Alan A. Boulton

2‐Phenylethylamine: A Modulator of Catecholamine Transmission in the Mammalian Central Nervous System?

Since the identification of 2‐phenylethylamine (β‐phenylethylamine; PE) as a biogenic amine, there has been much discussion about what role, if any, it may have in the CNS. Indeed, the low endogenous concentration of PE in the brain and its relatively low potency in behavioral and pharmacological experiments have led some researchers to conclude that perhaps PE possessed no physiological role at all but that it was merely a metabolic by‐product. Our findings have caused us to conclude otherwise, and in this article we review the neurochemical, neuropharmacological, and neurophysiological findings that lead us to propose that PE is a neuromodulator of catecholamine neurotransmission in the CNS.

Irreversible inhibition of monoamine oxidase by some components of cigarette smoke.

Inhibitory activity towards monoamine oxidase has been found in a solution of cigarette smoke. The inhibition was irreversible. When tissue slices of rat lung were incubated in the cigarette smoke solution or alternatively, exposed directly to cigarette smoke, monoamine oxidase activities were reduced drastically. Similarly, human saliva after cigarette smoking also exhibits considerable MAO inhibitory activity. When the amine substrates p-tyramine, serotonin and beta-phenylethylamine were incubated with the cigarette smoke solution, lipophilic adducts were formed non-enzymatically. The irreversible inhibition of MAO by cigarette smoke may well be related to the low platelet MAO associated with cigarette smokers as previously reported. The implication of such cigarette smoke-caused reduction of MAO activity in relation to Parkinsonism is discussed.

Regulation of Aromatic l‐Amino Acid Decarboxylase by Dopamine Receptors in the Rat Brain

Abstract: Decarboxylation of phenylalanine by aromatic l‐amino acid decarboxylase (AADC) is the rate‐limiting step in the synthesis of 2‐phenylethylamine (PE), a putative modulator of dopamine transmission. Because neuroleptics increase the rate of accumulation of striatal PE, these studies were performed to determine whether this effect may be mediated by a change in AADC activity. Administration of the D1 antagonist SCH 23390 at doses of 0.01–1 mg/kg significantly increased rat striatal AADC activity in an in vitro assay (by 16–33%). Pimozide, a D2‐receptor antagonist, when given at doses of 0.01–3 mg/kg, also increased AADC activity in the rat striatum (by 25–41%). In addition, pimozide at doses of 0.3 and 1 mg/kg increased AADC activity in the nucleus accumbens (by 33% and 45%) and at doses of 0.1, 0.3, and 1 mg/kg increased AADC activity in the olfactory tubercles (by 23%, 30%, and 28%, respectively). Analysis of the enzyme kinetics indicated that the Vmax increased with little change in the Km with l‐3,4‐dihydroxyphenylalanine as substrate. The AADC activity in the striatum showed a time‐dependent response after the administration of SCH 23390 and pimozide: the activity was increased within 30 min and the increases lasted 2–4 h. Inhibition of protein synthesis by cycloheximide (10 mg/kg, 0.5 h) had no effect on the striatal AADC activity or on the increases in striatal AADC activity produced by pimozide or SCH 23390. The results indicate that the increases in AADC activity induced by dopamine‐receptor blockers are not due to de novo synthesis of the enzyme. These results show that AADC activity in the striatum is regulated by D1 and D2 receptors and that the activities in the nucleus accumbens and olfactory tubercles are regulated by D2 receptors. The observation that dopamine‐receptor antagonists stimulate the synthesis of PE may be explained by the increase in AADC activity.

Glyceraldehyde-3-phosphate dehydrogenase and apoptosis

Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) has long been recognized as playing an integral role in glycolysis. During the past 20 years, however, a number of novel, additional functions for GAPDH have been described. These include acting as an uracil DNA glycosylase, activator of transcription, binding to RNA, and an involvement in tubulin assembly. One of the most intriguing functions which has recently been recognized is an involvement in the initiation of apoptosis. Further, GAPDH associates with proteins implicated in human neurodegenerative disorders. This review summarizes the evidence implicating GAPDH in the initiation of one or more apoptotic cascades. The possible functions of GAPDH in the nucleus which could result in the initiation of apoptosis are also discussed. J. Neurosci. Res. 1:150–154, 2000

Aromaticl-amino acid decarboxylase: A neglected and misunderstood enzyme

Classically, aromaticl-amino acid decarboxylase (AADC) has been regarded as an unregulated, rather uninteresting enzyme. In this review, we describe advances made during the past 10 years, demonstrating that AADC is regulated both pre- and post-translation. The significance of such regulatory mechanisms is poorly understood at present, but the presence of tissue specific control of expression raises the real possibility of AADC being involved in processes other than neurotrasmitter synthesis. We further discuss clinical and physiological situations in which such regulatory mechanisms may be important, including the intriguing possibility of AADC gene regulation being linked to that of factors thought to have a role in apoptosis and its prevention.

Gradation of Kainic Acid-induced Rat Limbic Seizures and Expression of Hippocampal Heat Shock Protein-70

Systemic injection of kainic acid (KA) induces limbic seizures in rats, which resemble human temporal lobe epilepsy, the most common form of adult human epilepsy. In this study, we have investigated KA‐elicited limbic seizures in the rats by correlating the severity of the seizure attacks with the expression of hippocampal heat shock protein‐70 (HSP70) which has been suggested to be a marker for neuronal injury/death in this model of seizures. After a systemic injection of KA, six stages of limbic seizures have been classified, namely, staring (stage 1), wet dog shake (stage 2), hyperactivity (stage 3), rearing (stage 4), rearing and falling (stage 5), and jumping (stage 6). Stages 4, 5 and 6 were further divided into mild and severe sub‐stages. HSP70 expression was not detected in animals with stages 1 and 2 seizures. At stage 3 a small amount of HSP70 immunoreactive neurons was detected in the CA3 field and the dentate hilus. From stage 4 to stage 5 the degree of HSP70 immunoreactivity increased in the CA1 field from a few positive cells in stage 4 mild to large numbers of immunoreactive neurons in stage 5 severe. HSP70 became detectable in pyramidal cells in the CA2 field from stage 5 severe and higher. In animals with stage 6 seizures, the majority of HSP70 expression became located in glial cells throughout the whole hippocampus. We concluded that HSP70 expression in the hippocampus positively correlates with the severity of KA‐elicited limbic seizures.

Voltammetric Methods in Brain Systems

Carbon Electrode Surface Chemistry: Optimization of Bioanalytical Performance. Diffusion and Ion Shifts in the Brain Extracellular Microenvironment and Their Relevance for Voltammetric Measurements: The Brain Is Not A Beaker: In Vitro vs In Vivo Voltammetry. Fast Cyclic Voltammetry in Brain Slices. Rapid Chronocoulometric Measurements of Norepinephrine Overflow and Clearance in CNS Tissues. Monitoring Dopamine and Noradrenaline Release in Central and Peripheral Nervous Systems with Treated and Untreated Carbon-Fiber Electrodes. Regional Differences in Dopamine Release, Uptake, and Diffusion Measured by Fast-Scan Cyclic Voltammetry. The Measurement of Brain Ascorbate and Its Link with Excitatory Amino Acid Neurotransmission. Voltammetric and Amperometric Probes for Single-Cell Analysis. Measurement of the Time-Resolved Kinetics of Biogenic Amine Release and Transporter Activity by Rotating Disk Electrode Voltammetry In Vitro. Index.

Schizophrenia, a neurodegenerative disorder with neurodevelopmental antecedents

Schizophrenia is a devastating disorder that has been referred to as youths greatest disabler. Although a number of hypotheses have been proposed in an attempt to explain the pathophysiology of schizophrenia no single theory seems to account for all facets of the disease. Each hypothesis explains some of the phenomena associated with schizophrenia and it is probable that many variables described in these hypotheses interact to produce a disorder characterized by heterogeneous symptomatology, progression and prognosis. Compelling evidence suggests that the primary disturbance is a neurodevelopmental abnormality, possibly resulting from a genetic defect(s), resulting in a predisposition to schizophrenia. Events later in life may then lead to the presentation of symptoms and a subsequent progression of the disease. Recent evidence suggests that the progressive course of schizophrenia is associated with ongoing neurodegenerative processes. Changes in brain derived neurotrophic factor (BDNF) may explain the various changes observed in schizophrenia.

Regulation of striatal aromatic L-amino acid decarboxylase: effects of blockade or activation of dopamine receptors.

Previous experiments have shown that blockade of dopamine D1 or D2 receptors by SCH 23390 or pimozide increases aromatic L-amino acid decarboxylase (AADC) activity in the rat striatum and the mesolimbic system. This study examined whether other dopamine receptor antagonists affect AADC activity and if there is an interaction between dopamine D1 and D2 receptor blockade on AADC activity. The possible effect of dopamine receptor agonists on AADC activity has been investigated as well. Administration of cis-flupenthixol (0.5 and 1 mg/kg) increased striatal AADC activity (by 25 and 26% above controls) and similar effects were observed with remoxipride (0.5-4 mg/kg) (by 18-27% above controls). Pretreatment with cycloheximide (10 mg/kg) did not change the increases produced by cis-flupenthixol (0.5 mg/kg). The administration of non-neuroleptic trans-flupenthixol did not change AADC activity. Combined treatment with SCH 23390 (0.1 mg/kg) and remoxipride (0.5 mg/kg), but not combination of SCH 23390 (0.1 mg/kg) and pimozide (0.3 mg/kg), showed higher increases of AADC activity than by the individual treatments, suggesting an interaction between the effects of the two drugs. Bromocriptine, but not (-)-quinpirole and d-amphetamine, significantly reduced the striatal AADC activity by 23% at the dose of 10 mg/kg. The results further demonstrate that AADC is a regulated enzyme in the rat brain.

Brain Trace Amines

The neologism “trace amines” was first adopted by a study group held under the auspices of the American College of Neuropsychopharmacology at its Puerto Rico meeting in 1975. The first book1 on this topic recorded the papers presented by the participants of this study group. The definition of a trace amine2 appears to include those monoamines whose tissue concentrations lie between 0.1 and 100 ng/g. That it is an inappropriate term follows from the fact that some of the well-known trace amines can exist in some tissues in amounts considerably in excess of 100 ng/g and indeed, in the presence of appropriate monoamine oxidase inhibitors, many of them exceed this level; it is also a fact that some of the well-known putative monoamine neurotransmitters may be present in trace quantities in some locations.