Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intrastriatal microdialysis

Abstract

Parkinson's disease (PD) patients express motor symptoms only after 60-80% striatal dopamine (DA) depletion. The presymptomatic phase of the disease may be sustained by biochemical modifications within the striatum. We used an appropriate specific 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model (Mounayar et al., 2007) to study the compensatory mechanisms operating in recovery from PD motor symptoms. We assessed the levels of DA and its metabolites (DOPAC, homovanillic acid), GABA, glutamate (Glu), serotonin (5-HT) and its metabolite (5HIAA) by repeated intracerebral microdialysis in awake animals before exposure to MPTP during full expression of the motor symptoms induced by MPTP and after recovery from these symptoms. Measurements were obtained from two functionally and anatomically different striatal areas: the associative-limbic territory and sensorimotor territory. Animals with motor symptoms displayed an extremely large decrease in levels of DA and its metabolites and an increase in Glu and GABA levels, as reported by other studies. However, we show here for the first time that serotonin levels increased in these animals. We found that increases in DA levels in the sensorimotor and/or associative-limbic territory and high levels of 5-HT and of its metabolite, 5HIAA, were associated with recovery from motor symptoms in this model. Determining whether similar changes in DA and 5-HT levels are involved in the compensatory mechanisms delaying the appearance of motor symptoms in the early stages of PD might make it possible to develop new treatment strategies for the disease.

Figure 1.

Histological controls of dialysis probe location. A, C, Schematic representation of dialysis probe location in the associative-limbic (A) and sensorimotor (C) striatal territories in the five monkeys studied. Solid lines indicate the first, second, and third dialyses, and dotted lines correspond to the fourth supplementary dialysis. SM, Sensorimotor striatum; Ass, associative striatum; Limb, limbic striatum. B, D, Locations of dialysis probes in the associative-limbic (B) and sensorimotor (D) striatum on a calbindin-immunostained coronal brain section. Scale bar, 1 mm. E–F', Dialysis probe traces at a higher magnification (6.5×) after immunostaining for calbindin (E, F) or GFAP (E', F') in the associative-limbic (E, E') or sensorimotor (F, F') territory. Scale bar, 100 μm.

Figure 2.

Tissue integrity in the vicinity of dialysis sites. A–D', TH (A–B') and 5-HT (C–D') immunostaining on coronal brain sections for the sensorimotor (A, A', C, C') and associative-limbic (B, B', D, D') territories. A', B', C', D', Enlargements (40×; scale bar, 25 μm) of A, B, C, and D, respectively (6.5×; scale bar, 100 μm).

Figure 3.

A–D, Schematic representation of dopamine (A), DOPAC (B), HVA (C) concentrations, and HVA/DA ratio (D) in sensorimotor and associative/limbic striatal territories during the normal, symptomatic, and recovery states. Results for the five monkeys (mean ± SEM) are shown for the motor symptom and recovery states, represented by a vertical bar. All of the concentrations are expressed as a percentage of basal levels (set at 100%) which are indicated by a dotted line. **p < 0.01 versus the normal state; ^†p < 0.05, ^††p < 0.01 versus the motor symptom state.

Figure 4.

A–C, Schematic representation of serotonin (A) and 5HIAA (B) concentrations and 5HIAA/5-HT ratio (C) in sensorimotor and associative-limbic striatal territories during the normal, symptomatic, and recovery states. Results for the five monkeys (mean ± SEM) are shown for the motor symptom and recovery states, represented by a vertical bar. All concentrations are expressed as a percentage of basal levels (set at 100%) which are represented by a dotted line. **p < 0.01 versus the normal state; ^††p < 0.01 versus the motor symptom state.

Figure 5.

A, B, Schematic representation of GABA (A) and glutamate (B) concentrations in sensorimotor and associative-limbic striatal territories during the normal, symptomatic, and recovery states. Results for the five monkeys (mean ± SEM) are shown for the motor symptom and recovery states, represented by a vertical bar. All concentrations are expressed as a percentage of the basal level (set at 100%) which is represented by a dotted line. **p < 0.01 versus the normal state.

Figure 6.

A–F, Correlation between neurochemistry and behavior (A, D), dopaminergic (B, C, F), and serotoninergic denervation (E) in the sensorimotor (A–C) and associative-limbic (D–F) territories. A, r = −0.89, p < 0.05; B, r = 0.95, p < 0.05; C, r = −0.89, p < 0.05; D, r = −0.92, p < 0.05; E, r = 0.98, p < 0.01; F, r = 0.98, p < 0.01.