Methylxanthines and ryanodine receptor channels.

Methylxanthines of either natural or synthetic origin have a number of interesting pharmacological features. Proposed mechanisms of methylxanthine-induced pharmacological effects include competitive antagonism of G-coupled adenosine A(1) and A(2A) receptors and inhibition of phosphodiesterases. A number of studies have indicated that methylxanthines also exert effects through alternative mechanisms, in particular via activation of sarcoplasmic reticulum or endoplasmic reticulum ryanodine receptor (RyR) channels. More specifically, RyR channel activation by methylxanthines was reported (1) to stimulate the process of excitation coupling in muscle cells, (2) to augment the excitability of neurons and thus their capacity to release neurotransmitters, and also (3) to improve their survival. Here, we address the mechanisms by which methylxanthines control RyR activation and we consider the pharmacological consequences of this activation, in muscle and neuronal cells.

Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels.

Epidemiological evidence suggests that caffeine or its metabolites reduce the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons, but the underlying mechanism is not clearly understood. Here, we show that the primary metabolite of caffeine, paraxanthine (PX; 1, 7-dimethylxanthine), was strongly protective against neurodegeneration and loss of synaptic function in a culture system of selective dopaminergic cell death. In contrast, caffeine itself afforded only marginal protection. The survival effect of PX was highly specific to dopaminergic neurons and independent of glial cell line-derived neurotrophic factor (GDNF). Nevertheless, PX had the potential to rescue dopaminergic neurons that had matured initially with and were then deprived of GDNF. The protective effect of PX was not mediated by blockade of adenosine receptors or by elevation of intracellular cAMP levels, two pharmacological effects typical of methylxanthine derivatives. Instead, it was attributable to a moderate increase in free cytosolic calcium via the activation of reticulum endoplasmic ryanodine receptor (RyR) channels. Consistent with these observations, PX and also ryanodine, the preferential agonist of RyRs, were protective in an unrelated paradigm of mitochondrial toxin-induced dopaminergic cell death. In conclusion, our data suggest that PX has a neuroprotective potential for diseased dopaminergic neurons.

Modelling Parkinson-like neurodegeneration via osmotic minipump delivery of MPTP and probenecid.

Mouse models of MPTP intoxication have been used extensively to explore the molecular mechanisms of Parkinson's disease. However, these models present some limitations since; (i) Dopaminergic (DA) cell death occurs rapidly in contrast to the presumably slow evolution of the disease process. (ii) Some of the key histological features of the disease such as Lewy body like inclusions and long-term inflammatory changes are lacking. Fornai et al. [Proc. Natl Acad. Sci. USA 102 (2005), 3413] suggested that continuous delivery of MPTP with Alzet osmotic minipumps may possibly circumvent these problems. Our results show, however, that MPTP infusion via Alzet osmotic minipumps (40 mg/kg/day) produces only a transient depletion in striatal dopamine (DA) without causing dopaminergic cell loss in the substantia nigra. Neuronal cell loss occurred, however, if MPTP was infused concomitantly with probenecid, an uricosuric agent which potentiates the effects of the toxin injected via the i.p. route. Even under these conditions, dopaminergic cell loss was moderate (-25%) and other neurodegenerative changes characteristic of Parkinson's disease remained undetectable.

Noradrenergic control of odor recognition in a nonassociative olfactory learning task in the mouse.

The present study examined the influence of pharmacological modulations of the locus coeruleus noradrenergic system on odor recognition in the mouse. Mice exposed to a nonrewarded olfactory stimulation (training) were able to memorize this odor and to discriminate it from a new odor in a recall test performed 15 min later. At longer delays (30 or 60 min), the familiar odor was no longer retained, and both stimuli were perceived as new ones. Following a post-training injection of the alpha(2)-adrenoceptor antagonist dexefaroxan, the familiar odor was still remembered 30 min after training. In contrast, both the alpha(2)-adrenoceptor agonist UK 14304 and the noradrenergic neurotoxin DSP-4 prevented the recognition of the familiar odor 15 min after the first exposure. Noradrenaline release in the olfactory bulb, assessed by measurement of the extracellular noradrenaline metabolite normetanephrine, was increased by 62% following dexefaroxan injection, and was decreased by 38%-44% after treatment with UK 14304 and DSP-4. Performance of mice in the recall test was reduced by a post-training injection of the beta-adrenoceptor antagonist propranolol or the alpha(1)-antagonist prazosin, thus implicating a role for beta- and alpha(1)-adrenoceptors in the facilitating effects of noradrenaline on short-term olfactory recognition in this model.

Extracellular hippocampal acetylcholine level controls amygdala function and promotes adaptive conditioned emotional response.

Ample data indicate that tone and contextual fear conditioning differentially require the amygdala and the hippocampus. However, mechanisms subserving the adaptive selection among environmental stimuli (discrete tone vs context) of those that best predict an aversive event are still elusive. Because the hippocampal cholinergic neurotransmission is thought to play a critical role in the coordination between different memory systems leading to the selection of appropriate behavioral strategies, we hypothesized that this cholinergic signal may control the competing acquisition of amygdala-mediated tone and contextual conditioning. Using pavlovian fear conditioning in mice, we first show a higher level of hippocampal acetylcholine release and a specific pattern of extracellular signal-regulated kinase 1/2 (ERK1/2) activation within the lateral (LA) and basolateral (BLA) amygdala under conditions in which the context is a better predictor than a discrete tone stimulus. Second, we demonstrate that levels of hippocampal cholinergic neurotransmission are causally related to the patterns of ERK1/2 activation in amygdala nuclei and actually determine the selection among the context or the simple tone the stimulus that best predicts the aversive event. Specifically, decreasing the hippocampal cholinergic signal not only impaired contextual conditioning but also mimicked conditioning to the discrete tone, both in terms of the behavioral outcome and the LA/BLA ERK1/2 activation pattern. Conversely, increasing this cholinergic signal not only disrupted tone conditioning but also promoted contextual fear conditioning. Hence, these findings highlight that hippocampal cholinergic neurotransmission controls amygdala function, thereby leading to the selection of relevant emotional information.

Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist.

The neurotransmitter noradrenaline (NA) exerts important antiinflammatory effects on glial cells including suppression of the inducible form of nitric oxide synthase (NOS2). The authors examined the consequences of manipulating NA in vivo by treating adult rats with the neurotoxin DSP4, which selectively lesions noradrenergic neurons of the locus ceruleus (LC), and reduces cortical NA levels. Following LC lesion, intracortical injection of aggregated amyloid beta 1-42 (Abeta1-42) caused appearance of NOS2 within neurons, and increased neuronal damage assessed by staining for nonphosphorylated neurofilament proteins with antibody SMI-32. Co-treatment with a selective alpha2-adrenergic antagonist reduced neuronal NOS2 staining as well as SMI-32 staining. Neuronal damage was dependent on NOS2 expression since injection of Abeta1-42 into DSP4-treated NOS2-deficient mice did not result in neuronal damage. These results demonstrate that decrease of NA levels in vivo can exacerbate inflammatory responses and neuronal damage due to inflammatory stimuli such as Abeta. These findings suggest that alpha2-adrenergic antagonists could provide therapeutic benefit in neurological diseases such as AD or PD where LC loss is known to occur.

The alpha2-adrenoceptor antagonist dexefaroxan enhances hippocampal neurogenesis by increasing the survival and differentiation of new granule cells.

The generation of new neurons in the hippocampus is a dynamic process regulated by environmental, endocrine, and pharmacological factors. Since enhancement of hippocampal neurogenesis has been associated with learning and memory, and the locus coeruleus-noradrenergic system has been shown to modulate these cognitive functions, we hypothesized that activation of noradrenergic neurotransmission might enhance neurogenesis in the adult hippocampus. To test this hypothesis in vivo, we induced the release of noradrenaline in the hippocampus by blocking presynaptic inhibitory autoreceptors with the selective alpha2-adrenoceptor antagonist dexefaroxan. Confocal microscopy showed that noradrenergic afferents make contact with proliferating and differentiating cells, suggesting a direct noradrenergic influence on neurogenesis. Chronic systemic treatment of rats with dexefaroxan did not affect cell proliferation per se in the dentate gyrus (as monitored by bromodeoxyuridine-labeling), but promoted the long-term survival of newborn neurons by reducing apoptosis. Dexefaroxan treatment also enhanced the number and complexity of the dendritic arborizations of polysialated neural cell adhesion molecule-positive neurons. The trophic effects of dexefaroxan on newborn cells might involve an increase in brain-derived neurotrophic factor, which was upregulated in afferent noradrenergic fiber projection areas and in neurons in the granule cell layer. By promoting the survival of new endogenously formed neurons, dexefaroxan treatment represents a potential therapeutic strategy for maintaining adult neurogenesis in neurodegenerative conditions, such as Alzheimer's disease, that affect the hippocampus.

Noradrenergic influences in the basolateral amygdala on inhibitory avoidance memory are mediated by an action on α2-adrenoceptors.

The role of norepinephrine (NE) in the consolidation of inhibitory avoidance learning (IA) in rats is known to involve α1- and ß-adrenoceptor systems in the basolateral nucleus of the amygdala (BLA). However, the amygdala also contains α2-adrenoceptor subtypes, and local microinfusions of the selective α2-adrenoceptor antagonist idazoxan and agonist UK 14,304 respectively into the BLA enhance and inhibit IA performances when administered before acquisition. The present study investigated whether the effects of idazoxan and UK 14,304 on IA were associated with changes in NE release within the BLA before and after one-trial inhibitory avoidance training. Male Sprague-Dawley rats were unilaterally implanted with a microdialysis probe in the BLA and were administered idazoxan (0.1mM) or UK 14,304 (10 µM) by retrodialysis infusion 15 min before the acquisition of IA. Dialysates were collected every 15 min for analysis of NE. Retrodialysis of idazoxan potentiated the release of NE induced by footshock application, whereas UK 14,304 decreased NE release to the extent that the footshock failed to induce any measurable effect on NE levels. Idazoxan infusion enhanced IA retention tested 24h later and this effect was directly related to the level of NE release in the BLA measured during IA acquisition. In contrast, the infusion of UK 14,304 did not modify IA performances in comparison to control animals, possibly due to compensatory activity of the contralateral BLA. These results are consistent with previous evidence that amygdala NE is involved in modulating memory consolidation, and provide evidence for an involvement of presynaptic α2-autoceptors in the BLA in this process.

The PARP inhibitor benzamide protects against kainate and NMDA but not AMPA lesioning of the mouse striatum in vivo.

Overactivation of poly(ADP-ribose) polymerase (PARP) in response to genotoxic insults can cause cell death by energy deprivation. We previously reported that neurotoxic amounts of kainic acid (KA) injected into the rat striatum produce time-dependent changes in striatal PARP activity in vivo. Here, we have investigated the time-course of KA-induced toxicity and the effects of the PARP inhibitor benzamide on KA, AMPA and NMDA neurotoxicities in vivo, by measuring changes in the volume of the lesion and in NAD+ and ATP levels induced by the intra-striatal injection of these excitotoxins in C57Bl/6N mice. The KA-induced lesion volume was dependent on the amount of toxin injected and the survival time. The lesion was well developed at 48 h and was almost undetectable after one week. KA produced an extensive astrogliosis at one week. Benzamide partially prevented both KA- and NMDA- but not AMPA-induced lesions when measured at 48 h after the treatment. The effects of benzamide appeared to be in part related to changes in energy metabolism, since KA produced decreases in striatal levels of NAD+ and ATP that were partially prevented by benzamide at 48 h and which returned to control levels at one week. NMDA did not affect NAD+ and induced little alteration in ATP levels. Benzamide had no effect on AMPA-induced decreases in either NAD+ or ATP levels at 48 h. These results (1) indicate that PARP overactivation and energy depletion could be responsible in part for the cellular demise during the development of the lesion induced by KA; (2) confirm that PARP is involved in NMDA but not AMPA toxicities; (3) suggest the existence of differences between KA and AMPA-mediated toxicities; and (4) provide further evidence supporting PARP as a novel target for new drug treatments against neurodegenerative disorders.

Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences.

We report the discovery of a new family of α(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human α(2) and α(1b) receptors as well as their functional activities at hα(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central α(2) antagonist activities were confirmed in mice after oral administration. Further studies on a selected example: (+)-4-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole, (+)-1 (F 14805), were undertaken to probe the potential of the series. On the one hand, (+)-1 increased the release of noradrenaline in mouse frontal cortex following acute systemic administration, the magnitude of this effect being much larger than that obtained with reference agents. On the other, (+)-1 produced minimal cardiovascular effects in intact, anesthetized rat, a surprising outcome that might be explained by its differential action at peripheral and central α(2) receptors. A strategy for improving the therapeutic window of α(2) antagonists is put forward.

Novelty determines the effects of olfactory enrichment on memory and neurogenesis through noradrenergic mechanisms.

Commonly used experimental paradigms of environmental enrichment combine increased social interactions and sensory inputs and renewal of the objects present in the environment. However, the specific contribution of novelty to the effects of enrichment is unclear. Here, we show that repeated daily exposure to single novel odorants and not to an enriched but stable olfactory environment improves short-term olfactory memory and neurogenesis in the mouse olfactory bulb. In addition, these positive effects are mediated by noradrenalin as they are blocked by a noradrenergic receptor antagonist. These data suggest that novelty recognition and noradrenergic mechanisms are crucial in mediating neural plasticity induced by olfactory enrichment.

F15063, a potential antipsychotic with dopamine D2/D3 receptor antagonist, 5-HT1A receptor agonist and dopamine D4 receptor partial agonist properties: influence on neuronal firing and neurotransmitter release.

F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-(3-cyclopenten-1-yl-benzyl)-amine) is a potential antipsychotic with dopamine D2/D3 receptor antagonist, 5-HT1A receptor agonist and dopamine D4 receptor partial agonist properties. Herein, we compared its effects on rat ventral tegmental area dopamine and dorsal raphe serotonin electrical activity with those of the dopamine D2 receptor partial agonist/5-HT1A receptor agonist, SSR181507. Further, we investigated the modulation of extracellular dopamine and noradrenaline in the medial prefrontal cortex and serotonin in the hippocampus of freely moving rats by F15063 using in vivo microdialysis. In the ventral tegmental area, F15063 (200-700 microg/kg, i.v.) did not alter the electrical activity of dopamine neurons whereas SSR181507 (250-1000 microg/kg, i.v.) partially inhibited it, consistent with dopamine D2 receptor partial agonism. Both compounds reduced the inhibition of firing rate induced by the full agonist apomorphine. In the dorsal raphe, both ligands suppressed firing activity, consistent with agonism at 5-HT1A autoreceptors, although SSR181507 (25-75 microg/kg, i.v.) was more potent than F15063 (100-300 microg/kg, i.v.). F15063 (0.63-40 mg/kg, i.p.) dose-dependently increased dopamine levels in the prefrontal cortex and decreased hippocampal 5-HT. These effects were reversed by the selective 5-HT1A receptor antagonist WAY100635 (0.16 mg/kg, s.c.), indicating that they were mediated by 5-HT1A receptors (at post- and pre-synaptic levels, respectively). In the medial prefrontal cortex, noradrenaline levels were moderately but significantly increased by F15063 at 2.5 mg/kg. In conclusion, whereas SSR181507 exhibits (partial) agonism at dopamine D2 and 5-HT1A receptors, F15063 blocks dopamine D2-like receptors whilst activating 5-HT1A receptors. Such a profile distinguishes F15063 from SSR181507 and currently available antipsychotic drugs.

Effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine: evidence from preclinical and clinical studies.

RATIONALE: Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man). OBJECTIVES: The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit. MATERIALS AND METHODS: In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects. RESULTS: In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time. CONCLUSION: These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated by brain-derived neurotrophic factor is enhanced by corticotropin releasing factor through the activation of a cAMP-dependent signaling pathway.

We have developed a model system of locus ceruleus (LC) neurons in culture, in which brain-derived neurotrophic factor (BDNF) induces the emergence of noradrenergic neurons attested by the presence of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase and the absence of phenylethanolamine N-methyl-transferase. Although inactive in itself, the neuropeptide corticotropin releasing factor (CRF) strongly amplified the effect of BDNF, increasing the number of cells expressing TH and the active accumulation of noradrenaline by a factor of 2 to 3 via a mechanism that was nonmitogenic. CRF also acted cooperatively with neurotrophin-4, which like BDNF is a selective ligand of the TrkB tyrosine kinase receptor. The effect of CRF but not that of BDNF was prevented by astressin, a nonselective CRF-1/CRF-2 receptor antagonist. However, only CRF-1 receptor transcripts were detectable in LC cultures, suggesting that this receptor subtype mediated the effect of CRF. Consistent with the positive coupling of CRF-1 receptors to adenylate cyclase, the trophic action of CRF was mimicked by cAMP elevating agents. Epac, a guanine nucleotide exchange factor directly activated by cAMP, contributed to the effect of CRF through the stimulation of extracellular signal-regulated kinases (ERKs) 1/2. However, downstream of ERK1/2 activation by CRF, the phenotypic induction of noradrenergic neurons relied upon the stimulation of the phosphatidylinositol-3-kinase/Akt transduction pathway by BDNF. Together, our results suggest that CRF participates to the phenotypic differentiation of LC noradrenergic neurons during development. Whether similar mechanisms account for the high degree of plasticity of these neurons in the adult brain remains to be established.

The neurotransmitter noradrenaline rescues septal cholinergic neurons in culture from degeneration caused by low-level oxidative stress.

We have developed a model system in which rat basal forebrain cholinergic neurons degenerate progressively when maintained in culture conditions that make them susceptible to low-level oxidative stress. In this study, we showed that cholinergic neurons identified by acetylcholinesterase cytochemistry or choline acetyl transferase immunocytochemistry are rescued efficiently by the neurotransmitter noradrenaline (NA). The effect of NA required neither adrenoceptor activation nor intracellular accumulation. NA operated via a mechanism that precluded activation of a cell death pathway in which reactive oxygen species (ROS) and proapoptotic caspases were crucially involved. It is noteworthy that NA remained protective even when applied late in the degenerative process but before intracellular ROS began to increase. The high efficacy of iron chelators and catalase in preventing the death of cholinergic neurons in this model suggested that NA neutralized the effects of hydroxyl radicals produced through a Fenton-type reaction. Pyrocatechol [the diphenolic moiety of NA] was sufficient in itself to prevent ROS production and cholinergic cell demise, indicating that the catechol structure was instrumental for the neuroprotective function of NA. Therefore, the noncatecholic neurotransmitter GABA failed to prevent neurodegeneration. Nerve growth factor and brain derived neurotrophic factor, two trophic peptides for septal cholinergic neurons, did not afford protection by themselves and did not improve neuroprotection provided by NA. However, in the presence of NA, they both retained their efficacy to stimulate cholinergic parameters. These data indicate that NA-based therapeutic strategies may be of interest in such neurodegenerative conditions as Alzheimer's disease, where progressive cholinergic deficits occur.

Activation of noradrenergic transmission by alpha2-adrenoceptor antagonists counteracts deafferentation-induced neuronal death and cell proliferation in the adult mouse olfactory bulb.

The olfactory bulb is the target of neural progenitor cells that are generated in the subventricular zone of the lateral ventricle in the adult brain. This permanent neurogenesis is likely influenced by olfactory input to the bulb since previous studies have shown that cell proliferation and/or apoptotic death are stimulated by naris closure or surgical transection of the olfactory nerve. Since the olfactory bulb is densely innervated by noradrenergic afferents originating in the locus coeruleus, we have studied the impact of pharmacologically activating this noradrenergic system on cell death and proliferation following unilateral olfactory axotomy in the adult mouse olfactory bulb. We found that noradrenaline release in the olfactory bulb was significantly increased by intraperitoneal injections of the selective alpha(2)-adrenoceptor antagonists, dexefaroxan (0.63 mg/kg) and 5-fluoro-methoxyidazoxan (F 14413; 0.16 mg/kg). A chronic treatment with either compound for 7 days following olfactory axotomy significantly reduced neuronal death, glial activation and cell proliferation in the deafferented olfactory bulb. These data (1) confirm that alpha(2)-adrenoceptor antagonists, presumably by facilitating central noradrenergic transmission, afford neuroprotection in vivo, as previously shown in models of cerebral ischemia, excitotoxicity and devascularization-induced neurodegeneration, and (2) support a role of the locus coeruleus noradrenergic system in promoting survival of neurons in areas of the brain where neurogenesis persists in the adult.

Effect of intrastriatal 6-OHDA lesion on dopaminergic innervation of the rat cortex and globus pallidus.

The present study examined in the rat the effect of a partial lesion of the nigrostriatal dopaminergic pathway induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA), on the dopaminergic innervation of the cortex and the globus pallidus as revealed using tyrosine hydroxylase (TH) immunoreactivity. Twenty-eight days after unilateral injection of 6-OHDA into the dorsal part of the striatum, TH-positive fiber density was reduced by 41% in the dorsal and central part of the structure, and was accompanied by a retrograde loss of 33% of TH-positive neurons in the substantia nigra (SN), while the ventral tegmental area was completely spared. In the SN, TH-positive cell loss was most severe in the ventral part of the structure (-55%). In the same animals, a substantial loss of TH-positive fibers was evident in the dorsal part of the globus pallidus, and involved both thick fibers of passage and thin varicose terminal axonal branches. In the cortex, a loss of TH-positive fibers was prominent in the cingulate area, moderate in the motor area and less affected in the insular area, while the noradrenergic innervation revealed using dopamine-beta-hydroxylase immunoreactivity was preserved in all of these cortical subregions. These results demonstrate that the intrastriatal 6-OHDA lesion model in rats produces a significant loss of dopaminergic axons in extrastriatal structures including the pallidum and cortex, which may contribute to functional sequelae in this animal model of Parkinson's disease.

Noradrenergic mechanisms in neurodegenerative diseases: a theory.

A deficiency in the noradrenergic system of the brain, originating largely from cells in the locus coeruleus (LC), is theorized to play a critical role in the progression of a family of neurodegenerative disorders that includes Parkinson's disease (PD) and Alzheimer's disease (AD). Consideration is given here to evidence that several neurodegenerative diseases and syndromes share common elements, including profound LC cell loss, and may in fact be different manifestations of a common pathophysiological process. Findings in animal models of PD indicate that the modification of LC-noradrenergic activity alters electrophysiological, neurochemical and behavioral indices of neurotransmission in the nigrostriatal dopaminergic system, and influences the response of this system to experimental lesions. In models related to AD, noradrenergic mechanisms appear to play important roles in modulating the activity of the basalocortical cholinergic system and its response to injury, and to modify cognitive functions including memory and attention. Mechanisms by which noradrenaline may protect or promote recovery from neural damage are reviewed, including effects on neuroplasticity, neurotrophic factors, neurogenesis, inflammation, cellular energy metabolism and excitotoxicity, and oxidative stress. Based on evidence for facilitatory effects on transmitter release, motor function, memory, neuroprotection and recovery of function after brain injury, a rationale for the potential of noradrenergic-based approaches, specifically alpha2-adrenoceptor antagonists, in the treatment of central neurodegenerative diseases is presented.

Effects of (+/-)-idazoxan alone and in combination with L-DOPA methyl ester in MPTP-induced hemiparkinsonian monkeys.

The effects of a combination of the alpha2-adrenergic receptor antagonist (+/-)-idazoxan with L-DOPA methyl ester were examined in three of four female adult monkeys (Macaca nemestrina) rendered hemiparkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). (+/-)-Idazoxan (0.16, 0.63, and 1.0 mg/kg) was given i.m. 10 min before L-DOPA methyl ester (12.5 mg/kg). (+/-)-Idazoxan reduced the maximum peak of contralateral circling elicited during the first hour following injection of L-DOPA methyl ester, but prolonged the duration of the circling response up to 50% (p < 0.05). The data support a role for alpha2-adrenergic receptor mechanisms in modulating the effects of L-DOPA on nigrostriatal dopamine function in the MPTP monkey model of hemiparkinsonism.

Effects of acute and subchronic administration of dexefaroxan, an alpha(2)-adrenoceptor antagonist, on memory performance in young adult and aged rodents.

The present study examined the influence of dexefaroxan, a potent and selective alpha(2)-adrenoceptor antagonist, on cognitive performance in rodents. In young adult rats, dexefaroxan reversed the deficits induced by UK 14304 [5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine], scopolamine, and diazepam in a passive avoidance task. In this test, dexefaroxan also attenuated the spontaneous forgetting induced by a 15-week training-testing interval. Moreover, dexefaroxan, given immediately after training, increased the memory performance of rats trained with a weak electric footshock in the passive avoidance test, facilitated spatial memory processes in the Morris water maze task in rats, and increased the performance of mice in an object recognition test. Thus, dexefaroxan appears to have a promnesic effect in these tests by facilitating the processes of memory retention, rather than acquisition or other noncognitive influences. The facilitatory effects of dexefaroxan in young adult rats persisted even after a 21- to 25-day constant subcutaneous infusion by using osmotic minipumps, indicating that tolerance to the promnesic effect of the drug did not occur during this prolonged treatment interval. Furthermore, in the passive avoidance and Morris water maze tests, dexefaroxan ameliorated the age-related memory deficits of 24-month-old rats to a level that was comparable to that of young adult animals, and reversed the memory deficits induced by excitotoxin lesions of the nucleus basalis magnocellularis region. Together, these findings support a potential utility of dexefaroxan in the treatment of cognitive deficits occurring in Alzheimer's disease.