Somatostatin antagonist induces catalepsy in the aged rat

Ionov, Ilya D.; Pushinskaya, Irina I.

doi:10.1007/s00213-012-2961-0

Cited by 15 publications

(23 citation statements)

References 28 publications

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“…As shown there, cycloSOM initiates cataleptic response at the dose of 10 µg, while smaller doses are inactive (8). Similar results were obtained in the present work, wherein cycloSOM at the doses of 0.2 -5.0 µg had no effects.…”

Section: Discussionsupporting

confidence: 92%

“…CycloSOM at the doses of 0.2, 1.0, 5.0, and 10.0 µg and histamine at the doses of 1.0 and 10.0 µg were administered intracerebroventricularly (i.c.v.). The doses were selected according to the previous studies (8,13).…”

Section: Drugsmentioning

confidence: 99%

“…In old Wistar rats, an inhibition of brain SOM receptors can produce catalepsy (8), an animal model of parkinsonian bradykinesia and rigidity. In light of these data, it appears that brain SOM deficiency may be of pathogenic relevance in PD.…”

Section: Introductionmentioning

confidence: 99%

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Histamine Potentiates Cyclosomatostatin-Induced Catalepsy in Old Rats

Ionov¹,

Turgeneva²

2015

Avicenna J Neuro Psych Physio

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Background:The decreased level of somatostatin and increased level of histamine are detected in the Parkinsonian brain. In old Wistar rats, the brain somatostatin deficiency can initiate catalepsy that suggests the pathogenic significance of this abnormality in Parkinson's disease (PD). The ability of histamine to affect the somatostatin deficiency action is not studied. Objectives: The current study aimed to examine if histamine alters the cataleptogenic activity of the brain somatostatin deficiency in Wistar rats. Materials and Methods:The animals used in the study were 100 -110 and 736 -767 days old. Catalepsy was evaluated by the bar test. The inhibition of the brain somatostatin activity was simulated by I.C.V. administration of cyclosomatostatin (cycloSOM), a somatostatin receptor antagonist. Results: CycloSOM (0.2, 1.0, and 5.0 µg) and histamine (1.0 and 10.0 µg) alone were ineffective in both young and old animals. In combination, however, cycloSOM and histamine initiated cataleptic response in old rats. Effect of the combination was inhibited by H1 and H2 but not H3 antagonists. Conclusions: CycloSOM and histamine synergistically exert catalepsy in old rats. In light of these data, the combination of the decreased brain level of somatostatin and increased brain level of histamine may be of pathogenic relevance for extrapyramidal signs in PD.

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Section: Discussionsupporting

confidence: 92%

Section: Drugsmentioning

confidence: 99%

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Histamine Potentiates Cyclosomatostatin-Induced Catalepsy in Old Rats

Ionov¹,

Turgeneva²

2015

Avicenna J Neuro Psych Physio

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“…We found that HAL increased the duration of cataleptic episodes, an often used marker of APD side-effects (Ionov et al, 2013), in a dose-dependent manner in both young and aged mice. However, the severity of cataleptic episodes is increased in aged mice, consistent with previous reports (Barnes et al 1990; Campbell et al 1988; Wiley and Evans 2008).…”

Section: Discussionmentioning

confidence: 74%

Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice

et al. 2017

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Background Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. Methods In this study, we treated young (2–3 months old) and aged (22–24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL. Results Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone trimethylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter. Conclusions These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.

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“…One of the iPD-associated brain abnormalities is a fall in somatostatin levels (for refs., see [8,9]). These changes may be of pathogenic importance as somatostatin can stimulate dopaminergic neurotransmission [10][11][12].…”

Section: Introductionmentioning

confidence: 98%

Cyclosomatostatin-induced catalepsy in the aged rat: a response to levodopa, diphenhydramine and nicotine

Ionov¹,

Pushinskaya²,

Gorev³

2018

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A decrease in somatostatin level is observed in parkinsonian brain. We recently reported that rats given an intracerebroventricular injection of a somatostatin antagonist, cyclosomatostatin, fall into catalepsy; the effect was observed in aged but not young animals. To evaluate the predictive validity of the cyclosomatostatin-induced catalepsy as a model of extrapyramidal disorders, the sensitivity of this catalepsy to clinically effective antiparkinsonian agents was determined. We examined the effects of levodopa and histamine antagonists; also, given an inverse association between Parkinson's disease and tobacco smoking, nicotine was tested. The experiments were conducted using 27-28month-old male Wistar rats. Catalepsy was measured using the bar test. Cyclosomatostatin-induced catalepsy was strongly antagonized by levodopa, which indicates a role for central dopaminergic deficiency in this model. Similarly, histamine H 1receptor antagonist, diphenhydramine, exhibited anticataleptic activity; in contrast, antagonists at H 2and H 3 -receptors were without effect. Cataleptic response was inhibited by nicotine; the nicotine sensitivity distinguishes this catalepsy from other models, in particular, from haloperidol-induced catalepsy. Diphenhydramine and nicotine alone only partly suppressed catalepsy; however, coadministration of these drugs almost totally reversed the cataleptogenic effect of cyclosomatostatin.Thus, a similarity between the cyclosomatostatininduced catalepsy and Parkinson's disease with regard to the sensitivity to anti-parkinsonian agents was found. This supports the validity of the model as well as the role of somatostatinergic deficiency in the mechanism of parkinsonian symptoms. Coadministration of diphenhydramine and nicotine appears to be a promising treatment for extrapyramidal disorders in Parkinson's disease.

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Somatostatin antagonist induces catalepsy in the aged rat

Abstract: The combination of aging and brain somatostatin deficiency can lead to catalepsy in rats. Since both factors are frequently observed in PD patients, the present results might be of relevance for pathogenesis of extrapyramidal signs in this disease.

Cited by 15 publications

References 28 publications

Histamine Potentiates Cyclosomatostatin-Induced Catalepsy in Old Rats

Histamine Potentiates Cyclosomatostatin-Induced Catalepsy in Old Rats

Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice

Cyclosomatostatin-induced catalepsy in the aged rat: a response to levodopa, diphenhydramine and nicotine

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