Arvid Carlsson

Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson's disease

Recent animal experiments suggest that dopamine plays a less crucial role than formerly supposed in the regulation of psychomotor functions. This is illustrated by the finding that even in the almost complete absence of brain dopamine, a pronounced behavioural activation is produced in mice following suppression of glutamatergic neurotransmission. This paper discusses the possibility that a deficient activity within the corticostriatal glutamatergic/aspartergic pathway may be an important pathophysiological component in schizophrenia, and that glutamatergic agonists may be beneficial in the treatment of this disease. In addition, it is suggested that glutamatergic antagonists may be valuable supplements in the treatment of Parkinsons disease.

Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase activity

WE have previously reported that cutting the nigrostriatal dopamine-carrying axons unexpectedly results in a transient increase in the rate of tyrosine hydroxylation in the rat forebrain (Carlsson, Kehr & others, 1972). It was suggested that striatal tyrosine hydroxylase activity is controlled via dopamine receptors at the synaptic cleft : when the impulse flow is interrupted by axotomy, the concentration of dopamine in the synaptic cleft decreases, and the ensuing reduction of dopamine receptor activity gives rise to a feedback activation of tyrosine hydroxylase, located in the striatal dopaminecarrying nerve terminals. The experiments now reported were made to test the above hypothesis. We argued that stimulation and blockade of dopamine receptors should result in inhibition and activation, respectively, of striatal tyrosine hydroxylase activity. Male Sprague-Dawley rats, 210-340 g, were used. Axotomy of the nigrostriatal dopamine fibres was performed under ether anaesthesia on the left side by means of a transverse cerebral hemisection, as previously described (BCdard, Carlsson&Lindqvist, 1972). At the same time (or in some experiments after 1 h) the aromatic amino-acid decarboxylase was inhibited by an intraperitoneal injection of NSD 101 5 (3-hydroxybenzylhydrazine HCl, 100 mg/kg). The animals were decapitated 30 min after the injection. The forebrains were analysed for dopa (Kehr, Carlsson & Lindqvist, 1972) and dopamine (Atack, to be published). For a direct activation of dopamine receptors, apomorphine HCl, 15 mg/kgf was injected intraperitoneally 7 min before the transection, and for blockade of these receptors haloperidol was given 1 h before the transection ( 5 mg/kg intraperitoneally, for references see AndCn, Carlsson & Haggendal, 1969). In some experiments both agents were given to the same animals. The levels of dopa in the forebrains are given in Fig. 1. As previously reported, inhibition of the aromatic amino acid decarboxylase causes the accumulation of dopa, which cannot be detected in the normal brain. This accumulation appears to be a useful indicator of the rate of tyrosine hydroxylation (Carlsson, Davis & others, to be published). In animals transected and treated simultaneously with NSD 101 5, the

Effect of ethanol on the hydroxylation of tyrosine and tryptophan in rat brain in vivo.

Various doses of ethanol were injected intraperitoneally into rats. After 20 min, 3‐hydroxybenzylhydrazine (NSD 1015), an inhibitor of aromatic amino‐acid decarboxylase was injected and 30 min later the animals were killed. The amount of dopa accumulating in brain as a consequence of decarboxylase inhibition was significantly increased by moderate doses of ethanol (up to 4 g kg−1). There was no corresponding effect on 5‐hydroxytryptophan. The effect on dopa was found both in a dopamine‐ and a noradrenaline‐dominated area of the brain, suggesting that catecholamine synthesis is stimulated by ethanol in both types of neuron. The data lend support to the hypothesis of Carlsson, Engel & Svensson (1972) that cerebral catecholamines are involved in the central stimulation induced by ethanol.

Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia

BACKGROUND Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans. METHODS In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM. RESULTS Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023). CONCLUSIONS The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.

Effects of a new type of 5-HT receptor agonist on male rat sexual behavior

8-Methoxy-2-(di-n-propylamino) tetralin (8-OMe-DPAT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) are two new drugs exerting selective actions on brain 5-HT neurotransmission. In the present experiments we have investigated the effects of these two drugs on male rat sexual behavior. It was found that both drugs reduce the number of intromissions preceding ejaculation and shorten the ejaculation latency. These effects are extremely pronounced and several animals ejaculate at the first intromission. In addition 8-OH-DPAT produced a slight reduction of the post-ejaculatory interval. There were no significant effects on latency to initiate copulation or in the number of mounts preceding ejaculation. Finally, sexual behavior was partly or completely restored in castrated male rats after injection with 8-OMe-DPAT or 8-OH-DPAT.

A method for the determination of 3,4-dihydroxyphenylalanine (DOPA) in brain

SummaryThe method is an extension of the chromatographic separation procedure for 5-HIAA and 5-HTP published by Lindqvist (1971). Brain tissue is extracted with perchloric acid. After adjustment of the pH to 2 the extract is passed through a Dowex 50W, X-4 column. 5-HIAA is eluted with 60% aqueous methanol, DOPA and tyrosine with 0.1 M sodium citrate buffer pH 4.5 and 5-HTP and tryptophan with 0.1 M sodium phosphate buffer pH 6.5. If the above procedure is combined with that published by Atack and Magnusson (1970) 9 different compounds can be estimated after a single column procedure. DOPA is assayed fluorimetrically using a modification of the trihydroxy-indole (THI) assay for noradrenaline (Bertler et al., 1958). The level of DOPA found in a normal rat brain was below the sensitivity of the method (10 ng/g). After inhibition of the aromatic amino acid decarboxylase a compound indistinguishable from authentic l-DOPA accumulated in the rat brain.

Neurotransmitter interactions in schizophrenia--therapeutic implications.

The search for new and improved antipsychotic agents has increased in intensity during the past five years. The era of searching for non-toxic copies of clozapine has been followed by several different lines of research, some of which pursue the traditional dopamine track, although at a higher level of sophistication, whereas others focus on other neurotransmitters, such as serotonin and glutamate. Emerging knowledge about the interactions between different neurotransmitters in complex neurocircuits opens up possibilities for achieving antipsychotic activity by interfering with many different neurotransmitters. Most intriguing is the finding in animal experimental models, indicating that it should be possible to alleviate psychotic conditions by stabilizing rather than paralyzing neurocircuits, thus avoiding the risk of motor and mental side effects of the currently used drugs. Among these new classes, dopaminergic stabilizers and 5-HT2A receptor antagonists appear to offer the most promise at present. In a longer perspective, drugs interfering with glutamate function via different mechanisms may also turn out to be useful, especially in the control of negative symptoms.

3-PPP, a new centrally acting DA-receptor agonist with selectivity for autoreceptors

Abstract The new dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propyl-piperidine, 3-PPP, synthesized in our laboratories, is a central DA-receptor agonist with a pharmacological profile indicative of preferential DA-autoreceptor interactions. This is suggested by the following experimental evidence: 1. a) 3-PPP causes a selective, dose-dependent decrease in rat brain DA-synthesis rate which can be blocked by haloperidol, 2. b) 3-PPP retards brain DA utilization (blocked by haloperidol), 3. c) 3-PPP dose-dependently suppresses spontaneous locomotor activity; the suppression is accompanied by reduced brain DOPAC levels and can be counteracted by an “autoreceptor” dose of haloperidol, 4. d) 3-PPP consistently fails to produce any signs of postsynaptic DA-receptor activation, as indicated by the absence of hypermotility and stereotypies, failure to antagonize the reserpine syndrome and failure to induce ipsilateral turning in unilaterally striatum-lesioned rats. In addition, 3-PPP does not affect the behavioural effects resulting from postsynaptic DA-receptor activation by apomorphine. In conclusion, 3-PPP appears to be a centrally acting, selective DA-autoreceptor agonist. It may prove useful as a tool for elucidating dopaminergic functions and in the treatment of psychotic disorders and other diseases states possibly associated with disturbances in central DA transmission.

Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

The putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) produced in rats an increase in the number of shocks accepted in a modified Vogels conflict test design. Subchronic pretreatment with p-chlorophenylalanine (PCPA) similarly caused release of the punished behavior. This anticonflict effect of PCPA was antagonized by both 5-hydrotryptophan and 8-OH-DPAT. Thus in naive animals 8-OH-DPAT exerting anticonflict effects acted like a 5-HT antagonist, whereas in subchronically PCPA-pretreated animals with presumably supersensitive 5-HT receptors, 8-OH-DPAT decreasing the number of accepted shocks acted like a 5-HT agonist.

Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. I. Review of the evidence.

The behavioural, biochemical, neuroendocrinological and electrophysiological actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, are extensively reviewed. (+)-3-PPP acts in a fashion similar to classical direct-acting DA agonists, stimulating both DA autoreceptors and postsynaptic DA receptors, although in some situations the drug appears to exhibit partial agonist activity. (-)-3-PPP exerts a variety of actions in different pharmacological models. Either agonistic, antagonistic or both agonistic and antagonistic activity are observed depending on the anatomical location of the relevant DA receptors and the experimental conditions. The actions of transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline (HW 165) are also discussed. These agents possess a similar spectrum of action to (-)-3-PPP suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors. Finally, evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors.