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Temporal Factors Modulate Haloperidol-Induced Conditioned Catalepsy.

ABSTRACT: Repeated pairings of a neutral context and the effects of haloperidol give rise to conditioned catalepsy when the context is subsequently presented in a drug-free test. In order to confirm whether this response is based on Pavlovian processes, we conducted two experiments involving two manipulations that affect conditioning intensity in classical conditioning procedures: time of joint exposure to the conditioned and the unconditioned stimulus, and the length of the inter-stimulus interval (ISI). The results revealed that both an increase in the length of context-drug pairings during conditioning and a reduced ISI between drug administration and context exposure increased conditioned catalepsy. These results are discussed in terms of the temporal peculiarities of those procedures that involve drugs as the unconditioned stimulus along with the role of Pavlovian conditioning in context-dependent catalepsy.

SUBMITTER: Carcel L

PROVIDER: S-EPMC8283013 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Temporal Factors Modulate Haloperidol-Induced Conditioned Catalepsy.

Cárcel Lucía L De la Casa Luis G LG

Frontiers in behavioral neuroscience 20210702

Repeated pairings of a neutral context and the effects of haloperidol give rise to conditioned catalepsy when the context is subsequently presented in a drug-free test. In order to confirm whether this response is based on Pavlovian processes, we conducted two experiments involving two manipulations that affect conditioning intensity in classical conditioning procedures: time of joint exposure to the conditioned and the unconditioned stimulus, and the length of the inter-stimulus interval (ISI). ...[more]

PMID: 34276319

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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.

Project description:Background/objectivesAntipsychotic medicines are used to treat several psychological disorders and some symptoms caused by dementia and schizophrenia. Haloperidol (Hal) is a typical antipsychotic usually used to treat psychosis; however, its use causes motor or extrapyramidal symptoms (EPS) such as catalepsy. Hal blocks the function of presynaptic D2 receptors on cholinergic interneurons, leading to the release of acetylcholine (ACh), which is hydrolyzed by the enzyme acetylcholinesterase (AChE).MethodsThis study was designed to investigate the Hal-inhibitory effects on AChE activity in regions representative of the cholinergic system of mice and potential associations between cataleptic effects generated by Hal using therapeutic doses and their inhibitory effects on AChE.ResultsThe distribution of the AChE activity in the different regions of the brain followed the order striatum > hippocampus > (prefrontal cortex/hypothalamus/ cerebellum) > brainstem > septo-hippocampal system. In ex vivo assays, Hal inhibited AChE activity obtained from homogenate tissue of the striatum, hippocampus, and septo-hippocampal system in a concentration-dependent manner. The inhibitory concentration of 50% of enzyme activity (IC50) indicated that the septo-hippocampal system required a higher concentration of Hal (IC50 = 202.5 µmol·L-1) to inhibit AChE activity compared to the striatum (IC50 = 162.5 µmol·L-1) and hippocampus (IC50 = 145 µmol·L-1). In in vivo assays, male Swiss mice treated with concentrations of Hal higher than 0.1 mg·kg-1 induced cataleptic effects. Positive correlations with Spearman's correlation were observed only between the lack of cataleptic effect and the decreased AChE activity of the hippocampus in the mice treated with 0.01 mg·kg-1 of Hal but not in the striatum and septo-hippocampal system.ConclusionsOur results suggest that Hal could increase cholinergic effects via AChE inhibition, in addition to its dopamine antagonist effect, as an alternative approach to the treatment of behavioral disturbances associated with dementia.

Dataset Information

Temporal Factors Modulate Haloperidol-Induced Conditioned Catalepsy.

Publications

Temporal Factors Modulate Haloperidol-Induced Conditioned Catalepsy.

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