Chronic pramipexole treatment induces compulsive behavior in rats with 6-OHDA lesions of the substantia nigra and ventral tegmental area.

Dopamine replacement therapy (DRT) reduces motor symptoms in Parkinson's disease (PD), but also induces impulsive-compulsive behavior (ICB) in up to 25% of PD patients. These non-motor side effects of DRT generally follow a gradual transition from impulsive to compulsive-like-i.e. repetitive, compelled, and non-pleasurable-behavior. Here, we investigated the effect of chronic pramipexole (PPX) treatment on the onset of compulsive-like behavior, measured via the post-training signal attenuation (PTSA) procedure, in rats with dopaminergic lesions. Accordingly, we aimed to mimic chronic DRT in a PD context, and obtain data on the brain regions that potentially sustain this type of compulsive behavior pattern in rats. We observed that the lesion or treatment alone did not induce compulsive lever pressing in rats. However, rats with lesions of the substantia nigra and ventral tegmental area as well as with chronic PPX treatment developed strong compulsive lever-pressing behavior, as measured via PTSA. Furthermore, when chronic PPX treatment was discontinued before the PTSA test, the lesioned rats showed the same level of compulsive behavior as sham-operated rats. In fact, lesioned, treated, and compulsive-like rats showed significantly higher Fos expression in the orbitofrontal cortex and dorsal striatum. Thus, chronic PPX treatment in PD rats induced a strong compulsive-like behavior. Furthermore, Fos expression mapping suggests that the behavior was sustained via the activation of the orbitofrontal cortex and dorsal striatum.

A role for Sv2c in basal ganglia functions.

SV2C is an isoform of the synaptic vesicle 2 protein family that exhibits a particular pattern of brain expression with enriched expression in several basal ganglia nuclei. In the present study, we have investigated SV2C implication in both normal and pathological basal ganglia functioning with a peculiar attention to dopamine neuron containing regions. In SV2C-/- mice, the expression of tyrosine hydroxylase mRNA in midbrain dopaminergic neurons was largely and significantly increased and enkephalin mRNA expression was significantly decreased in the caudate-putamen and accumbens nucleus. The expression of SV2C was studied in two models of dopaminergic denervation (6-OHDA- and MPTP-induced lesions). In dopamine-depleted animals, SV2C mRNA expression was significant increased in the striatum. In order to further understand the role of SV2C, we performed behavioral experiments on SV2C-/- mice and on knock-down mice receiving an injection of adeno-associated virus expressing SV2C miRNA specifically in the ventral midbrain. These modifications of SV2C expression had little or no impact on behavior in open field and elevated plus maze. However, even if complete loss of SV2C had no impact on conditioned place preference induced by cocaine, the specific knock-down of SV2C expression in the dopaminergic neurons completely abolished the development of a CPP while the reaction to an acute drug injection remains similar in these mice compared to control mice. These results showed that SV2C, a poorly functionally characterized protein is strongly involved in normal operation of the basal ganglia network and could be also involved in system adaptation in basal ganglia pathological conditions.

Distribution of SV2C mRNA and protein expression in the mouse brain with a particular emphasis on the basal ganglia system.

Synaptic vesicle 2 proteins (SV2), SV2A, SV2B and SV2C, are integral proteins localized on the surface of synaptic vesicles in all neurons. SV2 proteins appear to play an important, but not yet fully understood role in synaptic vesicle exocytosis and neurotransmitter release. Moreover, SV2 seems to be the receptor of the botulinum neurotoxin A. In the present study, using single and double-labeling fluorescent immunohistochemistry and in situ hybridization we have identified the brain pattern of SV2C mRNA and protein expression in mice. Our results indicated that SV2C protein was expressed in a small subset of brain regions including the olfactory bulb, olfactory tubercle, nucleus accumbens, caudate-putamen, ventral pallidum, globus pallidus, substantia nigra and the ventral tegmental area. These results were confirmed by means of in situ hybridization, except for the globus pallidus and the substantia nigra pars reticulata, in which no labeling was found, suggesting that SV2C-positive fibers in these areas are terminals of striatal projecting neurons. In the striatum, we found that, in addition to its presence in the projection neurons, SV2C was densely expressed in a fraction (around 45%) of cholinergic interneurons. In addition, our data also showed that SV2C was densely expressed in most dopaminergic neurons in the substantia nigra pars compacta and the ventral tegmental area (more than 70% of the dopaminergic neurons analyzed were SV2C-positive). Altogether, our results suggest that SV2C may contribute to the regulation of neurotransmitter release and synaptic transmission in the basal ganglia including cholinergic striatal interneurons and nigro-striatal/mesolimbic dopamine neurons.