[Biochemical characterization and differentiation of dopaminergic supersensitivity in the rat]. / Zur Frage der biochemischen Charakterisierung und Differenzierung der dopaminergen Supersensitivität bei der Ratte.

Parameters of dopamine turnover were measured after developing different forms of behaviour facilitation. The state of denervation supersensitivity is characterized biochemically by diminished dopamine turnover and enhanced receptor sensitivity whereas forms of innervation supersensitivity did not show such alterations.

[Dopamine sensitivity of brain-induced behavior after repeated administration of dopamine agonists and antagonists]. / Dopaminsensitivität von Hirngebieten nach wiederholter Gabe von Dopaminagonisten und -antagonisten.

Comparative investigations were carried out on dopamine sensitivity, as judged by the rotational behavior of rats, of different nuclear areas of the central nervous system following repeated application of dopaminergic agonists, or the dopamine antagonist, haloperidol. In the mesolimbic area and in the Nucleus caudatoputamen, repeated pretreatment with amphetamine alone or in combination with another agonist did not result in a change of sensitivity to dopamine. In contrast, dopamine sensitivity of these target areas increased strongly by repeated pretreatment with haloperidol. Pretreatment with dopaminergic agonists distinctly increased the rotation intensity following dopamine injection into the Globus pallidus and Substantia nigra, whereas haloperidole pretreatment reversed the rotational direction after pallidally injected dopamine, and left unaffected the sensitivity of the Substantia nigra. Thus, repeated treatment with dopaminergic agonists produces different patterns of sensibilization. This does lend support to the hypothesis that behavioral facilitation and dopaminergic supersensitivity are mediated differently.

[The effects of REM sleep deprivation on the motor behavior of rats]. / Auswirkungen des REM-Schlafentzuges auf das motorische Verhalten von Ratten.

The effects of rapid-eye-movement (REM) sleep deprivation for 72 h on motor behaviour of rats have been studied. It has been shown both an increased spontaneous locomotor activity and an enhanced rotational behaviour after unilateral intrastriatal injection of dopamine 24 h and 48 h after the end of REM sleep deprivation. The enhancement of motor activity after REM sleep deprivation points to changes in the dopaminergic transmission system. But it is not yet clear, if the main cause of these effects is the development of a super-sensitivity of postsynaptic dopaminergic receptors. In the same way interactions between the dopaminergic system and other inhibitory transmission systems may play an important role, explaining effects of REM sleep deprivation.

[Dopaminergic sensitivity after ethanol pretreatment and its relation to alcohol preference]. / Dopaminerge Sensitivitätsänderungen nach Athanolvorbehandlung und ihre Beziehung zur Alkoholpräferenz.

The interactions between ethanol and the central dopaminergic synaptic transmission also refer to the ethanol drinking behaviour. In mice the alteration of the locomotoric activity induced by apomorphine is influenced by ethanol pretreatment for 28 days in a different way referring to drinking behaviour. Ethanol preferent animals do not differ significantly from the ethanol untreated animals in respect to the apomorphine induced locomotion. The nonpreferent animals show, by comparison, a decrease of the sedative effect of low apomorphine doses (0.25 mg/kg; i.p.) and an increase of the stimulating effect of higher doses (1.0 mg/kg; i.p.). These behavioural alterations may be understood as an expression of dopaminergic presynaptic subsensitivity and of a postsynaptic supersensitivity in ethanol pretreated nonpreferent animals.

[Learning behavior in rats after chronic haloperidol treatment]. / Lernverhalten von Ratten nach chronischer Haloperidolvorbehandlung.

The effect of 3 week chronic haloperidol treatment has been investigated in rats by retention of active avoidance (pole jumping). In the period of dopaminergic supersensitivity, i.e. after withdrawal of haloperidol, pretreated rats showed a better retention of the learned reaction than controls. The results demonstrate that the neuroleptic-induced supersensitivity enhanced not only the spontaneous and stimulated locomotor activity, but also improved the retention of an active avoidance reaction.

Effects of nootropic drugs on dopaminergic systems in the CNS.

The effect of 3 nootropic drugs, meclofenoxat (MEC), piracetam (PIR) and orotic acid (methylglucamine orotate, MGO), on locomotor activity and on rotational behavior after intracerebral injection of dopamine was tested in female Wistar rats. Whereas MGO-pretreatment increased the dopaminergic supersensitivity following repeated haloperidol in both behavioral tests, the other nootropics were without influence on intensity and duration of supersensitivity. Stimulating and sedative action of apomorphine on locomotion (following 2 mg/kg and 40 micrograms/kg apomorphine sc, respectively) was found to be unchanged after single doses of nootropics (300 mg/kg PIR or MEC, 225 mg/kg MGO, 30 min before apomorphine). Preceding systemic application of nootropics did not change the rotational behavior following application of dopamine (200 micrograms/2 microliters) into nucleus accumbens or nucleus caudatoputamen. The results show that nootropic drugs are without influence on spontaneous and dopaminergically stimulated locomotor activity but in contrast to PIR and MEC, MGO is able to facilitate the dopaminergic supersensitivity.

Do cholinomimetics specifically antagonize rotational behavior?

Asymmetries of body posture and movement (rotational behavior) following intracerebral application of dopamine (DA, 200 micrograms/2 microliters) or carbachol (30 and 60 micrograms/2 microliters) were diminished by systemically applied oxotremorine (0.5-1.0 mg/kg IP). The combined intracerebral injections of DA and carbachol show localization-specific effects in caudate nucleus, substantia nigra and globus pallidus. The experiments point to specific dopaminergic-cholinergic interaction in different brain regions. Systemically applied cholinomimetics exert a generally suppressive action on motoric effects.

[Age related alterations of motor behavior and release of dopaminergic supersensitivity in rats]. / Altersbedingte Veränderungen des motorischen Verhaltens und der Auslösbarkeit der dopaminergen Supersensitivität bei Ratten.

Rats aged greater than or equal to 18 months show, aside from clearly diminished motor parameters (exploratory behavior, resting activity, nocturnal activity profile, rotation behavior), after intracerebral dopamine injection a considerably lower apomorphine hypermotility than young animals. The characteristic alteration of activity occurring in young rats during and following chronic administration of haloperidol (1 mg/kg . day, s.c. for 21 days) as an expression of developing dopaminergic supersensitivity does not appear in older animals. Repeated application of amphetamine (2 X 2 mg/kg daily) caused a significant increase in hypermotility. The results are interpreted as the consequence of a age-related reduction of the activity of central-dopaminergic transmission systems and are discussed with regard to possible differences in the realization of agonist- or antagonist-induced supersensitivity.

Effects of preceding sensibilization by reserpine and haloperidol on toxicity of dopaminergic agonists.

The effect of dopaminergic supersensitivity induced by repeated administration of neuroleptics on the toxicity of amphetamine in mice has been examined. As well as haloperidol, reserpine pretreatment increased the toxicity of amphetamine. Combined pretreatment did not cause a further increase of mortality following amphetamine. Dose response curves were not parallel, which might indicate different causes of death in naive and sensitized mice. Pretreatment with haloperidol did not change the toxicity of reserpine. The potentiating effects of neuroleptics on amphetamine toxicity may be connected with their ability to induce supersensitivity to dopaminergic agonists.

[Central depletion of transmitters by reserpine and motor behavior in the rat (author's transl)]. / Zentral Transmitterdepletion durch Reserpin und motorisches Verhalten der Ratte.

Reserpine treatment depletes the catecholamine content in diverse parts of the brain differently. Restoring proceeds slowly with different velocities. Dopaminergic areas tend to a faster repletion than noradrenergic ones. During long-term depletion a recovery of motoric behaviour occurs. This adaptive process is not correlated with the dopamine level in caudate nucleus. The latter depends on the dosage schedule and fails in developing adaptive changes to chronic reserpine administration.

[Supersensitivity by reserpine and means of antagonizing it]. / Supersensitivität durch Reserpin und deren Beeinflussbarkeit.

Single or repeated reserpine application elicited in rats a supersensitivity which is measurable both by the rotation behavior and motor activity. This supersensitivity is accompanied by enhanced responsiveness to unspecific stimuli and increased responsiveness to receptor-active substances (dopamine, noradrenaline, serotonin, carbachol). Pretreatment with actinomycin D can transiently inhibit the development of supersensitivity, while repeated lithium application has no effect on it. The results give evidence for the unspecificity of reserpine-induced supersensitivity, which comprises both aminergic transmission systems and cholinergic systems and can be antagonized by inhibitors of protein synthesis.

[Locomotor activity of rats following chronic pretreatment with haloperidol]. / Lokomotorische Aktivität von Ratten nach chronischer Vorbehandlung mit Haloperidol.

The spontaneous locomotor activity, the nocturnal action profile and exploratory behavior following chronic pretreatment with haloperidole was measured (2 mg/kg daily i. p. for 3 weeks). After this treatment all 3 parameters showed significant changes. The mean values of spontaneous activity during the night and the exploratory behavior during the day were strongly enhanced. The nocturnal action profile showed both amplification and a shift of the activity moves. The results give evidence of an increase and alteration of spontaneous motor actions, correlated with a relatively increased activity of the dopaminergic system due to the pretreatment.

Dopaminergic pathways in the rat central nervous system and rotational behavior.

Unilateral lesion of substantia nigra or ventral tegmental area causes ipsilateral rotational behaviour after receptor stimulation by apomorphine, whereas contralateral rotations were observed after lesion of globus pallidus. The alterations in dopamine and noradrenaline content of relating structures were determined by radiometric microassay. There is no strong correlation between transmitter depletion and motoric asymmetry. The site and extent of lesion seems to be more determinative to motoric disturbances.

Influence of lesion of the median raphe nucleus on motility and dopamine turnover.

Both the spontaneous locomotor activity and the locomotor activity stimulated by apomorphine are enhanced in raphe lesioned animals. The exploratory activity does not show clearcut differences. After unilateral microinjection of dopamine into dopaminergic areas intensity of rotation and dominance of direction are amplified in lesioned animals. Other regions fail to evoke asymmetric or enhanced motoric reactions. The sensitivity of the dopaminergic system of raphe lesioned animals is increased too against unspecific stimulation, but with less strong dominance of direction. The general enhancement of motor activity reflects the inhibitory influence of the serotonergic system. In parallel to the change of behavior we observed a moderate increase of dopamine content connected with an accelerated turnover in lesioned animals.

Pharmacological evidence for dopaminergic pallido-striatal interaction.

In rats the contents in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) of neostriatum (nucleus caudatoputamen, NCP) and paleostriatum (globus pallidus, GP) were measured after transection of the capsula interna (CI) or after injection of 6-hydroxydopamine (6-OHDA; 20 microgram/2 microliter) into the GP of one side. The circling behaviour of the lesioned animals following apomorphine was also studied. 6-OHDA as well as transection decreased the contents in DA and DOPAC in NCP and GP significantly. Following both treatments DA levels in neostriatum were lowest. Nigro-neostriatal pathway lesioned animals (transected or injected with 6-OHDA 16 microgram/2 microliter into substantia nigra, SN) rotated towards the side of lesion after apomorphine (5 mg/kg IP), whereas GP lesioned animals rotated towards the intact side. In animals with both GP and SN lesions at one side turnings of similar intensity towards both sides were seen. In intact rats DA injections (200 microgram/2 microliter) into SN or NCP exhibited contralateral, injections into GP exhibited ipsilateral rotations. The results strengthen the hypothesis on the participation of GP in the regulation of neostriatal content of DA and shows the interaction of the hypothetical dopaminergic pallido-striatal pathway with nigro-neostriatal pathways.

Asymmetric behaviour induced in caudate nucleus lesioned mice: interaction of aminergic and cholinergic agents.

Mice with unilateral caudate lesions exhibit a postural asymmetry or turning towards the lesioned side after application of apomorphine and towards the intact side after oxotremorine injections. The apomorphine effect was counteracted both by oxotremorine and by physostigmine. Both this antagonism and the oxotremorine effect itself were abolished by scopolamine. Adamantine reduced the effectiveness of oxotremorine in inducing asymmetric behaviour. The antagonism of oxotremorine and apomorphine was shifted in parachloramphetamine pretreated mice to an increased apomorphine reaction mode. The significance of lesions became apparent by a 50% decrease of dopamine content in the lesioned side. The 5-hydroxytryptamine content was unchanged. Parachloramphetamine lead to a small alteration of the 5-hydroxytryptamine and 5-hydroxyindolacetic acid content, different in normal and lesioned animals.