Bilateral 6-OHDA Lesions Research Articles

Cannabidiol improves non-motor symptoms, attenuates neuroinflammation, and favours hippocampal newborn neuronal maturation in a rat model of Parkinsonism.

To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions. Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioural paradigms to evaluate non-motor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis. 6-OHDA-lesioned rats exhibited memory impairments and despair-like behaviour in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. CBD decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behaviour that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favoured the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats. The present findings suggest a potential beneficial effect of CBD on non-motor symptoms induced by intra-nigral 6-OHDA infusion in rats.

Cellular, Behavioral, and Locomotor Effects of Oral Nicotine in Male Rats with Bilateral Lesions in the Ventrolateral Striatum Induced with 6-OHDA

Objective: Parkinson's disease is a progressive neurodegenerative disease having a spectrum of non-motor to motor symptoms. Unrelated to motor symptoms of sensory, autonomic, and neuropsychiatric symptoms often appear early in the course of the disease. It is a remarkable observation that patients in the premotor phase can easily quit smoking without help. This study was intended to investigate the interrelation between nicotine and the partial loss of dopaminergic innervation in the ventrolateral striatum induced by 6-OHDA. 
 Methods: We used an experimental premotor parkinsonism model. The oral nicotine preference of rats was investigated with the two-bottle free choice method. The behaviors related to locomotor activity and emotional state were evaluated with a locomotor activity test, elevated plus maze, and forced swimming test. Histopathological evaluation was performed in the striatum by staining techniques using hematoxylin+eosin (H&E) and immunohistochemistry markers (caspase-3, and MAP-2).
 Results: Bilateral 6-OHDA lesions did not lead to a significant alteration in the total locomotor activity or nicotine preference. Nicotine increased horizontal but decreased vertical movements in addition to increasing anxiolytic but also depressive effects in the OHDA lesion group. The number of apoptotic cells was significantly lower in the lesion group receiving nicotine compared to those not receiving nicotine.
 Conclusion: Our experimental study points to the role of oral nicotine in male rats with bilateral striatal 6-OHDA lesions in the ventrolateral striatum. Further studies are needed to understand the relationship between loss of dopaminergic innervation in the striatum and nicotine consumption.

Characterizing the relationship between L-DOPA-induced-dyskinesia and psychosis-like behaviors in a bilateral rat model of Parkinson's disease

Parkinson's disease associated psychosis (PDAP) is a prevalent non-motor symptom (NMS) that significantly erodes patients' and caregivers' quality of life yet remains vastly understudied. One potential source of PDAP in late-stage Parkinson's disease (PD) is the common dopamine (DA) replacement therapy for motor symptoms, Levodopa (L-DOPA). Given the high incidence of L-DOPA-induced dyskinesia (LID) in later phases of PD, this study sought to characterize the relationship between PDAP and LID in a bilateral medial forebrain bundle 6-hydroxydopamine hydrobromide (6-OHDA) lesion rat model. To assess PDAP in this model, prepulse inhibition (PPI), a well-validated assay of sensorimotor gating, was employed. First, we tested whether a bilateral lesion alone or after chronic L-DOPA treatment was sufficient to induce PPI dysfunction. Rats were also monitored for LID development, using the abnormal involuntary movements (AIMs) test, to examine PPI and LID associations. In experiment 2, Vilazodone (VZD), a serotonin transporter (SERT) blocker and 1A receptor (5-HT1A) partial agonist was administered to test its potential efficacy in reducing LID and PPI dysfunction. Once testing was complete, tissue was collected for high performance liquid chromatography (HPLC) to examine the monoamine levels in motor and non-motor circuits. Results indicate that bilateral DA lesions produced motor deficits and that chronic L-DOPA induced moderate AIMs; importantly, rats that developed more severe AIMs were more likely to display sensorimotor gating dysfunction. In addition, VZD treatment dose-dependently reduced L-DOPA-induced AIMs without impairing L-DOPA efficacy, although VZD's effects on PPI were limited. Altogether, this project established the bilateral 6-OHDA lesion model accurately portrayed LID and PDAP-like behaviors, uncovered their potential relationship, and finally, demonstrated the utility of VZD for reducing LID.

Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson’s disease (PD).A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L-dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH).Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with l-dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with l-dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic l-dopa exposure was observed.This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesion-induced anxiety-like behaviour. We did not report any effect of chronic l-dopa exposure in the context of partial nigral cell loss.

The histamine H3 receptor antagonist thioperamide rescues circadian rhythm and memory function in experimental parkinsonism

Parkinson’s disease (PD) is a common neurodegenerative disorder, characterized by motor impairment and a wide range of non-motor symptoms, including sleep disorders and cognitive and affective deficits. In this study, we used a mouse model of PD based on 6-hydroxydopamine (6-OHDA) to examine the effect of thioperamide, a histamine H3 receptor antagonist, on circadian activity, recognition memory and anxiety. A partial, bilateral 6-OHDA lesion of the striatum reduces motor activity during the active phase of the 24 h cycle. In addition, the lesion disrupts the endogenous circadian rhythm observed when mice are maintained in constant darkness. Administration of thioperamide to 6-OHDA-lesion mice rescues the normal rest/activity cycle. Moreover, thioperamide counteracts the deficit of novel object recognition produced by 6-OHDA. Our experiments show that this memory impairment is accompanied by disrupted gamma oscillations in the hippocampus, which are also rescued by thioperamide. In contrast, we do not observe any modification of the anxiogenic effect of 6-OHDA in response to administration of thioperamide. Our results indicate that thioperamide may act as a multifunctional drug, able to counteract disruptions of circadian rhythm and cognitive deficits associated with PD.

Implication of dorsostriatal D3 receptors in motivational processes: a potential target for neuropsychiatric symptoms in Parkinson\u2019s disease

Beyond classical motor symptoms, motivational and affective deficits are frequently observed in Parkinson’s disease (PD), dramatically impairing the quality of life of patients. Using bilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats, we have been able to reproduce these neuropsychiatric/non-motor impairments. The present study describes how bilateral 6-OHDA SNc lesions affect the function of the main striatal dopaminergic (DA) receptor subtypes. Autoradiography was used to measure the levels of striatal DA receptors, and operant sucrose self-administration and neuropharmacological approaches were combined to investigate the causal implication of specific DA receptors subtypes in the motivational deficits induced by a dorsostriatal DA denervation. We found that D3 receptors (D3R) exclusively are down-regulated within the dorsal striatum of lesioned rats. We next showed that infusion of a D3R antagonist (SB-277011A) in non-lesioned animals specifically disrupts preparatory, but not consummatory behaviors. Our findings reveal an unexpected involvement of dorsostriatal D3R in motivational processes. They strongly suggest an implication of dorsostriatal D3R in the neuropsychiatric symptoms observed in PD, highlighting this receptor as a potential target for pharmacological treatment.

Alterations in the motor cortical and striatal glutamatergic system and d-serine levels in the bilateral 6-hydroxydopamine rat model for Parkinson's disease

Parkinson's disease (PD) is hallmarked by progressive degeneration of the substantia nigra pars compacta (SNc) neurons and is associated with aberrant glutamatergic activity. However, studies on the glutamatergic system in the motor cortex and striatum, two motor loop-related areas, are lacking in the clinically relevant bilateral SNc 6-hydroxydopamine (6-OHDA) rat model, and therefore led to the rationale behind the present investigations. Using Western blotting, the expression levels of the glial glutamate transporters, GLT-1 and GLAST, as well as xCT, the specific subunit of system xc−, and the vesicular glutamate transporters, VGLUT1 and 2 were investigated at two different time points (1 week and 2 weeks) post-lesion. In addition, the total content of glutamate was measured. Moreover, the total d-serine levels were, to the best of our knowledge, studied for the first time in these two PD-related areas in the bilateral 6-OHDA rat model. In the motor cortex, no significant changes were observed in the different glutamate transporter expression levels in the bilaterally-lesioned rats. In the striatum, GLAST expression was significantly decreased at both time points whereas VGLUT1 and 2 expressions were significantly decreased 2 weeks after bilateral 6-OHDA lesion. Interestingly, bilateral 6-OHDA SNc lesion resulted in an enhancement of the total d-serine content in both motor cortex and striatum at 1 week post-lesion suggesting its possible involvement in the pathophysiology of PD. In conclusion, this study demonstrates disturbed glutamate and d-serine regulation in the bilateral SNc-lesioned brain which could contribute to the behavioral impairments in PD.

Long-term treatment with l-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease

Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior.We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.

P.6.c.019 Persistent microglia activation contributes to the depressive/psychotic-like phenotype induced by adolescent THC exposure in rats

Rodents rely upon their olfactory modality to perceive opposite-sex pheromonal odors needed to motivate courtship behaviors. Volatile and nonvolatile components of pheromonal odors are processed by the main (MOS) and accessory olfactory system (AOS), respectively, with inputs converging in the medial amygdala (Me). The Me in turn targets the mesolimbic dopamine system, including the nucleus accumbens core (AcbC) and shell (AcbSh), the ventral pallidum (VP), medial olfactory tubercle (mOT) and ventral tegmental area (VTA). We hypothesized that pheromone-induced dopamine (DA) release in the ventral striatum (particularly in the mAcb and mOT) may mediate the normal preference of female mice to investigate male pheromones. We made bilateral 6-OHDA lesions of DA fibers innervating either the mAcb alone or the mAcb + mOT in female mice and tested estrous females’ preference for opposite-sex urinary odors. We found that 6-OHDA lesions of either the mAcb alone or the mAcb + mOT significantly reduced the preference of sexually naïve female mice to investigate breeding male urinary odors (volatiles as well as volatiles + nonvolatiles) vs. estrous female urinary odors. These same neurotoxic lesions had no effect on subjects’ ability to discriminate between these two urinary odors, on their locomotor activity, or on their preference for consuming sucrose. The integrity of the dopaminergic innervation of the mAcb and mOT is required for female mice to prefer investigating male pheromones.

A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions.

Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals.

6-Hydroxydopamine lesions of the anteromedial ventral striatum impair opposite-sex urinary odor preference in female mice

Rodents rely upon their olfactory modality to perceive opposite-sex pheromonal odors needed to motivate courtship behaviors. Volatile and nonvolatile components of pheromonal odors are processed by the main (MOS) and accessory olfactory system (AOS), respectively, with inputs converging in the medial amygdala (Me). The Me in turn targets the mesolimbic dopamine system, including the nucleus accumbens core (AcbC) and shell (AcbSh), the ventral pallidum (VP), medial olfactory tubercle (mOT) and ventral tegmental area (VTA). We hypothesized that pheromone-induced dopamine (DA) release in the ventral striatum (particularly in the mAcb and mOT) may mediate the normal preference of female mice to investigate male pheromones. We made bilateral 6-OHDA lesions of DA fibers innervating either the mAcb alone or the mAcb+mOT in female mice and tested estrous females’ preference for opposite-sex urinary odors. We found that 6-OHDA lesions of either the mAcb alone or the mAcb+mOT significantly reduced the preference of sexually naïve female mice to investigate breeding male urinary odors (volatiles as well as volatiles+nonvolatiles) vs. estrous female urinary odors. These same neurotoxic lesions had no effect on subjects’ ability to discriminate between these two urinary odors, on their locomotor activity, or on their preference for consuming sucrose. The integrity of the dopaminergic innervation of the mAcb and mOT is required for female mice to prefer investigating male pheromones.

Motivational properties of D2 and D3 dopamine receptors agonists and cocaine, but not with D1 dopamine receptors agonist and l-dopa, in bilateral 6-OHDA-lesioned rat

Dopamine dysregulation syndrome in Parkinson's disease (PD) has been attributed to dopamine replacement therapy (DRT). We hypothesize that DRT can induce a potential rewarding effect in an animal model of PD.Using the conditioned place preference (CPP) paradigm, we investigated the motivational effects of l-dopa, dopamine receptor agonists (DRAs), and cocaine in rat with a bilateral 6-OHDA lesion of the nigrostriatal dopaminergic pathway.In 6-OHDA animals, D1 receptors agonist (SKF81297) revealed significantly a conditioned place aversion (CPA) at 3 mg/kg and 9 mg/kg doses. D2 receptors agonist (bromocriptine) induced both CPP and CPA at 1 mg/kg and 10 mg/kg doses respectively. D3 receptors agonist (PD128907) induced a CPP only at 1 mg/kg, comparable to that of cocaine. Sham animals revealed biphasic CPP curves, with significant dose effect, for the intermediate dose of the 3 DRAs. However, l-dopa induced no significant effect while cocaine induced CPP in both lesioned and sham animals.In conclusion, this study confirms the predominant roles of D2R class, and most specifically D3R subtypes, in rewarding properties of DRT.

Continuous reversal using internal or external cues: A novel test measuring set shifting in Parkinsonian rats

Parkinson’s disease (PD) is a predominant movement disorder, but profound cognitive deficits (e.g. bradyphrenia, memory, and set shifting) also occur. To model the deficits in set shifting using internal and external cues in rats we developed a continuous reversal task in which the active lever, left or right lever, alternated after a variable number of lever presses. In one task the active lever was signaled by a light (external cue condition, EC) whereas in the other task the active lever was not signaled (internal cue condition, IC). In this study we evaluated the effects of a partial bilateral striatal 6-OHDA lesion as model for PD on the performance in both tasks. Following behavioral testing the lesions were verified using tyrosine hydroxylase (TH) immunohistochemistry. The 6-OHDA lesioned animals were specifically impaired in the IC condition and not in the EC task. In other words, the lesioned animals kept pressing a lever longer although it was not longer active. The present response switching task is sensitive to 6-OHDA lesions and may mimic set-shifting deficits in PD. J. Exp. Clin. Med., 2012; 29:183-186

Inhibition of the Acquisition of Conditioned Place Aversion by Dopaminergic Lesions of the Central Nucleus of the Amygdala in Morphine-Treated Rats

The negative affective state of opiate abstinence plays an important role in craving and relapse to compulsive drug use. The dopamine system participates in the reward effects of opiate use and the aversive effect of opiate abstinence. The amygdala is an essential neural substrate for associative learning of emotion. To establish a model of conditioned place aversion (CPA) in morphine-treated rats, we used different visual and tactual cues as conditioned stimuli (CS) within a conditioning apparatus. An injection of naloxone served as the unconditioned stimulus (US). The 6-hydroxydopamine (6-OHDA) lesion technique was used to investigate the effects of the dopaminergic system of the central nucleus of the amygdala (CeA) on naloxone-induced CPA. Rats were rendered physically dependent via administration of increasing doses of morphine delivered via intraperitoneal injection. Doses increased by 20 % each day for 14 days, starting from an initial dose of 6 mg/kg. All rats also received a low dose of naloxone (0.1 mg/kg) by injection 4 hours after morphine treatment on days 11 and 13 to induce CPA in a biased two-compartment conditioned place apparatus. Morphine-dependent rats with sham lesions were found to develop significant CPA after naloxone treatment. Bilateral 6-OHDA lesions of the CeA impaired the acquisition of CPA but had no effect on locomotor activity. These results suggest that the dopaminergic system of the CeA plays an important role in the negative affective state of opiate abstinence.

L-DOPA-induced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson’s disease

Convergent evidence indicates that raphestriatal serotonin (5-HT) neurons can convert and release dopamine (DA) derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine (L-DOPA) as a treatment for Parkinson’s disease (PD). While aspects of such neuroplasticity may be beneficial, chronic L-DOPA may also modify native 5-HT function, precipitating the appearance prevalent non-motor PD symptoms such as anxiety and depression. To examine this, male Sprague–Dawley rats were rendered parkinsonian with bilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) infusions and treated for at least 28days with vehicle or L-DOPA. In the first experiment, striatal, hippocampal, amygdalar, and prefrontal cortex DA and 5-HT levels were examined at various post-treatment time-points. In experiment 2, L-DOPA’s effects on DA and 5-HT cell bodies in the substantia nigra pars compacta and dorsal raphe, respectively, were examined. Finally, the effects of L-DOPA on affective behaviors were assessed in locomotor chambers, social interaction, forced swim, and elevated plus maze behavioral tests. Bilateral 6-OHDA lesion induced approximately 80% DA and 30% 5-HT depletion in the striatum compared to sham-lesioned controls, while monoamine levels remained largely unchanged in extrastriatal regions. Tissue levels of DA were increased at the expense of 5-HT levels in parkinsonian rats subjected to chronic L-DOPA injections in all regions sampled, though DA or 5-HT cell bodies were unaffected. Behaviorally, rats could only be tested 24h after their last L-DOPA injection due to severe dyskinesia. Despite this, prior exposure to chronic L-DOPA treatment exerted a pronounced anxiogenic phenotype. Collectively, these results suggest that chronic L-DOPA treatment may interfere with the balance of DA and 5-HT function in affect-related brain regions and could induce and/or exacerbate non-motor symptoms in PD.

Chronic, systemic treatment with a metabotropic glutamate receptor 5 antagonist produces anxiolytic-like effects and reverses abnormal firing activity of projection neurons in the basolateral nucleus of the amygdala in rats with bilateral 6-OHDA lesions

Although 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 antagonist, improves the motor symptoms of Parkinson's disease (PD), the effects of MPEP on the psychiatric symptom of PD and the mechanism involved are still unclear. In the present study, we examined the effects of MPEP in anxiolytic-like behavior and firing activity of projection neurons in the basolateral nucleus of the amygdala (BLA) in rats with 6-hydroxydopamine (6-OHDA) injected bilaterally into dorsal striatum. Rats were divided into three groups, sham-operated group, 6-OHDA lesion with vehicle treatment group and 6-OHDA lesion with MPEP treatment group. Injection of 6-OHDA (10.5 μg) into the dorsal striatum produced 31.5% loss of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the SNpc. The 6-OHDA-lesioned rats showed anxiety behavior and the firing rate of BLA projection neurons decreased significantly compared with sham-operated rats, and no difference was found in the firing pattern of these neurons. Whereas chronic, systemic treatment of MPEP (3 mg/kg/day, i.p.; 14 days) attenuated loss of TH-ir neurons, produced anxiolytic-like effect and normalized the abnormal firing rate of projection neurons of the BLA in rats with the bilateral lesions. Systemic administration of cumulative apomorphine (10–160 μg/kg, i.v.) inhibited the firing rate of BLA projection neurons in sham-operated, 6-OHDA lesion with vehicle-treated and MPEP-treated rats, but the 6-OHDA lesion decreased the response of BLA projection neurons to apomorphine stimulation, while MPEP reversed the reactivity of these neurons. These data demonstrate that the partial lesion of the nigrostriatal pathway causes anxiety symptom and decreases firing rate of BLA projection neurons in the rat. Furthermore, chronic, systemic MPEP treatment has the neuroprotective and anxiolytic-like effects, and reverses the abnormal firing rate of BLA projection neurons, suggesting that MPEP has important implication for the treatment of PD.

Acquisition and performance in a rat sequential reaction time task is not affected by subtotal ventral striatal 6-OHDA lesions

Based on findings of experiments with humans, non-human primates and rodents, it is commonly accepted that dopaminergic basal ganglia processes play a crucial role in procedural and sequential learning. Primal evidence for this hypothesis came from serial reaction time tasks (SRTT) studies, demonstrating that healthy controls show increased reaction times when visual stimulus presentation switches from a previously learned sequence to random stimulus presentation. This so-called interference effect was reduced in patients with Parkinson's disease. Since ethical and methodical aspects limit neurobiological research in human subjects, we developed a rat version of the human SRTT, which can be used to study experimentally induced brain damage. In the present experiment we investigated the effects of bilateral 6-OHDA lesions of the ventral striatum on sequential learning. The lesions led to subtotal dopaminergic depletions in the ventral striatum (58–60%) and also minor depletions in the medial neostriatum (32–46%). These lesions impaired task acquisition only moderately and did not worsen sequential performance since lesion and control animals showed a comparable interference effect when the trained sequence was tested against random stimulus presentation or violated sequences. In contrast, in an earlier SRTT experiment with medial neostriatal dopaminergic lesions (58–66%), the lesion animals were clearly impaired in their sequential learning as compared to controls. Therefore, we assume that subtotal dopamine loss in the medial neostriatum, rather than the ventral striatum, has a substantial effect on sequential learning.

Sequential bilateral striatal lesions have additive effects on single skilled limb use in rats

Unilateral dopamine depletion in rats induced by injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal system causes permanent impairments in limb use. The disturbances in limb use, including impairments in skilled reaching, are most severe on the side contralateral to the lesion. A number of studies, however, have also described ipsilateral deficits in skilled reaching. The purpose of this study was to investigate the effects of sequential bilateral striatal 6-OHDA lesions on skilled reaching movements in rats to compare the contribution of contra- versus ipsilateral motor control. Rats were trained in a reaching task to grasp food pellets with their preferred paw prior to receiving an intrastriatal 6-OHDA injection on the side contralateral to the preferred paw. The lesion significantly reduced reaching success along with qualitative impairments in limb use. In addition, animals displayed asymmetry in limb use and contraversive rotation bias after an apomorphine challenge. Three weeks later, animals received a second lesion induced by intrastriatal 6-OHDA injection into the hemisphere ipsilateral to the preferred paw. This lesion exaggerated the previous impairments in limb use and further reduced reaching success of the preferred paw. In the ladder rung walking task, additional impairments were found only in the forelimb ipsilateral to the first lesion. The findings of additive effects of sequential bilateral lesions suggest that both the contra- and ipsilateral striatum control single limb use. This supports the notion of bilateral control of skilled forelimb use by the mesostriatal dopaminergic system.

Selective effects of partial striatal 6‐OHDA lesions on information processing in the rat

The present study was aimed at characterizing the cognitive deficits caused by the degeneration of nigrostriatal dopamine (DA) pathways by using the additive factor logic [Sternberg, S. (1969) Acta Psychol., 30, 276-315], a powerful reaction time (RT) method developed in humans and recently introduced in the rat [Courtiere, A., Hardouin, J., Hasbroucq, T., Possamai, C.-A. & Vidal, F. (2000) Behav. Process., 50, 113-121]. Long-Evans rats were trained to respond to left or right (lateral) visual cues in a choice RT task. Two task factors, signal intensity and force requirement, were manipulated. Partial bilateral 6-OHDA lesions of DA nerve terminals in the striatum were then performed and their effects tested for up to 7 weeks following surgery. Reaction time was lengthened from the 2nd to the 4th week postlesion. This alteration was independent of force requirement, thereby suggesting that the related motor processes were not influenced by the DA depletion. During the 2nd week postlesion, the RT increase was accompanied by a disappearance of the effect of signal intensity, showing that the lesion altered stimulus-related processes. From the 3rd week the signal intensity effect was re-established although RT was still increased, indicating that the stimulus-related processes had recovered while other central processes were still impaired. From the 5th week after surgery, the lesioned animals had completely recovered from the RT deficits induced by the lesion. These results point at the involvement of striatal DA in sensory and central information processes.

6-hydroxydopamine lesions in anuran amphibians: a new model system for Parkinson's disease?

We investigated the effects of dopamine depletion on acoustically guided behavior of anurans by conducting phonotaxis experiments with female gray treefrogs (Hyla versicolor) before and 90 min after bilateral injections of 3, 6, or 12 microg 6-hydroxydopamine (6-OHDA) into the telencephalic ventricles. In experiments with one loudspeaker playing back a standard artificial mating call, we analyzed the effects of 6-OHDA on phonotactic response time. In choice tests we measured the degree of distraction from the standard call (20 pulses/s) by three different variants with altered pulse-rate (30/s, 40/s, 60/s). Five days after experiments, brains were immunostained for tyrosine hydroxylase. Labeled neurons were counted in the suprachiasmatic nucleus, posterior tuberculum, interpeduncular nucleus, and locus coeruleus, and correlation between neuronal numbers and behavioral scores was tested. Response times increased together with 6-OHDA concentrations, which was mainly due to longer immobile periods before the animals started movement. In choice tests the most irrelevant stimulus (60/s) distracted 6-OHDA injected females from the standard stimulus, while sham injected controls were undistracted. The number of catecholaminergic neurons decreased with increasing 6-OHDA concentration in the suprachiasmatic nucleus, posterior tuberculum, and interpeduncular nucleus. The normalized number of immunoreactive neurons in the posterior tuberculum was positively correlated with phonotaxis scores in the one-speaker test, demonstrating that motor deficits are a function of tubercular cell loss. We conclude that bilateral 6-OHDA lesions in anuran amphibians cause motor (difficulty to start movements) as well as cognitive symptoms (higher distraction by irrelevant stimuli) that have also been described for human Parkinson patients.