Jørgen Scheel-Krüger

Behavioural stimulation induced by muscimol and other GABA agonists injected into the substantia nigra

The unilateral injection of putative GABA agonists, muscimol, baclofen, imidazole acetic acid and GABA into the caudal area of substantia nigra (SN, zona reticulata) induced immediately a contralateral turning, whereas the antogonists picrotoxin and bicuculline methiodide induced ipsilateral turning. In the rostral area picrotoxin induced contralateral turning. Muscimol (10 ng bilaterally injected into SN) induced behavioural stimulation and antagonism of catelepsy in rats pretreated with high subcutaneous doses of perphenazine, haloperidol or reserpine and alpha-methyltyrosine. The muscimol behavioural stimulation seems dependent on a non-catecholaminergic neuronal pathway, probably present in the SN with GABA as the mediating neurotransmitter.

Cocaine: Discussion on the Role of Dopamine in the Biochemical Mechanism of Action

The central stimulant effect of cocaine is generally considered related to its potentiating effect on biogenic amines. However, the individual role and significance of the amines involved in various stimulant effects of cocaine are still a controversial topic. Cocaine is a potent inhibitor of noradrenaline uptake (Hertting, Axelrod, and Whitby, 1961; Ross and Renyi, 1967; Langer and Enero, 1974; Azzaro, Ziance, and Rutledge, 1974), dopamine uptake (Fuxe, Hamberger, and Malmfors, 1967; Ross and Renyi, 1967; Harris and Baldessarini, 1973; Heikkila, Orlansky, Mytilineou, and Cohen, 1975), and serotonin uptake (Ross and Renyi, 1969; Friedman, Gershon, and Rotrosen, 1975). High affinity uptake of tryptophan into synaptosomes is also inhibited (Knapp and Mandell, 1972). In vivo studies have shown that cocaine induces a short-lasting uptake inhibition into brain tissues of noradrenaline (Schanberg and Cook, 1972), dopamine (Fuxe, Ham-berger, and Malmfors, 1967), and serotonin (Ross and Renyi, 1969).

Relation of spatial learning of rats in the Morris water maze task to the number of viable CA1 neurons following four-vessel occlusion.

Male Wistar rats were tested in the Morris water maze task 1 week after 6, 9, or 12 min of transient global ischemia. The 9-min and 12-min ischemia groups were significantly impaired in the acquisition and the reversal experiment. A systematic counting of CA1 neurons in the whole hippocampal formation revealed a unilateral number of CA1 neurons of 286,000 in the sham group, of which 2/3 were located in the dorsal hippocampus. The ischemia groups showed a significant decline in the number of dorsal CA1 neurons, whereas only the 12-min ischemia group showed a significant but minor decline (10%-15%) in the number of ventral CA1 neurons. A correlation analysis showed that the escape distance declined with increasing number of viable CA1 neurons, but poor correlation coefficients were obtained. Thus, some of the ischemic rats with even very few viable CA1 neurons in the dorsal hippocampus were capable of performing this spatial learning task at sham-group level.

GABA in the ventral tegmental area: differential regional effects on locomotion, aggression and food intake after microinjection of GABA agonists and antagonists.

Abstract The potent and specific GABA agonists muscimol and THIP have been injected into the caudal and rostral parts of the ventral tegmental area (VTA) containing the A 10 dopaminergic cell bodies. Muscimol (10 and 25 ng), THIP (100–500 ng) and GABA (100 μg) all induced a compulsive hypermotility with low exploratory activity following bilateral injection into the caudal VTA. In addition, the rats showed fighting, attack behavior and increased food intake. The hypermotility was attenuated by picrotoxin (3 mg/kg), haloperidol (0.1–0.5 mg/kg) and completely prevented by reserpine (7.5 mg/kg) plus α-methyltyrosine (200 mg/kg). Picrotoxin (100 ng) injected into the caudal VTA induced mild sedation whereas bicuculline methiodide (BMI) (120 ng) induced convulsions. Morphine (5 μg) injected bilaterally into the caudal VTA induced a different behavioral stimulation shown as rearing, motility, sniffing and licking. Bilateral apomorphine (5 μg) and carbachol (2.5 μg) injections into caudal VTA produced sedation and catalepsy. In the rostral VTA muscimol and THIP decreased spontaneous activity, whereas BMI and picrotoxin induced strong hypermotility. The results indicate that different kinds of hyperactivity can be elicited from the VTA and it is suggested that this reflects the regional and topographical organization of the VTA dopamine projections to cortical and limbic areas. The effects of GABA agonists injected into caudal VTA seem to mimic the effects described after electrolytic or 6-hydroxydopamine lesions of VTA, whereas the morphine response resembles the behavioral stimulation produced by systemic administration of dopaminergic stimulants such as amphetamine or cocaine.

GABAergic and glycinergic mechanisms within the substantia nigra: Pharmacological specificity of dopamine-independent contralateral turning behavior and interactions with other neurotransmitters

The pharmacological specificity of the GABA agonist muscimol-induced contralateral turning behavior after unilateral injection into substantia nigra pars reticulata (SNR) has been studied. Muscimol-induced turning was antagonized by intranigral bicuculline methochloride (BMC) and picrotoxin, whereas antagonists of glycine, morphine, dopamine, noradrenaline, and serotonin were ineffective. Glycine induced a qualitatively similar turning behavior which was strychnine-sensitive but relatively BMC and picrotoxin-insensitive. Other drugs, including substance P, kainic acid, clonidine, oxymetazoline, serotonin, and carbachol, induced turning that could be dissociated from the effect of muscimol. Muscimol-induced turning was dopamine-independent, indicated by resistance to haloperidol (1 mg/kg), to pretreatment with reserpine (7.5 mg/kg) plus α-methyl-p-tyrosine (200 mg/kg), to haloperidol injections into the SNR, striatum and nucleus accumbens, and finally to kainic acid lesions of the striatum. 6-Hydroxydopamine lesions increased the efficacy of intranigral muscimol, while kainic acid lesions of the SNR antagonized muscimol. Muscimol-induced turning was inhibited by oxotremorine (0.25 mg/kg), by intranigral carbachol, and by apomorphine (0.1–0.5 mg/kg), but only moderately by intranigrally injected apomorphine. These data suggest specificity of GABA-agonist-induced contralateral turning and indicate an interaction between nigral GABA and other neurotransmitters, particularly dopamine and acetylcholine.

Cueing effects of amphetamine and LSD: elicitation by direct microinjection of the drugs into the nucleus accumbens.

Two groups of rats were trained to discriminate either d-amphetamine sulphate (AMPH; 1 mg/kg) or d-lysergic acid diethylamide bitartrate (LSD; 0.16 mg/kg). Microinjection of AMPH into the nucleus accumbens elicited a cueing effect which was similar to that of systemically administered AMPH in AMPH-trained animals (ED50 was 0.24 micrograms). Co-injection of (-)-sulpiride (50 or 100 ng) into the accumbens antagonized the effect of a fixed dose of AMPH (1 microgram) which, alone, produced 76% of the systemic AMPH cue effect. Microinjections of AMPH (1-5 micrograms) into either the anterior dorsomedial or the anterior ventrolateral striatum failed to elicit the cueing effect of AMPH. In LSD-trained animals a dose of 1 microgram LSD injected into the accumbens produced 84% of the systemic cueing effect of LSD. These results suggest that dopamine (DA) receptors in the nucleus accumbens are involved in AMPH discrimination. Furthermore, since both classical and atypical antipsychotic drugs block the AMPH cue, the results provide indirect evidence for involvement of mesolimbic DA in antipsychotic drug action.

Evidence that the anticonflict effect of midazolam in amygdala is mediated by the specific benzodiazepine receptors.

The benzodiazepine midazolam produced an anticonflict effect in rats measured in a water lick paradigm following local injection into the basolateral and lateral complex of the amygdala. This effect of midazolam seems to involve specific benzodiazepine receptors, since the systemic injection of benzodiazepine antagonists Ro 15-1788, ZK 93426, FG 7142 and CGS 8216 produced strong antagonism of the effect of midazolam in doses not affecting the non-punished drinking behaviour.

Studies of Various Amphetamines, Apomorphine and Clonidine on Body Temperature and Brain 5-Hydroxytryptamine Metabolism in Rats

Amphetamine and various amphetamine derivatives, phenmetrazine, pipradrol, methylphenidate and NCA can increase the concentration of 5-HIAA in the rat brain without changing that of 5-HT. Metamphetamine produced a decrease in 5-HT and no effect on 5-HIAA whereas p-hydroxyamphetamine produced no effects on 5-HT and 5-HIAA. The experiments performed at different environmental temperatures (12–14‡C, 21–22‡C and 21–28‡C) with simultaneous measurements of the body temperature indicate that no simple correlation exists between the drug induced hyperthermia and the effect on 5-HIAA. The amphetamine and phenmetrazine effect on 5-HIAA seems to be related to hyperthermia whereas the pipradrol and methylphenidate effect on 5-HIAA appears independent of hyperthermia. Apomorphine (2×2.5 mg/kg) which activates central dopamine receptors produced a significant increase in 5-HIAA whereas clonidine (0.5 mg/kg) which activates central noradrenaline receptors produced a significant decrease in 5-HIAA.In conclusion, the effect of various amphetamines on 5-HT metabolism seems very complex in mechanism of action and might be related to hyperthermia, to a direct effect on 5-HT neurons and to the ratio between central dopamine/noradrenaline receptor activation of these drugs.

Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.

Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.

Intranigral gaba antagonists produce dopamine-independence biting in rats

Behavioural effects following bilateral intranigral administration of GABA antagonists have been investigated. Bicuculline methiodide (BMI), picrotoxin and isopropylbicyclophosphate all induced biting behaviour, teeth-chattering and chewing. Sub-threshold doses for biting induced locomotor activity and sniffing. The strongest response was observed after injection into the caudal pars reticulata, whereas weaker effects were seen after injection into the rostral pars reticulata or the pars compacta. The biting induced by intranigral BMI was not antagonized by prior catecholamine depletion with reserpine plus alpha-methyl-p-tyrosine or by dopamine receptor blockade with haloperido. Concomitant intranigral injection of the GABA agonists muscimol and THIP, however, completely antagonized biting. Systemic GABAergic drugs also antagonized the BMI-induced biting: the benzodiazepine, diazepam and the GABA transaminase inhibitor, gamma-acetylenic GABE, were most effective, whereas muscimol was only partially effective and THIP was without effect. It is suggested that this animal model may be used for the evaluation of antidyskinetic drugs.