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H C Fibiger

Publications and source records attributed to H C Fibiger.

At least 55 records · Page 3Linked to original sources
PubMed1994

Induction patterns of Fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity.

Clozapine and haloperidol produce different induction patterns of c-fos expression in the forebrain, with haloperidol increasing Fos-like immunoreactivity (FLI) in the striatum, nucleus accumbens, lateral septal nucleus and clozapine producing such effects in the nucleus accumbens, prefrontal cortex and lateral septal nucleus. Accordingly, it was deemed possible that this approach may be useful in characterizing compounds with known or suggested antipsychotic actions. We therefore examined the effects of 17 compounds considered to be either typical, or atypical, antipsychotics on FLI in the prefrontal cortex, medial and dorsolateral striatum, nucleus accumbens and the lateral septal nucleus. Consistent with the hypothesis that the prefrontal cortex may be a target for some antipsychotic actions, FLI was elevated in this structure by clozapine, ICI 204,636, fluperlapine, RMI-81,582, remoxipride, molindone, melperone and tiospirone. Likewise, the ability of all of the compounds, except for risperidone, to enhance FLI in the lateral septal nucleus suggests that this limbic region also may be an important locus of antipsychotic action. All of the compounds examined elevated FLI in the nucleus accumbens and medial striatum, indicating that potential antipsychotic activity is predicted most consistently on this basis. Neuroleptics with a clearly documented liability for producing extrapyramidal side effects (EPS) such as chlorpromazine, fluphenazine, haloperidol, loxapine, metoclopramide and molindone elevated FLI in the dorsolateral striatum. In contrast, compounds unlikely to produce EPS such as clozapine, thioridazine, risperidone, remoxipride, fluperlapine, sulpiride, melperone and RMI-81,582 either failed to increase or produced minor elevations in FLI in the dorsolateral striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

State-dependent release of acetylcholine in rat thalamus measured by in vivo microdialysis.

Mesopontine cholinergic neurons have long been thought to play a key role in behavioral state control. In particular, they have been implicated in the process of EEG desynchrony and in the generation of rapid eye movement (REM) sleep. However, the behavioral profile of identified mesopontine cholinergic neurons has not been unequivocally demonstrated. In an attempt to address this issue, in vivo microdialysis was used to monitor acetylcholine (ACh) release across behavioral state in the rat thalamus, a major projection site of mesopontine cholinergic neurons. Because REM periods in rats are of short duration, a method was developed to collect and accumulate sufficiently large samples from each of the individual states of wake, slow-wave sleep, and REM sleep to permit off-line analysis via (HPLC-ECD). Probe placement and the source of cholinergic innervation to the vicinity of the microdialysis probe were verified using retrograde tracing combined with ChAT immunohistochemistry. Finally, the sodium and calcium dependence of ACh measured in the thalamus were tested using TTX and calcium-free dialysates. The results showed that (1) extracellular ACh concentrations in the thalamus are high during both wake and REM sleep and significantly lower during slow-wave sleep, (2) the majority of cholinergic projections to the vicinity of the dialysis probes originate in the mesopontine tegmentum, and (3) ACh release in the thalamus is due to sodium- and calcium-dependent mechanisms. In contrast to predictions of some previous hypotheses, these results demonstrate that mesopontine cholinergic neurons are active during both wake and REM sleep.

Acetylcholine↗
PubMed1993

ECS-induced dopamine release: effects of electrode placement, anticonvulsant treatment, and stimulus intensity.

Although electroconvulsive therapy (ECT) remains an important therapy for severe depression, its mechanism of action remains elusive. We previously demonstrated that there is a significant increase of interstitial dopamine of neuronal origin in the rat striatum after electroconvulsive shock (ECS) but not after chemically (flurothyl) induced seizures. The present studies examined how electrode placement, stimulus intensity, and the administration of an anticonvulsant affect ECS-induced dopamine release in the rat striatum. Bilateral electrode placement resulted in greater dopamine release than that produced by a unilaterally applied stimulus. Pretreatment with sodium pentobarbital markedly decreased seizure duration but had no effect on the magnitude of the increase in interstitial dopamine. Finally, a higher voltage applied longer resulted in greater dopamine release without a concomitant increase in seizure duration. These data suggest that the passage of current may be directly responsible for certain ECS-induced chemical changes. These findings are discussed in the context of clinical observations that challenge the traditional view that the production of generalized seizures of adequate duration is both necessary and sufficient for a therapeutic response to ECT.

Animals↗
PubMed1993

Dopamine transmission increases in the nucleus accumbens of male rats during their first exposure to sexually receptive female rats.

In vivo microdialysis was used to monitor extracellular concentrations of dopamine (DA), and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the nucleus accumbens of sexually naive male rats during their first exposure to sexually receptive or nonreceptive females. DA, DOPAC, and HVA increased progressively and significantly in males that copulated to ejaculation with receptive females. In contrast, DA, DOPAC, and HVA did not increase significantly in males exposed to non-receptive females, despite several attempts by these males to mount the non-receptive females. These results indicate that DA is released unconditionally in the nucleus accumbens of male rats by exposure to sexually receptive female rats, and that copulation with intromission, but not mounting alone, leads to further increases in DA release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Electrical stimulation of reward sites in the ventral tegmental area increases dopamine transmission in the nucleus accumbens of the rat.

In vivo microdialysis with HPLC-ED was used to measure dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens of the rat, prior, during, and after 15-min periods of electrical brain stimulation at sites in the ventral tegmental area (VTA) that supported intracranial self-stimulation (ICSS). In the first experiment, both ICSS and yoked stimulation of the VTA evoked significant increases in extracellular concentrations of DA, its metabolites, and 5-HIAA. Comparable results from ICSS and yoked groups were interpreted as evidence that the rewarding properties of VTA stimulation were a causal factor in the elevated DA transmission in the nucleus accumbens, rather than intense operant behavior. Further evidence for this hypothesis came from a second set of data in which changes in extracellular DA levels during the measurement of rate/intensity functions for ICSS were positively correlated. 5-HIAA concentrations also increased during ICSS but these changes were not correlated with either ICSS rate or current intensity, suggesting that changes in serotonin metabolism were unlikely to subserve brain stimulation reward in the VTA. These results add to the growing body of evidence linking changes in extracellular DA in the mesolimbic DA system with both brain stimulation reward and the conditioned and unconditioned rewarding effects of biologically relevant stimuli.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Enhanced stress-induced dopamine release in the prefrontal cortex of amphetamine-sensitized rats.

This study examined the extent to which chronic d-amphetamine administration sensitizes animals to some behavioral and neurochemical effects of foot shock stress. Rats received daily injections of saline for 14 days or d-amphetamine (2 mg/kg 7 days and 4 mg/kg 7 days). After a 7 day drug abstinent period, extracellular dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations were measured in the medial prefrontal cortex using in vivo microdialysis in freely moving rats. The behavioral responses to mild foot shock stress were enhanced in the d-amphetamine-pretreated subjects. Concomitant with this behavioral sensitization, d-amphetamine-pretreated subjects showed greater stress-induced increases in extracellular dopamine in the medial prefrontal cortex than in controls. d-Amphetamine (2 mg/kg)-induced stereotyped behavior was also enhanced in the amphetamine-pretreated animals compared to controls; however, d-amphetamine-induced increases in extracellular dopamine in the medial prefrontal cortex were not enhanced in the amphetamine-pretreated group. These results suggest that the mesocortical dopaminergic system is involved in cross-sensitization between d-amphetamine and stress, but not in d-amphetamine-induced behavioral sensitization.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference.

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This type of classical conditioning is of considerable clinical relevance, as intense drug craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. Given the large body of evidence that implicates the amygdaloid complex in the learning of stimulus-reward associations, the present experiments examined the effects of quinolinic acid lesions of the amygdala on cocaine-induced conditional locomotion and conditioned place preference (CPP). Destruction of the amygdala did not affect basal or cocaine-induced locomotion, suggesting that the amygdala does not mediate the unconditioned psychomotor stimulant effects of this drug. Preconditioning lesions also failed to affect cocaine-induced conditional locomotion. Specifically, exposure of both lesioned and non-lesioned rats to a cocaine-paired environment produced significant conditional increases in locomotion. This lack of effect was contrasted by a complete blockade of cocaine-induced CPP by the amygdaloid lesions. These data demonstrate that cocaine-induced stimulus-reward conditioning can be differentially affected by lesions of the amygdala.

Amygdala↗
PubMed1993

Dopaminergic regulation of cortical acetylcholine release: effects of dopamine receptor agonists.

The regulation of the basal forebrain cholinergic system by D1 and D2 dopamine receptors was assessed in the rat using in vivo microdialysis of cortical acetylcholine. The D1 agonist CY 208-243 significantly increased cortical acetylcholine release; in contrast, the D2 agonists quinpirole and (+)-4-propyl-9-hydroxynaphthoxazine were without significant effects. Moreover, when administered in combination with CY 208-243, quinpirole failed to potentiate the D1 agonist-induced increases in cortical acetylcholine release. The non-selective dopamine receptor agonist apomorphine also increased cortical acetylcholine release, and this was completely blocked by the selective D1 receptor antagonist SCH 23390 and slightly, but not significantly attenuated by the D2 antagonist raclopride. The present results indicate that stimulation of D1 receptors activates cortically-projecting cholinergic neurons; however, a minor contribution of D2 receptors cannot be excluded.

Acetylcholine↗
PubMed1993

Electrical stimulation of the medial prefrontal cortex increases dopamine release in the striatum.

Exogenous and endogenous glutamate has been shown to evoke dopamine (DA) release in the striatum using both in vitro and in vivo techniques. We hypothesized that stimulation of the prefrontal cortex (PFC) would phasically enhance striatal DA release via the glutamatergic corticostriatal pathway. To test this hypothesis, in vivo brain microdialysis was employed to measure extracellular concentrations of DA in the striatum during electrical stimulation of the PFC. Five rats were implanted with bilateral electrodes located in the medial PFC and dialysis probes in the dorsal striatum. Two days later the PFC of these awake, freely moving rats was stimulated first at 50 microA and then at 100 microA for 20 minutes at 2-hour intervals. Both currents significantly increased DA release. Extracellular DA rose rapidly during stimulation, peaked immediately afterward, and then slowly returned to baseline values. Dopamine reached 118% of baseline values with 50 microA stimulation and 138% with 100 microA stimulation. Histologic analysis using the fluorescent retrograde dye Fluoro Gold confirmed that cells projecting to the vicinity of the striatal dialysis probe originated in the vicinity of the PFC electrodes. These results provide direct evidence for phasic, excitatory modulation of striatal DA release by the PFC.

Animals↗
PubMed1993

In vivo comparisons of the effects of quinpirole and the putative presynaptic dopaminergic agonists B-HT 920 and SND 919 on striatal dopamine and acetylcholine release.

The extent to which the putative dopamine (DA) autoreceptor agonists B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5d]azepine dihydrochloride) and SND 919 (2-amino-4,5,6,7-tetrahydro-6-propylamino- benzthiazol dihydrochloride) and the potent D2 receptor agonist quinpirole have differential effects on pre- and postsynaptic DA receptors was determined by using in vivo microdialysis to monitor the effects of these compounds on extracellular concentrations of DA and acetylcholine (ACh) in the striata of freely moving rats. B-HT 920 and SND 919 reduced interstitial concentrations of DA, but not ACh, when administered s.c. at doses of 0.05 and 0.1 mg/kg. Quinpirole (0.05 and 0.2 mg/kg) decreased extracellular concentrations of both DA and ACh. Hence, relative to its effects on DA, quinpirole was more potent than the other drugs at DA receptors controlling ACh release. These results are consistent with the hypothesis that B-HT 920 and SND 919 have preferential actions on DA autoreceptors. Local application of the selective D2 receptor antagonist raclopride produced similar dose-dependent increases in DA and ACh release. It is unlikely therefore that differences in the degree to which endogenous DA inhibits transmitter release from nigrostriatal terminals and cholinergic neurons can account for the greater sensitivity of the former to the depressant actions of systemically administered B-HT 920 and SND 919. As was the case with systemic administration, local striatal application of B-HT 920 produced larger decreases in extracellular DA than ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro- and antero-grade transport and immunohistochemical study.

Increasingly strong evidence suggests that cholinergic neurons in the mesopontine tegmentum play important roles in the control of wakefulness and sleep. To understand better how the activity of these neurons is regulated, the potential afferent connections of the laterodorsal (LDT) and pedunculopontine tegmental nuclei (PPT) were investigated in the rat. This was accomplished by using retrograde and anterograde axonal transport methods and NADPH-diaphorase histochemistry. Immunohistochemistry was also used to identify the transmitter content of some of the retrogradely identified afferents. Following injections of the retrograde tracer wheatgerm agglutinin-conjugated horseradish peroxidase (WGA-HRP) into either the LDT or the PPT, labelled neurons were seen in a number of limbic forebrain structures. The medial prefrontal cortex and lateral habenula contained more retrogradely labelled neurons from the LDT, whereas in the bed nucleus of the stria terminalis and central nucleus of the amygdala, more cells were labelled from the PPT. Moderate numbers of neurons were seen in the magnocellular regions of the basal forebrain, and many labelled neurons were observed in the lateral hypothalamus, the zona incerta, and the midbrain central gray from both the LDT and the PPT. Accessory oculomotor nuclei in the midbrain as well as eye movement-related structures in the lower brainstem contained some neurons labelled from the LDT, and fewer neurons from the PPT. A few labelled neurons were seen in somatosensory and other sensory relay nuclei in the brainstem and the spinal cord. Retrograde labelling was seen in a number of extrapyramidal structures, including the globus pallidus, entopenduncular and subthalamic nuclei, and substantia nigra following PPT injections; with LDT injections, labelling was similar in density in the substantia nigra but virtually absent in the entopeduncular and subthalamic nuclei. Data with the fluorescent retrograde tracer fluorogold combined with immunofluorescence indicated that many neurons in the zona incerta-lateral hypothalamic region that were retrogradely labelled from the LDT contained alpha-melanocyte-stimulating hormone. Numerous neurons were labelled throughout the reticular formation of the brainstem following either LDT or PPT injections. Many neurons retrogradely labelled in the LDT and PPT, the dorsal and median raphe nuclei, and the locus ceruleus contained choline acetyltransferase, serotonin, and tyrosine hydroxylase, respectively. The anterograde tracers WGA-HRP and phaseolus vulgaris leucoagglutinin were used to confirm some of the projections indicated by the retrograde labelling data; anterograde labelling was seen in the LDT and PPT following injections of one of these tracers into the medial prefrontal cortex, lateral hypothalamus, and the contralateral LDT.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1992

Lesions of the mesotelencephalic dopamine system enhance the effects of selective dopamine D1 and D2 receptor agonists on striatal acetylcholine release.

In vivo microdialysis was used to determine the effects of 6-hydroxydopamine (6-OHDA) lesions of the mesotelencephalic dopamine system on dopamine receptor agonist induced changes in extracellular acetylcholine (ACh) concentrations in the striatum. Such lesions increased the inhibitory effect of a low dose of the D2 receptor agonist quinpirole (0.05 mg/kg s.c.) on striatal ACh release. In addition, 6-OHDA lesions enhanced the facilitatory effect of the selective D1 receptor agonist CY 208-243 on striatal ACh release, enabling a subthreshold (0.2 mg/kg s.c.) dose to increase striatal dialysate concentrations of ACh by over 60%. These results indicate that denervation supersensitivity potentiates both the facilitatory effects of D1 receptor agonists and the inhibitory effects of D2 receptor agonists on striatal cholinergic activity. It was also found that the 6-OHDA lesions reduced basal interstitial ACh concentrations by 75% in the ipsilateral striatum. The later results are consistent with the hypothesis that the prepotent action of dopamine in the forebrain is to enhance striatal ACh release via a D1 receptor mechanism.

Acetylcholine↗
PubMed1992

Scopolamine attenuates haloperidol-induced c-fos expression in the striatum.

Haloperidol increases the expression of Fos, the protein product of the proto-oncogene c-fos, in some parts of the central nervous system. Haloperidol also produces catalepsy in rodents and extrapyramidal side effects in humans, both of which are reduced by muscarinic receptor antagonists. In order to gain insight into the neurochemical and neuroanatomical substrates of haloperidol-induced catalepsy we examined the effects of the muscarinic receptor antagonist scopolamine on haloperidol-induced Fos expression in the striatum, nucleus accumbens and lateral septal nucleus. At a dose that reduced the cataleptic effect of haloperidol, scopolamine decreased the neuroleptic-induced Fos expression in the striatum and lateral septal nucleus but not the nucleus accumbens. These results indicate that haloperidol may increase c-fos expression in medium spiny striatal neurons indirectly by enhancing striatal acetylcholine release. They are also consistent with the hypothesis that neuroleptic-induced increases in striatal c-fos expression are predictive of extrapyramidal side effects produced by these compounds.

Animals↗
PubMed1992

The neurobiology of cocaine-induced reinforcement.

Cocaine has potent pharmacological actions on a number of monoaminergic systems in the brain, including those that use noradrenaline, dopamine and serotonin as neurotransmitters. There is growing evidence that cocaine's effects on dopaminergic neurons, particularly those that make up the mesolimbic system, are closely associated with its rewarding properties. For example, low doses of dopamine receptor antagonists reliably influence cocaine self-administration, whereas noradrenaline and serotonin receptor antagonists are without consistent effects. Similarly, selective lesions of dopaminergic terminals in the nucleus accumbens, a major target of the mesolimbic dopamine projection, disrupt cocaine self-administration in a manner that is consistent with loss of cocaine-induced reward. The introduction of in vivo brain microdialysis as a tool with which to investigate the neurochemical correlates of motivated behaviour has provided new opportunities for investigating the role of dopamine in the nucleus accumbens in the acquisition and maintenance of cocaine self-administration. Although the body of literature that has been generated by this approach appears to contain some important inconsistencies, these probably reflect the use of inappropriate microdialysis conditions by some investigators. A critical review of the literature suggests that microdialysis results are generally consistent with a role for mesolimbic dopamine in cocaine-induced reward, although it does not seem to be the case that animals will work to maintain consistent increases in extracellular concentrations of dopamine in the nucleus accumbens in all experimental conditions. Elucidation of the complete neural circuitry of cocaine-induced reward remains an important priority for future research.

Animals↗
PubMed1992

Dopaminergic regulation of cortical acetylcholine release.

The extent to which the activity of basal forebrain cholinergic neurons is influenced by dopamine (DA) was investigated using in vivo microdialysis of cortical acetylcholine (ACh). Systemic administration of the DA receptor agonist apomorphine significantly increased dialysate concentrations of ACh. Systemic, but not local, administration of d-amphetamine produced similar effects. Both D1 (SCH 23390) and D2 (haloperidol, raclopride) DA receptor antagonists attenuated the amphetamine-induced increase in cortical ACh release; however, only the D1 antagonist significantly reduced basal output of cortical ACh. These findings suggest that the activity of cortically projecting cholinergic neurons in the nucleus basalis is regulated in an excitatory manner by central dopaminergic neurons and that both D1 and D2 receptors are involved.

Acetylcholine↗
PubMed1992

Benzodiazepine-induced decreases in extracellular concentrations of dopamine in the nucleus accumbens after acute and repeated administration.

In vivo microdialysis was used to assess the effects of acute and repeated injections of the benzodiazepine midazolam on extracellular dopamine (DA) concentrations in the nucleus accumbens. Acute administration of midazolam (5 mg/kg, SC) elicited a 22% decrease in extracellular DA in the nucleus accumbens but failed to affect DA concentrations in the striatum. Similarly, six spaced intravenous infusions of midazolam, at a dose that has previously been found to support self-administration (0.05 mg per infusion), produced a 50% decrease in extracellular DA in the nucleus accumbens. In order to assess the effects of subchronic midazolam injections, two groups of rats were given injections of saline or midazolam (5 mg/kg, SC) for 14 days (two injections per day). A subsequent challenge injection of midazolam (5 mg/kg) decreased extracellular DA in the nucleus accumbens by 25% in both groups, indicating that neither tolerance nor sensitization occurred during the repeated drug administration. These experiments indicate (1) that midazolam differentially affects meso-accumbens and nigrostriatal DA neurons, and (2) that the midazolam-induced decrease in extracellular DA in the nucleus accumbens is not affected by repeated drug administration. The data further suggest that the rewarding effects of midazolam are not associated with increased release of DA in the nucleus accumbens.

3,4-Dihydroxyphenylacetic Acid↗