doses given within 24 hours. LD50 (median lethal dose), oral, is a statistically derived single dose of a substance that can be expected to cause death in 50 per cent of animals when administered by the oral route. Our acute toxicity study was performed on albino Wistar rats. Animals were randomised in three experimental and one control group, each of 5 males and 5 females. Study was based on the administration of a single oral dose of the test substance (polyenylphosphatidylcholine) to each experimental animal. There were three dose-levels of the test substance: 300, 500 and 1000 mg/kg. Test substance administration day was the first day of the observation period that lasted 14 days. Control animals were given milk vehicle. At the end of the study, no statistically significant differences between experimental and control animals were observed concerning the recorded parameters: body weight, respiratory rate, tremor, faeces and phonation quality, indicating the absence of the test substance acute toxicity.

Alterations in Behavioral Responses to a Cholinergic Agonist in Post-Pubertal Rats with Neonatal Ventral Hippocampal Lesions: Relationship to Changes in Muscarinic Receptor Levels

Excitotoxic neonatal ventral hippocampal (NVH) lesion in rats is considered as a putative animal model of schizophrenia as lesioned animals show characteristic post-pubertal emergence of neurochemical and behavioral abnormalities analogous to some of those seen in this disease. Converging evidence points to the involvement of central cholinergic system in this neuropsychiatric disorder, and our previous studies have suggested that cholinergic neurotransmission may be altered in post-pubertal NVH lesioned rats. We investigated here muscarinic receptor reactivity in NVH lesioned animals by measuring the effects of the muscarinic receptor agonist oxotremorine on physiological responses known to be modulated by these receptors such as body temperature, salivation, tremor, pain, and prepulse inhibition of the acoustic startle (PPI). Quantitative receptor autoradiography revealed that post-pubertal NVH lesioned animals display increased levels of [3H]pirenzepine/M1-like and [3H]AFDX-384/M2-like receptor binding sites in the striatum, nucleus accumbens, and in subareas of the dorsal hippocampus. Moreover, in response to the systemic administration of oxotremorine (0.25 mg/kg), post-pubertal NVH lesioned rats exhibited increases in salivation and tremor, and a greater reduction in body temperature compared to sham control animals. Increases in the hot-plate latency were also observed suggesting enhanced antinociceptive effects of oxotremorine in post-pubertal NVH lesioned animals. Finally, oxotremorine (0.1 and 0.25 mg/kg) disrupted PPI in post-pubertal sham control rats while the muscarinic receptor antagonist biperiden (0.5 and 1.0 mg/kg) normalized this behavior in NVH lesioned rats. Taken together, these findings reveal that post-pubertal NVH lesioned rats display enhanced muscarinic receptor responsiveness, which may relate to some behavioral abnormalities reported in this animal model.

GM2-gangliosidosis variant 0 (Sandhoff-like disease) in a family of Japanese domestic cats

A five-month-old, female Japanese domestic shorthair cat with proportionate dwarfism developed neurological disorders, including ataxia, decreased postural responses and generalised body and head tremors, at between two and five months...

N1-Dansyl-spermine: a potent polyamine antagonist

The potential polyamine antagonist action of N 1-dansyl-spermine (a potent NMDA antagonist) was assessed in two in vivo mouse models of polyamine action. Co-administration of N 1-dansyl-spermine (2–10 μg, i.c.v.) with spermine (100 μg, i.c.v.) resulted in a dose-dependent antagonism of the spermine-induced CNS excitation (body tremor and fatal tonic convulsions). In addition, the same dose of N 1-dansyl-spermine antagonised spermine's enhancement of NMDA-induced convulsions. These results suggest that N 1-dansyl-spermine is in vivo a potent antagonist of the CNS effects of spermine and of its action at the positive polyamine modulatory site on the NMDA receptor.

GDNF and IGF-I trophic factors delay hereditary Purkinje cell degeneration and the progression of gait ataxia

Neurotrophic factors GDNF and/or IGF-I were chronically infused into shaker mutant rats to rescue cerebellar Purkinje neurons from adult-onset heredodegeneration. The natural expression of the shaker mutation is characterized by spatially restricted degeneration of Purkinje cells that occurs earlier and faster in an anterior vermal compartment and slightly later and more slowly in a posterior vermal compartment. Gait ataxia and whole body tremor develop concomitant with the degeneration of Purkinje neurons. The number and spatial distribution of surviving Purkinje neurons, identified by cell-specific calbindin immunoreactivity, were quantitatively analyzed in mid-sagittal sections and correlated with quantitative movement analysis of hindlimb gait patterns. Compared to the number of surviving Purkinje cells in age-matched, non-infused, or saline-infused control mutants, 4 weeks of infusion of GDNF or IGF-I rescued many anterior compartment Purkinje cells from early degeneration. However, 2 and 4 weeks after cessation of GDNF or IGF-I infusion, respectively, the number and spatial distribution of surviving Purkinje cells was comparable to that observed in age-matched controls. Eight weeks of infusion of trophic factors did not support the continued survival of most anterior compartment Purkinje cells and was partially, and probably only transiently, neuroprotective for some posterior compartment Purkinje cells. When GDNF and IGF-I were infused together for 4 weeks the number of surviving Purkinje cells was additively greater than with either factor alone. Behaviorally, 4 weeks of infusion of trophic factors delayed the development of gait ataxia. Infused GDNF appeared to preserve hip stability, whereas IGF-I stabilized step length. Tremor was attenuated with 8 weeks of infusion of GDNF or IGF-I. GDNF-infused animals showed low power tremor frequencies, whereas IGF-I infusion resulted in a single large power peak with decreased numbers of low-amplitude frequencies. Collectively these findings indicate that exogenous trophic factors can delay the onset of hereditary Purkinje cell degeneration and gait ataxia. Quite surprisingly, GDNF and IGF-I appeared to act on disparate populations of mutant Purkinje cells, whose differential survival affected different aspects of locomotion.

Decreased prepulse inhibition during nicotine withdrawal in DBA/2J mice is reversed by nicotine self-administration

We characterized spontaneous and mecamylamine-precipitated nicotine withdrawal using intravenous nicotine self-administration, the acoustic startle response, prepulse inhibition and somatic signs of withdrawal in DBA/2J mice. Nicotine dependence was induced by continuous nicotine infusion through osmotic minipumps. Nicotine self-administration was studied before and after the induction of dependence. The initial test revealed significant nicotine self-administration at the 0.048 μg/infusion dose. During the second self-administration test, saline-treated mice exhibited increased aversiveness of response-contingent infusions of high nicotine doses; these changes were not seen in the nicotine-treated animals reflecting tolerance to nicotine's effects. Neither mecamylamine administration nor spontaneous withdrawal affected the expression of somatic signs, except that increases in jumping were observed during spontaneous withdrawal. Finally, nicotine withdrawal increased general activity in the startle chambers when no stimuli were presented, possibly reflecting increased body tremor and/or agitation, and decreased prepulse inhibition reflecting a sensorimotor gating deficit; the last two effects were reversed by nicotine self-administration. Thus, nicotine withdrawal results in modest, but yet detectable, changes in the behavior of mice.