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Biomedical subjects

L T Young

Publications and source records attributed to L T Young.

At least 91 records · Page 5Linked to original sources
PubMed1993

CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia.

Until recently, research on the neurochemical basis of affective disorders (AD) and schizophrenia (SCZ) focused on detecting postulated disturbances in presynaptic neurotransmitter release and metabolism, or postsynaptic receptor function. New insights into the molecular mechanisms involved in the propagation of neurotransmitter signals across biological membranes and in the regulation of neuronal responses have allowed the development of novel hypotheses, which may explain the altered postsynaptic neuroreceptor responsivity thought to be integral to the pathophysiology of these disorders. In this review we evaluate evidence from both basic science and clinical research implicating disturbances in postreceptor signal transduction in the pathophysiology and pharmacotherapy of AD and SCZ. Specific findings regarding potential postreceptor sites of pathophysiology are highlighted in each of these disorders, together with the growing body of data on the possible postreceptor loci of psychotropic drug action, especially lithium and antidepressants.

Animals↗
PubMed1993

Anxious and non-anxious bipolar disorder.

Eighty-one outpatients with bipolar disorder (BD) were grouped by SADS anxiety symptom scores (high vs. low) or diagnosis of generalized anxiety disorder, and/or panic disorder. BD patients with high anxiety scores were more likely to have suicidal behaviour (44% vs. 19%), alcohol abuse (28% vs. 6%), cyclothymia (44% vs. 21%) and an anxiety disorder (56% vs. 25%) with a trend toward lithium non-responsiveness. Diagnosis of an anxiety disorder was related only to high anxiety and lower GAS scores. Thus, anxiety may have similar clinical relevance in BD as it does in unipolar patients.

Adult↗
PubMed1993

Regional distribution of guanine nucleotide binding proteins (Gs and Gi alpha) in human brain: correlation with adenylyl cyclase activity.

Gs and Gi alpha immunoreactivities and adenylyl cyclase activity were measured in autopsied human brain. Highest levels of Gs 52 kDa and Gi alpha subunits occurred in frontal cortex, and highest Gs 45 kDa levels in caudate. Although basal adenylyl cyclase activity was similar in all regions, GTP gamma S-stimulated adenylyl cyclase activity and forskolin-stimulated activity showed specific brain regional patterns which correlated with Gs 45 kDa and Gi alpha levels underscoring an important functional relationship between these measures.

Adenylyl Cyclases↗
PubMed1993

Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder.

Experimental animal and peripheral blood cell studies point to guanine nucleotide regulatory (G) protein disturbances in bipolar affective disorder. We have previously reported elevated prefrontal cortex Gs alpha protein in bipolar affective disorder and have now extended these preliminary observations in a larger number of subjects, assessing the brain regional specificity of these changes in greater detail, determining the functional biochemical correlates of such changes, and evaluating their diagnostic specificity. Membrane G protein (Gs alpha, Gi alpha, Go alpha, and G beta) immunoreactivities were estimated by western blotting in postmortem brain regions obtained from 10 patients with a DSMIII-R diagnosis of bipolar affective disorder and 10 nonpsychiatric controls matched on the basis of age, postmortem delay, and brain pH. To examine whether there were functional correlates to the observed elevated Gs alpha levels, basal and GTP gamma S- and forskolin-stimulated cyclic AMP production was determined in the same brain regions. Compared with controls, Gs alpha (52-kDa species) immunoreactivity was significantly (p < 0.05) elevated in prefrontal (+36%), temporal (+65%), and occipital (+96%) cortex but not in hippocampus (+28%), thalamus (-23%), or cerebellum (+21%). In contrast, no significant differences were found in the other G protein subunits (Gi alpha, Go alpha, G beta) measured in these regions. Forskolin-stimulated cyclic AMP production was significantly increased in temporal (+31%) and occipital (+96%) cortex but not in other regions. No significant differences were apparent in basal or GTP gamma S-stimulated cyclic AMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

Psychiatric consultation in the eastern Canadian Arctic: I. Development and evolution of the Baffin Psychiatric Consultation Service.

The Baffin Consultation Service of the Clarke Institute of Psychiatry has been providing psychiatric consultation services to the Baffin Island region of the Eastern Canadian Arctic since 1971. This report describes the background history, development and evolution of the service. Attention is focused on aspects of the consultation visits, educational activities of the project and the development of a mental health network. It is suggested that this is a useful model for the provision of psychiatric services to remote areas with limited resources.

Arctic Regions↗
PubMed1993

Psychiatric consultation in the eastern Canadian Arctic: II. Referral patterns, diagnoses and treatment.

The clinical activities of the Baffin Consultation Service of the Clarke Institute of Psychiatry were examined. Demographic and clinical data are described based on clinical interviews and questionnaire items from 581 initial psychiatric referrals. More women than men were referred to the service; the mean age of the patients seen was 27.3 +/- 13.4 years. The majority of referred patients were single and unemployed. The most common reasons for referral were depression, suicidal ideation, suicide attempts and family problems. The major diagnoses made were adjustment reactions and depressive disorders. Treatment was largely carried out in an outpatient setting through local health care professionals. The implications of these findings for this population and the development of community-based intervention programs are discussed.

Adolescent↗
PubMed1993

Psychiatric consultation in the eastern Canadian Arctic: III. Mental health issues in Inuit women in the eastern Arctic.

This report describes mental health issues affecting Inuit women as seen in psychiatric consultation. Recent public and governmental attention has focused on the emotional and behavioural sequelae of rapid cultural change, spousal assault and sexual violence. The process of psychiatric consultant with the Inuit woman patient will be described. The need for innovative, community-based treatment strategies in this population will be emphasized.

Adult↗
PubMed1992

Striatal monoamine neurotransmitters and metabolites in dominantly inherited olivopontocerebellar atrophy.

We measured the levels of the monoamine neurotransmitters and metabolites in striatum of 14 patients with end-stage dominantly inherited olivopontocerebellar atrophy (OPCA). On average, dopamine levels were reduced in putamen (-53%), caudate (-35%), and nucleus accumbens (-31%). However, individual patient values showed a wide variation, indicating that mild to moderate striatal dopamine loss is a common but not constant feature of OPCA. Seven patients had marked putamen dopamine loss (-62% to -81%) but without evidence of correspondingly severe substantia nigra cell damage; this suggests the possibility of a "dying-back" phenomenon in which nerve terminal loss precedes cell body degeneration. Severe substantia nigra cell loss with almost total (-95% to -99%) putamen and caudate dopamine depletion was present in two patients; however, none of the 14 patients had had a clinical diagnosis of parkinsonism or was receiving antiparkinsonian medication. Mean striatal serotonin levels were normal, whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were elevated by 47% to 63%; this suggests increased activity of raphe dorsalis serotonin neurons innervating the striatum, which might aggravate the functional consequences of the dopamine deficit.

Biogenic Amines↗
PubMed1991

Maturational and aging effects on guanine nucleotide binding protein immunoreactivity in human brain.

Age-related changes in transmembrane signal transduction have been reported for a number of hormonal receptors in human tissues. Guanine nucleotide binding proteins (G-proteins) are major regulatory components in the signal transduction processes for numerous receptors. Developmental changes in the abundance of specific G-protein alpha subunits, especially for Go, have already been shown in rat brain and in neuronal cell lines. In this study, immunoblotting analyses were performed with specific rabbit polyclonal antisera to Gs alpha, Gi alpha, Go alpha, and G beta subunits to estimate semi-quantitatively these G-protein subunits in samples of parietal cortex obtained postmortem from 18 subjects free of neurologic or psychiatric disease whose ages ranged from 3 days to 92 years. The Gs and Gi alpha subunit immunoreactivities were correlated significantly and inversely with age. The Gi alpha immunoreactivity declined markedly (46%) after the age of 40. As other G-protein subunit concentrations showed no age-dependent changes, the observed relationship between Gs and Gi alpha subunits and age is not likely due to cell loss occurring with advancing age. Of particular interest, the ratio of 52 to 45 kDa Gs alpha subunit immunoreactivities was significantly higher in infants than that found for adult parietal cortex. Given that changes in G-protein subunit abundance directly affect receptor-G-protein-effector functionality and response, these age-related alterations may be of importance in cerebral dysfunction and the development of neuropsychiatric disease in the later years of life.

Adolescent↗
PubMed1991

Postmortem cerebral cortex Gs alpha-subunit levels are elevated in bipolar affective disorder.

We examined the relative abundance of G-protein subunits in postmortem brain obtained from 7 patients with bipolar affective disorder (BAD) compared with 7 age- and sex-matched controls. G-protein subunit immunoreactivities were determined in membranes prepared from postmortem prefrontal cortex using SDS-PAGE and immunoblotting with specific polyclonal antisera against selected G-protein subunits: Gsa, Gi(1&2) alpha, Go alpha and G beta(1&2). Of these G-protein subunits, only Gs alpha immunoreactivity was found to be significantly elevated in frontal (+ 34%), and occipital (+ 80%) cortex (P less than 0.05) in BAD compared with control subjects. Smaller increments (+ 22%) in cerebellar Gs alpha immunoreactivity were also found but were not statistically significant. On the basis that increased Gs alpha immunoreactivity may reflect enhanced functional responsiveness of the receptor-effector units to which this coupling protein is integral, the present findings suggest that disturbances in Gs-mediated signal transduction may be involved in the pathophysiology of BAD.

Bipolar Disorder↗
PubMed1991

Effects of endogenous dopamine on kinetics of [3H]N-methylspiperone and [3H]raclopride binding in the rat brain.

Competition by endogenous dopamine with the binding of D2 dopamine receptor ligands may be important in the interpretation of positron emission tomography (PET) neuroreceptor studies. PET studies with N-methylspiperone (NMSP) have revealed increased D2 dopamine receptors in schizophrenia, whereas studies with raclopride (RAC) have not detected such differences. This may be due, at least in part, to differences in competition with endogenous dopamine for ligand binding. To determine effects of endogenous dopamine on in vivo receptor binding, adult male rats were preinjected with amphetamine and reserpine prior to [3H]NMSP or [3H]RAC. Striatal to cerebellar ratios of ligand binding were determined. To approximate the conditions of a PET study, a kinetic model was employed to examine effects of pharmacologically increasing brain dopamine levels (amphetamine pretreatment) on PET ligand binding. In these experiments, tail veins and arteries were cannulated and kinetic parameters determined from normalized integral plots in rats treated with amphetamine prior to radioligand injection. Both [3H]NMSP (43.5%) and [3H]RAC (41.5%) binding were significantly decreased after amphetamine pretreatment, whereas after reserpine pretreatment [3H]RAC binding was increased (52.7%). Kinetic studies revealed a marked resistance of [3H]NMSP to competition with endogenous dopamine released by amphetamine. In contrast, kinetic parameters of [3H]RAC were markedly reduced at all time intervals. This suggests significant differences in competition with endogenous dopamine by [3H]NMSP and [3H]RAC, determined kinetically. These findings may have important implications for the interpretation of PET neuroreceptor studies.

Amphetamine↗
PubMed1988

Decreased brain [3H]inositol 1,4,5-trisphosphate binding in Alzheimer's disease.

Inositol 1,4,5-trisphosphate (IP3) receptor binding sites were studied in autopsied brains from 10 subjects with dementia of the Alzheimer type (DAT) and 10 age-matched controls. In the parietal cortex and hippocampus, there was a 50-70% loss of [3H]IP3 binding whereas no significant changes were observed in frontal, occipital and temporal cortices, caudate or amygdala. Scatchard analysis confirmed a reduction in receptor density rather than a change in affinity. Since muscarinic receptors are robustly coupled to IP3 formation, our data demonstrate abnormalities beyond the muscarinic receptor recognition site in DAT.

Alzheimer Disease↗
PubMed1988

[3H]inositol 1,4,5-triphosphate binding in human cerebral cortex.

Specific, saturable and reversible binding of [3H]inositol 1,4,5-triphosphate (IP3) was demonstrated to membranes prepared from autopsied cerebral cortices from 6 subjects who were free from psychiatric or neurological disease. The binding has an affinity of 27 +/- 8 nM (mean +/- S.E.M.); capacity (Bmax) of 1.09 +/- 0.18 pmol/mg protein and is reversible in the presence of an excess of unlabelled IP3. These [3H]IP3 binding sites are likely to be physiologically significant receptors which merit further characterization in the normal and diseased human brain.

Adolescent↗