Contralateral Turns Research Articles

Efficacy of the Technologically Processed Antibodies to the Brain-Specific S100 Protein in a Rat Model of Hemorrhagic Stroke.

We studied the ability of technologically processed antibodies to the brain-specific S100 protein (drug Prospekta) to reduce the brain lesion area, neurological disorders, and mortality in a rat model of hemorrhagic stroke. Technologically processed antibodies to S100 exerted a positive effect on all these parameters (brain lesion area, survival rate, neurological status according to the Menzies scale, and proportion of contralateral turns). This allows us to recommend further research into the spectrum of pharmacological activity and the mechanism of action of technologically processed antibodies to S100 in order to expand the indications for their use after the necessary clinical trials.

Function of the Intrinsic Foot Muscles During Balance and Turning

Atrophy of the intrinsic foot muscles (IFM) has been associated with pathologies such as diabetic foot ulcers, plantar fasciitis, and instability in the elderly, however the mechanisms by which IFM influence these pathologies remain unclear. Previous studies have illustrated the role of IFM in longitudinal arch support and have suggested a role in balance. We hypothesize that IFM that abduct/adduct the toes (e.g. abductor hallucis, ABDH; abductor digiti minimi, ABDM; dorsal and plantar interossei, PDIO, PPIO) regulate the relative position of the midfoot and forefoot elements during turning/cutting and balance. We predict a) that muscles on the same side of the second‐digit pedal axis will act together during balance tasks and turning, b) muscles on the medial side of the axis (ABDH, PDIO1) will be active to facilitate ipsilateral turns while muscles on the lateral side of the axis (ABDM, PDIO3) will be active during contralateral turns, and c) increases in center of pressure (COP) movement and velocity will be associated with increased IFM activity during balance tasks.We used surface electromyography (EMG) to measure activity in 6 IFMs in 12 healthy subjects (age 18‐25) during 3 balance tasks, walking, and ipsilateral/contralateral turns on an EMED/E plantar pressure mat. We filtered, smoothed, and normalized the EMG data to the peak for each subject. We quantified peak pressures in 13 regions of the foot, COP movement and COP velocity throughout each step. We used analysis of variance to compare activity in each muscle across walking and balance trial types. We examined the relationship between COP movement/velocity and EMG in muscles on the medial and lateral side of the pedal axis to assess the relationship of COP movement/velocity, measures of instability, with IFM activity.All of the IFM with an abduction component (ABDH, ABDM, PDIO1,3) were more active during turns than walking straight ahead (p<0.01), while flexor digitorum brevis (FDB) was not. ABDH was more active during ipsilateral than contralateral turns or straight walking (p<0.01). PDIO1 was most active during ipsilateral 90° turns (p<0.01). PDIO3 was more active during turning trials compared to straight ahead walking (p<0.01), but it was active during both ipsilateral and contralateral turns, possibly because of crosstalk with PPIO2. FDB and ABDM exhibited no differences among trial types. While few overall differences were exhibited across balance trial types, increases in COP velocity were associated with increased activity in the IFM, and COP shifts were associated with EMG activity on the contralateral side of the pedal axis.These data suggest the IFM, especially those that abduct and adduct, counteract instability during balance and assist stable turning/cutting by moving the midfoot/rearfoot relative to the forefoot while maintaining forefoot contact with the ground. Understanding the role of the intrinsic foot muscles in balance and turning maneuvers is critical to our comprehension of the etiology of foot pathology and instability in individuals with atrophy of these muscles and to the development of methods for strengthening them.

Arachidonyl-2′-chloroethylamide (ACEA), a synthetic agonist of cannabinoid receptor, increases CB1R gene expression and reduces dyskinesias in a rat model of Parkinson's disease

l-Dopa is the most effective drug used for Parkinson's disease (PD), but after long-term treatment, the vast majority of PD patients develop abnormal involuntary movements (AIMs) termed l-Dopa-induced dyskinesia (LID). Cannabinoid receptors in the basal ganglia can modulate motor functions, but their role in the treatment of LID is controversial. Therefore, the aim of this study is to evaluate the motor behavior and mRNA expression of the cannabinoid receptor-1 (CB1R), encoded by the Cnr1 gene, in the striatum and globus pallidus of a 6-hydroxydopamine rat model of PD. The evaluated rats had 6-hydroxydopamine-induced injury, LID, and LID treated with arachidonyl-2′-chloroethylamide (ACEA), a cannabinoid receptor agonist. Contralateral turns and AIMs were recorded to assess motor behavior. Gene expression was quantified by reverse transcription coupled with quantitative polymerase chain reaction using TaqMan probes. Behavioral evaluations demonstrated that dyskinetic rats treated with ACEA had a significant reduction in AIMs compared to the dyskinetic group. The expression of CB1R mRNA was significantly decreased in the 6-hydroxydopamine-injured and dyskinetic rats, compared to intact rats. The striata of dyskinetic rats treated with ACEA exhibited highly significant increases in CB1R mRNA expression. Contrary to results in the striatum, a lower CB1R expression was observed in globus pallidus from dyskinetic ACEA-treated group. In summary, significant differences in mRNA expression of CB1R were found between the evaluated groups of rats, suggesting the occurrence of compensatory mechanisms that may result in the ACEA-mediated reduction of dyskinesias in a rat model of PD.

Conditioned Medium Protects Dopaminergic Neurons in Parkinsonian Rats.

Objective Adipose derived stem cells (ASCs) secrete numerous neurotrophic factors and cytokines in conditioned medium (CM), which protect neurons by its antioxidative and trophic effects. This research assesses the neuroprotective effect of ASC- CM on neurotrophins genes expressions and tyrosine hydroxylase positive (TH+) cell density in male Wistar rats lesioned by 6-hydroxydopamine (6-OHDA). Materials and Methods In this experimental study, the groups consisted of lesioned and sham rats with unilateral injections of 20 µg of 6-OHDA neurotoxin and phosphate buffered saline (PBS) into the striatum, respectively. Another groups received intravenous injections of 3×106 cells (ASCs group), 500 µl of CM (ASC-CM group) or medium [α-minimal essential medium (α-MEM) group)]. All rats underwent evaluations with the rotarod and apomorphine-induced rotation tests at 2, 4, 6, and 8 weeks post-injection. At 8 weeks we sacrificed some of the animals for real-time polymerase chain reaction (PCR) analysis, and evaluation of TH+cell counts. Results We observed a significant decrease in contralateral turns to the lesions in the ASCs and ASC-CM groups compared to the neurotoxin lesioned or α-MEM groups at 8 weeks post transplantation. Cell and CM- injected rats showed a significant increase of staying on the rotarod compared to the lesion or α-MEM groups. Cell and CM-treated rats showed significant increases in the NGF and NT3 genes, respectively, compared with the lesion group. Both treated groups showed significant increases in BDNF gene expression and TH+ cell density. ConclusionThe results suggested that ASCs and ASC-CM protected dopaminergic neurons through the expressions of neurotrophin genes.

Effects of Hypericum perforatum on turning behavior in an animal model of Parkinson's disease

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the slow and progressive death of dopaminergic neurons in the (substantia nigra pars compact). Hypericum perforatum (H. perforatum) is a plant widely used as an antidepressant, that also presents antioxidant and anti-inflammatory properties. We evaluated the effects of H. perforatum on the turning behavior of rats submitted to a unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle as an animal model of PD. The animals were treated with H. perforatum (100, 200, or 400 mg/kg, v.o.) for 35 consecutive days (from the 28th day before surgery to the 7th day after). The turning behavior was evaluated at 7, 14 and 21 days after the surgery, and the turnings were counted as contralateral or ipsilateral to the lesion side. All tested doses significantly reduced the number of contralateral turns in all days of evaluation, suggesting a neuroprotective effect. However, they were not able to prevent the 6-OHDA-induced decrease of tyrosine hydroxylase expression in the lesioned striatum. We propose that H. perforatum may counteract the overexpression of dopamine receptors on the lesioned striatum as a possible mechanism for this effect. The present findings provide new evidence that H. perforatum may represent a promising therapeutic tool for PD.

Intranasally-administered deferoxamine mitigates toxicity of 6-OHDA in a rat model of Parkinson׳s disease

Deferoxamine (DFO) has shown therapeutic promise for the treatment of Parkinson׳s disease (PD) as it has reduced both behavioral and biochemical deficits when injected into the brain of rodent models of PD. Intranasally administered DFO targets the brain directly but non-invasively and has been effective in animal models of stroke and Alzheimer׳s disease. In this study we sought to determine whether intranasal (IN) DFO could be neuroprotective for PD in a rat model. PD was induced with a unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, while sham surgery rats received saline injections. Rats were pre-treated three times with either IN DFO or saline (starting 4 days before 6-OHDA), and post-treated twice/wk for one month before behavioral tests. In the apomorphine-induced rotational test, IN DFO significantly decreased the number of contralateral turns after injection of apomorphine HCl (p<0.05). Also, IN DFO significantly decreased limb asymmetry in the rearing tube as measured with contralateral limb touches (p<0.05). The IN DFO treatment yielded a trend towards decreased contralateral foot-slips on the tapered balance beam, though the difference was not significant. Finally, IN DFO-treated rats had increased preservation of tyrosine hydroxylase immunoreactive neurons in the substantia nigra (p<0.05). These results confirm that DFO is beneficial in a 6-OHDA model and demonstrate improvement in motor deficits and dopaminergic neuronal survival with non-invasive intranasal delivery, making this an attractive potential treatment for PD.

Intranasally applied l-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions

l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

Responses of Reticulospinal Neurons in the Lamprey to Lateral Turns

When swimming, the lamprey maintains a definite orientation of its body in the vertical planes, in relation to the gravity vector, as the result of postural vestibular reflexes. Do the vestibular-driven mechanisms also play a role in the control of the direction of swimming in the horizontal (yaw) plane, in which the gravity cannot be used as a reference direction? In the present study, we addressed this question by recording responses to lateral turns in reticulospinal (RS) neurons mediating vestibulospinal reflexes. In intact lampreys, the activity of axons of RS neurons was recorded in the spinal cord by implanted electrodes. Vestibular stimulation was performed by periodical turns of the animal in the yaw plane (60 degrees peak to peak). It was found that the majority of responding RS neurons were activated by the contralateral turn. By removing one labyrinth, we found that yaw responses in RS neurons were driven mainly by input from the contralateral labyrinth. We suggest that these neurons, when activated by the contralateral turn, will elicit the ipsilateral turn and thus will compensate for perturbations of the rectilinear swimming caused by external factors. It is also known that unilateral eye illumination elicits a contralateral turn in the yaw plane (negative phototaxis). We found that a portion of RS neurons were activated by the contralateral eye illumination. By eliciting an ipsilateral turn, these neurons could mediate the negative phototaxis.

Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions

Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di- n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5–10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways.

A novel therapeutic approach to 6-OHDA-induced Parkinson’s disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase

The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61 kD was successfully transduced (1 μM) into the dopaminergic SH-sy5y human neuroblastoma cells in vitro and visualized by immunohistochemical assay. An in vivo experiment in rats showed that the iv administered PTD-TH protein (8 mg/kg) permeated across the blood–brain barrier, penetrated into the striatum and midbrain, and peaked at 5–8 h after the injection. The behavioral effects of PTD-TH on the apomorphine-induced rotations in the PD model rats 8 weeks after the 6-OHDA lesion showed that a single bolus of PTD-TH (8 mg/kg) iv injection caused a decrement of 60% of the contralateral turns on day 1 and 40% on days 5–17. The results imply that iv delivery of PTD-TH is therapeutically effective on the 6-OHDA-induced PD in rats, the PTD-mediated human TH treatment opening a promising therapeutic direction in treatment of PD.

Flight reactions to nitric oxide in the inferior colliculus of rats depend on NMDA receptor activation

The dorsolateral periaqueductal grey (dlPAG) is proposed to play a role in the elaboration of defensive behaviors. Nitric oxide (NO) donors, injected into this region, induce flight reactions. The reactions have also been observed after electrical or chemical stimulation of the inferior colliculus (IC). The enzyme responsible for NO formation, neuronal nitric oxide synthase (nNOS), is expressed in the IC. The aims of this study were to investigate if NO donors injected into the IC would also cause aversive reactions and if these reactions would involve activation of NMDA receptors. The results showed that 3-morpholinosylnomine hydrochloride (SIN-1; 300 nmol), an NO donor, injected into the central nucleus but not into the dorsal cortex of the IC (CIC and DCIC, respectively) of male Wistar rats induced flight reactions characterized by galloping and jumps. Pretreatment (10 min) with methylene blue (MB; 100 or 200 nmol), a guanylate cyclase (GC) inhibitor, partially inhibited this flight reaction, decreasing the number of jumps. 8-Bromo-cGMP (8-Br-GMP), a membrane-permeable cGMP analogue, increased the number of contralateral turnings. Pretreatment (10 min) with the NMDA receptor antagonist amino-7-phosphonoheptanoic acid (AP7; 2 nmol) completely prevented the effects of SIN-1. It is concluded that NO may induce aversive reactions in the CIC and that these reactions depend on NMDA receptor activation. They may also partially involve facilitation of GC activity.

Motor stimulant effects of the adenosine A(2A) receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats.

Several evidences indicate that the selective blockade of adenosine A(2A) receptors counteracts the motor activity impairment in experimental models of Parkinson's disease. In the present study, the effects of the adenosine A(2A) receptor antagonist, SCH 58261 (5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine, were assessed following a repeated treatment schedule in the contralateral turning behavior rat model of Parkinson's disease. Unilateral lesions of the nigrostriatal pathway were induced by injecting 6-hydroxydopamine (6-OHDA) in medial forebrain bundle. Repeated administration of SCH 58261 was performed either alone (7 and 14 days repeated SCH 58261) or together with L-dopa (19 days repeated SCH 58261 plus L-dopa or L-dopa alone). After a 7- and 14-day repeated administration schedule, SCH 58261 (5 mg/kg) maintained its ability to potentiate the contralateral turning behavior induced by a subthreshold dose of L-dopa (2 mg/kg i.p.), showing no tolerance to its stimulant effects. SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) or L-dopa (6 mg/kg) alone induced, at these dosages, the same number of contralateral turnings after the first administration. While chronic intermittent SCH 58261 plus L-dopa did not lead to a modified turning behavior during treatment, L-dopa alone produced a progressive increase in turning behavior intensity and duration. These results provide evidence that SCH 58261 retains its ability to potentiate L-dopa effects in a validated rat model of Parkinson's disease even after repeated treatments. Moreover, these results suggest that adenosine A(2A) blockade prevents the appearance of motor response alterations in L-dopa-treated rats, supporting the concept that A(2A) receptor antagonists have a therapeutic potential for the treatment of Parkinson's disease. Copyright 2001 Wiley-Liss, Inc.

Stimulation of adenosine A1 receptors attenuates dopamine D1 receptor-mediated increase of NGFI-A, c-fos and jun-B mRNA levels in the dopamine-denervated striatum and dopamine D1 receptor-mediated turning behaviour.

Adenosine A1 receptors antagonistically and specifically modulate the binding and functional characteristics of dopamine D1 receptors. In the striatum this interaction seems to take place in the GABAergic strionigro-strioentopeduncular neurons, where both receptors are colocalized. D1 receptors in the strionigro-strioentopeduncular neurons are involved in the increased striatal expression of immediate-early genes induced by the systemic administration of psychostimulants and D1 receptor agonists. Previous results suggest that a basal expression of the immediate-early gene c-fos tonically facilitates the functioning of strionigro-strioentopeduncular neurons and facilitates D1 receptor-mediated motor activation. The role of A1 receptors in the modulation of the expression of striatal D1 receptor-regulated immediate-early genes and the D1 receptor-mediated motor activation was investigated in rats with a unilateral lesion of the ascending dopaminergic pathways. The systemic administration of the A1 agonist N6-cyclopentyladenosine (CPA, 0.1 mg/kg) significantly decreased the number of contralateral turns induced by the D1 agonist SKF 38393 (3 mg/kg). Higher doses of CPA (0.5 mg/kg) were necessary to inhibit the turning behaviour induced by the D2 agonist quinpirole (0.1 mg/kg). By using in situ hybridization it was found that CPA (0.1 mg/kg) significantly inhibited the SKF 38393-induced increase in the expression of NGFI-A and c-fos mRNA levels in the dopamine-denervated striatum. The increase in jun-B mRNA expression could only be inhibited with the high dose of CPA (0.5 mg/kg). A stronger effect of the A1 agonist was found in the ventral striatum (nucleus accumbens) compared with the dorsal striatum (dorsolateral caudate-putamen). The results indicate the existence of antagonistic A1-D1 receptor-receptor interactions in the dopamine-denervated striatum controlling D1 receptor transduction at supersensitive D1 receptors.

MPTP-Induced Hemiparkinsonism in Nonhuman Primates 6–8 Years after a Single Unilateral Intracarotid Dose

Five female adultMacaca nemestrinamonkeys, given a unilateral intracarotid (ic) infusion of 2.3–3.5 mg of MPTP-HCl, were studied for 6–8 years. Two to 3 days after MPTP, the animals developed hemiparkinsonism characterized by rigidity and flexed posture of the arm contralateral to the side of infusion with episodes of tremor, circling ipsilateral to the lesioned side, a slight balance disturbance, and stooped posture. Rating of parkinsonian features 4 months after ic infusion, and yearly thereafter, did not show any statistically significant changes. The animals maintained their usual appetite and body weight increased normally. Each animal responded tol-DOPA methyl ester with decreased parkinsonian signs and symptoms and increased contralateral turning. In contrast, after control vehicle administration, the animals continued to have the same parkinsonian signs and predominant ipsilateral turns. In three of the five monkeys, contralateral turns after vehicle significantly increased after 6–8 years. Unilateral intracarotid MPTP induced asymmetric motor behavior that remained stable after 6–8 years. Animals that showed an increased frequency of contralateral circling after control vehicle showed a decrease in contralateral turns afterl-DOPA methyl ester, suggesting neuroplastic changes over the years.

The effects of chronic continuous versus intermittent levodopa treatments on striatal and extrastriatal D 1 and D 2 dopamine receptors and dopamine uptake sites in the 6-hydroxydopamine lesioned rat — an autoradiographic study

The effects of chronic ‘continuous’ infusion and ‘intermittent’ modes of levodopa/carbidopa administration on apomorphine induced circling behaviour, DA uptake sites (labelled with [ 3H]mazindol) and D 1 and D 2 DA receptor binding (labelled with [ 3H]SCH 23390 and [ 3H]sulpiride, respectively) were investigated in rats with unilateral 6-OHDA lesions of the medial forebrain bundle. The circling behaviour in response to apomorphine was greatly enhanced following chronic ‘intermittent’ but not ‘continuous’ levodopa treatments. Following the ‘intermittent’ regime, the lower dose of apomorphine induced a period of intense circling with delayed onset and rapid offset, than in rats given either ‘continuous’ infusion of levodopa or saline. The 6-OHDA lesion itself induced gross depletion of [ 3H]mazindol binding in all striatal subregions, NAc and OT, but not frontal cortex. [ 3H]Sulpiride binding in the ventrolateral striatal quadrant was increased on the denervated side and this correlated with the peak contralateral turns in response to 0.5 mg/kg apomorphine challenge. This asymmetry in striatal [ 3H]sulpiride binding was reduced in both groups of rats receiving levodopa. [ 3H]sulpiride binding in the NAc and OT and [ 3H]SCH 23390 binding in the striatum, NAc, OT and SNr were unaffected by DA denervation or either regime of levodopa treatments. ‘Continuous’ infusion and not ‘intermittent’ injections of levodopa reduced [ 3H]mazindol binding in the striatal subregions and the frontal cortex on both the denervated and intact sides. The potentiation of the behavioural response to apomorphine by chronic ‘intermittent’ levodopa treatment does not correspond with the levodopa induced alterations in striatal or extrastriatal DA receptors. In the same group of animals the narrowing of the duration of response to the lower dose of apomorphine may mimic the fluctuations in response to levodopa, seen clinically in long-term levodopa treated parkinsonian patients.

Chronic flurazepam differentiallu regulates a behavioral effect of GABA agonists

Subsensitivity to γ-aminobutyric acid (GABA) agonists was sought in rats treated 1 or 4 weeks with flurazepam (FZP). Sensitivity to GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) was assessed by measuring contralateral rotation following unilateral microinjection of drug into the substantia nigra pars reticulata (SNpr). Immediately and 48 h after chronic treatment GABA, 200 μg or THIP, 60 ng was infused into SNpr. Immediately, but not 48 h after 1 week of FZP treatment, GABA subsensitivity was shown by a significantly reduced total number of contralateral turns and peak rotation rare. There was no change in the response to THIP after 1 week FZP treatment. Following 4 week FZP treatment, no subsensitivity to GABA or THIP was evident. Previous results showed subsensitivity to muscimol after 4, but not 1 week of FZP treatment. Since muscimol and THIP are not subject to uptake, there may be increased uptake of GABA after 1 week of FZP treatment, though it may not persist during continued treatment. Differential regulation of GABA agonist effects in SNpr may be related to their acting at differing GABA A receptor subpopulations, and variable responses of these subpopulations to chronic BZ treatment.

Age-related differences in the sensitivity of rats to a selective sigma ligand

Differences in sigma binding parameters and behavioral responses to injections of a selective sigma ligand were found in adult rats of different ages. Middle-aged rats (5–6 months old) had fewer sigma binding sites and sites with lower affinity for [ 3 H]di-o- tolylguanidine than young adult animals (2–3 months old). The older animals also exhibited a decreased behavioral response to the selective sigma ligand, di- o-tolyguanidine (DTG). Unilateral microinjection of DTG into the substantia nigra of rats produced fewer net contralateral turns in middle-aged animals, compared to younger rats. Likewise, the postural changes produced by unilateral microinjection of DTG into the red nucleus were less pronounced in the older animals. These data suggest that changes in the number and affinity of sigma binding sites may affect movement and posture as an organism ages.

Rotational behaviour induced by theophylline in 6-OHDA nigrostriatal denervated rats is dependent on the supersensitivity of striatal dopaminergic receptors

We studied apomorphine- and theophyslline-induced rotational behaviour in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. It was seen that there was a direct correlation between the number of apomorphine- and theophylline-induced contralateral turns. These data suggest the existence of a relationship between theophylline-induced rotational behaviour and the degree of supersensitivity of the striatal dopaminergic receptors. Because the rotational behaviour induced by theophylline is in the same direction as dopaminergic agonists, contralateral to the nigrostriatal pathway lesion, these results suggest the possibility of a direct dopaminergic agonism of methylxanthines.