National Institute on Drug Abuse research monograph series最新文献

In Parkinson's disease there is a derangement of the metabolism of at least 3 major brain monoamines, namely, dopamine (DA), norepinephrine (NE) and serotonin (5-HT). Of these alterations the severe deficiency of DA in the striatum is most characteristic, being (a) found in Parkinsonian syndromes of any etiology and (b) significantly correlated with the degree of cell loss in the substantia nigra, and the severity of the main symptoms. On the basis of neurochemical-clinical correlations Parkinson's disease may be subdivided into (a) an asymptomatic stage during which the striatal DA deficiency may reach a marked degree but can be compensated by the remaining DA neurons, and (b) the stage of decompensation (i.e. clinically manifest disease) which ensues when the depetion of striatal DA reaches 70% or more. L-Dopa's main feature as a specific antiparkinson drug may be seen in its potential to revert the decompensated stage of the disease to the stage of functional compensation. This is in many cases possible because (a) the DA turnover in the remaining DA neurons is increased, providing for a high rate of formation (from L-dopa) and release of DA; (b) the "denervated" striatal receptors are supersensitive to DA; and (c) the newly-formed DA can be expected to reach a wide area of the striatum due to the high degree of divergence of the dopaminergic innervation. Compared with the striatal DA deficiency, the degree of NE and 5-HT decrease in the Parkinsonian brain is moderate. The decrease in NE may be due to the (moderate) cell loss in the locus coeruleus; at present no morphological basis for the lowering of brain 5-HT is known. The functional significance of the changes in brain NE may be an aggravation of akinesia. The decrease in brain 5-HT may be related to aspects of Parkinson's disease in turn related to affective behavior and mood.

Haloperidol caused a significant reduction in the spontaneous locomotor activity of mice when added to their diet for 11 days. Upon removal of the drug from their diet these mice exhibited withdrawal hyperactivity for several days that was characterized by an increase in activity over control or pre-halopericol values. Similar results were obtained when mice were fed a diet containing pimozide. Withdrawal hyperactivity was not detected after 1 or 3 days of haloperidol containing diet, but was maximal after 6 days of this diet. Dose-response curves of apomorphine-stimulated motor activity and rearing behavior were shifted to the left when determined in mice during the period of withdrawal hyperactivity. Dopaminergic agonists (apomorphine, piribedil, L-DOPA and d-amphetamine) induced gnawing at lower doses in mice removed from a chronic haloperidol-containing diet for 2 days than in mice maintained on a control diet. These results support the hypothesis that prolonged blockade of central dopaminergic receptors by neuroleptics causes subsequent behavioral effects that may be due to the development of enhanced receptor sensitivity.

A critical review of the evidences relating the biogenic amines serotonin and norepinephrine to the states of slow-wave and rapid eye movement (REM) sleep is presented. Various alternative explanations for specific chemical regulation of the individual sleep states, including the phasic events of REM sleep, are evaluated within the overall framework of the monoamine theory of sleep. Several critical neuropsychopharmacological studies relating to metabolsim of the amines in relation to sleep-waking behavior are presented. Models of the chemical neuronal circuitry involved in sleep-waking activity are derived and interactions between several brainstem nuclei, particularly the raphé complex and locus coeruleus, are discussed. Activity in these aminergic systems in relation to oscillations in the sleep-waking cycles is evaluated. In particular, the assessment of single cell activity in specific chemical systems in relations to chemical models of sleep is reviewed. Overall, it appears that the biogenic amines, especially serotonin and norepinephrine, play key roles in the generation and maintenance of the sleep states. These neurotransmitters participate in some manner in the "triggering" processes necessary for actuating each sleep phase and in regulating the transitions from sleep to waking activity. The biogenic amines are, however, probably not "sleep factors" or direct inducers of the sleep states. Rather, they appear to be components of a multiplicity of interacting chemical circuitry in the brain whose activity maintains various chemical balances in different brain regions. Shifts in these balances appear to be involved in the triggering and maintenance of the various states comprising the vigilance continuum.

We have previously reported that, from a phenomenological standpoint, the behavioral manifestations of cats chronically intoxicated with amphetamine parallel the evolution of the paranoid psychosis induced by the drug in humans. However, certain manifestations in the cat, such as frozen postures, disjunctive behaviors and postures, cataleptic-like phenomena, obstinate progression, loss of righting reflex and pupillary changes, did not appear to be consistent with the phenomenology of the paranoid psychosis. Since treatment of schizophrenic patients with disulfiram, an inhibitor of norepinephrine synthesis that acts at the level of the enzyme dopamine beta-hydroxylase, thereby leading to increased dopamine concentrations, had been found to profoundly exaggerate psychotic symptomatology, amphetamine behavioral syndrome in the cat as it is modified by pretreatment with disulfiram. Following such pretreatment, a faster development of certain end-stage components of the amphetamine syndrome was obtained. Thus, on the first day, development of a Reactive attitude and of more prominent behavioral disjunction occurred with the combined drug administration as compared with amphetamine alone. In contrast with the facilitation of these behaviors was the absence of dyskinesias and hyperreflexia on that day. Stereotyped behavior, loss of motor initiative and hyperkinetic activity were markedly enhanced and appeared with a shorter latency period on subsequent days of the intoxication cycle. Loss of righting reflex was an early manifestation in these animals. During the later days, the particularly high level of compulsive activity was evident from the occurrence of an obstinate progression syndrome and the performance of stereotyped movements of the head in the presence of a crucifixion posture. In general, modification of the amphetamine effects on behavior was in a direction consistent with comparable features in experimental catatonia and the catatonic form of schizophrenia. The need to integrate such phenomena in any amphetamine model of psychosis is stressed and analogies are drawn with similar features reported in animals treated with bulbocapnine or other psychotogenic compounds and with symptoms of human amphetamine psychosis and schizophrenia.

Experiments involving three models of aggression (shock-induced fighting, ranacide and septal lesion-induced hyperirritability) are employed to demonstrate classically different sub-types of aggressive behavior. These categories are shown to be distinct entities when compared on the basis of hormonal dependency, central anatomical and peripheral autonomic involvement and inhibition or enhancement through pharmacological manipulations. Investigations into brain monoamine functioning (norepinephrine, dopamine and serotonin) demonstrate the heterogeneity of correlations which may exist between aggressive behaviors and brain amines. Data are analyzed on the basis of individual amine alterations and changes in monoaminergic neuronal balances. Thus, higher levels of shock-induced aggressive behavior is associated with higher NE/5-HT and DA/K-HT ratioes whereas similar alterations in these biochemical indices occur without observable changes in ranacide behavior. Septal lesion induced hyperirritability is correlated with precisely opposite aminergic changes, namely, decreases in NE/5-HT ratioes. These results demonstrate the necessity of precise aggressive model evaluation prior to attempts at biochemical mechanism elucidation.

In a study of the effects of heroin administration in nine human subjects, urinary catecholamines and metabolites were examined during an initial drug-free baseline period, a ten-day period of heroin administration and a subsequent period of methadone detoxification. All catecholamines and metabolites tended to be increased over baseline values on the first day of heroin administration. However, markedly different patterns of change emerged on subsequent days of heroin administration. Norepinephrine and normetanephrine remained increased throughout heroin administration. Epinephrine was increased during the early phase of heroin administration but returned to baseline values during the latter phase of heroin administration. After the increase on the first day of heroin administration, metanephrine decreased and substantial decrements below baseline values occurred during the latter phase of heroin administration. After increasing on the first day of heroin administration, 3-methoxy-4-hydroxy-mandelic acid (VMA) returned to approximately baseline values. During heroin administration, an increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion was observed in a subgroup of four of the nine subjects studied. This is in contrast to the increase in normetanephrine excretion and the decrease in metanephrine excretion that was observed in the entire group of nine subjects. It is conceivable that persistance of, or development of, tolerance might account for the failure to observe an increase in MHPG excretion in all of the subjects. It appeared as if the increase in MHPG excretion began on the day prior to the administration of heroin in the subgroup of patients with increased MHPG excretion during heroin administration, suggesting the possibility of an anticipatory or conditioned response, with the anticipation of heroin producing an increase in MHPG excretion.

The psychopharmacology of electrical self-stimulation of the lateral hypothalamus was studied using 6-hydroxydopamine, alpha-methyltyrosine, U-14, 624, and d-amphetamine. Reduction of brain dopamine, but not norepinephrine, with 6-hydroxydopamine produced an acute depression of responding which eventually recovered to pretreatment levels. A low dose of alpha-methyltyrosine, which did not affect responding in control rats, significantly depressed responding in the rats with brain dopamine reduced. This treatment did not alter responding of rats with norepinephrine reduced by 6-hydroxydopamine. A dopamine-beta-hydroxylase inhibitor, U-14, 624, depleted norepinephrine an additional 70% yet failed to alter self-stimulation in any of the groups. In other experiments, the 6-hydroxydopamine treatment which reduced brain dopamine was found to block the facilitation of self-stimulation produced by d-amphetamine. This facilitation of lateral hypothalmic self-stimulation was not influenced by treatments which reduced brain norepinephrine. An experiment suggesting that dopamine is of importance to locus coeruleus self-stimulation is also described. Implications of these data indicating a role for dopamine in self-stimulation responding are discussed in relation to the "catecholamine hypothesis of self-stimulation".

Blood platelet monoamine oxidase (MAO) activity was evaluated in twenty-four anergic, schizophrenic outpatients during a double-blind study comparing a chlorpromazine-imipramine combination to thio-thixeneplacebo. Platelet MAO activity was determined on blood samples drawn after a two-week drug-free washout and once weekly over a four-week on-drug period. Schizophrenic patients could be classified according to their blood platelet MAO activity into either a low-MAO or a high-MAO group. In neither group of this population of schizophrenics did blood platelet MAO activity correlate with any of the primary or secondary symptoms of schizophrenia. Ten alcoholics and seven volunteer non-patients could similarly be divided into low- and high-MAO groups. Mean blood platelet MAO activity for these groups was not significantly different from the mean values of the low and high-MAO groups of the schizophrenics. These findings do not support published reports of low blood platelet activity as a genetic marker for schizophrenia. Discriminate function analysis of symptomatology ratings at baseline was used to characterize the low- and high-MAO schizophrenic patient groups. Individuals in the low-MAO group were distinguished by hyperactivity, anergia and sleep disturbance.