Hans Fibiger - Academia.edu (original) (raw)

Papers by Hans Fibiger

Brain Research, 1990

Central dopamine transmission was examined in the nucleus accumbens and striatum of sexually expe... more 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.

Pharmacology Biochemistry and Behavior, 1984

ASIN, K. E. AND H. C. F1BIGER. tqnce requirement~ in h'ver-pre,s,~ing aml responding a l?er halop... more ASIN, K. E. AND H. C. F1BIGER. tqnce requirement~ in h'ver-pre,s,~ing aml responding a l?er haloperidol. PHARMACOI, BIOCHEM BEHAV 2th3) [323][324][325][326] 1984.--One hypothesis regarding the actions of neuroleptic drugs on operant responding is that they interfere in some manner with the motoric capability of the animal. To further explore this possibility, we investigated the effects of haloperidol on a bar press response after animals were trained on levers with different force requirements. In the first experiment, two groups of rats were trained to press levers having either low (30 g) or high ( It30 g) force requirements. The effects of haloperidol on bar pressing when both groups were responding on the light lever v, erc then examined. Under these conditions, the groups showed similar declines in response rates, indicating little transfer between previous experience on the heavy lever and responding in the presence of halopcridol. In the second experiment, the same groups of rats received further training exclusively on either the heavy or the light lever: the rate of responding was similar for the two groups. The effects of haloperidol on pressing either the heavy or the light lever were then examined. It was found that the rate-decreasing effects of haloperidol were similar in both groups. However, when the lever-pressing response was subsequently extinguished, rats working on the heavy lever were significantly more resistant to extinction than the light lever groups. The results of these experiments fail to indicate that the putative motoric effects of haloperidol interact significantly with response force demands. Furthermore, the data provide yet further evidence that blockade of dopamine receptors and removal of reinforcement are not equivalent.

Life Sciences, 1982

The effects of central norepinephrine depletion produced by DSP-4 on drug-induced catalepsy and p... more The effects of central norepinephrine depletion produced by DSP-4 on drug-induced catalepsy and pot-decapitation convulsions were examined in the rat. Haloperidol-induced catalepsy was potentiated in DSP-4 treated rats, while arecoline-induced catalepsy was attenuated. Furthermore, post-decapitation convulsions were eliminated in DSP-4 treated animals. DSP-4 may prove to be a useful tool with which to investigate the behavioral consequences of damage to the locus coeruleus noradrenergic system.

Brain Research, 1983

Key words: locomotor activity -limbic-midbrain region -serotonin -behavior -nucleus medianus raph... more Key words: locomotor activity -limbic-midbrain region -serotonin -behavior -nucleus medianus raphe -5,7-dihydroxytryptamine Electrolytic lesions of the median nucleus of the raphe (MR) are known to result in large increases in motor activity. The present studies were concerned with identifying the neuronal elements within or near the M R (e.g. fibers of passage, serotonergic or non-serotonergic cells) which, when destroyed, lead to these increases in ambulation. Groups of rats were given either an electrolytic MR lesion or were injected locally with the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or the excitotoxin ibotenic acid, and their subsequent locomotor activities were compared in the open field and in photocell cages.

Behavioural Brain Research, 1984

Key words: nucleus medianus raphe -serotonin -lesion -median raphe -spontaneous alternation -dela... more Key words: nucleus medianus raphe -serotonin -lesion -median raphe -spontaneous alternation -delayed spatial alternation -serotonin and behavior -rat

Molecular Brain Research, 1992

The influence of cocaine self-administration on the expression of messenger RNAs for dynorphin, e... more The influence of cocaine self-administration on the expression of messenger RNAs for dynorphin, enkephalin and substance P was analyzed in the rat striatum with in situ hybridization histochemistry. Cocaine, an indirect dopamine agonist, was found to differentially affect the levels of mRNA encoding these neuropeptides in different subregions of the striatum. Following a 7 day period of variable free access to cocaine, dynorphin and substance P mRNA levels were elevated throughout the striatum, but the increases were substantially greater in the dorsal striatum than in the nucleus accumbens. Enkephalin mRNA was not significantly altered in the dorsal striatum but was slightly elevated in the nucleus accumbens. These results suggest that cocaine self-administration has differential effects on striatonigral and striatopallidal projection neurons, and that these effects vary in subregions of the striatum.

European Journal of Pharmacology, 1991

... Acknowledgements Erin Brown is supported by a Medical Research Council of Canada Studentship.... more ... Acknowledgements Erin Brown is supported by a Medical Research Council of Canada Studentship. This work was supported by the Medical Re search Council of Canada (PG23). References DeliniStula. ... 6(1. 27.1. Muscat. R.. D. Sampson und P. Willner. 1WO. ...

Neuroscience, 1992

The potent reinforcing effects of cocaine can readily become associated with salient environ-

Annals of the New York Academy of Sciences, 1992

Ciba Foundation symposium, 1992

Cocaine has potent pharmacological actions on a number of monoaminergic systems in the brain, inc... more 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 do...

Experimental Brain Research, 1989

Two experiments were conducted to determine the effects of conditioned circling on the concentrat... more Two experiments were conducted to determine the effects of conditioned circling on the concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) within discrete regions of the striatum (STR). The first study assessed the inherent regional distributions of these compounds with respect to the three primary axes: anterior-posterior, dorsal-ventral and medial-lateral. Concentrations of DA, DOPAC and HVA and the ratios of each metabolite to DA were found to vary across each dimension. However, the topographical distribution of each compound was unique. The results of the first experiment confirm that the STR is not a homogeneous structure. It is possible that the regional variations in dopamine metabolism underly the diverse functions which the STR is thought to modulate. The second experiment determined whether specific regions of the STR were differentially involved in the mediation of conditioned circling. DA metabolism, as estimated by metabolite concentrations and metabolite to DA ratios, was bilaterally increased within the anterior dorsomedial and dorsolateral STR, relative to noncircling, water-deprived controls. DOPAC and the corresponding ratio were enhanced selectively within the dorsomedial region, whereas HVA and its ratio to DA were increased preferentially within the dorsolateral STR. The ratio of DOPAC to DA was also enhanced within the anterior ventromedial STR. No other significant neurochemical effects were detected. These results support the hypothesis that the dorsal STR critically subserves circling. Moreover, it is possible that the medial and lateral regions of the dorsal STR are differentially involved in circling. These results also confirm previous reports of bilateral augmentation of striatal DA Offprint requests to: H.C. Fibiger (address see above) metabolism in association with high rates of conditioned circling.

Behavioural Brain Research, 1986

Rotation induced by electrical stimulation of the medial forebrain bundle at the level of the lat... more Rotation induced by electrical stimulation of the medial forebrain bundle at the level of the lateral hypothalamus was associated with increases in dopamine (DA), 3,4-dihydroxypbenylacetic acid (DOPAC) and homovanillie acid (HVA) in the striatum ipsilateral to the site of stimulation (i.e. contralateral to direction of turning). The concentrations ofDA, DOPAC and HVA within the nucleus accumbens (NAS) were not altered. In the olfactory tubercle (OT), concentrations of DA and both metabofites were, in general, elevated ipsilateral to the electrode. However, relative to non-stimulated controls, HVA concentrations were increased bilaterally in rats exhibiting circling. Stimulation-induced circling also resulted in a bilateral enhancement of striatal serotonin (5-HT) metabolism as indicated by elevated 5-hydroxyindoleacetic acid: 5-HT ratios. No changes in 5-HT metabolism were observed in the NAS. The utilization of 5-HT was elevated in the OT ipsilateral to the electrode in rats that exhibited stimulation-induced rotation. While most subjects that exhibited contraversive rotation in response to the stimulation demonstrated enhanced DA activity, the neuroehemical changes were not observed in all subjects. As such, it is concluded that while stimulation of the mesotelencephalic DA system can be associated with stimulation-induced rotation it is not necessary for its elicitation.

Behavioural Pharmacology, 1989

The present experiments further characterized intravenous self-administration of the short-acting... more The present experiments further characterized intravenous self-administration of the short-acting benzodiazepine midazolam in rats under conditions of unlimited access to the drug. The results of the first experiment demonstrated that rats responded at higher rates on a lever that produced an infusion of 0.05mg midazolam than on a lever that did not result in reinforcement, and that they transferred responding to the other lever when the reinforcement contingencies were reversed. These results provide further evidence of the reinforcing effects of midazolam. In the second experiment, rats responding at stable rates for 0.05mg midazolam per infusion exhibited increased responding when transferred to a lower dose (0.0125mg/infusion) and decreased responding when transferred to a higher dose (0.20mg/infusion) of the drug. However, the inverse relationship between responding and drug dose was apparent only during the first transfer session, after which no consistent relationship was observed. In support of previous observations, all rats exhibited a temporal pattern of responding for midazolam over the 24h sessions, with maximal responding occurring during the dark phase of the 12h light/dark cycle. However, the present results also provide preliminary evidence that rats given prolonged access to midazolam (more than 49 days) develop a more constant within session pattern of responding for midazolam. This may be related to the development of physical dependence and reflect an attempt to avoid withdrawal effects by maintaining a stable intake of midazolam within a session.

Neuroscience, 1988

High rates of conditioned circling have previously been associated with a bilateral augmentation ... more High rates of conditioned circling have previously been associated with a bilateral augmentation of striatal dopamine metabolism. These results suggest that both striata subserve this response. The present experiment further assessed this po~ibiIity by d~te~ining the effects of unilateral ~hydroxydopamine lesions of the mesoteIen~phaiic dopamine system on conditioned circling. Rats were initially trained to circle in their preferred direction for water reinforcement. Upon establishment of this response, they received unilateral lesions at the level of the lateral hypothalamus either contralateral or ipsilateral to the reinforced direction of circling. Reinforced responding was virtually abolished in rats with contralateral lesions. In contrast, rats lesioned ipsilateral to the direction of reinforced circling exhibited only a 50% decrease in rate of reinforced responding. Non-reinforced responding was increased only in rats with contralaterally placed lesions. Following 5 postoperative test sessions, the experimental contingencies were reversed. 'Ipsilater~ly lesioned' rats were now required to circb away from their lesion whereas 'contraiateratly Iesioned' rats had to turn towards their lesion. The 'Contralateral' group acquired the reversal, such that reinforced responding occurred more frequently than non-reinforced responding. However, reinforced rates of responding did not reach preoperative rates. Conversely, 'ipsilaterahy lesioned' rats could not learn to turn contraversively and now made more non-reinforced than reinforced responses.

Behavioral Neuroscience, 1989

High rates of conditioned circling have been associated with a bilateral increase in striatal (ST... more High rates of conditioned circling have been associated with a bilateral increase in striatal (STR) dopamine (DA) metabolism in rats. Experiments 1 and 2 examined the extent to which inherent directional biases, which are critical in determining the magnitude and direction of drug-induced circling, would influence the acquisition and performance of conditioned circling. No behavioral effects were evident. However, a symmetrical bilateral enhancement in DA metabolism was observed in the STR irrespective of directional biases. These results provide further evidence for the bilateral involvement of the mesotelencephalic DA projection in conditioned circling. Although conditioned circling could be established and maintained by reinforcing the response with food (Experiment 3), food itself influenced DA metabolism and therefore precluded the detection of changes in DA metabolism specific to the circling response. Specifically, DA metabolism was augmented to a similar extent in animals given noncontingently presented food.

British Journal of Pharmacology, Mar 1, 1990

1 B-HT 920, a D2 dopamine receptor agonist, was tested for its ability to exert presynaptic actio... more 1 B-HT 920, a D2 dopamine receptor agonist, was tested for its ability to exert presynaptic actions in normosensitive rats, and for possible postsynaptic actions in rats made 'supersensitive' to apomorphine. 2 In normosensitive rats, B-HT 920 (0.01-0.3mg kg-1, i.p.) increased dopamine concentrations and lowered metabolite levels to a similar extent in all four terminal regions examined (medial prefrontal cortex, olfactory tubercle, nucleus accumbens, caudate-putamen). Analogous effects were seen for 5hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid. 3 Rats which received bilateral 6-hydroxydopamine (6-OHDA) infusions into the caudate-putamen showed signs of postsynaptic dopamine receptor activation (stereotyped behaviour) in response to B-HT 920 (0.1 and 1.0mgkg-1, i.p.) and to apomorphine (0.2mgkg-1, s.c.). Similarly, B-HT 920 (0.1 mgkg 1) induced contralateral circling in rats that had received unilateral 6-OHDA infusions into the medial forebrain bundle; the rate of circling increased gradually over several weeks. 4 In contrast, bilateral 6-OHDA infusions into the nucleus accumbens resulted in a supersensitive (locomotor stimulant) response to a low dose of apomorphine (0.1 mgkg 1, s.c.), but not to B-HT 920 (0.01 and 0.1 mgkg'-).

Science, 1978

Kainic acid lesion of cell bodies in the dorsal striatum enhanced the stereotypy-producing effect... more Kainic acid lesion of cell bodies in the dorsal striatum enhanced the stereotypy-producing effects of d-amphetamine without affecting the stereotypy produced by the direct receptor agonist apomorphine. This pattern of results parallels that found in patients suffering from Huntington's chorea, thus strengthening the parallels between the kainic acid animal model and the human disease state initially suggested on biochemical grounds. The present results further suggest a dissociation of the mechanisms involved in the production of stereotypy by these two drugs, perhaps in terms of differential involvement of the striato-nigral negative feedback loop.

Neuropsychopharmacology, 1991

This study examined the effects of electroconvulsive shock (ECS) on interstitial concentrations o... more 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.

Synapse, 1995

Psychostimulant drugs have been reported to increase the expression of some immediate-early genes... more Psychostimulant drugs have been reported to increase the expression of some immediate-early genes in the cerebellum. In the present study, immunohistochemical techniques were used to assess the pattern of c-fos expression in the cerebellum produced by d-amphetamine or cocaine. Systemic administration of d-amphetamine (1.5, 6 mg/kg) or cocaine (10, 20 mg/kg) increased locomotor activity, which at low doses was blocked by pretreatment with the dopamine D1 receptor antagonist SCH 23390 (1 mg/kg). Within the cerebellum, basal levels of c-fos expression were abolished by SCH 23390, with the exception of lobule VI. Dose-dependent increases in Fos-like immunoreactivity were elicited by d-amphetamine and cocaine. Pretreatment with SCH 23390 greatly reduced the extent to which either stimulant increased c-fos expression. Psychostimulant-induced Fos-like immunoreactive nuclei were generally restricted to the granule cell layer within each of the midvermal cerebellar lobules (I-X), although occasional nuclei were found in the Purkinje cell layer. In addition, a homogeneous pattern of Fos-like immunoreactive nuclei, of sparse density, was also found near the pial surface of the molecular layer following d-amphetamine but not cocaine. Within the granule cell layer dense clusters of Fos-like immunoreactive neurons extended from the molecular layer to the Purkinje cell layer and were found at both the pial surface as well as in the deep portions of individual folia. These data add to a growing body of evidence indicating that the induction of regionally specific alterations in c-fos expression by psychostimulants is mediated via a D1 receptor mechanism.

European Journal of Pharmacology, 1990

The effect of selective D1 receptor agonists on acetylcholine (ACh) release in the striatum was i... more 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.