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H C Fibiger

Publications and source records attributed to H C Fibiger.

At least 91 records · Page 5Linked to original sources
PubMed1991

Cholinergic mechanisms in learning, memory and dementia: a review of recent evidence.

The discovery in the late 1970s that cholinergic neurons in the basal forebrain degenerate in Alzheimer's disease (AD) greatly accelerated research on the role of cholinergic mechanisms in learning and memory. As is often the case in science, the early enthusiasm for the cholinergic hypothesis has been tempered by the results of subsequent research. Although there is substantial pharmacological evidence that unspecified cholinergic systems in the brain play important roles in some forms of learning and memory, recent findings in humans indicate that antimuscarinic drugs do not model the deficits seen in AD. In addition, the goal of elucidating the functions of these basal forebrain neurons in animals has proved to be difficult and is yet to be achieved. Despite substantial effort, therefore, the cognitive and behavioral consequences of cholinergic pathology in AD remain unknown. Under these circumstances, attempts to develop cholinergic pharmacotherapies for these deficits in AD are based on questionable assumptions.

Animals↗
PubMed1991

Characterization of extracellular histamine in the striatum and bed nucleus of the stria terminalis of the rat: an in vivo microdialysis study.

The intracerebral microdialysis technique, coupled with a sensitive radioenzymatic assay, was employed to study histamine release in the striatum and in the bed nucleus of the stria terminalis (BNST) in conscious, freely moving rats. In these brain regions, extracellular histamine concentrations decreased by 20% when calcium was omitted from the perfusion solution. Extracellular histamine was insensitive to the addition of tetrodotoxin to the perfusion medium. In striatum, extracellular histamine concentrations declined in an apparent biexponential manner after the administration of alpha-fluoromethylhistidine, an inhibitor of histamine synthesis. The half-lives for the disappearance of histamine were 32 min and 7.7 h, indicating the presence of at least two histamine pools. Histidine loading resulted in a nearly twofold increase in histamine outflow in striatum. In the BNST, yohimbine increased the extracellular histamine content by 50%, suggesting that histamine release is subject to alpha 2-adrenergic regulation in vivo. The extent to which histamine detected in cerebral microdialysis samples is of neurogenic origin remains to be established.

Animals↗
PubMed1991

Interstitial 3-methoxytyramine reflects striatal dopamine release: an in vivo microdialysis study.

Previous ex vivo studies have provided indirect evidence that the dopamine (DA) metabolite 3-methoxytyramine (3-MT) may be a useful index of DA release in vivo. In the present study, in vivo microdialysis was utilized to assess directly the relationship between extracellular DA and 3-MT in the striatum of rats following a variety of pharmacological manipulations. Apomorphine, a DA receptor agonist, produced a rapid, transient decrease in both DA and 3-MT. Conversely, the DA receptor antagonist haloperidol produced a concomitant increase in extracellular DA and 3-MT. Increases in DA and 3-MT were also noted following the administration of the DA uptake inhibitor, bupropion. Local application of tetrodotoxin resulted in the complete elimination of measurable amounts of DA and 3-MT in the dialysate, gamma-Butyrolactone also greatly decreased DA and 3-MT. Finally, d-amphetamine produced a large increase in DA and 3-MT in animals that had been treated previously with gamma-butyrolactone. The Pearson correlation coefficients for DA and 3-MT following these manipulations ranged from 0.87 to 0.97. These data indicate that interstitial 3-MT is an accurate index of DA release. However, when compared with previous ex vivo findings, the present results also suggest that changes in tissue concentrations of 3-MT may not reliably reflect DA release following certain pharmacological manipulations.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Electroconvulsive shock produces large increases in interstitial concentrations of dopamine in the rat striatum: an in vivo microdialysis study.

This study examined the effects of electroconvulsive shock (ECS) on interstitial concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the purine metabolite uric acid, in the striatum using on-line microdialysis in freely moving rats. Interstitial striatal DA increased to 1310% of baseline when the ECS was administered 18 to 24 hours after implantation of the dialysis probe. DOPAC (+ 19%), HVA (+ 30%), 5-HIAA (+10%), and uric acid (+111%) were increased to a smaller extent. The ECS-induced increase in DA was derived from a Ca++ sensitive pool since perfusion of a modified solution in which Ca++ had been replaced with Mg++ blocked this effect.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Characterization of dopamine release in the substantia nigra by in vivo microdialysis in freely moving rats.

Dopamine (DA) is released not only from the terminals of the nigrostriatal projection, but also from the dendrites of these neurons, which arborize in the substantia nigra pars reticulata (SNR). Although striatal DA release has been extensively studied by in vivo microdialysis, dendritic DA release in the SNR has not been characterized by this technique. Extracellular DA was monitored simultaneously in the ipsilateral striatum and SNR. The nigral probe was implanted at a 50 degree angle, permitting 2.5 mm of SNR to be dialyzed. Delivery of the tracer Fluoro-Gold into the striatal probe retrogradely labeled tyrosine hydroxylase-positive cell bodies and dendrites in the vicinity of the nigral probe. Hence, it could be demonstrated that dopaminergic neurons near the nigral probe projected to the vicinity of the striatal probe. Addition of 50 mM KCl to the SNR perfusion solution produced a 3.5-fold increase in DA and a 50% reduction in dihydroxyphenylacetic acid (DOPAC) in the SNR; in contrast, this manipulation in the SNR caused DA release in the striatum to be decreased by 20%, while striatal DOPAC was increased by 50%. Local administration of nomifensine (10 microM) in the SNR produced a sevenfold increase in SNR DA but had no effect on striatal DA. Systemic injection of d-amphetamine (2 mg/kg, s.c.) elevated DA in the SNR and striatum five- to sevenfold, while DOPAC was decreased in both structures by at least 40%. To determine the effect of tetrodotoxin (TTX), basal concentrations of DA in the SNR were first elevated threefold by including nomifensine (1 microM) in the nigral perfusion solution.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Dopaminergic regulation of striatal acetylcholine release: importance of D1 and N-methyl-D-aspartate receptors.

The dopaminergic regulation of striatal cholinergic activity was studied using in vivo microdialysis to measure interstitial concentrations of acetylcholine (ACh) and choline in the striata of freely moving rats. The quaternary acetylcholinesterase inhibitor neostigmine (100 nM) was included in the perfusion solution to increase the recovery of ACh. d-Amphetamine (2 mg/kg, s.c.) and nomifensine (5 mg/kg, s.c.) increased the concentration of ACh in the striatal dialysate by 40 to 60%. Interstitial choline concentrations were reduced by both drugs. Administration of the selective D1 receptor antagonist SCH 23390 (0.3 mg/kg, s.c.) decreased the concentration of ACh in the striatal dialysate by 15 to 20%; in contrast, the selective D2 antagonist raclopride (1 mg/kg, s.c.) increased striatal ACh release by 50 to 60%. Raclopride also briefly increased the extracellular concentration of choline. Raclopride blocked the increase in locomotor activity produced by d-amphetamine, but did not further enhance ACh release. In contrast, SCH 23390 completely antagonized the increases in locomotion and striatal ACh release produced by d-amphetamine. These results indicate that d-amphetamine increases ACh release in the striatum via a D1 receptor mechanism. Consistent with this hypothesis, the selective D1 receptor agonist CY 208-243 (1 mg/kg, s.c.) increased striatal ACh release by approximately 60%. In contrast, local application of CY 208-243 (10 microM) and SCH 23390 (10 microM) failed to alter ACh concentrations in the striatal dialysate. Inclusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (10 microM) in the striatal perfusion solution significantly attenuated the increase in striatal ACh release produced by systemic CY 208-243.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Behavioral and neurochemical interactions between cocaine and buprenorphine: implications for the pharmacotherapy of cocaine abuse.

Intravenous self-administration studies in nonhuman primates suggest that the opioid receptor agonist-antagonist buprenorphine may be useful in the pharmacotherapy of cocaine abuse. In the present studies, behavioral and neurochemical interactions between cocaine and buprenorphine were examined using a conditioned place preference (CPP) procedure and in vivo microdialysis. Cocaine-induced CPP was linearly related to the dose administered (0-5.0 mg/kg). Buprenorphine (0-0.9 mg/kg) also elicited CPP in a dose-related manner; an inverted U-shaped function was obtained. Subthreshold doses of cocaine (1.5 mg/kg) and buprenorphine (0.01 mg/kg), themselves incapable of eliciting CPP, produced a significant CPP when given together. Moderate doses of cocaine (5.0 mg/kg) and buprenorphine (0.075 mg/kg), which were individually capable of eliciting CPP, produced a significantly larger CPP when given in combination. In the in vivo microdialysis studies, a low dose of buprenorphine (0.01 mg/kg) produced a progressive increase in extracellular dopamine in the nucleus accumbens, reaching approximately 200% of basal levels after 5 hr. Cocaine (5.0 mg/kg) rapidly increased extracellular dopamine concentrations (180% of basal values within 20 min), which returned to baseline in 2 to 3 hr. This effect of cocaine was significantly potentiated by coadministering buprenorphine (0.01 mg/kg); under this condition the peak increase in extracellular dopamine reached 260% of baseline values. These neurochemical findings are consistent with the CPP results and indicate that buprenorphine can interact with cocaine in a synergistic manner. In contrast to previous speculations, these results suggest that buprenorphine may enhance rather than attenuate the rewarding properties of cocaine.

Animals↗
PubMed1990

Sexual behavior enhances central dopamine transmission in the male rat.

Central dopamine transmission was examined in the nucleus accumbens and striatum of sexually experienced male rats during mating behaviour using in vivo brain microdialysis. Dopamine release increased significantly in the nucleus accumbens when males were placed in a novel mating chamber and when a receptive female was introduced behind a screen partitioning this chamber. Subsequently, during copulation dopamine transmission increased sharply, this being followed by a gradual decrease after the female was removed. In contrast, striatal dopamine transmission increased significantly only during copulation. These data provide a neurochemical basis for the well-known interactions between dopaminergic drugs and male sexual behaviour and demonstrate the feasibility of using brain microdialysis to elucidate the neurochemical correlates of motivated behaviour.

Animals↗
PubMed1990

Dopamine D1 receptor stimulation increases striatal acetylcholine release in the rat.

The effect of selective D1 receptor agonists on acetylcholine (ACh) release in the striatum was investigated using in vivo microdialysis. Administration of the reactive enantiomer, (+)-SKF 38393 (2, 10 mg/kg s.c.), doses which elevate grooming and sniffing behaviour, increased ACh release by 40 and 75%, respectively. Another D1 receptor agonist CY 204-283 (1 mg/kg s.c.) also produced a 75% increase in ACh output. The racemate (+/-)-SFK 38393 (20 mg/kg s.c.) increased ACh output by 60% and this was completely blocked by the D1 receptor antagonist SCH 23390 (0.3 mg/kg s.c.). In contrast, administration of the D2 receptor antagonist raclopride (1 mg/kg s.c.), 60 min after (+/-)-SKF 38393 (20 mg/kg s.c.), further increased ACh release. These results suggest that activation of D1 receptors increases ACh release in vivo and that D1 and D2 receptors have opposing roles in the regulation of striatal ACh release.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Striatonigral projection neurons contain D1 dopamine receptor-activated c-fos.

Dopamine receptor agonists which stimulate the D1 receptor have been shown to activate c-fos in the striatum ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. In the present study, striatal neurons ipsilateral to a 6-OHDA lesion of the medial forebrain bundle were retrogradely labelled by injection of the fluorescent tracer Fluoro-Gold into the substantia nigra pars reticulata. Five days later, c-fos was induced in the 6-OHDA-denervated striatum by injection of the selective D1 agonist SKF 38393. C-fos-positive nuclei were frequently found in medium-sized striatal cell bodies labelled with Fluoro-Gold. These results indicate that D1 agonists activate c-fos in medium-sized neurons that project to the substantia nigra pars reticulata.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Amphetamine-like stimulus properties produced by electrical stimulation of reward sites in the ventral tegmental area.

The present study examined whether the stimulus properties of D-amphetamine could be mimicked by electrical stimulation of the ventral tegmental area (VTA). Rats trained to discriminate 1.0 mg/kg D-amphetamine from saline were given generalization tests with a range of D-amphetamine doses administered either alone or in combination with VTA stimulation. The results suggested that the VTA stimulation could enhance the cueing effects of D-amphetamine, as levels of responding on the D-amphetamine-appropriate lever during stimulation trials were increased relative to tests without stimulation. Individual differences were observed in the amount of drug-lever responding elicited by the VTA stimulation during drug-free substitution tests, and the different levels of drug-lever responding correlated positively with the response rates obtained from these rats during subsequent intracranial self-stimulation tests. These finding suggest that VTA stimulation can have D-amphetamine-like stimulus properties and such stimulus properties may be related to the rewarding effects of the brain stimulation.

Animals↗
PubMed1990

Reinforced alternation performance is impaired by muscarinic but not by nicotinic receptor blockade in rats.

In pre-trained rats, food-rewarded reinforced alternation in a T-maze was markedly impaired by scopolamine, but unaffected by the centrally-active nicotinic antagonist mecamylamine (0.2-6.3 mg/kg s.c.). The nicotinic antagonist chlorisondamine (10 micrograms i.v.t.) was also ineffective, despite demonstrated blockade of nicotine-induced locomotor depression. These results question the extent to which central nicotinic receptors are involved in memory function.

Animals↗
PubMed1990

In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis.

In vivo brain microdialysis was used to characterize the effects of some dopamine uptake inhibitors on the extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striata of awake, freely moving rats. d-Amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, bupropion, and benztropine were administered directly to the striatum via the perfusion fluid in increasing concentrations (1-1,000 microM). All drugs increased extracellular DA in a dose-dependent manner; however, only d-amphetamine produced dose-dependent decreases in DOPAC and HVA concentrations. The shapes of the dose-response functions differed considerably between the drugs. At 100 and 1000 microM d-amphetamine had biphasic effects (an increase followed by a decrease) on dialysate DA concentrations. GBR 12909, methylphenidate, and benztropine also had biphasic effects when applied at the 1,000 microM concentration. In contrast, cocaine, nomifensine, and bupropion produced relatively monophasic increases in extracellular DA. Tetrodotoxin (TTX), which prevents action potentials by blocking voltage-dependent Na+ channels, did not prevent d-amphetamine induced increases in extracellular DA, but blocked completely the effects of cocaine, nomifensine, bupropion, and methylphenidate. While low doses (10 microM) of GBR 12909 and benztropine were highly sensitive to TTX, the toxin was only partially effective against higher doses of the compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Dopaminergic regulation of striatal cholinergic interneurons: an in vivo microdialysis study.

In vivo microdialysis was used to study the putative inhibitory effects of dopamine on cholinergic interneurons in the striatum of conscious rats. The dopamine receptor agonists apomorphine (0.3 and 3 mg/kg, s.c.) and (+/-)N-0437 (1.4 mg/kg, s.c. decreased interstitial concentrations of acetylcholine while increasing those of choline. In contrast, the dopamine receptor antagonists haloperidol (0.1 and 1 mg/kg, i.p.) and (+/-)sulpiride (20 mg/kg, i.p.) enhanced striatal acetylcholine output but had little effect on choline. Previously, a lack of effect of these drugs on striatal acetylcholine was reported. The main methodological difference between these studies was that the calcium concentration of the microdialysis perfusion solution was 3.4 mM in the former study versus 1.2 mM in the present experiments. The results of this study reemphasize the importance of the calcium concentration in determining the effects of drugs on central neurotransmitter release, and confirm a role of dopamine in the regulation of striatal cholinergic interneurons.

Acetylcholine↗
PubMed1990

Dopaminergic-cholinergic interactions in the striatum: the critical significance of calcium concentrations in brain microdialysis.

Brain microdialysis experiments were performed to assess the effects of calcium (1.2 mmol/l and 3.4 mmol/l) in the perfusion solution on a variety of pharmacological treatments known to affect the release of dopamine (DA) and/or acetylcholine (ACh). Intrastriatal infusion of the muscarinic receptor agonist oxotremorine (100 microM), the selective dopamine D-2 receptor agonist (-)-N-0437 (1 microM), and the indirect DA agonists (+)amphetamine (10 microM) and nomifensine (1 microM) via the dialysis probe did not affect the overflow of ACh when the perfusion fluid contained 3.4 mmol/l calcium. In contrast, these compounds produced pronounced decreases in the overflow of ACh at 1.2 mmol/l calcium. Intrastriatal infusion of the muscarinic receptor antagonist atropine (1 microM) increased the output of ACh both at 1.2 mmol/l and 3.4 mmol/l calcium. The selective DA D-2 receptor antagonist (-)-sulpiride (1 microM) did not affect the overflow of ACh at either calcium concentration. Infusion of oxotremorine and atropine had no effect on the overflow of DA at either 1.2 mmol/l at 3.4 mmol/l calcium. (-)-N-0437 decreased and (-)-sulpiride increased DA overflow, both effects being independent of the calcium concentration in the perfusion fluid. Nomifensine and (+)amphetamine caused relatively (but not absolutely) larger increases in the overflow of DA at 1.2 mmol/l calcium. These findings emphasize the critical importance of the calcium concentration of the perfusion fluid in determining the nature of pharmacological responses in microdialysis experiments, and demonstrate that locally applied dopaminergic drugs can modulate striatal cholinergic function.

Acetylcholine↗
PubMed1990

Loss of striatal somatostatin neurons following prenatal methylazoxymethanol.

Prenatal administration of methylazoxymethanol acetate (MAM), which kills neuroblasts undergoing mitosis, was used to lesion striatal somatostatin neurons. Previous [3H]thymidine autoradiographic studies had indicated that striatal somatostatin neurons undergo their final mitotic division at Gestational Days (G) 15 and 16. Therefore, pregnant Sprague-Dawley rats received an intraperitoneal injection of MAM (25 mg/kg) on G15. Neurochemical and histological examination of the mature offspring indicated the loss of half the striatal aspiny interneurons in which somatostatin, neuropeptide Y, and NADPH diaphorase coexist, with relative sparing of the cholinergic interneurons and medium spiny projection cells. This prenatal MAM treatment was without apparent effect on the patch-matrix organization of the striatum.

Animals↗