Effect of Bilateral 6-Hydroxydopamine Lesions of the Medial Forebrain Bundle on Reaction Time

Abstract

Overt symptoms of Parkinson's disease do not manifest themselves until there is a substantial loss of the dopaminergic nigrostriatal projection. However, as neuroprotective strategies are developed, it will be essential to detect the disease in its preclinical phase. Performance on conditioned reaction time tasks is known to be impaired by extensive 6-hydroxydopamine-induced lesions of theThe primary neuropathology of Parkinson's disease is the loss of dopamine (DA) neurons within the substantia nigra (SN) and massive depletion of DA in the striatum, the terminal region of the SN. This loss of DA appears to be responsible for the most prominent symptoms of Parkinson's disease. The degree of neurological deficit is related to the loss of striatal DA (Hornykiewicz and Kish 1987). The neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), used extensively to induce selective loss of DA neurons within the SN, provide animal models that share several of the characteristics of Parkinson's disease (see reviews by Zigmond and Keefe 1997;Jenner and Marsden 1986;Gerlach and Riederer NO . 6 Bilateral 6-OHDA on Reaction Time 7571996; Przedborski and Jackson-Lewis 1998). In addition, whereas intrastriatal injection of indirect DA agonists induces stereotypy (Costall et al. 1973;Statton and Solomon 1984), 6-OHDA lesions of the striatum block this stereotyped behavior (Price and Fibiger 1974). Finally, chronic administration of DA receptor antagonists produce extrapyramidal effects reminiscent of Parkinson's disease, and this is believed to be due to their action at D 2 receptors located in the striatum (Coffin et al. 1989). Although resting tremor and muscular rigidity are generally not reported in rodents after pharmacological manipulation of the nigrostriatal pathway, deficits in movement initiation and execution have been studied using several tests including a conditioned reaction time task. In this task, animals are typically required to respond in a particular way and within a limited period in order to receive a reward, such as a food pellet. This behavioral paradigm is responsive to pharmacological manipulation of dopaminergic neurotransmission mediated by the D 2 subtype of DA receptors Koob 1987, 1989;Amalric et al. 1993Amalric et al. , 1995Smith et al. 2000). For example, we have shown that low dose blockade of D 2 receptors, but not D 1 or D 3 receptors, decreased correct responses in the conditioned reaction time task, increased delayed responses, and lengthened reaction time in a manner suggestive of dysfunctions in movement initiation (Amalric et al. 1993;Smith et al. 2000). Moreover, deficits in reaction time have also been reported in Parkinson's disease (Evarts et al. 1981;Gauntlett-Gilbert and Brown 1998;Berry et al. 1999). These deficits appear to be mediated by the nigrostriatal dopaminergic pathway, as 6-OHDA-induced loss of SN neurons and striatal DA, and not accumbal DA, produces impairments in this task (Amalric and Koob 1987), and intrastriatal infusion...

Lesion to the Nigrostriatal Dopamine System Disrupts Stimulus-Response Habit Formation

“…Similar perseverative behavior has often been associated with response deficits observed in animals with lateral striatum excitotoxic or 6-OHDA lesions (Kirkby, 1969;Amalric et al, 1995;Devan et al, 1996;Eagle et al, 1999;El Massioui et al, 2001;Smith et al, 2002) and was interpreted as either an inability to inhibit ongoing actions or as a failure to initiate a new response. Moreover, the lack of response latency impairment could be attributable to the extent of our striatal DA depletion, because 6-OHDA infusion in the medial forebrain bundle that induces similar DA depletion produces no reliable impairment in a reaction time task (Smith et al, 2002) or skilled paw use (Przedborski et al, 1995;Lee et al, 1996). Significant impairment in skilled paw reaching does not appear unless 80 -90% of striatal TH-positive fibers density or 60 -80% of TH-positive neurons in substantia nigra are lost (Barneoud et al, 1991;Lee et al, 1996).…”

Early use of oleanolic acid provides protection against 6-hydroxydopamine induced dopamine neurodegeneration

“…Smith et al (2002) showed that maximum degeneration of striatal DA is observed between day 5 and 7 days post-intracerebral injection of 6-OHDA into the medial forebrain bundle. Therefore, oleanolic acid could not exert its beneficial effects and provide neuroprotection in this group.…”

Hemispheric differences in the mesostriatal dopaminergic system

“…Following these procedures the experimental contingencies were reversed such that all rats had to turn in the untrained direction. After the reversal, the contralaterally lesioned group had to turn toward the lesion and consequently easily acquired the reversal, however, reinforced rates of responding did not reach preoperative rates possibly due to altered motivation (Mogenson et al, 1980; Smith et al, 2002; Wise, 2002; Solstad et al, 2008). Conversely, the ipsilaterally lesioned group had to turn away from the lesion and consequently was unable to acquire the reversal and continued to turn in the originally trained direction (Szostak et al, 1988).…”