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During the last 15 years, the methods proposed to study the regulation of cholinergic transmission in vivo have required the labeling of the acetylcholine (ACh) and choline stored in neurons by injecting labeled precursors of ACh, and by measuring simultaneously the changes with time in the specific activities of choline and ACh (Cheney et al., 1974, 1975a; Costa et al. 1975; Dross and Kewitz, 1966; Hanin et al., 1973; Jenden et al., 1974; Racagni et al., 1974; Saelens et al., 1973; Schuberth et al., 1969; Zsilla et al., 1977). In addition to these isotopic methods, various nonisotopic approaches have been suggested to estimate the fractional rate constant of ACh efflux (Bartholmi et al., 1976; Celesia and Jasper, 1966; Hemsworth and Neal, 1968; Mitchell, 1960; Pepeu et al, 1975; Smith, 1972; Szerb, 1975; Yaksh and Yamamura, 1975). Some of the nonisotopic methods have used drugs to instantaneously inhibit synthesis, metabolism, or transport of ACh, its precursor, or metabolites (Costa and Neff, 1966). A flaw common to all the methods involving the use of inhibitors derives from the widely spread assumption that drugs are so specific that, even in high doses, they selectively inhibit a given metabolic step. Obviously, such specificity is exceptional; more often, drugs that inhibit ACh metabolism exert collateral actions on other processes that directly or indirectly regulate a number of other metabolic steps. [ABSTRACT FROM AUTHOR]

The neurotransmitter amines, dopamine (DA), norepinephrine (NE), epinephrine (EPI), and serotonin (5-hydroxytrypt-amine, 5-HT) are continuously released and destroyed at various rates, yet their content in neuronal tissue remains relatively constant. Thus, it is not possible to evaluate neuronal function solely from the content of the transmitter in a tissue. A better estimate of neuron function can be obtained from the rate of formation of the amines. The hypothesis is that there is increased amine formation and turnover when neurons are actively firing. Presently, there are two general techniques for estimating the rate of amine formation (see reviews by Costa and Neff, 1970: Neff, 1972; Costa et al., 1975, and Korf 1985). There are the steady-state methods where an isotope-labeled amine (radioactive or stable isotope) or a precursor is administered, and following uptake into nerve endings, the decline of the specific radioactivity of the transmitter is followed with time. The rate of loss of radioactive amine under steady-state conditions is proportional to its turnover. The higher the neuronal firing rate, the faster the rate of decline of the specific radioactivity of the transmitter amine. [ABSTRACT FROM AUTHOR]

The purpose of the present chapter is not to review all drug-induced animal models of psychiatric and neurological diseases, but to discuss a number of models that highlight their usefulness and limitations. I have made my choice of models to discuss partly on the basis of their role (putative or actual) in modeling diseases, partly on their heuristic value in stimulating research, and partly because of my own personal interests. Some diseases will not be covered at all in this chapter because I do not think there are any adequate drug-induced models [e.g., depression; for models, see Everitt and Keverne (1979), Bollini et al (1984), Willner (1984), Cooper et al (1983), Telner and Singhal (1984), and Suomi (1983)] Other models will only be discussed in part (e.g., anxiety and schizophrenia) The philosophical, psychological, and ethical considerations underlying animal models have been explored by many able authors in considerable depth, and the reader is referred to Bond (1984), Abramson and Seligman (1977), Bowd (1980), and Russell (1964) for detailed discussions. [ABSTRACT FROM AUTHOR]

Most studies concerning the mechanism of action of psychotropic drugs are based on pharmacological interactions. A drug known to block, for instance, the dopaminegic system is utilized to establish whether another drug exerts its pharmacological effects via that monoammergic system. d-Amphetamme is believed to act on the dopaminergic system because some, but not all, pharmacological effects are inhibited by antidopammergic agents [ABSTRACT FROM AUTHOR]

There are several dopaminergic pathways present in mammalian brain (Ungerstedt, 1971a, b, c, d; Schultz, 1982). Perhaps the most studied of these is the nigrostriatal pathway, which arises from pigmented cell bodies in the zona compacta of the substantia nigra and projects rostrally to the neostriatum (corpus striaturn). Parkinson's disease is a syndrome of diverse etiology that is characterized by a degeneration of the above-mentioned nigrostriatal pathway. It has been estimated that the incidence of parkinsonism in the general population ranges from 100 to 150 cases per 100,000, with the prevalence being considerably greater in an older population sample (Schoenberg, 1987; Yahr, 1977). Biochemical and pathological characteristics of this disease include a greatly diminished neostriatal content of dopamine (DA) and its major metabolites and a marked loss of nerve cells in the zona compacta of the substantia nigra. Additional neuronal systems involved include noradrenergic and cholinergic systems. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5-HT), was discovered as a serum factor that exerts tonic effects on blood vessels; its chemical structure was elucidated in 1948. The compound gained wide interest among pharmacologists, and in a short time a great number of in vitro and in vivo pharmacological tests had been developed, and a variety of drugs interacting with the actions of serotonin were rapidly discovered. In 1966, Gyermek, in a review on "Drugs which antagonize 5-hydroxytryptamine and related indolealkylamines," compiled a table with 384 compounds with serotonin antagonistic properties; these compounds belonged to more than 18 different chemical and pharmacological classes. In addition, an impressive list was reported that consisted of 26 different tests for measuring serotonergic effects on isolated organs and 33 tests related to the action of serotonin in vivo, plus a number of indirect effects. At that time, the author wondered whether the vast interest paid to serotonin was fully deserved. He stated, "It turned out that besides the potent pharmacological actions of exogenous serotonin, the endogenous amine in mammals does not play many well-defined physiologic or pathologic roles." Existing drugs were found to be nonselective, and it was hoped that "specific antagonists" would be developed for analyzing the effects of indolealkylamines in various organisms (Gyermek, 1966). [ABSTRACT FROM AUTHOR]

What we know today about dopamine (DA) receptors stems directly from the discovery of potent and selective neuroleptic drugs. These compounds are not only essential tools in neuropharmacology, but are also guides that neurobiologists follow to identify, isolate, and even dismantle the molecular structure of brain neuroreceptors. For many people, it is not clear why potent neurotransmitter antagonists are an absolute requirement for these studies when the endogenous neurotransmitters are available. In fact pharmacologists have known for a long time that "classical" neurotransmitters [acetylcholine (ACh), dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT), gammaaminobutyric acid (GABA), and so on] elicit a physiological response at micromolar concentrations (Table 1). Since binding studies are not feasible at such high concentrations because of high nonspecific binding, one needs substances that are endowed with high-affinity properties. Potent neuroleptics fulfil these conditions: they possess high affinity at nanomolar concentrations. In fact, the problem is not new; α-bungarotoxin was an absolute requirement for looking at the molecular structure of the nicotinic receptor (Changeux, 1981). [ABSTRACT FROM AUTHOR]

The catecholamine (CA) neurotoxins are so extensively used in neuroscience research today, for chemical lesioning of noradrenergic and/or dopaminergic neurons, that a comprehensive review on all aspects of neurotoxin use is virtually an insurmountable task The focus of this review article on CA neurotoxins is on the general utility of these substances, regarding expected pharmacological actions for given agents. Because of the relative specificity of the widely used 6-hydroxydopamine (6-OHDA) as a neurotoxin for CA neurons, the major portion of the review is devoted to this agent. It is expected, after reading this review, that the naive scientist will be able to reasonably develop a suitable experimental protocol for chemical lesioning of noradrenergic and/or dopaminergic nerves for particular studies. For the scientist who is experienced in the use of chemical neurotoxins, this review article should serve to highlight the critical aspects of neurotoxic drugs, while summarizing the mechanisms by which each of the various agents acts and indicating the practical uses of each agent. [ABSTRACT FROM AUTHOR]

As with any neurotransmitter, there are two basic ways to decrease the synaptic action of γ-aminobutync acid (GABA) in order to establish its functional role at particular synapses in the nervous system. They are to reduce its availability and release through a presynaptic action or to reduce its effects with appropriate postsynaptic antagonists. The former might be achieved by specifically destroying GABA-containing neurons, inhibiting its synthesis, or interfering in some way with its actual release. All of these approaches, however, suffer from the disadvantage of a very slow onset and an effect that, even if reversible, is likely to be prolonged and not easily quantified. There are no specific neurotoxins for GABA neurons similar to 6-hydroxydopamine for catecholamme systems, and although antibodies raised to the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD), can be used to destroy (lyse) synaptosomes containing GABA in vitro (Docherty et al., 1983), the method is not applicable in vivo. Intracerebral injection of tetanus toxin has been shown to reduce GABA-mediated inhibition by reducing release of the transmitter (Collingridge and Davies, 1982), but this toxin has a number of actions, including an effect on glycine release, and it is obviously not specific for GABA. Many inhibitors of GAD have been described (see Woodbury, 1980); unfortunately, many of them not only reduce GABA levels, but also raise the concentration of its precursor glutamate. Their use also suffers from the disadvantage that the rate of decline of GABA depends on the rate of its utilization, which will vary from neuron to neuron, and we do not know to what extent GABA levels must be reduced before its release and function are significantly impaired. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) is known to be a neurotransmitter in the nervous systems of vertebrates and invertebrates. The fact that numerous plants, animals, and bacteria have evolved toxins that selectively interfere with cholinergic transmission is an indication of the relative importance of ACh as a neurotransmitter substance. In order for a toxin to be biologically effective, it must produce a sustained action at low concentrations. The high potency and selectivity of these toxins have allowed them to play a crucial role in understanding ACh's physiological effects and in identifying the properties of the enzymes and receptors subserving cholinergic neurotransmission. For example, snake venom α-neurotoxins have been valuable tools in identifying and purifying nicotinic acetylcholine receptors. In fact, the availability of the α-neurotoxins is a major reason the vertebrate muscle nicotinic receptor is currently the best characterized of all neurotransmitter receptors. [ABSTRACT FROM AUTHOR]

The indoleamme serotonin (5-hydroxytryptamine, 5-HT) was described in the central nervous system (CNS) more than 30 years ago (Amin et al., 1954; Bogdanski et al., 1956; De Robertis, 1964; Twarog and Page, 1953; Zieher and De Robertis, 1963) based on biochemical determinations of this amine in different brain regions. These studies were rapidly followed by the use of histofluorescent microscopy (Anden et al., 1965, 1966, 1967; Dahlstrom and Fuxe, 1964; Fuxe, 1965; Moore et al., 1978; Ungerstedt, 1971) and measurements of the activity of tryptophan hydroxylase and 5-HT uptake (Kuhar et al., 1972). This work was later complemented by anatomical descriptions of the now chemically identified neurotransmitter systems using radioautographic tracing techniques that take advantage of the uptake properties of the 5-HT system (Azmitia, 1978; Azmitia and Segal, 1978; Beaudet and Descarrres, 1981, Parent et al, 1981) as well as by the use of immunocytochemrcal methods with antibodies against 5-HT itself (Steinbusch, 1981, Steinbusch et al , 1978; Steinbusch and Nreuwenhuys, 1983). [ABSTRACT FROM AUTHOR]