Biomedical subjects

H C Fibiger

Publications and source records attributed to H C Fibiger.

At least 145 records · Page 8Linked to original sources

PubMed1987

Increased in vivo tyrosine hydroxylase activity in rat telencephalon produced by self-stimulation of the ventral tegmental area.

Changes in the activity of dopaminergic neurons associated with intracranial self-stimulation of the ventral tegmentum were assessed by measuring the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD-1015. When compared to implanted unstimulated controls, DOPA concentrations were elevated significantly in the nucleus accumbens, striatum and olfactory tubercle in the hemisphere ipsilateral to the electrode, after a 30 min session of self-stimulation. The concentration of DOPA in the contralateral nucleus accumbens and striatum did not differ from control levels, although relative to control values it was significantly increased in the contralateral olfactory tubercle. A similar analysis of in vivo tyrosine hydroxylase activity in these brain regions following a 30 min session of lever pressing for food reward on a fixed-ratio (FR-8) schedule failed to reveal any significant changes relative to control subjects. These results are consistent with a role for dopamine in brain-stimulation reward obtained from electrical stimulation of the ventral tegmental area but do not provide evidence for dopaminergic mediation of the rewarding properties of food.

Animals↗

PubMed1987

Effects of haloperidol and d-amphetamine on perceived quantity of food and tones.

The hypothesis that dopamine (DA) receptor agonists and antagonists affect "hedonia" associated with natural rewards was tested, using a psychophysical procedure previously shown to be sensitive to both the sweetness of food and the motivational state of rats. Rats were first trained to discriminate between two different quantities of a rewarding stimulus by pressing one of two levers. Perceived quantity was subsequently derived from generalization trials of intermediate quantities. Haloperidol (0.03-0.083 mg/kg), a DA receptor antagonist, did not influence perceived food quantity, an indirect marker of hedonic value. On the other hand, d-amphetamine (0.25-1.0 mg/kg) affected perceived food quantity in a dose-dependent fashion, and in the same direction as occurs after increasing hunger or food sweetness. Both haloperidol and amphetamine influenced the perceived quantity of a stimulus without natural reinforcing properties (a tone), but the effect of amphetamine on the perceived quantity of this initially neutral stimulus was opposite in direction to that observed with food. These results suggest that whereas amphetamine affects hedonic processes, haloperidol does not. In addition, it seems that haloperidol probably produces its actions through effects on motor mechanisms or by interfering with the response-facilitating properties of rewards.

Animals↗

PubMed1987

Apparent absence of nicotine-induced conditioned place preference in rats.

The conditioned place preference (CPP) paradigm was used in order to assess the reinforcing actions of nicotine in rats. Subjects were tested in "unbiased" two-compartment shuttle boxes, so-called because neither compartment was consistently preferred prior to drug conditioning. In the first experiment, subjects that were initially drug naive showed neither a preference nor an aversion to the compartment that had been paired on four occasions with injection of nicotine (0.2-0.8 mg/kg SC); a similar result occurred in another group given daily injections of nicotine in the home cage prior to the experiment. In a second experiment, nicotine (0.4, 0.8 mg/kg SC) again failed to produce a CPP, whereas marked CPPs were seen in parallel groups of rats tested with either d-amphetamine or methylphenidate. Although nicotine has been reported to produce conditioned place preference, the present results suggest that it is not a robust phenomenon.

Animals↗

PubMed1987

Neuroleptic-induced oral dyskinesias: effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities.

The development of vacuous chewing movements (VCMs), and changes in glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in extrapyramidal nuclei were examined in rats treated chronically with neuroleptics. Animals were injected with flupenthixol (FLU) or haloperidol (HAL) decanoate for 16, 40 or 48 weeks and were then sacrificed. Another group of rats was treated with FLU or HAL for 48 weeks, and then withdrawn from the neuroleptics for 16 weeks before sacrifice. VCMs were assessed weekly, and the effects of the GABA agonist progabide on VCMs and locomotor activity were examined. GAD and ChAT activities were determined at death. The concentrations of Calbindin D28K (CaBP) and parvalbumin (PV) were determined in rats receiving 48 weeks of neuroleptic treatment. VCMs first appeared after 8-10 weeks of neuroleptic administration, reached asymptotic rates after 18-20 weeks, and then remained stable for the remainder of the chronic drug administration period. During withdrawal, there was a steady decline in the VCM rate. The GABA receptor agonist progabide reduced VCMs and locomotor activity. Significant decreases in nigral GAD activity were observed after 40, but not after either 16 or 48 weeks of neuroleptic administration. CaBP and PV were unchanged after 48 weeks of neuroleptic treatment. In addition, ChAT activities in 16, 40 or 48 week treated animals did not show consistent changes after either neuroleptic. Chronic neuroleptic administration followed by 16 weeks of withdrawal also did not have any significant effects on GAD or ChAT activity in any of the brain areas examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Intravenous self-administration of the short-acting benzodiazepine midazolam in the rat.

Intravenous self-administration of the short-acting benzodiazepine midazolam was assessed in rats under conditions of unlimited access to the drug (24 hr/day). Evaluation of the temporal pattern of responding within a session revealed that maximal responding occurred during the dark phase of the 12 hr light/dark cycle. Upon attaining stable rates of responding for midazolam, the rats were tested under extinction conditions (saline). Responding progressively decreased with repeated extinction sessions. Over the course of subsequent reacquisition sessions responding increased, such that asymptotic levels of responding were similar to, or greater than, the rates obtained during the initial acquisition phase. In addition, the total number of sessions required to approach asymptote were fewer than during the initial acquisition phase. Thus, rats given continuous access to midazolam exhibited reliable and stable rates of intravenous self-administration of this short-acting benzodiazepine.

Animals↗

PubMed1987

Dissociation of dopaminergic and non-dopaminergic substrates for cues produced by electrical stimulation of the ventral tegmental area.

The present study provides evidence for the existence of multiple substrates for cues produced by electrical stimulation of the ventral tegmental area in rats. Two different procedures were employed to assess the effects of amphetamine and haloperidol on the discrimination of high and low intensity cues produced by electrical brain stimulation (EBS). When the procedure involved frequent presentation of brief trials, amphetamine and haloperidol had no effect on the discrimination of EBS. In contrast, when the trials were less frequent and extended in duration, amphetamine enhanced the perceived intensity of the cues whereas haloperidol had the opposite effect. These results indicate that the use of different discrimination procedures may result in the measurement of separate dopaminergic and non-dopaminergic substrates for cue properties of EBS in the ventral tegmental area.

Amphetamine↗

PubMed1987

Differential effects of physostigmine on cues produced by electrical stimulation of the ventral tegmental area using two discrimination procedures.

Two procedures were employed to assess the effects of physostigmine on the discrimination of cues produced by either high or low intensity electrical brain stimulation (EBS) of the ventral tegmental area in rats. When the procedure involved frequent presentation of brief trials, physostigmine enhanced the perceived intensities of the cues, causing the rats to respond to low intensities as though they had higher values. In contrast, physostigmine had no effects on the discrimination when the trials were less frequent and extended in duration. These results confirm the existence of multiple substrates for cues produced by stimulation of the ventral tegmental area in rats and implicate cholinergic neurons as substrates for the non-dopaminergic cues identified in the companion paper.

Animals↗

PubMed1987

Factors affecting the stability and separation of biogenic amines and their metabolites. Simultaneous measurement by HPLC with electrochemical detection.

We describe a simple and sensitive method for the rapid and simultaneous quantification of dopamine, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan in the picogram range in small samples of brain tissue. After minimal sample preparation the amines were analyzed utilizing isocratic separation and reversed-phase high-performance liquid chromatography with amperometric detection. The effects of pH and methanol concentration in the solvent on the retention times of the amines on two different C-18 columns were investigated. Stabilities of the amines in solution were determined under various conditions. Light and air were found to be detrimental to the stability of indoles. In the absence of light, their stability was dependent on temperature and the presence of air; however, in the absence of air, light and/or temperature had little effect. The catechols were stable under most of these conditions. The assay has been applied to study the postmortem stability of dopamine, serotonin, and their metabolites in the striatum of rat brain. In the striatum 4 hr after death, the content of dopamine and 3,4-dihydroxyphenylacetic acid decreased by less than 20%, and 3-methoxytyramine increased by 158%, with no changes in serotonin, 5-hydroxyindoleacetic acid, and homovanillic acid.

Animals↗

PubMed1987

Physiological evidence for subpopulations of cortically projecting basal forebrain neurons in the anesthetized rat.

Sixty-three cortically projecting basal forebrain neurons were identified in chloral hydrate anesthetized rats by antidromic activation from the cerebral cortex. Two subpopulations were noted: type I neurons exhibited two antidromic action potentials of constant latency and identical waveform in response to double pulse cortical stimulation. In contrast, type II neurons exhibited two antidromic action potentials of constant latency but differing waveforms in response to the double pulse paradigm. The phenomenon exhibited by type II cortically projecting basal forebrain neurons is interpreted as evidence for loss of the somatodendritic portion of the antidromic action potential with high frequency stimulation. The median latency to antidromic activation of type II neurons (13.5 ms) was significantly longer than that of type I neurons (3.9 ms). Spontaneous firing rates varied over a wide range (0-49 Hz), and there was no significant difference between the rates of type I and type II neurons. These data underscore the physiological heterogeneity of this presumptive cholinergic cortical afferent system. Anatomical studies have shown that most, but possibly not all cortically projecting basal forebrain neurons are cholinergic. The relative proportions of type I (87%) and type II (13%) neurons encountered in this study suggest that type I neurons might be cholinergic and type II neurons non-cholinergic. If substantiated, this hypothesis would permit cholinergic and non-cholinergic cortically projecting basal forebrain neurons to be distinguished using a simple test of antidromicity.

Afferent Pathways↗

PubMed1987

Morphology of cortically projecting basal forebrain neurons in the rat as revealed by intracellular iontophoresis of horseradish peroxidase.

The intracellular horseradish peroxidase technique was employed to study the morphology of basal forebrain neurons that were identified as cortically projecting by antidromic invasion from the cerebral cortex. Four neurons were examined in detail; they were located at different rostrocaudal levels within the basal forebrain. Their somata were large, 30-50 microns in longest dimension, and gave rise to three to eight primary dendrites, which ramified into third- to fifth-order dendrites. The longest observed dendrite in each neuron terminated at a distance of 600-900 microns from the soma. The sizes of soma and dendritic field of the two most rostrally located cells were smaller than those of the other two cells located more caudally. Dendritic spines were seen in all four cortically projecting basal forebrain neurons. Spines had shafts of variable lengths, and usually had spherical or elongated heads. The density of spines varied among the four neurons; one neuron, a type II cortically projecting basal forebrain neurons as defined physiologically by Reiner et al., had a much greater number of dendritic spines than the other three neurons, which were type I neurons. No somatic spines were observed. Presumptive axons were identified in three of the four cortically projecting basal forebrain neurons. These axons originated from either the soma or a primary dendrite, and two of them gave off local collaterals, which displayed occasional bouton-like swellings. The above observations confirm and extend previous findings that cortically projecting neurons in the basal forebrain are large multipolar cells, and provide evidence to support the conclusion that these cells, although somewhat variable in size, generally have extensive dendrites which display frequent spines.

Afferent Pathways↗

PubMed1987

Neurotransmitters in the mammalian striatum: neuronal circuits and heterogeneity.

The major input and output pathways of the mammalian striatum have been well established. Recent studies have identified a number of neurotransmitters used by these pathways as well as by striatal interneurons, and have begun to unravel their synaptic connections. The major output neurons have been identified as medium spiny neurons which contain gamma-aminobutyric acid (GABA), endogeneous opioids, and substance P. These neurons project to the pallidum and substantia nigra in a topographic and probably chemically organized manner. The major striatal afferents from the cerebral cortex, thalamus, and substantia nigra terminate, at least in part, on these striatal projection neurons. Striatal interneurons contain acetylcholine, GABA, and somatostatin plus neuropeptide Y, and appear to synapse on striatal projection neurons. In recent years, much activity has been directed to the neurochemical and hodological heterogeneities which occur at a macroscopic level in the striatum. This has led to the concept of a patch-matrix organization in the striatum.

Acetylcholine↗

PubMed1987

Dopamine and preparatory behavior: I. Effects of pimozide.

The involvement of dopaminergic systems in appetitive and ingestive feeding behaviors was investigated in two experiments. Conditioned preparatory responses to a conditional stimulus (CS+) signaling delivery of a meal were attenuated in rats by doses of 0.4 and 0.6 mg/kg of the dopamine receptor antagonist pimozide. In contrast, animals responded in a normal fashion following the delivery of food. Similarly, in a separate study, the 20-min free-feeding intake of liquid diet by rats that had been deprived of food for 23 hr was unaffected by doses of pimozide as high as 0.6 mg/kg. These findings are consistent with the involvement of dopamine in the production of preparatory behaviors elicited by incentive stimuli.

Animals↗

PubMed1987

The role of dopamine in intracranial self-stimulation of the ventral tegmental area.

The role of dopaminergic (DA) neurons in brain stimulation reward produced by electrical stimulation of the ventral tegmental area (VTA) was investigated in the rat. In the first experiment, extensive 6-hydroxydopamine lesions of the ascending fibers of the mesotelencephalic DA projections resulted in significant changes in intracranial self-stimulation (ICS) rate-current intensity functions when the lesion was ipsilateral to the stimulating electrode. Similar contralateral lesions had no effect on these functions, thus ruling out lesion-induced performance deficits as being responsible for the decreases in ICS rates across the wide range of current intensities that occurred after the ipsilateral lesions. In the second experiment, ICS obtained from electrodes in the VTA resulted in significant increases in the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, nucleus accumbens, and olfactory tubercle ipsilateral to the stimulating electrode. The ratios of DOPAC and HVA to DA, considered to be indices of DA utilization, were also increased in these brain regions ipsilateral to the electrode. No changes were observed in the contralateral striatum, nucleus accumbens, and olfactory tubercle. Similar increases were observed in stimulated "yoked" animals that received brain stimulation at identical rates and currents but did not lever-press for this stimulation. The third experiment examined the effects of lever-pressing for food on an FR8 schedule of reinforcement on DA utilization in the striatum, nucleus accumbens, and olfactory tubercle. Despite high rates of responding, no effects were observed on DOPAC:DA or HVA:DA ratios in these brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Cholinergic neurons of the laterodorsal tegmental nucleus: efferent and afferent connections.

The ascending projections of cholinergic neurons in the laterodorsal tegmental nucleus (TLD) were investigated in the rat by using Phaseolus vulgaris leucoagglutinin (PHA-L) and wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) anterograde tracing techniques. Two ascending pathways were identified after iontophoretic injections of PHA-L into the TLD. A long projection system courses through the dorsomedial tegmentum, caudal diencephalon, medial forebrain bundle, and diagonal band. Different branches of this system innervate the midbrain (superior colliculus, interstitial magnocellular nucleus of the posterior commissure, and anterior pretectal nucleus), the diencephalon (lateral habenular nucleus, parafascicular, anteroventral, anterodorsal, mediodorsal, and intralaminar thalamic nuclei), and the telencephalon (lateral septum and medial prefrontal cortex). The second system is shorter and more diffuse and innervates the median raphe, interpeduncular, and lateral mammillary nuclei. Retrograde tracing with WGA-HRP, combined with choline acetyltransferase immunohistochemistry, revealed that most of the TLD projections to the tectum, pretectum, thalamus, lateral septum, and medial prefrontal cortex are cholinergic. Afferents to the TLD were studied by anterograde and retrograde tracing techniques. Injection of tracers into the TLD retrogradely labelled neurons bilaterally in the midbrain reticular formation, the periaqueductal gray, the medial preoptic nucleus, the anterior hypothalamic nucleus, and the perifornical and lateral hypothalamic areas. Retrogradely labelled cells were also located bilaterally in the premammillary nucleus, paraventricular hypothalamic nucleus, zona incerta, and lateral habenular nucleus. In the telencephalon, the nucleus of the diagonal band and the medial prefrontal cortex contained retrogradely labelled neurons ipsilateral to the TLD injection site. The projections of the medial prefrontal cortex, the bed nucleus of the stria terminalis, and the lateral habenular nucleus to the TLD were confirmed in anterograde tracing studies. These findings indicate that the TLD gives rise to several ascending cholinergic projections that innervate diverse regions of the forebrain. Afferents to the TLD arise in hypothalamic and limbic forebrain regions, some of which appear to have reciprocal connections with the TLD. The latter include the lateral habenular nucleus and medial prefrontal cortex.

Animals↗

PubMed1986

The effect of pramiracetam (CI-879) on the acquisition of a radial arm maze task.

The effect of the nootropic drug pramiracetam (CI-879) on acquisition of a radial arm maze task was examined in the rat. Two doses of pramiracetam (7.5 mg/kg and 15 mg/kg) were administered daily prior to testing for 7 weeks in a 16-arm radial maze in which nine arms were baited with food. This procedure permitted a distinction between working memory (short-term) and reference memory (long-term). Both doses of pramiracetam significantly improved performance in the reference memory component of the task, but did not significantly affect the working memory component. These data indicate that pramiracetam can enhance some aspects of spatial learning and memory in the rat.

Animals↗

PubMed1986

6-Hydroxydopamine lesions of the medial prefrontal cortex fail to influence intravenous self-administration of cocaine.

It has been suggested that the initiation and maintenance of cocaine self-administration (SA) is critically dependent on the dopaminergic (DA) projection to the medial prefrontal cortex (mPFC). Evidence for this hypothesis has been obtained from intracranial SA of cocaine, but a role of the mPFC in IV cocaine SA has not been established. The present experiment investigated the effect of destruction of DA-containing terminals in the mPFC on the rate and pattern of IV cocaine SA. Rats were trained to self-administer cocaine during daily 3-h sessions. After stable response patterns were obtained, the rats received either bilateral injections of 6-hydroxydopamine (6-OHDA) into the mPFC, or sham operations. The lesions did not affect either the rate or pattern of IV cocaine SA, despite producing substantial DA depletions in the mPFC. Thus, the mPFC does not appear to be a critical substrate for the maintenance of IV cocaine SA. The 6-OHDA lesions of the mPFC resulted in an apparent increase in DA turnover in both the striatum and the nucleus accumbens, suggesting that DA terminals in the mPFC may have an inhibitory influence on the activity of subcortical DA projections.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

The effects of haloperidol on amphetamine- and methylphenidate-induced conditioned place preferences and locomotor activity.

Place preferences induced by the indirect dopamine (DA) receptor agonists amphetamine (AMP) and methylphenidate (MPD) were investigated using an unbiased compartment procedure. In this procedure, prior to drug conditioning, rats did not exhibit preferences for either of the two compartments in a shuttle box. Both stimulants produced place preferences. Repeated testing of the MPD conditioned animals revealed an extinction-like decrease in preferences, suggesting that place preferences produced by MPD result from conditioning of MPD's reinforcing properties to environmental cues. During conditioning, the DA receptor antagonist haloperidol was administered prior to drug (S+) treatments, or prior to both drug and vehicle (S-) treatments. Haloperidol pretreatment blocked place preferences induced by AMP but not by MPD. In contrast, haloperidol blocked locomotor activity stimulated by either AMP or MPD. These results suggest that the reinforcing properties of MPD and AMP may be mediated by different mechanisms, while the locomotor stimulant effects of the two drugs have common neural substrates.

Animals↗

PubMed1986

Cholinergic innervation of the rat's labyrinth.

Efferent vestibular and cochlear neurons were identified in the rat's brain stem by retrograde labelling with True Blue (TB) or wheat germ agglutinin - horseradish peroxidase (WGA-HRP) injected into the utricle. Such cells were found at the same locations described in 1983 by White and Warr (ipsilateral superior olivary nucleus (LSO), bilateral latero-ventral nucleus of the trapezoid body (LTz) bilateral group E medial and lateral to the genu facialis) and, in addition, bilaterally in the caudal pontine reticular nucleus (CPR) at the level of the descending facial nerve. Cholinergic neurons were identified by counterstaining sections containing TB filled perikarya for acetylcholinesterase (AChE) following pretreatment with diisopropylfluorophosphate (DFP) or choline acetyltransferase (ChAT), by immunohistochemistry with highly specific monoclonal antibodies. Many, but not all, vestibular efferent cell bodies located in group E were shown to be cholinergic. These and other recently published data suggest that the efferent octavus system may consist of a number of chemically distinct cell groups.

Acetylcholinesterase↗