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.

Cyclosomatostatin-induced catalepsy in aged rats: Specific change of brain c-Fos protein expression in the lateral entorhinal cortex.

Aging represents the largest risk factor for developing Parkinson's disease (PD); another salient feature of this disorder is a decreased brain levels of somatostatin. Recently, in aged Wistar rats, we simulated the central somatostatinergic deficiency by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin (cSST). The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease; young animals were insensitive to cSST. The neuroanatomical substrates responsible for the increased cataleptogenic activity of cSST in aged animals, are currently unknown. To study this issue, we assessed the cSST effect on brain c-Fos-protein expression in aged and young rats; thirty three brain regions were examined. cSST was employed at the dose cataleptogenic for aged animals and non-cataleptogenic for young ones. c-Fos expression patterns in the 'cataleptic' and 'non-cataleptic' animals were very similar, with the only distinction being a decrease in the c-Fos expression in the aged lateral entorhinal cortex (LEntCx). This decrease was not observed when the cSST-induced cataleptic response was inhibited by administration of diphenhydramine and nicotine. Thus, the development of catalepsy in the aged Wistar rats appeared to be associated with a hypoactivation of the LEntCx; possibly, there exists a mechanistic link between the LEntCx hypoactivation and increased susceptibility of aged rats to catalepsy. Apparently, these findings may provide novel insight into the link between mechanisms of parkinsonian motor disorders and aging.

Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and Δ9 -tetrahydrocannabinol.

BACKGROUND AND PURPOSE: Memantine and marijuana smoking have been found to inhibit tremor in parkinsonian patients, although the observed effects were relatively weak. The tremorolytic effects of combinations of memantine and cannabinoids have not been studied. Here, we have evaluated the anti-tremor activity of memantine, Δ9 -tetrahydrocannabinol (THC) given alone and of their combination. The involvement of some neuroanatomical structures in the effects of the combination was evaluated. EXPERIMENTAL APPROACH: Haloperidol-induced tremulous jaw movements (TJMs) in rats were used as a model of parkinsonian-like tremor. To evaluate the role of central receptor systems in the drug effects, receptor ligands were administered locally into certain brain areas. KEY RESULTS: Memantine and THC alone were without effect, although co-administration of these drugs decreased the number of haloperidol-induced jaw movements. The anti-tremor activity of the combination was antagonized (a) by injections of l-glutamate into the dorsal striatum, entopeduncular nucleus, substantia nigra pars reticulata, globus pallidus, and supratrigeminal and trigeminal motor nuclei but not into the subthalamic and cuneiform nuclei; (b) by injections of CGS 21680 into the ventrolateral striatum; and (c) by injections of bicuculline into the rostral part of the parvicellular reticular nucleus. CONCLUSIONS AND IMPLICATIONS: Memantine and THC supra-additively inhibit haloperidol-induced TJMs, suggesting that co-administration of these drugs might be a new approach to the treatment of tremor. Our results identified brain areas influencing parkinsonian-like tremor in rats and can help advance the development of novel treatments for repetitive involuntary movements.

Antidepressants upregulate c-Fos expression in the lateral entorhinal cortex and hippocampal dorsal subiculum: Study in rats.

Neural circuits involved in the development of depression are currently poorly understood. To provide insight into this issue, we evaluated the influence of seven clinically effective antidepressants on neuronal activity in thirty rat brain areas. Drugs belonging to all major groups of antidepressants (imipramine, reboxetine, fluoxetine, bupropion, mirtazapine, agomelatine, and phenelzine) were examined; since antidepressants typically require weeks of continued administration before they achieve a therapeutic effect, we administered these drugs for 21 days. The experiments were conducted with male Wistar rats. To identify the neuroanatomical targets for antidepressants, the alterations of c-Fos expression in different brain areas were measured using ELISA assay. The drugs were examined at doses sufficient to produce behavioral effect in the rat forced swim test (FST). All the drugs at the behaviorally relevant doses activated two brain areas, the lateral entorhinal cortex and dorsal subiculum of the hippocampus; none of the drugs affected the c-Fos expression in the medial orbital, prelimbic and infralimbic cortex, caudate putamen, nucleus accumbens core, bed nucleus of stria terminalis, hipothalamic paraventricular nucleus, medial amygdaloid nucleus, lateral habenula, substantia nigra pars compacta and pars reticulata, ventral tegmental area, hippocampal ventral subiculum, dorsal and ventral periaqueductal gray matters, and medial entorhinal cortex. These findings suggest that the stimulation of the lateral entorhinal cortex and hippocampal dorsal subiculum play a role in therapeutic effects of antidepressants.

Synergistic anticataleptic effect of imipramine and nicotine in a rotenone-induced rat model.

RATIONALE: Some antidepressants have been previously found to produce anti-parkinsonian effect; nicotine was known to mitigate experimental neurotoxic lesions. The anticataleptic efficacy of antidepressant-nicotine co-administration is unstudied. OBJECTIVES: This work aimed to evaluate anticataleptic action of imipramine-nicotine combination in rotenone model. METHODS: Catalepsy was measured by the bar test. Concentrations of tyrosine hydroxylase, dopamine, and DOPAC were determined in the substantia nigra and dorsal striatum using ELISA and HPLC techniques; additionally, dopamine/DOPAC ratio was calculated for both areas. RESULTS: Imipramine and nicotine alone were ineffective; however, co-administration of the drugs significantly (p < 0.01) inhibited rotenone-induced catalepsy and mitigated neurochemical changes in the nigrostriatal system. Anticataleptic effect of the combination exceeded that of levodopa, a standard drug for anti-parkinsonian treatment. CONCLUSION: The combined use of imipramine and nicotine at relatively low doses inhibits neurotoxin-induced catalepsy and nigrostriatal neurochemical changes. The co-administration of these drugs might be a new approach to the treatment of extrapyramidal dysfunctions.

Cetirizine and thalidomide synergistically inhibit mammary tumorigenesis and angiogenesis in 7,12-dimethylbenz(a)anthracene-treated rats.

OBJECTIVE: Cetirizine (CET) and thalidomide (THA) have been previously found to influence angiogenesis. The present study aimed to assess the ability of these drugs to influence mammary carcinogenesis in rats. MATERIALS AND METHODS: Sixty Sprague-Dawley female rats, aged 8 weeks, received 15 mg of 7,12-dimethylbenz(a)anthracene (DMBA) intragastrically. CET and THA (1.0 and 3.0 mg/kg, respectively) were administered orally for 118 days after DMBA administration. At the end of the treatment period, mammary tumors were counted and weighed, and their morphology was analyzed using light microscopy. In tumor tissue, proliferation and apoptotic indices and microvessel density were determined using immunohistochemical techniques; the levels of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, were measured by western blotting. RESULTS: CET and THA, administered separately, failed to influence tumor formation and angiogenesis. In contrast, the drug combination decreased latency to first tumor (significant difference from vehicle-treated control and groups that received either drug alone, P<0.01) and significantly lowered tumor number per rat, number of malignant tumors per rat, tumor burden, and tumor number per tumor-bearing animal (P<0.05 or <0.01). In tissue of malignant tumors, the drug combination decreased the number of proliferating cells, microvessel density, and levels of vascular endothelial growth factor and basic fibroblast growth factor and stimulated apoptosis (difference from all other groups, P<0.01). CONCLUSION: It was shown for the first time that H1-antagonist and THA synergistically inhibit DMBA-induced mammary carcinogenesis; this effect was associated with a decrease in tumor angiogenesis. Further study of the anticancer and antiangiogenic activity of the combination may provide a new approach to breast cancer treatment.

Cyclosomatostatin- and haloperidol-induced catalepsy in Wistar rats: Differential responsiveness to sleep deprivation.

Total sleep deprivation (SD) has been found to mitigate motor dysfunctions in Parkinson's disease. Apparently, the similar sensitivity of an animal model for parkinsonism would support the model's validity. Recently, we described catalepsy induced in Wistar rats by somatostatin antagonist, cyclosomatostatin (cSST); this model simulates such a disease-associated abnormality as a fall in brain somatostatin levels. To evaluate the similarity between the cSST model and Parkinson's disease, we assessed here the responsiveness of cSST-induced catalepsy to 1-h and 3-h SD. In parallel, the influence of SD on catalepsy induced by a dopamine receptor antagonist, haloperidol, was examined. It was found that the short-term SD failed to influence cataleptic responses of both types (sleep deprived rats and undisturbed ones displayed a similar duration of immobility, p > 0.05). By contrast, 3-h SD suppressed (p < 0.01) cSST-induced catalepsy, however, enhanced (p < 0.01) cataleptic response to haloperidol. Thus, the anti-cataleptic effect of SD appears to be cSST-specific. These findings support the validity of the cSST-induced catalepsy in Wistar rats as a model for parkinsonian motor dysfunctions.

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 induces catalepsy in the aged rat.

RATIONALE: 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 brain somatostatin deficiency and aging. OBJECTIVES: This study aimed to examine whether an inhibition of the brain somatostatin system can initiate catalepsy, a model of extrapyramidal disorders, in young and aged rats. METHODS: The animals of 100-110 and 540-560 days of age were used. Catalepsy was measured using the bar test. The inhibition of the brain somatostatin activity was simulated by intracerebroventricular administration of a somatostatin antagonist, cyclosomatostatin. RESULTS: Cyclosomatostatin dose-dependently induced catalepsy in aged, but not in young rats. The cataleptic response was reversed by a somatostatin analog, octreotide. CONCLUSIONS: 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.

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.

Coadministration of bicuculline and NMDA induces paraplegia in the rat.

Motor neurons (MNs) of an adult rat are normally insensitive to the neurotoxic action of NMDA. Meanwhile, the experiments in non-motor neurons showed that sensitivity to NMDA can be increased by bicuculline, an antagonist at GABA(A) receptors. The aim of the present work was to examine whether bicuculline would produce such an effect in the adult MNs. In adult Wistar rats, intrathecal injection of bicuculline and NMDA individually failed to affect motor activity of the extremities. In contrast, bicuculline-NMDA combination dose-dependently impaired hindlimb functions. At the 9th day after injections of the combination, a paraplegia with persistent bilateral spastic extension developed in all animals. Light microscopic assessment showed that the development of the motor deficit is associated with pathological changes in spinal motor neurons (swelling, accumulation of the Nissl substance near nucleus, hyperchromatosis, shrinkage, and chromatolysis), mainly in the lumbar ventral horns. Additionally, distinct abnormalities were observed in the white matter of the lumbar cords. The bicuculline-NMDA combination induced a loss of spinal cord MNs while sparing the dorsal horn neurons. The effects of the combination were reversed by muscimol, a GABA(A) agonist. Thus, an inhibition of GABA(A)ergic processes can induce NMDA sensitivity in adult MNs. The present data may provide new insights into the mechanism of motor disorders in amyotrophic lateral sclerosis and other states wherein the combination of glutamatergic overstimulation and GABA(A)ergic understimulation takes place.