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ABSTRACT: Rolipram, a specific phosphodiesterase 4 inhibitor (PDE4), is suggested to facilitate functional recovery following brain injury by activation of cAMP/CREB pathway. We examined the effect of rolipram on sensorimotor recovery in rats following transient occlusion of the middle cerebral artery (MCAO).
Rats were subjected to transient MCAO for 2 h. Rolipram was administered at a dose of 0.1 or 1 mg/kg (i.p., twice a day, for 13 days) starting administration on postoperative day 2. Sensorimotor outcome was assessed using limb-placing, beam-walking and cylinder tests at baseline and 7, 14, and 21 days after MCAO.
Rolipram decreased locomotor activity and rearing, produced atypical head twitches, and possible hyperalgesia immediately after treatments, which were all considered as acute side effects. The analysis of hindlimb function utilizing beam-walking tests showed that overall performance was impaired in MCAO vehicle rats (p < 0.01) and MCAO rats treated with rolipram, at a dose of 0.1 mg/kg (p < 0.01), compared to sham-operated rats. Interestingly, MCAO rats treated with rolipram at a dose of 1.0 mg/kg had significantly fewer slips when traversing an elevated beam than those treated with a dose of 0.1 mg/kg (p < 0.05) indicating improved sensorimotor function. More importantly, hindlimb function at the higher rolipram dose was not different from sham-operated rats after cessation of drug treatment at day 21. There was a significant group effect (p < 0.001) in the cylinder test, however, this was due to the decreased use of the impaired forelimb in MCAO rats compared to sham-operated rats at day 7, 14 and 21. In addition, MCAO rats treated with rolipram seemed to use their impaired forelimbs less compared to MCAO controls. Limb-placing performance was severely impaired but not different among MCAO rats.
The present data suggest that rolipram provides some improvement in sensorimotor recovery in MCAO rats possibly by augmenting cAMP/CREB signalling, but this is masked by its side effects.
Restorative neurology and neuroscience 02/2008; 26(6):493-9. · 2.51 Impact Factor
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ABSTRACT: Atipamezole is an alpha2-adrenoceptor antagonist with an imidazole structure. Receptor binding studies indicate that its affinity for alpha2-adrenoceptors and its alpha2/alpha1 selectivity ratio are considerably higher than those of yohimbine, the prototype alpha2-adrenoceptor antagonist. Atipamezole is not selective for subtypes of alpha2-adrenoceptors. Unlike many other alpha2-adrenoceptor antagonists, it has negligible affinity for 5-HT1A and I2 binding sites. Atipamezole is rapidly absorbed and distributed from the periphery to the central nervous system. In humans, atipamezole at doses up to 30 mg/subject produced no cardiovascular or subjective side effects, while at a high dose (100 mg/subject) it produced subjective symptoms, such as motor restlessness, and an increase in blood pressure. Atipamezole rapidly reverses sedation/anesthesia induced by alpha2-adrenoceptor agonists. Due to this property, atipamezole is commonly used by veterinarians to awaken animals from sedation/anesthesia induced by alpha2-adrenoceptor agonists alone or in combination with various anesthetics. Atipamezole increased sexual activity in rats and monkeys. In animals with sustained nociception, atipamezole increased pain-related responses by blocking the noradrenergic feedback inhibition of pain. In tests assessing cognitive functions, atipamezole at low doses has beneficial effects on alertness, selective attention, planning, learning, and recall in experimental animals, but not necessarily on short-term working memory. At higher doses atipamezole impaired performance in tests of cognitive functions, probably due to noradrenergic overactivity. Recent experimental animal studies suggest that atipamezole might have beneficial effects in the recovery from brain damage and might potentiate the anti-Parkinsonian effects of dopaminergic drugs. In phase I studies atipamezole has been well tolerated by human subjects.
CNS Drug Reviews 02/2005; 11(3):273-88. · 4.92 Impact Factor
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ABSTRACT: Aging is associated with at least down-regulation of several cellular functions and diminished responsiveness to internal and external signals, and possibly with direct cell death. Consequently, pharmacological manipulations may be less effective in aged than in young organisms. In the present study, we investigated whether the basal forebrain cholinergic neurons and the estrogen receptor alpha (ERalpha) which they contain respond to changes in estrogen availability in aged female mice. The mice were sham-operated, ovariectomized, or ovariectomized and treated with 17beta-estradiol at the age of 18 months. Three months later, the mice were perfused and brain sections were double immunostained for choline acetyltransferase (ChAT) and ERalpha. Cell counting with a stereological method revealed that changes in the estrogen level have no effect on the total number of ChAT-immunoreactive (ir) neurons in the basal forebrain. However, the percentage of ChAT-ir neurons containing ERalpha-ir was higher in the ovariectomized mice than in the sham-operated or estrogen-treated mice. This was specific for the medial septum and vertical diagonal band of Broca. The findings indicate that even at old age the ERalphas in cholinergic cells are able to respond to changes in estrogen levels, though in a region-specific manner. This is naturally important for studies aiming to develop therapies for the elderly.
Brain Research 11/2004; 1022(1-2):148-56. · 2.73 Impact Factor
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ABSTRACT: Overexpression of human alpha-synuclein in model systems, including cultured neurons, drosophila and mice, leads to biochemical and pathological changes that mimic synucleopathies including Parkinson's disease. We have overexpressed both wild-type (WT) and mutant alanine53-->threonine (A53T) human alpha-synuclein by transgenic injection into Caenorhabditis elegans. Motor deficits were observed when either WT or A53T alpha-synuclein was overexpressed with a pan-neuronal or motor neuron promoter. Neuronal and dendritic loss were accelerated in all three sets of C. elegans dopaminergic neurons when human alpha-synuclein was overexpressed under the control of a dopaminergic neuron or pan-neuronal promoter, but not with a motor neuron promoter. There were no significant differences in neuronal loss between overexpressed WT and A53T forms or between worms of different ages (4 days, 10 days or 2 weeks). These results demonstrate neuronal and behavioral perturbations elicited by human alpha-synuclein in C. elegans that are dependent upon expression in specific neuron subtypes. This transgenic model in C. elegans, an invertebrate organism with excellent experimental resources for further genetic manipulation, may help facilitate dissection of pathophysiologic mechanisms of various synucleopathies.
Journal of Neurochemistry 07/2003; 86(1):165-72. · 4.06 Impact Factor
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ABSTRACT: alpha(2)-ARs regulate brain monoaminergic function by inhibiting neuronal firing and release of monoamine neurotransmitters, noradrenaline (NA), serotonin (5-HT) and dopamine (DA). Both alpha(2A)- and alpha(2C)-AR inhibit monoamine release in vitro in brain slices, but the in vivo roles of individual alpha(2)-AR subtypes in modulating monoamine metabolism have not been characterised. Metabolism of brain monoamine neurotransmitters, locomotor activity and body temperature were investigated in mice with targeted inactivation of the gene encoding alpha(2A)-AR (alpha(2A)-knockout, alpha(2A)-KO) and wild-type (WT) mice after treatment with the alpha(2)-AR agonist dexmedetomidine and the antagonist atipamezole. Dexmedetomidine caused profound hypothermia (up to 14.7 degrees C mean reduction in rectal temperature) and locomotor inhibition in WT mice, and inhibited the turnover of NA, 5-HT and DA, but increased NA turnover in alpha(2A)-KO mice. alpha(2)-AR agonist-induced hypothermia and locomotor inhibition were attenuated, but not totally abolished, in alpha(2A)-KO mice. These results suggest that alpha(2A)-ARs are principally responsible for the alpha(2)-AR mediated inhibition of brain monoamine metabolism, but other alpha(2)-ARs, possibly alpha(2C)-ARs, are also involved, especially in the striatum. However, secondary effects of the physiological alterations caused by drug administration, especially hypothermia, may have contributed to the observed neurochemical changes in WT mice.
Neuropharmacology 07/2003; 44(7):882-92. · 4.81 Impact Factor
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ABSTRACT: The activation of 5-HT2A receptors has been shown to enhance the probability of premature responding, regarded as a form of motor impulsive behaviour. At the behavioural level, the interaction of alpha-adrenoceptors and 5-HT2 receptors has been linked to head twitch behaviour, regarded as an experimental model of compulsive behaviour. The aim was to determine whether the probability of premature responding induced by an excess activation of 5-HT2A receptors can be modulated by the blockade of alpha1- or alpha2- adrenoceptors. In the experiments, the 5-choice serial reaction time task was used to measure attention and response control of the rats. The experiments assessed the effects of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) 0.1-0.2 mg/kg subcutaneously, a 5-HT2A/2C agonist, and prazosin, an alpha1-adrenoceptor antagonist, alone or in combination, on the performance of rats. In an additional experiment to examine the possible role of the alpha2-adrenoceptors, a potent, selective and specific alpha2-adrenoceptor antagonist, atipamezole, was given alone or in combination with DOI. Results showed that DOI increased the probability of premature responses, but it did not affect the choice accuracy. Prazosin (0.1 or 0.3 mg/kg, subcutaneously), given on its own had no effects on probability of responding prematurely, but prazosin (0.3 mg/kg.) was able to attenuate the DOI-induced responding. Atipamezole (0.1 mg/kg, s.c.) did not attenuate the effect of DOI on probability of premature responding. When given at lower doses, DOI (0.03 mg/kg) and atipamezole (0.03 mg/kg) synergistically increased the probability of premature responding, whereas a higher dose of atipamezole (0.3 mg/kg) on its own increased the probability of responding prematurely, but this effect was not additive to that of 0.1 mg/kg DOI. These data indicate that 5-HT2 receptor activation enhances impulsive responding and this effect can be diminished by the blockade of alpha1-adrenoceptors. Atipamezole, an alpha2-antagonist, enhances the probability of premature responding and shares the mechanism of action with the 5-HT2 agonist in this respect. These results provide evidence for an interaction between the serotonergic 5-HT2 receptors and alpha-adrenoceptors in the modulation of response control to the motor impulsivity type of behaviour (premature responding) in addition to that of compulsory behaviour (head shakes) found previously.
Pharmacology & Toxicology 06/2003; 92(5):214-25.
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ABSTRACT: The possible effect of atipamezole, a potent and specific alpha(2)-adrenoceptor antagonist, on the development and expression of d-amphetamine-induced behavioural sensitization was evaluated in mice. Male (C57Bl/6J) mice were given daily doses of d-amphetamine (2 mg/kg). In addition, groups of mice received injections of atipamezole (0.3 or 1 mg/kg) 20 min before d-amphetamine or vehicle administration. Idazoxan (1 mg/kg) was used in some experiments to extend the results to other alpha(2)-adrenoceptor antagonists. Challenge doses of d-amphetamine were administered to the mice on days 7-9 to evaluate the effects of alpha(2)-adrenoceptor antagonists on the d-amphetamine sensitization, evidenced by increased locomotor activation. Mice treated repeatedly with d-amphetamine developed strong locomotor sensitization that was reduced by pretreatment with alpha(2)-adrenoceptor antagonists. Acute atipamezole at both doses attenuated the expression of d-amphetamine-induced sensitization. Atipamezole at 1 mg/kg alone had no effect on locomotor activity, but the lower dose (0.3 mg/kg) increased locomotor activity after repeated administration. These results indicate that alpha(2)-adrenoceptor antagonists modulate the actions of d-amphetamine in a manner not explicable by their enhancing actions on noradrenaline and dopamine release, and may thus provide a novel approach to the treatment of motor complications caused by dopaminergic agents, such as dyskinesias, and perhaps also drug dependence.
Archiv für Experimentelle Pathologie und Pharmakologie 04/2003; 367(3):274-80. · 2.65 Impact Factor
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ABSTRACT: The effects of atipamezole, an alpha(2)-adrenoceptor antagonist, L-3,4-dihydroxyphenylalanine (L-DOPA) and the combination of these drugs on dopamine overflow were studied in dopaminergic presynaptic terminals of rat caudate and nucleus accumbens. Dopamine overflow evoked by 100 pulses of electrical stimulation of the medial forebrain bundle at a low (20 Hz) and high (50 Hz) frequency was measured by in vivo voltammetry. L-DOPA (15 mg/kg) increased dopamine overflow in the caudate nucleus, but this dose had no effects in the nucleus accumbens. Atipamezole (300 microg/kg) had no effects on its own on dopamine overflow, but it did increase the size of the readily releasable storage pool and the effects of L-DOPA treatment in both structures. The combination of the drugs increased dopamine overflow to a larger extent at high compared to low stimulation frequencies. We conclude that the rat caudate nucleus is more sensitive than the nucleus accumbens to the effects of L-DOPA, and the effects of L-DOPA treatment might be effectively enhanced by antagonism of alpha(2)-adrenoceptors.
European Journal of Pharmacology 03/2003; 462(1-3):83-9. · 2.52 Impact Factor
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ABSTRACT: Overexpression of human a-synuclein in model systems, including cultured neurons, drosophila and mice, leads to biochemical and pathological changes that mimic synucleo-pathies including Parkinson's disease. We have over-expressed both wild-type (WT) and mutant alanine53 fi threonine (A53T) human a-synuclein by transgenic injection into Caenorhabditis elegans. Motor deficits were observed when either WT or A53T a-synuclein was overexpressed with a pan-neuronal or motor neuron promoter. Neuronal and dendritic loss were accelerated in all three sets of C. elegans dopaminergic neurons when human a-synuclein was over-expressed under the control of a dopaminergic neuron or pan-neuronal promoter, but not with a motor neuron promoter. There were no significant differences in neuronal loss between overexpressed WT and A53T forms or between worms of different ages (4 days, 10 days or 2 weeks). These results demonstrate neuronal and behavioral perturbations elicited by human a-synuclein in C. elegans that are dependent upon expression in specific neuron subtypes. This transgenic model in C. elegans, an invertebrate organism with excellent experimental resources for further genetic manipu-lation, may help facilitate dissection of pathophysiologic mechanisms of various synucleopathies. Synucleopathies represent a large range of neuropatholog-ically defined conditions that include Parkinson's disease (PD), dementia with Lewy bodies, Pick's disease and multiple system atrophy (Spillantini et al. 1997, 1998; Baba et al. 1998; Takeda et al. 1998). PD is a neurode-generative disorder that affects 1% of the population over the age of 50 years. PD neurodegeneration is found predominantly in dopaminergic neurons of the substantia nigra where the pathological hallmark is the appearance of intracellular inclusions termed Lewy bodies. These bodies consist of protein complexes that include neurofilaments, ubiquitin and a-synuclein (Forno 1996 2 ; Spillantini et al. 1997). Rare familial forms of PD have provided an opportunity to understand the pathophysiologic mechanisms of this disease and at least eight PD loci have been identified (Lansbury and Brice 2002). Autosomal dominant forms of PD have been linked to mutations in a-synuclein.
J. Neurochem. 01/2003; 86:165-172.
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ABSTRACT: The present study examined whether housing in an enriched environment affects hippocampal function in responding to the challenge of a spatial water maze task in naive rats and following transient global ischemia. The enriched-environment housing was used for 11 days and was instituted the day after the induction of 20-min ischemia. Thereafter, the rats were tested in the water maze. The function of hippocampal neurons was assessed by Fos-immunostaining in ischemic and sham-operated rats 3 h after water maze testing. Rats housed in an enriched environment had an increased number of Fos-positive neurons per section in the granule cell layer of the dentate gyrus compared to rats housed individually in standard cages. This increase was observed in both ischemic and sham-operated rats. The experimental groups showed no differences in the number of Fos-positive cells in different hippocampal areas when the rats were placed in the enriched environment for the same period without the learning task. These results suggest that the number of neurons responding with altered gene expression in the dentate gyrus is increased in rats housed in an enriched environment following training in a water maze task. The altered gene expression is also preserved in ischemic rats.
Neuropharmacology 04/2001; · 4.81 Impact Factor
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ABSTRACT: Purpose: The present study investigated the effects of fluoxetine, a serotonin reuptake blocker, on behavioral deficits of rats subjected to transient focal cerebral ischemia. Methods: The right middle cerebral artery of rats was occluded for 120 min using the intraluminal filament method. Fluoxetine treatment (5 mg/kg, i.p.) was started 2 days after ischemia induction and treatment was continued for 10 days thereafter. Sensorimotor recovery was assessed using the limb-placing test and cognitive impairment was assessed using a water-maze test at the end of the experiment. Results: Fluoxetine treatment did not improve performance of ischemic rats in the limb-placing test. Nor was the ischemia-induced deficit in the water-maze test affected by fluoxetine. The infarct volumes in the cortex or striatum, determined after the experiment, were not different between ischemic groups. Conclusion: These results suggest that subchronic fluoxetine treatment following experimental focal cerebral ischemia is not detrimental to behavioral outcome, but it also does not enhance spontaneous sensorimotor recovery or attenuate spatial learning deficits.
Restorative neurology and neuroscience 02/2000; 17(4):211-216. · 2.51 Impact Factor
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ABSTRACT: WE have investigated the expression of the mRNAs for brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in the hippocampus before and after induction of long term potentiation (LTP) of synaptic transmission in the dentate gyrus through stimulation of the perforant path (PP). A unilateral PP stimulation produced a bilateral increase in the mRNA for both BDNF and NGF in granular neurones of the dentate gyrus but not in other neurones in the hippocampus. The mRNA for neurotrophin-3 (NT-3) was bilaterally decreased by LTP but that of NT-4 remained at the basal level. These results suggest that individual neurotrophic factors may play different roles in neuronal plasticity.
(C) Lippincott-Raven Publishers.
Neuroreport 06/1993; 4(7). · 1.66 Impact Factor
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ABSTRACT: Previous studies have suggested that carbamazepine (CBZ), a potent antiepileptic drug, affects the somatostati-nergic system in humans and animals; but the results have been contradictory. In the present study we further evaluated the effect of CBZ administration on somatostatin-like immunoreactivity (SLI) in cisternal cerebrospinal fluid (CSF) and in different areas of the rat brain. Somatostatin receptor binding in the cortex of CBZ-treated rats was also studied. Two hours after administration of CBZ at a dose of 30 mg/kg intraperitoneally, which resulted in a serum CBZ concentration of 64 μM, the SLI in CSF was lower than in vehichle-injected controls (P = 0.024, MANOVA). In the hippocampus SLI was elevated to 132% that of vehicle-injected controls (P = 0.016, Mann-Whitney U-test). At a dose of 15 mg/kg a slight decrease in SLI was seen in CSF compared to vehicle-injected controls (P = 0.034, MANOVA) but no change was observed in the hippocampus. After administration of CBZ for 7 days (30 mg/kg intraperitoneally twice a day) we were not able to demonstrate any definitive change in SLI of rat CSF (MANOVA). In these rats the SLI in the hypothalamus was elevated compared to vehicle-injected controls (132%, P = 0.016, Mann-Whitney U-test). In experiments with both acute and chronic administration of CBZ, the somatostatin receptor binding was unchanged. The present study suggests that administration of CBZ only slightly affects the somatostatinergic system in the rat brain.
Pharmacology & Toxicology 02/1989; 64(3):266 - 271.
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ABSTRACT: The present experiments were carried out in order to study the interaction between alpha2-noradrenergic and muscarinic systems in regulating high voltage spindle (HVS) activity in neocortex. Alpha2-antagonist (atipamezole 1 and 10 mg/kg) blocked HVS activity. Atipamezole at 0.1 mg/kg dose had no effect on HVS activity. Alpha2-agonist (guanfacine 0.004, 0.02 and 0.1 mg/kg) increased dose dependently HVSs. Guanfacine-induced HVSs were blocked by nucleus reticularis (NRT) lesions and by stimulation of either noradrenergic or cholinergic (pilocarpine) systems. Moreover, combined injections of atipamezole 1 mg/kg and pilocarpine 3 mg blocked HVSs more effectively than either of the drugs alone. Our results suggest that the NRT is jointly modulated by the noradrenergic and cholinergic afferents.
Brain Research Bulletin.
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ABSTRACT: The behavioral effects of amygdala kindling, a model of experimental epilepsy in rats, are reported. The animals were stimulated twice a day until stage 5 (generalized clonic) seizures were obtained three times. Two weeks later the performance of the amygdalakindled and sham-operated rats was tested in the open-field test, on the elevated plus maze, elevated bridges, and in the Morris water maze. The results show that amygdala kindling decreased exploratory and other motor activity in the open-field test, had anxiogenic effects on the elevated plus-maze, decreased boldness on the elevated bridges, but had a negligible affect in the spatial memory task. These results suggest that amygdala kindling affects the normal fear reaction of rats, a response that is known to be mediated through the amygdaloid pathways.
Physiology & Behavior.
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ABSTRACT: The present experiments investigated the effects of a specific and potent α2-adrenoceptor antagonist, atipamezole (as a stimulator of the noradrenergic system) on cognitive performance in rats. Atipamezole enhanced the acquisition of a linear-arm maze test and also improved the choice accuracy of poorly performing rats in a delayed (20 min) three-choice maze test. Furthermore, atipamezole improved the achievement of a one-trial appetite-maze when injected immediately after teaching, thus having an effect on consolidation. Atipamezole clearly impaired the acquisition of the active avoidance test. The present results indicate that stimulation of noradrenergic system by atipamezole improves the performance of animals in tasks assessing relational learning and memory, possibly affecting attention, short-term memory and the speed of information processing. It has also an effect on a consolidation process unrelated to attentional or motivational mechanisms. In a stressful test, stimulation of noradrenaline release leads to impairment of performance.
European Journal of Pharmacology.
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ABSTRACT: α2-ARs regulate brain monoaminergic function by inhibiting neuronal firing and release of monoamine neurotransmitters, noradrenaline (NA), serotonin (5-HT) and dopamine (DA). Both α2A- and α2C-AR inhibit monoamine release in vitro in brain slices, but the in vivo roles of individual α2-AR subtypes in modulating monoamine metabolism have not been characterised. Metabolism of brain monoamine neurotransmitters, locomotor activity and body temperature were investigated in mice with targeted inactivation of the gene encoding α2A-AR (α2A-knockout, α2A-KO) and wild-type (WT) mice after treatment with the α2-AR agonist dexmedetomidine and the antagonist atipamezole. Dexmedetomidine caused profound hypothermia (up to 14.7° C mean reduction in rectal temperature) and locomotor inhibition in WT mice, and inhibited the turnover of NA, 5-HT and DA, but increased NA turnover in α2A-KO mice. α2-AR agonist-induced hypothermia and locomotor inhibition were attenuated, but not totally abolished, in α2A-KO mice. These results suggest that α2A-ARs are principally responsible for the α2-AR mediated inhibition of brain monoamine metabolism, but other α2-ARs, possibly α2C-ARs, are also involved, especially in the striatum. However, secondary effects of the physiological alterations caused by drug administration, especially hypothermia, may have contributed to the observed neurochemical changes in WT mice.
Neuropharmacology.
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ABSTRACT: Sustained electrical stimulation of the perforant pathway was used to induce long-lasting hippocampal seizures in conscious rats. One hour prior to stimulation, rats were given i.p. injections of either saline or a commonly used antiepileptic drug, carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide; CBZ; 20 mg/kg). When tested 2 weeks later in a water maze, both the saline- and the carbamazepine-pretreated rats showed similarly a severe impairment in spatial learning compared to non-stimulated controls. Histological evaluation revealed that the pyramidal cell damage was (P < 0.05) milder in the carbamazepine-pretreated group in the CA1, but not the CA3c subfield. However, the number of somatostatin-immunoreactive neurons in both stimulated groups was reduced equally. Thus, at the dose of 20 mg/kg, which is a usual anticonvulsive dose in humans, carbamazepine seems to offer only partial protection against pyramidal cell damage, but no protection against the hilar somatostatin-immunoreactive neuron loss or the spatial learning deficit after perforant pathway stimulation in rats. The result clearly differs from that obtained either with a GABA (γ-aminobutyric acid)-enhancing drug and a novel antiepileptic, vigabatrin (4-amino-hex-5-enoic acid) or with a competitive NMDA (N-methyl-d-aspartate) receptor antagonist, CGP 39551 (dl-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid carboxyethylester) in the same test situation.
European Journal of Pharmacology.
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ABSTRACT: Adrenoceptors presently are classified into three main subclasses: α1-, α2-, and β-receptors, each with three (perhaps more) subtypes. All three α1-adrenoceptor subtypes are present in rat brain. The purpose of this review is to assess the role of α1-adrenoceptors in the modulation of synaptic transmission and plasticity, as well as their ability to modulate higher cerebral functions, such as attentional and memory processes. However, since there are no truly subtype-specific agonists or antagonists available at present, it is virtually impossible to allocate a particular central effect to one or other of the subtypes. The activation of α1-adrenoceptors reduces the firing probability and glutamate release in the cornu ammonis of the hippocampus. α1-Adrenoceptors may flexibly modulate weak and strong activation of the pyramidal neurones in the neocortex. α1-Adrenoceptors play only a minor role in the modulation of long-term potentiation in the hippocampus, and may influence many brain functions also via non-neuronal mechanisms, since glial cells can express α1-adrenoceptors. At the behavioural level, the activation of α1-adrenoceptors promotes vigilance and influences working memory and behavioural activation, while having only a minor role in the modulation of long-term memory.
Pharmacology & Therapeutics.
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ABSTRACT: The present study compares, using a double-blind, placebo controlled design the effects of two α2-agonists, clonidine (0.5, 2, and 5 μg/kg) and guanfacine (7 and 29 μg/kg) on spatial working memory, planning and attentional set-shifting, functions thought to be dependent on the “central executive” of the prefrontal cortex. Blood pressure and the subjective feeling of sedation were affected equally by clonidine and guanfacine. The 0.5 μg/kg and 5 μg/kg doses of clonidine disrupted spatial working memory, but the medium dose had no effect. The 0.5 and 2 μg/kg doses of clonidine increased impulsive responding in the planning test. The 5 μg/kg dose of clonidine slowed responding at effortful levels of planning and attentional set-shifting tests. The 29 μg/kg dose of guanfacine improved spatial working memory and planning. Guanfacine had no effect on attentional set-shifting. These data indicate that guanfacine improved planning and spatial working memory, but clonidine dose-dependently disrupted performance. It is possible that the greater selectivity of guanfacine for α2A-adrenoceptor subtype may underlie its differences from clonidine.
Neuropsychopharmacology.
