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Haloperidol-induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus.

ABSTRACT: Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson's disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500?Hz electrical stimulation of the IC elicits escape behaviour and interferes with haloperidol-induced catalepsy in rats, a state reminiscent of Parkinsonian akinesia, but clinical implication is limited since the protocol is aversive. However, typical DBS stimulation frequencies range between 20-180?Hz. We therefore tested the effects of a low-frequency 30?Hz-DBS protocol on haloperidol-induced catalepsy and aversive behaviour in rats. We show that low-frequency 30?Hz-DBS targeted at the IC strongly ameliorates haloperidol-induced catalepsy without any evidence of stimulation-induced escape behaviour. Furthermore, 30?Hz-DBS of the IC produced no place avoidance in a place conditioning paradigm and induced no anxiety-related behaviour on the elevated plus maze, indicating that the protocol has no aversive or anxiogenic side effects. Our findings provide first evidence that the IC can serve as an alternative, non-conventional DBS target.

SUBMITTER: Engelhardt KA

PROVIDER: S-EPMC5797241 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Haloperidol-induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus.

Engelhardt K-Alexander KA Marchetta Philine P Schwarting Rainer K W RKW Melo-Thomas Liana L

Scientific reports 20180202 1

Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson's disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500 Hz electrical stimulation of the IC elic ...[more]

PMID: 29396521

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Project description:In animal models, the administration of the dopaminergic D2 antagonist haloperidol affects the nigrostriatal pathway, inducing catalepsy, a state of immobility similar to Parkinson's disease (PD) bradykinesia and akinesia. In PD, the motor impairments are due to difficulties in selecting and executing motor actions, associated with dopamine loss in basal ganglia and cortical targets. Motor and affective limbic networks seem to be integrated via a striato-nigro-striatal network, therefore, it is not surprising that the motor impairments in PD can be influenced by the patient's emotional state. Indeed, when exposed to aversive stimuli or life-threatening events, immobile patients are capable of performing sudden movements, a phenomenon known as paradoxical kinesia. Thus, the present study investigated the effects of unconditioned and conditioned aversive stimulation on haloperidol-induced catalepsy in rats. First, male Wistar rats received intraperitoneal administration of saline or haloperidol (1 or 2 mg/kg) and were evaluated in the catalepsy bar test to assess the cataleptic state induced by the different doses of haloperidol over time. Next, we evaluated the effects of two types of unconditioned aversive stimuli-100 lux light (1 and 20 s) or 0.6 mA footshock (1 s)-on the catalepsy. Finally, we evaluated the effects of light conditioned stimuli (Light-CS), previously paired with footshocks, on the cataleptic state. Catalepsy was observed following haloperidol 1 and 2 mg/kg administration. Exposure to footshocks, but not to light, significantly reduced step-down latency during the catalepsy test. Although unconditioned light did not affect catalepsy, paired Light-CS did reduce step-down latency. Here, we have provided evidence of face validity for the study of paradoxical kinesia. In addition to demonstrating that immediate exposure to an aversive stimulus is capable of disrupting the cataleptic state, our findings show that haloperidol-induced catalepsy seems to be differently influenced depending on the modality of aversive stimulation. Our data suggest that the selective recruitment of threat response systems may bypass the dysfunctional motor circuit leading to the activation of alternative routes to drive movement.

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Haloperidol-induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus.

Publications

Haloperidol-induced catalepsy is ameliorated by deep brain stimulation of the inferior colliculus.

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