Activation of pallidal H2 receptors induces catalepsy in Wistar rats: A regulatory role of CRF1 receptors.

An increased concentration of histamine was found in the globus pallidus of parkinsonian patients. The role of this abnormality in the development of parkinsonism is unclear. We examined cataleptogenic activity of histamine injected into the globus pallidus (GP); also, the role of H2 receptors in histamine effect was evaluated. Given a possible role of the GP in integration and processing of stress signals, we tested the involvement of CRF1 receptors in the regulation of histamine effect. The experiments were conducted with male Wistar rats, catalepsy was assessed using bar test. The entopeduncular nucleus (EPN) was used as a neuroanatomical control. Intrapallidal injections of histamine (1.0 and 10.0 µg) produced clear cataleptic response whereas intra-EPN injections were ineffective. Histamine-induced catalepsy was dose-dependently attenuated by H2 receptor antagonist ranitidine and CRF1 receptor antagonist NBI 35965. The results suggest the involvement of pallidal H2 and CRF1 receptors in the development of catalepsy in rats. These findings may provide novel insight into the mechanism of parkinsonian-like disorders. In light of the presented data, H2 and CRF1 receptors might be potential targets for therapy of parkinsonism.

Histamine H1 receptors regulate anhedonic-like behavior in rats: Involvement of the anterior cingulate and lateral entorhinal cortices.

A decreased H1 receptor activity is observed in the anterior cingulate cortex (aCgCx) of depressed patients. The role of this abnormality in the development of depression-related processes is unstudied. We examined the influence of a decreased brain H1 receptor activity on rat behavior in the sucrose preference test. The H1 receptor deficit was simulated by injection of an H1 antagonist into the aCgCx; also, two aCgCx projection areas, lateral and medial entorhinal cortices were examined. A blockade of H1-receptors in the aCgCx and lateral entorhinal cortex (LEntCx) significantly reduced sucrose preference. These findings suggest the existence of H1 receptor-mediated aCgCx-LEntCx circuitry mechanism regulating anhedonic-like behavior in rats. The presented data suggest that H1 receptor-mediated processes might be a therapeutic target in depressive disorders.

Anticataleptic activity of nicotine in rats: involvement of the lateral entorhinal cortex.

RATIONALE: Recently, it was found that cyclosomatostatin-induced catalepsy in middle-aged rats is accompanied by neuronal hypoactivation in the lateral entorhinal cortex (LEntCx); this hypoactivation was reversed by systemic administration of nicotine combined with diphenhydramine. These findings suggest the ability of nicotine to regulate catalepsy and the involvement of the LEntCx in this nicotine effect. OBJECTIVES: The study was aimed to assess whether nicotine alone influences catalepsy when injected into the LEntCx and some other neuroanatomical structures. METHODS: Experiments were conducted with male Wistar rats of 540-560 days of age. Catalepsy was induced by intracerebroventricular injection of cyclosomatostatin and assessed by the standard bar test. Nicotine was injected into the LEntCx, prelimbic cortex (PrCx), or basolateral amygdala (BLA). The tissue levels of tyrosine hydroxylase, dopamine, and DOPAC in the substantia nigra pars compacta and dorsal striatum were measured with use of HPLC and ELISA. RESULTS: Injections of nicotine into the LEntCx but not into the PrCx and BLA produced anticataleptic effect; the nicotine effect was significantly reversed by intra-LEntCx administration of NMDA and non-NMDA glutamate receptor antagonists. Nicotine also attenuated cataleptogen-induced changes in nigrostriatal dopamine metabolism. CONCLUSIONS: This may be the first demonstration of anticataleptic activity of nicotine. The results show that the effect is mediated by nicotine receptors in the LEntCx, via a glutamatergic mechanism. These findings may help advance the development of novel treatments for extrapyramidal disorders, including parkinsonism.

Brain sites mediating cyclosomatostatin-induced catalepsy in Wistar rats: A specific role for the nigrostriatal system and locus coeruleus.

A decrease in somatostatin activity is observed in the Parkinsonian brain. In recent experiments on rats, we simulated this abnormality by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin. The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease. The neuroanatomical substrates mediating the catalepsy-inducing effect of cyclosomatostatin are unknown. To clarify this issue, we assessed here the action of cyclosomatostatin injected into the substantia nigra pars compacta (SNc), dorsal striatum (DS), locus coeruleus (LC), pedunculopontine tegmental nucleus (PPTg), and inferior colliculus (IC). The experiments were conducted with male Wistar rats of 270-290 g bw, catalepsy was evaluated by using the bar test. The injections into the PPTg and IC were without effect whereas the intra-SNc, intra-DS, and intra-LC administrations produced distinct cataleptic response. Thus, it was shown for the first time that the LC is a brain center capable of causing catalepsy. These data provide new insights into the neuroanatomical organization of the catalepsy-initiating mechanism and suggest the LC representing a potential target for therapeutic manipulations of extrapyramidal dysfunctions.

Somatostatin antagonist potentiates haloperidol-induced catalepsy in the aged rat.

Extrapyramidal motor signs are the major features of Parkinson's disease (PD). It is unclear whether there is a link between these signs and such PD-associated factors as aging and somatostatin deficiency. In this study, the intensity of haloperidol-induced catalepsy was examined in young and aged rats with decreased brain somatostatinergic activity. Catalepsy was measured using the bar test. The inhibition of the brain somatostatin activity was simulated by i.c.v. administration of a somatostatin antagonist, cyclosomatostatin. The drug potentiated the haloperidol-induced catalepsy in aged but not young rats. This action of cyclosomatostatin was inhibited by a somatostatin receptor agonist, octreotide. The results suggest that aging and somatostatin deficiency may be of pathogenic relevance for extrapyramidal signs in PD.

Histamine- and haloperidol-induced catalepsy in aged mice: differential responsiveness to L-DOPA.

RATIONALE: In rodents and dog, histamine induces catalepsy, a dopamine-dependent phenomenon that resembles the extrapyramidal signs of Parkinson's disease (PD). Histamine was also found to damage the dopaminergic neurons in rat substantia nigra. These facts, as well as an increase in brain histamine levels in Parkinsonian patients, suggest a pathogenic role for histamine in PD. As it seems, a comparison between pattern of experimental brain histamine toxicity and signs of PD would elucidate the role of histamine in PD pathogenesis. OBJECTIVE: This study aimed to examine whether mouse histamine-induced catalepsy shares such age-related traits of PD as disease aggravation and underresponsiveness to 3,4-dihydroxy-L: -phenylalanine (L: -DOPA) in aged patients. For comparison purposes, haloperidol-induced catalepsy was studied. METHODS: The intensity of catalepsy was measured as the time the mouse maintained an abnormal posture. The cataleptogens, histamine or haloperidol, were administered intracerebroventricularly and subcutaneously, respectively. RESULTS: The cataleptogenic activity of histamine was significantly higher in 18-19-month-old and 22-23-month-old mice than 3-4-month-old ones. Aging was found to decrease the responsiveness of the histamine-induced catalepsy to L: -DOPA. The intensity of the haloperidol-induced catalepsy and its sensitivity to L: -DOPA were found independent of the animal's age. CONCLUSIONS: The mouse histamine-induced catalepsy, unlike haloperidol-induced one, displays the same pattern of age dependency as PD. These findings support an involvement of histamine in the PD pathogenesis.