Brain aging and neuronal plasticity.
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Aging↗
Biomedical subjects
K Fuxe
Publications and source records attributed to K Fuxe.
Evidence for specific N-terminal galanin fragment binding sites in the rat brain.
The existence and widespread distribution of specific [125I]galanin-(1-15) fragment binding sites in the rat brain was demonstrated by using [125I]galanin-(1-15) as a radioligand in quantitative receptor autoradiographical studies. These binding sites were also present in several areas lacking or having very few [125I]galanin-(1-29) binding sites, such as the dorsal hippocampal formation, the neocortex and the neostriatum. [125I]Galanin-(1-15) binding sites showed a high selectivity for the fragment, since galanin-(1-15) could displace 80% of the binding whereas porcine galanin-(1-29) could only displace 30%. The binding was saturable with a Kd of 0.63 +/- 0.02 nM and a Bmax of 15.3 +/- 1.7 fmol/mg in sections from the dorsal hippocampal formation. Thus, a new type of galanin receptor selective for N-terminal galanin fragments may exist in the rat brain.
Animals↗
Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum.
We have previously found, in striatal membrane preparations from young (2 months old) rats, that stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) increases the dissociation constants of high- (Kh) and low-affinity (Kl) dopamine D2 binding sites (labelled with the selective dopamine D2 antagonist [3H]raclopride) without changing the proportion of high affinity binding sites (Rh). In the present study in striatal preparations from adult (6 months old) rats, it was found that in addition to the increase in both Kh and Kl values, stimulation of adenosine A2 receptors is associated with an increase in Rh. These results suggest that, in the adult rat, adenosine A2 stimulation may inhibit the behavioural effects induced by dopamine D2 stimulation both by decreasing the affinity and the transduction of dopamine D2 receptors. We have also studied the intramembrane A2-D2 receptor interaction in an experimental model of Parkinson's disease, namely in rats with a unilateral 6-OH-dopamine-induced lesion of the nigro-striatal dopamine pathway. It was found that a unilateral dopamine denervation is associated with a higher density of striatal dopamine D2 receptors in the order of 20%, without any change in their affinity compared with the unlesioned neostriatum. Furthermore, the density (Bmax values) of dopamine D2 receptors in the contralateral neostriatum was significantly higher (about 20%) than in the striatum from naive animals. This finding suggests that an unilateral dopamine denervation also induces compensatory long-lasting changes of dopamine D2 receptors in the contralateral neostriatum.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The distribution of angiotensin II AT1 receptor subtype mRNA in the rat brain.
The present study demonstrates the existence and regional distribution of angiotensin II AT1 receptor subtype mRNA expression in the rat brain by the use of in situ hybridization and RNase protection assay. Substantial expression levels in the brain have only been detected in certain distinct areas, such as the subfornical organ, the parvocellular part of the paraventricular hypothalamic nucleus, and the median preoptic nucleus. The results give further evidence for the involvement of the angiotensin II AT1 receptor subtype in the classical functions of central angiotensin II, like blood pressure control, body fluid homeostasis and in corticotropin-releasing factor (CRF) secretion.
Angiotensin II↗
Coactivation of dopamine D1 and D2 receptors increases the affinity of cholecystokinin-8 receptors in membranes from post-mortem human caudate-putamen.
The effects of dopamine in vitro were investigated on the binding sites for cholecystokinin-8 (sulphated, CCK-8) and neurotensin in membrane preparations of the caudate-putamen and nucleus accumbens of post-mortem human brains. Dopamine reduced the IC50 value of competition curves with CCK-8 for [125I]CCK-8 binding in membranes from the caudate-putamen, but not the nucleus accumbens, with a maximal decrease of -25 +/- 9% at 300 nM of dopamine. This decrease could be antagonized by 100 nM of SCH 23390 or 100 nM of raclopride. Kinetic analysis of [125I]CCK-8 binding showed a decrease in the first order dissociation rate constant and in the kinetic Kd (-22 +/- 6% and -24 +/- 6%, respectively) at 300 nM of dopamine, without any significant effect on the apparent or actual association rate constant. Competition curves with neurotensin versus [125I]neurotensin were not affected by dopamine (10-1000 nM) in membranes from the caudate-putamen or the nucleus accumbens. These results suggest that dopamine, by synergistic stimulation of both D1 and D2 receptors, selectively increases the affinity of CCK-8 receptors in the human caudate-putamen, by a selective inhibition of ligand dissociation. This increase may reflect a positive feed-back mechanism, further enhancing the modulatory effects of CCK-8 on dopamine neurotransmission.
Adult↗
Muscarinic modulation of acetylcholine release from slices of guinea pig nucleus basalis magnocellularis.
Spontaneous and electrically evoked endogenous acetylcholine release and [3H]-choline efflux from slices of guinea pig nucleus basalis magnocellularis (nbM) were studied. Tetrodotoxin reduced the spontaneous endogenous release by 55%, while the Ca(2+)-free medium reduced it by about 30%. Evoked [3H]-choline efflux was Na+ and Ca2+ dependent and frequency related. Physostigmine, 30 microM, nearly halved the stimulation-evoked efflux; atropine, 0.15 microM, not only antagonized, but even reversed this effect into facilitation. Pirenzepine, 1 microM, and AFDX 116, 1 microM, were less effective than atropine, and reversed the inhibitory effect of physostigmine only when applied together. 4-DAMP, 0.01 microM, was ineffective. These findings indicate that acetylcholine release in guinea pig nbM slices is inhibited by the cooperation of muscarinic autoreceptors, possibly belonging to the M1 and M2 subclasses.
Acetylcholine↗
Intracerebroventricularly administered pertussis toxin blocks the central vasopressor action of neuropeptide Y(13-36) in the awake unrestrained male rat.
The effects of intracerebroventricular (i.v.t.) injections of pertussis toxin (PTX) (10 micrograms/30 microliters, 48 h) were studied on the cardiovascular actions of i.v.t. administered neuropeptide Y(13-36) (NPY(13-36)) as evaluated in the awake unrestrained male rat. The vasopressor action of NPY(13-36) in the peak dose of 3000 pmol per rat was significantly inhibited by pretreatment by PTX. Pertussis toxin treatment alone significantly reduced the baroreceptor reflex elicited by L-phenylephrine. The results are compatible with the view that G-proteins mediate the central vasopressor actions of NPY(13-36) and thus probably are involved in NPY Y2-receptor transduction in cardiovascular areas of the brainstem.
Animals↗
Evidence for a substrate of neuronal plasticity based on pre- and postsynaptic neurotensin-dopamine receptor interactions in the neostriatum.
The major mechanism underlying the neuroleptic action of the tridecapeptide neurotensin (NT) appears to be an interaction with dopamine receptor mechanisms based on biochemical binding and behavioral experiments. In vivo microdialysis was used in conscious rats to investigate the effects of local perfusion with NT on the sensitivity of striatal dopamine D1 and D2 receptors for their selective agonists by monitoring extracellular dopamine, 3,4-dihydroxyphenylacetic acid, homovanilic acid, and gamma-aminobutyric acid levels in the awake unrestrained male rat. Perfusion with NT (10 nM) counteracted the inhibitory effects of the dopamine D2 agonist pergolide (500 nM) on extracellular levels of dopamine and gamma-aminobutyric acid. In contrast, NT (10 mM) significantly enhanced the reduction of extracellular striatal levels of dopamine after perfusion with the D1 agonist SKF 38393 (5 microM), and this combined treatment also resulted in a significant increase in the extracellular striatal levels of gamma-aminobutyric acid. These results provide in vivo evidence that NT regulates central dopamine transmission by reducing pre-and postsynaptic dopamine D2 and enhancing D1 receptor sensitivity possibly through an antagonistic NT receptor-D2 receptor interaction. This heteroregulation has the potential to substantially increase the plasticity within the dopamine synapse.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Feeding and drinking responses to neuropeptide Y injections in the paraventricular hypothalamic nucleus of aged rats.
Neuropeptide Y (NPY), a peptide of the pancreatic polypeptide family, exerts a potent stimulatory action on eating when injected into the paraventricular hypothalamic nucleus (PVN) in rats. Several NPY-containing systems are altered with advancing age, and aged rodents develop anorexia and a modified daily cycle pattern of feeding. These findings suggest that a relationship may exist between the aging-related anorexia and the reduced function of NPY-containing systems projecting to the PVN. In the present study eating and drinking behavior in satiated or fasted young (3 months) and aged (24 months) rats have been investigated over 22 h after NPY injection into the PVN. The levels of NPY immunoreactivity (IR) in PVN were also evaluated by means of semiquantitative immunocytochemistry. NPY injections into PVN increased food and water consumption in both young and aged satiated rats 30, 90 and 240 min after injection. However, the feeding and drinking responses elicited by 0.05, 0.10 and 1.0 nmol of NPY were significantly attenuated in the aged rats when compared to young rats. In aged rats, 24 h of food and water deprivation produced significant increase of food consumption measured at 30, 90 min and 22 h, which was equivalent to that induced by 1.0 nmol NPY injection. Administration of 1.0 nmol NPY in PVN did not further increase the 24 h deprivation effect on feeding in both groups of rats, but enhanced drinking in deprived young rats. This effect was not present in aged rats. In addition, aged rats showed a stronger response to 24 h deprivation than to 1.0 nmol NPY administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
The effects of neurotensin on GABA and acetylcholine release in the dorsal striatum of the rat: an in vivo microdialysis study.
The effects of local perfusion with the tridecapeptide neurotensin (NT) on endogenous gamma-aminobutyric acid (GABA), acetylcholine (ACh) and choline release in the dorsal neostriatum were monitored using in vivo microdialysis in the halothane anaesthetized rat. The results show that NT (10 and 1000 nM) differentially regulates striatal GABA release without significantly influencing the release of either striatal ACh or choline. NT increased striatal GABA release both in the absence and presence of the ACh esterase inhibitor neostigmine (neo; 10 microM) in the perfusion medium. However, both basal GABA levels and responsitivity to NT were elevated in the presence of neo. The NT induced increase in striatal GABA release was reversed by the addition of tetrodotoxin (TTX; 1 micron) to the perfusion medium. These data suggest that (1) NT may play a role in modulating GABAergic neurotransmission in the dorsal neostriatum and (2) that the increase in GABA release may occur independently of an increase in the cholinergic component in the dorsal neostriatum, possibly via high affinity NT receptors located on striatal GABAergic neurons.
Acetylcholine↗
High blood pressure in transgenic mice carrying the rat angiotensinogen gene.
Transgenic mice were generated by injecting the entire rat angiotensinogen gene into the germline of NMRI mice. The resulting transgenic animals were characterized with respect to hemodynamics, parameters of the renin angiotension system, and expression of the transgene. The transgenic line TGM(rAOGEN)123 developed hypertension with a mean arterial blood pressure of 158 mmHg in males and 132 mmHg in females. In contrast, the transgenic line TGM(rAOGEN)92 was not hypertensive. Rat angiotensinogen was detectable only in plasma of animals of line 123. Total plasma angiotensinogen and plasma angiotensin II concentrations were about three times as high as those of negative control mice. In TGM(rAOGEN)123 the transgene was highly expressed in liver and brain. Transcripts were also detected in heart, kidney and testis. In TGM(rAOGEN)92 the brain was the main expressing organ. In situ hybridization revealed an mRNA distribution in the brain of TGM(rAOGEN)123 similar to the one in rat. In TGM(rAOGEN)92 the expression pattern in the brain was aberrant. These data indicate that overexpression of the angiotensinogen gene in liver and brain leads to the development of hypertension in transgenic mice. The TGM(rAOGEN)123 constitutes a high angiotensin II type of hypertension and may provide a new experimental animal model to study the kinetics and function of the renin angiotensin system.
Angiotensinogen↗
Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms.
The effects of modafinil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3-30 mg/kg s.c. modafinil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i.p.) but not prazosin (0.14 mg/kg, i.p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT2 receptors, since the action of modafinil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT2 antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafinil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafinil at least in the striatum. The reduction of cortical GABA outflow via 5-HT2 receptors by modafinil is probably related to some of its actions on the central nervous system including behavioural effects.
Acetylcholine↗
Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis.
Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse.(ABSTRACT TRUNCATED AT 400 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Involvement of local ischemia in endothelin-1 induced lesions of the neostriatum of the anaesthetized rat.
The present study examines the possibility that lesions induced by intrastriatal injections of endothelin-1 (ET-1, 0.43 nmol/0.5 microliter) are ischemic in nature due to a vasoconstriction of the cerebral microvessels. In time course and dose-response experiments with ET-1 and in comparisons with ET-3, the volume of the lesions has been determined based mainly on the disappearance of striatal nerve cells, using a computer assisted morphometrical analysis. The blood flow in the neostriatum close to the site of injection of ET-1 was determined acutely by Laser-Doppler flowmetry. The acute metabolic effects of ET-1 were also studied on striatal superfusate levels of lactate, pyruvate, dopamine and its metabolites DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) using an intrastriatal microdialysis probe. Dose related striatal lesions were observed with ET-1 (0.043-0.43 nmol) with a peak lesion volume after 24-48 h and the possible existence of a penumbra area. ET-3 showed a reduced potency to produce striatal lesions compared to ET-1. The lesions induced by ET-1 were prevented by coinjection with dihydralazine, a vasodilator drug. Acutely ET-1 (0.43 nmol/0.5 microliter) produced a prolonged reduction of the cerebral blood flow down to 40% of control values and temporary increases of striatal lactate and DA efflux, the latter change being very marked. Also a significant reduction of DOPAC and HVA was observed. These neurochemical changes were all prevented by treatment with dihydralazine.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Neuropeptides, excitatory amino acid and adenosine A2 receptors regulate D2 receptors via intramembrane receptor-receptor interactions. Relevance for Parkinson's disease and schizophrenia.
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Animals↗
Adenosine-dopamine interactions in the brain.
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Adenosine↗
Ganglioside GM1 counteracts the enhancing effects of subacute toluene exposure on apomorphine-induced locomotor activity.
Previous studies indicate that subacute toluene exposure enhances the effects of postsynaptic doses of apomorphine on locomotor activity in the rat. We have now studied the effects of the ganglioside GM1 on toluene-affected apomorphine-induced (1 mg/kg, s.c.) locomotion, motility, and rearing. Treatment with GM1 (10 mg/kg, i.p., 1 h before exposure) was found to counteract or even reverse the enhancing effect of toluene on apomorphine-induced locomotion and rearing, but had similarly to toluene no significant effects on apomorphine-induced motility or on spontaneous locomotor activity. The antagonistic effects of GM1 may be due to its ability to block toluene-induced changes in D2 receptor binding.
Animals↗
The brain renin-angiotensin system: localization and general significance.
This report summarizes the present data about the existence of components of the renin-angiotensin system in the rat brain. Angiotensinogen mRNA, mas proto-oncogene mRNA, angiotensin II (Ang II), and Ang II receptors have been mapped in the brain by using in situ hybridization, immunocytochemistry, and receptor autoradiography. These markers turned out to be widely distributed throughout the brain and to be not only restricted to areas related to cardiovascular control, but also to be present in functionally different areas, suggesting also other functions of angiotensin peptides. The distribution patterns of these components were correlated with data on the distribution of angiotensinogen, renin, angiotensin converting enzyme, and angiotensin fragments that revealed substantial topological mismatches. Using the model of "volume transmission," possible explanations for these mismatches are proposed. In this regard, a possible involvement of angiotensin fragments and the mas proto-oncogene in the functioning of the brain renin-angiotensin system is also discussed, demonstrating the increasing complexity of this central regulatory system.
Angiotensinogen↗