Maria 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.

The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice

It was shown in the present study that the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine] caused a pronounced and dose-dependent increase in locomotion in mice pretreated with a combination of reserpine and α-methyl-para-tyrosine. Haloperidol pretreatment did not antagonize the MK-801-induced stimulation of locomotion. The findings are discussed in relation to the concept of a corticostriatothalamocortical negative feedback loop serving to protect the cortex from an overload of information and hyperarousal. Such a feedback loop would encompass i.a. corticostriatal glutamatergic neurons and it would be modulated by mesencephalostriatal dopaminergic neurons.

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.

Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice.

The present study corroborates previous findings showing that the selective, non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5 H-dibenzo(a,d)-cyclohepten-5,10-imine] produces a dose-dependent increase in locomotion in mice pretreated with a combination of the monoamine-depleter reserpine and the catecholamine synthesis inhibitor α-methyl-para-tyrosine. Moreover, the present investigation demonstrates a synergistic interaction between MK-801 and the α-adrenergic agonist clonidine in monoamine-depleted mice: MK-803 in a dose of 1 mg/kg and clonidine in a dose of 2 mg/kg hardly affected locomotion when given separately, but when the two drugs were combined a dramatic enhancement of motor activity was observed. This effect was effectively antagonized by the α2-adrenergic blockers idazoxan and yohimbine, as well as by the “atypical” neuroleptic clozapine. Likewise, a clear-cut synergism was observed when a low dose of the dopamine receptor agonist apomorphine (0.1 mg/kg), which did not per se affect motor activity, was combined with MK-801 (1.5 mg/kg); however, the synergism between apomorphine and MK-801 was less dramatic than that observed between MK-801 and clonidine. The results may have important neuropsychiatric implications related to, e.g. the treatment of Parkinsons disease and the pathogenesis of schizophrenia.

NEUROTRANSMITTER ABERRATIONS IN SCHIZOPHRENIA : NEW PERSPECTIVES AND THERAPEUTIC IMPLICATIONS

The dopamine hypothesis has dominated schizophrenia research for decades but is now yielding to a more diversified view, where the interaction of several neurotransmitters in complex circuitries is under scrutiny. Especially, glutamatergic and serotonergic mechanisms are attracting attention. However, the role of dopamine also needs further exploration and may still turn out to have novel therapeutic applications. In the present minireview an attempt is made to integrate preclinical and clinical data on neurotransmitter aberrations in schizophrenia and to discuss their therapeutic implications.

Schizophrenia: From Dopamine to Glutamate and Back

The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.

A regional study of sex differences in rat brain serotonin

1. Male and female rats were compared with respect to serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) levels in five brain regions (brainstem, hypothalamus/preoptic area, corpora striata, limbic forebrain and cortex). Brain 5-HT synthesis rate was also studied in the two sexes. 2. There were no consistent gender differences in the dopaminergic system. 3. In contrast, the serotonergic system was more expressed in females: 5-HT levels were significantly higher in females than in males in the brainstem and limbic forebrain and tended to be so in the cortex. 5-HIAA levels were significantly higher in females in all five brain regions. The 5-HIAA/5-HT ratios were significantly higher in females in the hypothalamus/preoptic area and limbic forebrain and tended to be so in the striatum and cortex. Tryptophan concentrations were significantly higher in females in the brainstem, striatum and cortex. In no brain region were 5-HT, 5-HIAA or tryptophan levels higher in males. Following L-amino acid decarboxylase inhibition 5-hydroxytryptophan (5-HTP) accumulation was more pronounced in the female rat brain. 4. Taken together these results suggest that the brain 5-HT system has a higher potential in female than in male rats. This sex difference is not restricted to a specific region but seems to exist generally in the brain.

(+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia

Dopaminergic agonists and NMDA-receptor antagonists form the basis for the dopamine and glutamate models of schizophrenia, respectively. In human subjects dopaminergic agonists evoke a psychosis resembling positive symptoms of schizophrenia, while NMDA-receptor antagonists produce both positive and negative symptoms. Consequently, the glutamate model may be considered the most complete of the two models. Alterations in animal behaviour, in response to amphetamine or NMDA-receptor antagonists, are widely used to model schizophrenia. NMDA-receptor antagonist induced social withdrawal in rat is an established model for negative symptoms of schizophrenia. In this study we have set up an automated method, based on video tracking, to assess social behaviour, motor activity and movement pattern in rats. This method was then used to evaluate the effects of amphetamine and the NMDA-receptor antagonist (+)-MK-801, administered as single intraperitoneal injections, on rat behaviour. Amphetamine caused significantly increased motor activity and a tendency towards stimulation of social interactions. (+)-MK-801 also stimulated motor activity, but induced a significant inhibition of social interactions. These results indicate that a single injection of (+)-MK-801 to rats models both positive and negative symptoms of schizophrenia. Amphetamine, in contrast, reflects only the positive symptoms of schizophrenia in this model.

Rat brain serotonin: biochemical and functional evidence for a sex difference.

Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the “5-HT behavioural syndrome” was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.

Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats.

THE NMDA receptor antagonist phencyclidine (PCP) has low micromolar affinity for the 5-HT reuptake site, but it is uncertain whether PCP blocks 5-HT reuptake when given systemically to rats in behaviourally stimulating doses. We here report for the first time that systemically administered PCP (5 mg/kg, s.c.) increases extracellular 5-HT levels in the rat medial prefrontal cortex (to 322%) and dorsal hippocampus (to 233%). Increases were found also when citalopram (μM) was included in the perfusion medium (to 184 and 180%, respectively). Extracellular 5-HIAA concentrations increased during both conditions, and extracellular GABA decreased in the dorsal hippocampus. It is concluded that systemic PCP treatment elevates extracellular 5-HT levels, probably through mechanisms other than a blockade of 5-HT reuptake