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Delusional disorder is characterized by mono-symptomatic paranoid symptoms without other schizophrenic symptoms. Thus, delusional disorder can be a good clinical model for investigating the molecular genetic mechanisms for paranoid symptoms. In this study, we hypothesized that a hyperdopaminergic state in the brain is responsible for producing paranoid symptoms. To test this hypothesis, we (1) compared neuroleptic responses between patients with delusional disorder and schizophrenia, (2) measured plasma levels of homovanillic acid (pHVA), an indicator of brain dopamine activity, in patients with delusional disorder, and (3) analysed the polymorphism of dopamine receptors (DRs) and its synthesizing enzyme gene.

Current modelling of carotid body (CB) chemotransduction postulates an essential role for neurotransmitters, including dopamine (DA). Catecholamines (CA) released from incubated/superfused cat CBs has often been reported to diminish rapidly over the course of the exposure. The purpose of the first set of experiments was to determine the effects of including L-dihydroxyphenylalanine (L-DOPA), the immediate precursor to DA, in the incubation medium. CBs were removed from deeply anesthetized cats, cleaned of connective tissue, and placed in separate incubation tubes containing Krebs Ringer Bicarbonate solution (KRB) at 37 degrees C. One tube contained 40 microM L-DOPA. Both tubes were bubbled for 2 hr with a normoxic gas mixture (21% O2/6% CO2). This was followed immediately by a 30-minute exposure to a hypoxic gas mixture (4% O2/5% CO2). The mean amounts of DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and norepinephrine (NE) released during 30 min exposures were always greater when L-DOPA was present. The use of gas mixture like the above normoxic gas mixture in incubation studies has often been considered quasi-hypoxic. Hence, in a second set of experiments we tested the effect of high oxygen mixture (95% O2/5% CO2). All other features of these experiments were the same as the above. The high oxygen environment correlated with lower DA release suggesting a reduced excitation/inhibition. The subsequent exposure to hypoxia, however, provoked a much larger release of DA and NE. The data demonstrate the substantial effect of oxygen on the release of CAs and the apparent need of a DA precursor like L-DOPA to allow detection of the changes in CA release from the CBs upon exposure to a hypoxic stimulus.

As is known, brain dopamine is metabolised by the enzymes monoamine oxydase and catechol-O-methyl transferase into the final metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The very existence of two main pathways of this process gives rise to some important and so far untackled questions: what is the reason of there being two, in what way are they related and what mechanisms underlie the trafficking? In earlier studies on 8 inbred mouse strains, we established that there was a negative genotypic correlation between brain levels of DOPAC and HVA (1). At the same time, we demonstrated that while the level of either metabolite undergoes genetically defined changes, the others may remain unchanged. Rats selected for lack of aggressiveness, displayed a lower level of HVA in nucleus accumbens (2), while those selected for predisposition to catalepsy displayed a higher one (3), levels of DOPAC in both staying unchanged. These data on selective changes in HVA level in n. accumbens imply that the idea that both ways of dopamine metabolism are open at a time or that they are reciprocal, should be replaced by the hypothesis of a more or less independent functioning of either.

Alcohol has a wide range of biochemical and physiological effects on the central nervous system. It has been reported to cause disturbances in cellular metabolism, induce cellular stress as indicated by increased expression of heat shock protein mRNA, inhibit the activities of several enzymes, increase production of free radicals, induce apoptosis, alter the function of a variety of neurotransmitter systems, etc. Several studies have also provided evidence that dopaminergic neurotransmission is affected by alcohol. The effect is dependent on the concentration of alcohol given and the experimental model used. Alcohol, in in vitro studies, has been shown to significantly inhibit dopamine release from striatal slices4,15,17,25 and striatal synaptosomes.15 Acute doses of alcohol (1–3 g/kg), however, have been reported to increase dopamine release and/or turnover as evaluated by increased level of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).3,7,12,16,20 Imperato and Di Chiara,11 using in vivo microdialysis, demonstrated that alcohol, at 0.5–2.5 g/kg, elevated dopamine release in the nucleus accumbens and to a lesser extent in the caudate. In contrast, in studies on anesthetized rats, addition of alcohol to the dialysate caused a dose dependent increase in dopamine release in both the nucleus accumbens and the caudate but with a greater effect in nucleus accumbens.26 Several studies also have reported that low doses of alcohol increased functional activity of the dopaminergic system.22 It has been suggested that this behavioral stimulation is mediated by activation of dopaminergic transmission.1,5,6,10 The mechanisms by which alcohol alters dopaminergic turnover have not been fully elucidated.

In the early 1960s, reports appeared describing characteristic reductions in cerebral monoamine levels in patients with Parkinson’s disease (for references, see Hornykiewicz58). A few years earlier, the observation had been made that central monoamine depletion by reserpine produced a Parkinson-like syndrome in rodents that could be reversed when brain dopamine levels were restored through the systemic administration of the immediate precursor of dopamine, L-DOPA.20 These key observations pointed the way to the successful development of dopamine-replacement therapy for the relief of parkinsonian signs.

Whilst previous studies point to a loss of noradrenergic neurons in Alzheimer-type dementia (ATD) (Bondareff et al., 1981; Yates et al., 1981; Cross et al., 1981) there are conflicting reports of normal (Mann et al., 1980) and reduced (Adolfsson et al., 1979) dopamine function in this disease. Observations that ATD patients who die below the age of 80 years have a greater loss of choline acetyltransferase activity from the cerebral cortex (Rossor et al., 1981) and of neurons from the locus coeruleus (Bondareff et al, 1981; Tomlinson et al., 1981) suggest that early onset (pre-senile) ATD may differ biochemically from late onset (senile) ATD. We have examined this possibility by measuring dopamine, its metabolite homovanillic acid (HVA) and noradrenaline in brains from cases of pre-senile ATD, senile ATD and Down syndrome. All values are means ± S.D.

Spinal fluid levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-4 dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were evaluated in off-medication chronic schizophrenic patients with (N=B) and without (N=43) evidence of brain atrophy of computerized tomography (CT) scans. Patients with brain atrophy showed significantly lower levels of these spinal fluid constituents except MHPG. These CSF findings support the proposed subdivision of schizophrenia with and without brain atrophy. Future CSF studies need to take brain atrophy into account among variables as diet, age, sex, sleep (hours), drug conditions, clinical state, anxiety and activity.

Probenecid was administered to 7 unipolar depressed patients, 7 parkinsonians and 7 extrapyramidal patients with senile dementia matched for age and sex. Before and after the administration of probenecid, the levels of 5 hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were determined in the cerebrospinal fluid (CSF) of all patients in order to study the central turnover rate of serotonin and dopamine. Unipolar depressed patients showed a significantly lower increase in CSF 5HIAA levels after probenecid than parkinsonians. Patients with Parkinsonism had a reduced increment of CSF HVA levels following probenecid administration when compared to unipolar depressed and extrapyramidal patients with senile dementia.

Most of the work on transmitter replacement therapy by means of precursor loading has been directed toward manipulation of neurotransmitters synthesized from aromatic amino acids (47). However, beginning in the mid 1970’s, clinical investigators became interested in the use of choline (Ch) to treat disorders in which too little acetylcholine (ACh) was formed in the brain, or in which the formation of an excess of the neurotransmitter was believed to be desirable. This interest in Ch as a therapeutic agent was triggered by basic research showing that the administration of Ch to laboratory animals could cause an increase in the level of ACh in the brain, a phenomenon first described in 1972 by Kuntscherova (32). Although the beneficial effects of Ch in some disorders such as tardive dyskinesia (see 2) may reside in other properties of the molecule (e.g. a direct postsynaptic muscarinic action of Ch has been demonstrated (9,20,31)), there is evidence that part of the effect of Ch is elicited through stimulation of ACh synthesis and release. This evidence is reviewed in the first part of this report.

The purpose of this chapter is not to review the properties of monoamine oxidase, since an extensive earlier literature on the properties and physiological function of monoamine oxidase is available (Blaschko, 1952; 1953; 1963; 1966; Zeller, 1952; Davison, 1958). However, in light of recent advances made in this field it is necessary to survey some of its most recently discovered properties (see Tipton, 1975; Sandler and Youdim, 1972; Youdim, 1975; for reviews).

Regional differences in drug effects on dopamine (DA) turnover are often taken as indications for differential effects in functional activity of the various dopaminergic systems. Functional activity of central dopaminergic neurones may be estimated by measurement of the levels of the acidic DA metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) (Roth et al., 1976). Another frequently used method is the estimation of DA decay after inhibition of its synthesis with α-methyl-p-tyrosine (aMpT) (Anden et al.,1971, see Sharman this volume). However, these two indices of dopaminergic nerve activity do not always give concordant results (Waldmeier & Maftre, 1976; Wuerthele & Moore, 1979).

Relative to baseline, one day of alcohol ingestion by chronic alcoholics demonstrated significant increases in SWS, decreases in REM sleep and decreases in CSF levels of cyclic AMP and 5-HIAA.

Although the precise relationship between the level and turnover of biogenic amines in brain and mental disorders is not known, there is almost general agreement that these neurotransmitters play a central role in Parkinsonism, manic-depression and schizophrenia.

Studies of the effects of psychoactive drugs have contributed much to the present knowledge of the role of catecholamines in behavioral physiology. Since drugs are never completely specific, i.e., no drug acts on only one system in the brain, the knowledge derived from pharmacological experiments is beset with a corresponding uncertainty. Evidence from several experiments, preferably carried out using very different methods, is therefore necessary for conclusions about association between a specific system in the brain and a certain behavior. In the following we shall try to expound such evidence about the association of catecholaminergic systems in the brain with behavioral activation and stereotypy, and we shall explore the possible relations of animal experiments with clinical observations comprising also mental phenomena such as thinking and mood.

It has been demonstrated that phospholipids and their lyso - derivatives are capable of stimulating the incorporation of 32Pi into the phospholipids of various tissues.

Postmortem studies in brains from parkinsonian patients consis tently reveal a minimum loss of 75% of the nigrostriatal dopamine neurons. This indicates that over a prolonged period, before Parkinson’s disease is clinically evident, there is a physiological compensation for the slow loss of dopamine neurons (i.e. compensated stage of Parkinson’s disease). Only when the dopamine neuron loss is sufficiently severe (greater than 75% of nigrostriatal dopamine neurons) does the disease become clinically evident (decompensated state). Postmortem examination of Parkinson’s disease brains and study of animal models indicate that the following mechanisms may contribute to this CNS compensation

Figure 1 shows the chemical structures of clozapine, perlapine and fluperlapine. Clozapine is a dibenzodiazepine, whereas perlapine and fluperlapine are dibenzazepines.

Intensive investigations over the past two decades provide strong evidence that abnormalities in central monoamines may lie at the core of, and significantly influence the development and course of clinically relevant aberrations in central nervous system (CNS) functioning. Such a notion mandates a more detailed understanding of brain neurotransmitter mechanisms if we are to better comprehend and ultimately unravel and treat those complex and enigmatic neuropsychiatric disorders affecting children. However, the study of central monoamines in human disorders presents both theoretical and practical obstacles. Thus, while a number of different strategies have been employed to assess monoamine metabolism within the CNS of man, they all have in common the dependence on indirect estimates of CNS monoaminergic function. One approach relies on the determination of monoamines or their related enzymes in peripheral blood or urine. A considerable and rapidly expanding literature documents the peripheral concentrations of monoamine oxidase (MAO),56 dopamine-β-hydroxylase (DBH),33 and serotonin77 in a variety of human disorders. However, there is no assurance that the activity or level of a monoaminergic enzyme or monoamine itself in the plasma reflects the activity of that enzyme in brain.

During the 1960s, histochemical, biochemical, and pharmacological evidence accumulated supporting the existence of specific dopamine (DA) containing neurons in the central nervous system (Carlsson, 1959; Hor-nykiewicz, 1964; Anden et al., 1964a, 1965a). At that time, more than 50 years had elapsed since the chemical synthesis of DA was first described by Mannich and Jacobsohn (1910). Although at an early stage DA was found to exert pharmacological effects on blood pressure and smooth muscle preparations (Barger and Dale, 1910), it was not until 1939 that Blaschko suggested a physiological role for this compound in tissue catecholamine synthesis. In his proposal for the biochemical pathway of catecholamine synthesis, Blaschko suggested DA to be the immediate precursor of norepinephrine. It was not until 1950, however, that McGoodall identified DA as a natural constituent of the heart and the adrenal gland (McGoodall, 1950a,b). Schumann (1956) demonstrated the occurrence of the compound in sympathetic nerves and ganglia. Montague (1957) was the first to present evidence for the presence of DA in the central nervous system. Up to the middle 1950s, DA was thought to play only a precursor role in the biosynthesis of norepinephrine and epinephrine.

Determination of neurotransmitter precursors, neurotransmitters, and their metabolites in cerebrospinal fluid (CSF) has recently become a popular method for studying pathological and drug-induced alterations in central nervous system metabolism of living patients. According to Moir et al.,58 interpretation of this CSF analysis requires the absence of CSF contamination with peripheral neurotransmitters and their metabolites. The CSF should also reflect the chemical composition of adjacent areas of nervous tissue. Unfortunately, CSF circulation, regional selective neurochemical absorption, and pathological alterations in the blood-CSF barrier complicate data evaluation.

In this paper we will review previous data and present new data on the clinical effects of L-dihydroxyphenylalanine (L-DOPA) and alpha-methyl-para- tyrosine (α-MPT) in the affective disorders and on the biochemical pharmacology of these agents in man and in the laboratory animal. These studies were prompted by the catecholamine hypothesis, which remains of central importance in current research in the affective disorders (Bunney and Davis 1965; Schildkraut 1965). This hypothesis proposes that some, if not all, depressions are associated with a deficiency of catecholamines at functionally important adrenergic sites in brain, and that mania may be associated with an excess of these amines (Schildkraut 1965). Pharmacologic agents that cause an increase in active catecholamines released by appropriate neurons should be associated with alleviation of depression or production of mania, and pharmacologic agents that cause a decrease in the amount of catecholamines available to the receptor should be associated with worsening of depression or improvement of mania.