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D M Donovan

Publications and source records attributed to D M Donovan.

At least 19 recordsLinked to original sources
PubMed1992

Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding.

Polar amino acids lying within three hydrophobic regions of the dopamine transporter (DAT) are analogous to those important for ligand recognition by catecholamine receptors. Possible functional significance of these amino acids was examined by expressing DAT cDNAs mutated in these polar residues. Replacement of aspartate at position 79 with alanine, glycine, or glutamate dramatically reduced uptake of [3H]dopamine and the tritium-labeled Parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and reduced the mutants' affinity for the tritium-labeled cocaine analog (-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) without affecting Bmax. Replacement of the serine residues at positions 356 and 359 in the seventh hydrophobic region by alanine or glycine caused reductions in [3H]dopamine and [3H]MPP+ uptake, whereas [3H]CFT binding was less affected. Substitution of two serines in the eighth hydrophobic region yielded wild-type values for [3H]dopamine and [3H]MPP+ uptake and [3H]CFT binding. These results demonstrate that aspartate and serine residues lying within the first and seventh hydrophobic putative transmembrane regions are crucial for DAT function and provide identification of residues differentially important for cocaine binding and for dopamine uptake.

1-Methyl-4-phenylpyridinium↗
PubMed1992

Preproenkephalin promoter "cassette" confers brain expression and synaptic regulation in transgenic mice.

The preproenkephalin A gene is a neurotransmitter gene whose expression can be modulated "trans-synaptically" by changes in neuronal activity. DNA sequences lying within 200 base pairs of this gene's transcription start site resemble consensus binding sites for several transcription factor families. In nonneuronal cell cultures, this promoter region is sufficient to mediate gene responses to depolarization, phorbol esters, adenylate cyclase, and calcium fluxes. To assess the role that these cis-acting elements could play in preproenkephalin expression and regulation in vivo, the expression of a construct containing this 200-base-pair region fused to the chloramphenicol acetyltransferase gene was examined in transgenic mice. This promoter confers modest expression in brain, adrenal, and small intestine, with substantially higher levels in testis. These elements confer trans-synaptic regulation in two well-studied models of trans-synaptic preproenkephalin upregulation but not in a third system, underscoring the specificity of the regulatory sequence elements implicated in the synaptic regulation of neuronal genes.

Afferent Pathways↗
PubMed1992

Conservation of mouse alpha A-crystallin promoter activity in chicken lens epithelial cells.

Previous transfection experiments have shown that 162 base pairs (bp) of the 5' flanking sequence of the chicken alpha A-crystallin gene are required for promoter activity in primary chicken lens epithelial cells (PLE), while only 111 bp of the 5' flanking sequence are needed for activity of the mouse alpha A-crystallin promoter in transfected chicken PLE cells or in a SV40 T-antigen-transformed transfected mouse lens epithelial cell line (alpha TN4-1). The effect of site-directed mutations covering positions -111 to -34 of the mouse alpha A-crystallin promoter fused to the bacterial chloramphenicol acetyltransferase (CAT) gene was compared in transfected chicken PLE cells and mouse alpha TN4-1 cells; selected mutations were also examined in a nontransformed rabbit lens epithelial cell line (N/N1003A). In general, the same mutations reduced promoter activity in the transfected lens cells from all three species, although differences were noted. The mutations severely affected regions -111/-106 and -69/-40 regions in all the transfected cells examined; by contrast, mutations at positions -105/-99 and -87/-70 had a somewhat greater effect in the chicken PLE than the mouse alpha TN4-1 cells, while mutations of the -93/-88 sequence reduced expression in the alpha TN4-1 but not the PLE cells. A partial cDNA with sequence similarity to alpha A-CRYPB1 of the mouse has been isolated from a chicken lens library; mouse alpha A-CRYBP1 is a putative transcription factor which binds to the -66/-55 sequence of the mouse alpha A-crystallin promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Primary afferent stimulation acts through a 193 base pair promoter region to upregulate preproenkephalin expression in dorsal horn of transgenic mice.

The expression of the principal opioid peptide gene, preproenkephalin A, is exquisitely regulated by primary afferent inputs to the spinal and medullary dorsal horns. This regulated expression in response to neural synaptic activity has been referred to as trans-synaptic regulation. To define which DNA regions could mediate this trans-synaptic regulation, transgenic 'HEC' mice whose genomes include 193 bp of the human preproenkephalin A promoter fused to a chloramphenicol acetyltransferase (CAT) reporter gene were studied. Mice received unilateral electrical stimulation of the trigeminal ganglion or adjuvant injection into the hindpaw, stimuli known to regulate dorsal horn proenkephalin expression in vivo. CAT activity conferred by this promoter displayed trans-synaptic upregulation with both stimuli. Although the level of the upregulation was 2- to 3-fold higher than the change in the wild type gene, several features of this induction paralleled aspects of the behavior of the wild-type gene: the rapidity of responses to trigeminal ganglion stimulation, the stimulation intensity dependence of responses to trigeminal ganglion stimulation and the time course of upregulation noted following adjuvant injection. Regulatory proteins binding to this restricted promoter region are thus likely to mediate aspects of dorsal horn enkephalin regulation by pain and other somatic stimuli.

Afferent Pathways↗
PubMed1992

Combat-related posttraumatic stress disorder and severity of substance abuse in Vietnam veterans.

This study examined the effects of Vietnam war-zone duty and combat-related posttraumatic stress disorder (PTSD) on severity of drug- and alcohol-abuse disorders among veterans seeking treatment for substance dependence. Combat-exposed Vietnam-theater veterans (N = 108) were compared with Vietnam-era veterans without war-zone duty (N = 151) on psychometric measures of drug and alcohol abuse. There were no differences between theater and era veterans on these measures. However, Vietnam-theater veterans with PTSD experienced more severe drug- and alcohol-abuse problems than did theater veterans without PTSD and were at greater risk for having both forms of substance abuse. Further analyses showed that PTSD was significantly related to some dimensions of drug- and alcohol-abuse problems but not to other dimensions. These findings indicate that PTSD, rather than combat stress per se, is linked to severity of substance abuse. Finally, reexperiencing and avoidance/numbing components of PTSD were more strongly associated with drug abuse than alcohol abuse, but physiological arousal symptoms of PTSD were more highly correlated with alcohol abuse.

Adaptation, Psychological↗
PubMed1991

Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina.

Type A gamma-aminobutyric acid (GABAA) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. We have used these highly conserved regions to identify additional members of this family by using the polymerase chain reaction (PCR). One PCR product was used to isolate a full-length cDNA from a human retina cDNA library. The mature protein predicted from this cDNA sequence in 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABAA subunits. This gene is expressed primarily in the retina but transcripts are also detected in the brain, lung, and thymus. Injection of Xenopus oocytes with RNA transcribed in vitro produces a GABA-responsive chloride conductance and expression of the cDNA in COS cells yields GABA-displaceable muscimol binding. These features are consistent with our identification of a GABA subunit, GABA rho 1, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family.

Amino Acid Sequence↗
PubMed1991

Combat-related PTSD and psychosocial adjustment problems among substance abusing veterans.

The purpose of this study were the following: a) to determine the prevalence of combat-related posttraumatic stress disorder (PTSD) symptoms among veterans seeking assistance at a Veterans Administration medical center substance abuse treatment facility, b) to examine the relative contribution of Vietnam war zone variables to PTSD symptom development, and c) to study psychosocial adjustment problems associated with Vietnam combat exposure and with PTSD symptoms among help-seeking substance abusing men. Of 489 male veterans presenting for treatment, 10.7% had significant Vietnam combat-related PTSD symptoms as measured by the Mississippi Scale for Combat-Related PTSD. Clinically significant PTSD symptoms occurred among 46% of the subsample of combat-exposed Vietnam veterans with substance abuse problems. Degree of combat exposure was the most important military stressor that distinguished Vietnam veterans with PTSD from those without PTSD, but the groups also differed on age of war zone duty, duration of war zone duty, and whether they were wounded. Veterans who served in Vietnam did not differ from veterans who had no war zone duty on various parameters of psychosocial adjustment. However, the subgroup of Vietnam veterans with PTSD symptoms reported significantly greater psychosocial adjustment problems than their counterparts who did not have PTSD. The deleterious effects associated with combat-related PTSD appeared to be confined to adjunctive psychiatric difficulties and unemployment and did not increase risk of arrests for antisocial conduct beyond that found for veterans without PTSD. Methodological and clinical implications of these findings are discussed.

Adaptation, Psychological↗
PubMed1990

Predicting drinking outcome: demography, chronicity, coping, and aftercare.

The contribution of demographics (age, martial status), chronicity (previous alcohol hospitalizations, years of problem drinking), coping (temptation, cognitive coping), and early aftercare attendance, in predicting drinking outcomes was examined using hierarchical regression and discriminant analyses. Six-month followup data were available for 37 of 39 male alcoholics. Previous hospitalizations significantly predicted all drinking outcomes. Abstinence for the six-month followup was predicted by years of problem drinking and cognitive coping. Early aftercare attendance added significantly to the prediction of consumption, drinking days, and abstinence. Demographics were not significant predictors of outcome. The results support the continued utility of chronicity variables as predictors of outcome, underscore the importance of coping, and suggest that early aftercare attendance be monitored and investigated further.

Adaptation, Psychological↗
PubMed1990

Regulation of the mouse alpha A-crystallin gene: isolation of a cDNA encoding a protein that binds to a cis sequence motif shared with the major histocompatibility complex class I gene and other genes.

We have shown by site-directed mutagenesis that the sequence between positions -69 and -40 of the mouse alpha A-crystallin gene is crucial for tissue-specific gene expression in a transfected mouse lens epithelial cell line transformed with the early region of simian virus 40. Gel retardation experiments with synthetic oligodeoxynucleotides revealed a mouse lens nuclear protein which bound specifically to the palindromic sequence 5'-GGGAAATCCC-3' at positions -66 to -57 in the alpha A-crystallin promoter. By screening a bacteriophage lambda gt11 expression library of the transformed lens cells, we isolated a 2.5-kilobase-pair cDNA encoding a fusion protein which bound to this sequence and to the regulatory element of the major histocompatibility complex (MHC) class I gene. This cDNA hybridized to a 10-kilobase-pair polyadenylated RNA present in many different tissues, including lens. It encoded a protein, tentatively called alpha A-CRYBP1, containing at least two zinc fingers. alpha A-CRYBP1 is either homologous or very similar to the human nuclear proteins MBP-1 (Baldwin et al., Mol. Cell. Biol. 10:1406-1414, 1990), PRDII-BFI (Fan and Maniatis, Genes Dev. 4:29-42, 1990), and HIV-EP1 (Maekawa et al., J. Biol. Chem. 264:14591-14593, 1989), which bind to regulatory elements of the MHC class I, beta interferon, and human immunodeficiency virus genes, respectively. Our results suggest that the lens-specific alpha A-crystallin, MHC class I, beta interferon and other genes have a similar cis-acting DNA regulatory motif that shares alpha A-CRYBPI, MBP-1, PRDII-BF1, HIV-EP1, or other closely related proteins as trans-acting factors.

Amino Acid Sequence↗
PubMed1990

Bad drivers: identification of a target group for alcohol-related prevention and early intervention.

Individuals arrested for driving while intoxicated (DWI) have been targeted for preventive intervention of alcohol-related problems. However, high rates of diagnosed alcoholism among DWI arrestees suggest a need to identify individuals at risk earlier in the developmental process. The present study investigates one such group, namely male "bad drivers" with a history of multiple nonalcohol-related driving convictions. Over 11% of a sample of 254 men identified as bad drivers during an index year received an initial DWI arrest over a subsequent 3-year follow-up period. This was over five times greater than the rate of initial DWI arrest among a representative sample of men from the general driving population over the same time period. The same high rate of subsequent DWI arrest among drivers having four or more driving offenses within the index year was replicated in a 1% probability sample of over 39,000 drivers from the general driving population. Those individuals from the original group of 254 bad drivers who received an initial DWI had significantly higher levels of drinking at the time of their original identification as bad drivers than did those who did not receive a DWI. The results were discussed in terms of early identification and preventive interventions within the population of bad drivers.

Adult↗
PubMed1989

The paraconscious.

A new concept, the paraconscious, is presented as the third complementary member of the conscious/unconscious paradigm. A form of cognition dating from early intrauterine existence to sometime in the first year of life, the nature of the paraconscious is determined by the incompleteness of developing cognitive structures, giving rise to a form of knowing that does not allow for the generation of voluntarily retrievable mental representations. The paraconscious provides a conceptual framework for the understanding of "conflict-free" psychic development, thereby linking such apparently disparate phenomena as Stoller's core gender identity and primary transsexualism, Bruch's primary anorexia nervosa, night terrors, and ubiquitous convictions such as the belief in telephathy and the survival of death by human consciousness. It has profound implications for the treatment (or nontreatment in the case of primary male transsexualism) of significant psychiatric syndromes and raises crucial questions about the nature of learning during the earliest moments of our cognitive existence, about the nonlinguistic transmission of information and about the origin of certain widely held beliefs.

Adult↗
PubMed1989

The Alcohol Dependence Scale: a validation study among inpatient alcoholics.

The present study investigated whether the degree of alcohol dependence, as operationalized by Skinner and Allen's Alcohol Dependence Scale (ADS), covaried with concurrent and predictive criteria in a sample of hospitalized alcoholics. As previously reported, the ADS was found to be unidimensional and internally consistent. However, compared to Skinner and Allen's findings, these inpatients had significantly lower ADS scores. Correlations with concurrent measures of cognitive functioning, psychiatric and physical symptoms tended to be smaller than, but in the same direction as, those previously reported using an outpatient sample. ADS scores did not significantly predict attrition from inpatient treatment, self-reported alcohol consumption over 9-month follow-up or duration of aftercare involvement. Patients who relapsed reported significantly higher ADS scores at admission, however, the magnitude of this relationship was modest (r = .16). In its present form, the ADS appears to have fair concurrent validity, but limited predictive utility within a sample of inpatient alcoholics.

Adult↗
PubMed1989

Drinking-related locus of control and the drinking status of urban Native Americans.

Although promising, the available data concerning drinking-related locus of control have been almost entirely limited to treatment samples of white men. The major purpose of this study was to extend our understanding by comparing the drinking-related expectancies of three groups of Native Americans: problem drinkers, nonproblem drinkers and recovered alcoholics. Multivariate analyses were employed to control statistically for important sociodemographic differences between groups and included a test of the possibility that sex moderated the relationship between drinking status and drinking expectancies. As predicted, problem drinkers reported significantly less personal control of alcohol use than either nonproblem drinkers or recovered alcoholics. There were no significant differences between nonproblem drinkers and recovered alcoholics. Native American men were found to hold significantly more external orientations towards drinking than did women. The results were discussed in terms of comparisons with the available literature, and future research needs were identified. The findings provide indirect support for current treatment philosophies that seek to modify patient perceptions of the controllability of drinking behavior in a more internal direction.

Adult↗
PubMed1979

Application of discriminant analysis to level of performance of alcoholics and nonalcoholics on Wechsler-Bellevue and Halstead-Reitan subtests.

Investigated the utility of subtests from the Wechsler-Bellevue Intelligence Scale and the Halstead-Reitan Neuropsychological Test Battery to differentiate between alcoholics and nonalcoholics (N = 76). Analyses of variance indicated that the alcoholics were more impaired than nonalcoholics. It was found that the Wechsler-Bellevue Performance subtests were more discriminative than were Verbal subtests, with performance on the Halstead-Reitan variables being intermediate. The nine measures that differentiated most significantly between groups were subjected to a stepwise multivariate discriminant analysis. The resulting function correctly classified Ss with an overall accuracy of 74.7%. It was found that the Block Design subtest was the best single discriminator. The findings were discussed in relationship to previous findings and with respect to general issues of clinical neuropsychological assessment.

Alcoholism↗
PubMed1979

Implicit preadmission screening criteria in an alcoholism treatment program.

The fact that alcoholism programs are biased in terms of the kind of patients admitted to treatment is well recognized. The authors examined the possible bias of preadmission screening procedures in an alcoholism treatment program and investigated some of the criteria used by staff clinicians in determining an applicant's acceptability for treatment. They found that accepted and rejected applicants had highly similar characteristics, differing only in age (accepted applicants were slightly younger than those rejected) and source of referral. The overall findings suggest that clinicians implicitly evaluate problem drinkers along dimensions related to their perceived "treatability" in a given therapeutic setting.

Adult↗
PubMed1979

Validation of a subjective helplessness measure.

Investigated the potential utility and validity of a measure of subjective helplessness, the H25. Helplessness is defined as the degree to which the individual perceives him/herself to be unable to influence or control the initiation and outcome of a variety of potentially reinforcing activities. Alcoholic subjects were classified into three levels of self-reported helplessness. An initial multivariate analysis of variance indicated that the groups differed with respect to severity level across a number of dimensions of depressive symptomatology, with the High Helplessness group appearing significantly more depressed on each of the measures than Low Helplessness subjects. Subsequent analyses supported the construct validity of the H25. Those measures found to be most descriminating between groups and most predictive of the level of helplessness reflected a dimension of behavioral retardation consistent with the motivational dificits noted in the learned helplessness model. Recommendations for the future validation of individual difference measures of helplessness are discussed.

Adult↗