Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway.

Increases in the intracellular concentration of calcium ([Ca2+]i) activate various signaling pathways that lead to the expression of genes that are essential for dendritic development, neuronal survival, and synaptic plasticity. The mode of Ca2+ entry into a neuron plays a key role in determining which signaling pathways are activated and thus specifies the cellular response to Ca2+. Ca2+ influx through L-type voltage-activated channels (LTCs) is particularly effective at activating transcription factors such as CREB and MEF-2. We developed a functional knock-in technique to investigate the features of LTCs that specifically couple them to the signaling pathways that regulate gene expression. We found that an isoleucine-glutamine ("IQ") motif in the carboxyl terminus of the LTC that binds Ca2+-calmodulin (CaM) is critical for conveying the Ca2+ signal to the nucleus. Ca2+-CaM binding to the LTC was necessary for activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, which conveys local Ca2+ signals from the mouth of the LTC to the nucleus. CaM functions as a local Ca2+ sensor at the mouth of the LTC that activates the MAPK pathway and leads to the stimulation of genes that are essential for neuronal survival and plasticity.

Mitotic histone H3 phosphorylation by the NIMA kinase in Aspergillus nidulans.

Phosphorylation of histone H3 serine 10 correlates with chromosome condensation and is required for normal chromosome segregation in Tetrahymena. This phosphorylation is dependent upon activation of the NIMA kinase in Aspergillus nidulans. NIMA expression also induces Ser-10 phosphorylation inappropriately in S phase-arrested cells and in the absence of NIMX(cdc2) activity. At mitosis, NIMA becomes enriched on chromatin and subsequently localizes to the mitotic spindle and spindle pole bodies. The chromatin-like localization of NIMA early in mitosis is tightly correlated with histone H3 phosphorylation. Finally, NIMA can phosphorylate histone H3 Ser-10 in vitro, suggesting that NIMA is a mitotic histone H3 kinase, perhaps helping to explain how NIMA promotes chromatin condensation in A. nidulans and when expressed in other eukaryotes.

Simultaneous pontine and basal forebrain microinjections of carbachol suppress REM sleep.

This study was performed to test the hypothesis that cholinoceptive basal forebrain systems can significantly influence cholinoceptive pontine mechanisms known to be important for generating rapid eye movement (REM) sleep. This hypothesis was examined by microinjecting the cholinergic agonist carbachol or saline (vehicle control) into the pons, the basal forebrain, or simultaneously into the pons and basal forebrain, while quantifying the effects on sleep and wakefulness in unanesthetized, chronically instrumented cats. All microinjections were made during wakefulness and were followed by 2 or 4 hr of recording. Polygraphic records were scored for wakefulness, non-REM sleep, REM sleep, and the REM sleep-like state evoked by pontine administration of carbachol (DCarb). Dependent variables quantified following each microinjection included the percentage of recording time spent in each state, the latency to onset of non-REM, REM, and DCarb, the number of episodes per hour of each state, and the duration of the longest episode of each state. A total of 149 microinjections were made into 15 forebrain and 11 pontine sites in eight cats. Basal forebrain administration of carbachol significantly increased wakefulness. Pontine microinjection of carbachol produced a state that polygraphically and behaviorally resembled REM sleep. This REM sleep-like state occurred in amounts significantly greater than natural REM sleep. Pontine carbachol also significantly decreased wakefulness and non-REM sleep. Simultaneous injection of carbachol into the pons and basal forebrain enhanced REM sleep, but the magnitude of this enhancement was significantly less than the increase in REM sleep evoked by carbachol injection into the pons alone. The results show that cholinoceptive regions of the basal forebrain can increase wakefulness and reduce the ability of pontine carbachol to evoke the REM sleep-like state. These findings suggest that basal forebrain administration of carbachol activates an arousal-generating system that can successfully compete with the powerful cholinergic REM sleep-generating system of the pons.

Drugs and personality: comparison of drug users, nonusers, and other clinical groups on the 16PF.

This article reviews published 16PF research on drug users. It also compares the 16PF scores of a new sample of nonusers with scores of matched groups of heavy, chronic users of cocaine, amphetamine, opiates, and barbiturates/sedative hypnotics, as well as combined groups of stimulant users, depressant users, and a combined group of users of all substances. No significant differences were found among drug user groups, but the profile of the nonuser group was distinctive. K-Means Cluster Analyses, as well as Cattell's Similarity and Pearson Product Moment Correlation Coefficients, were used to compare profiles of these new samples with the 19 groups described in an earlier meta-analysis of published 16PF studies. Data from the new samples did not cluster with data from other published research, although certain specific similarities appeared in more detailed correlational analyses. Methodological problems are discussed, and it is recommended that in future studies drug user groups be more carefully selected and defined, sample descriptions be more thorough and complete, complete profile information be routinely provided, and efforts be made to explore the utility of the Cattell CAQ in studies of drug users/misusers.

Drug misuse and psychopathology: a meta-analysis of 16PF research.

This report presents a meta-analysis of a series of published 16PF findings which describe score profiles of nine groups of substance users/abusers, a nonuser comparison group, seven psychiatric groups, a group of criminals, and a group of gang delinquents. Analytical procedures include K Means Clustering, Cattell's rp statistic, and Pearson r. Although drug use was found to be associated with various forms of psychiatric diagnoses, it was not found to be associated with any particular form of psychopathology. The 16PF profiles of groups of users of different substances were not homogeneous within groups. Some similarity, however, was found among profiles of alcoholics. No evidence could be found to support the contention that groups of substance abusers yield the particular profile pattern on the 16PF that was ascribed to them in an earlier meta-analyses. Due to the inadequacies of the 16PF in diagnosing psychiatric conditions, it is suggested that a more fruitful direction of future research might be to use Cattell's Clinical Analysis Questionnaire (CAQ).

Drug injection injuries of the upper extremity.

The increasing incidence of illicit intravenous drug abuse has reached epidemic proportions in western society. Although the accompanying infectious complications such as hepatitis and acquired immunodeficiency syndrome receive the most notoriety, injection injuries are causing an increasing number of problems. A retrospective review of patients requiring admission for acute or chronic drug injection injuries of the upper extremities was made at the Detroit Receiving Hospital from 1980 through 1985. The demographical, historical, physical, microbiological, and follow-up data were analyzed. The majority of the injuries involved subcutaneous injections into the hand with accompanying inflammatory or infectious complications. The bacteriological data revealed unique characteristics and did not reflect patterns expected from inoculation of normal skin flora. A treatment regimen based on the data is proposed.

Drugs and personality: dependence of findings on method.

Past studies on relationships between drug use and personality are open to criticism on theoretical and methodological grounds. Properly conducted research may show relationships that have been previously undiscovered. The present studies examined 45 carefully selected, noninstitutionalized men in four matched groups of heavy, chronic drug users and a nonuser comparison group. A variety of instruments, all of which presumably measure the propensity to seek novel and varied sensations, were administered. When used to evaluate hypotheses derived from Optimal Level of Arousal (OLA) theory, data from this study showed an association between the trait measured and drug(s) of choice among men committed to the heavy, chronic use of particular substances. However, the association was not that anticipated by OLA theory. Instead, it appeared that, among heavy, chronic users, drug preference and sensation seeking are related to extraversion and introversion. The findings were consistent with a theory of psychological individuation that was developed from thorough clinical assessment of every individual in the research program.

A new perspective on intervention in heavy, chronic drug use.

No single intervention strategy can solve all problems of drug abuse. Large-scale methods do not contribute to understanding or solving the problems of individual persons. Research on individuals shows that each major drug of abuse produces a distinctive ego state. Heavy, chronic users choose drugs which generate states that provide the illusion of solving personal problems, the origins of which are traceable to early personal development. A previously described theory attributed these problems to difficulties in Ego development. It is also necessary, however, to account for numinous factors. This is accomplished by postulating the existence of the Self, an unconscious counterpart of the Ego. Successful personal development carries both Ego and Self along a spiraling course through the major crises of individuation. The relationship of Self and Ego is expressed by life themes. These derive from myths that live themselves out as autonomous complexes in an individual's life. Therapists who treat individuals must work with the Self as well as the Ego. This means recognizing and dealing with mythic factors. Although the basic theory in this paper was derived from studying heavy, chronic drug users, it is general in nature and applies to all persons.

A theory of adolescent substance abuse.

This report applies a theory of psychological individuation to inferences drawn from an 8-year series of clinical studies of men who practice heavy, chronic use of different drugs. Each man was studied intensively over a period of 4-5 months, using interviews and a comprehensive battery of dimensional and morphogenic assessment procedures. Users of barbiturates and sedative hypnotics were found to be least mature, followed by users of opiates, users of amphetamine, users of cocaine, and nonusers of drugs, who were found to be most mature. A theory is described which conceives adolescent substance abuse as rooted in dysfunctional relationships with parental figures which block or delay the normal individuation process. Comparable sets of representative case studies of heavy, chronic users of alcohol and marihuana are recommended to facilitate the development of treatment programs that take into account the special needs of persons who practice heavy, chronic use of different substances.

The phenomenological structure of drug-induced ego states. II. Barbiturates and sedative-hypnotics: phenomenology and implications.

Empirically derived descriptions of experiential states, induced by heavy, chronic consumption of drugs, provide valuable information for treatment personnel as well as for scientists studying drug abuse or pharmacology. A 7-year program of research has studied persons committed to heavy, long-term use of several prominent substances of abuse. This report results from that research and provides a phenomenological description of the psychological state induced by heavy, chronic use of barbiturates and sedative-hypnotics. Interview, Q-sort and semantic differential data indicate the barbiturate state is intensely unpleasant: a state in which users lose desired characteristics, take on undesired characteristics, engage in self-destructive acts, and emerge in worse condition than before entering it. Explaining why people choose to enter such a state is difficult. Several theoretical alternatives for doing so are considered. Psychotherapy with these individuals must deal with the theme of abandonment/rejection that permeates their lives and with the diffuse hostility, expectations of failure and defeat, self-destructive tendencies, and feelings of hopelessness that they display. Suggestions are presented for treatment of individual cases.

Drug-induced ego states. I. Cocaine: phenomenology and implications.

The ego state experienced by chronic users of cocaine is described in terms of sensorimotor functioning, cognitive functioning, emotionality, spatiality , temporality , causality, and materiality . At low use levels the state is pleasurable, but at high levels fear, anxiety, and paranoia increase, and ultimately reality contact breaks down. Q-sort, Semantic Differential, and other data suggest that low-level users take cocaine to overcome personal insecurities and relieve boredom. Heavy users take it to support overvaulting ambitions and intense strivings for self-sufficiency. Psychotherapy with such persons must deal with their counterdependency , anger, and despair, and with their underlying sense of betrayal . These persons have unacknowledged needs for spiritual experience that must be dealt with openly. A description of persons most vulnerable to heavy use of cocaine is provided, and recommendations for research and social policy are presented.

Correlates of sensation seeking by heavy, chronic drug users.

Product-moment correlations among number of drugs used and several measures of constructs related to sensation seeking were examined for four matched groups of chronic drug users and two supplementary groups of nine persons each. Number of drugs used correlated positively with all scores on the Sensation Seeking Scales, the Extraversion and Neuroticism Scales of the Eysenck Personality Inventory, and the Change Seeker Index. The pattern is consistent with the proposition that a need for stimulation or change underlies experimentation with a large number of chemical substances. The general pattern of correlations among tests resembled that reported by other investigators. The construct validity of the General Score from the Sensation Seeking Scales is enhanced by these findings. The data suggest that this score measures much the same construct as the Change Seeker Index.

Drugs and personality: extraversion-introversion.

Eysenck theorizes that stimulants induce introversion and that depressants induce extraversion; common sense suggests opposite expectations. Scores on the extraversion scale of the Eysenck Personality Inventory yielded statistically significant differences among carefully matched series of heavy, chronic users of cocaine, amphetamine, opiates, barbiturate/sedative-hypnotics, and a comparable series of nonusers. Cocaine users and opiates users were found to be more introverted; amphetamine users, barbiturates users, and nonusers were more extraverted . These findings did not fully support either set of hypotheses. These data also implied that, if drugs influence extraversion, they do so only by suppressing it. Data from two other measures of extraversion were consistent with this hypothesis.

Psychopathology and chronic drug use: a methodological paradigm.

Four carefully matched groups, each containing nine male, chronic users of a specific type of substance, were compared with each other and with a group of nine nonusers. Each person was elaborately studied in a representative case research, but this report presents only data from two tests of intelligence (the Revised Beta and the WAIS) and two tests of personality (the MMPI and 16 PF). Extensive descriptive information is presented to characterize the participants. Groups were found not to differ on scores on intelligence tests, and the MMPI was found to reveal more group differences than the 16 PF. Users of barbiturates and sedative-hypnotics were most severely maladjusted, followed by users of opiates, users of cocaine, users of amphetamine and its congeners, and nonusers. Differences also appeared between combined users of stimulants, combined users of depressants, and nonusers, as well as between all drug users (as a group) and nonusers. This research is offered as a methodological paradigm for evaluating future studies. It illustrates how the representative case method may be expanded to permit comparisons among groups.

Ego development, dragon fights, and chronic drug abusers.

Developmental antecedents of adult behavior are described for four matched groups of chronic drug users (cocaine, amphetamine, opiates, barbiturates, and sedative-hypnotics) and a comparable group of nonusers, each group having been studied intensively for approximately 1.5 years. Integration is provided by a theory that views psychological development as a series of ego transformations, which appear metaphorically in legend and mythology as dragon fights. Each group is characterized theoretically by a core conflict, an upper limit on individuation, and a typical character. Results imply that radically new approaches to psychological treatment may be needed, especially for chronic users of barbiturates, opiates, and cocaine.