Carla Drebing

Smoking and mental illness.

Patients with mental illness have a higher incidence of smoking than the general population and are the major consumers of tobacco products. This population includes subjects with schizophrenia, manic depression, depression, posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), and several other less common diseases. Smoking cessation treatment in this group of patients is difficult, often leading to profound depression. Several recent findings suggest that increased smoking in the mentally ill may have an underlying biological etiology. The mental illness schizophrenia has been most thoroughly studied in this regard. Nicotine administration normalizes several sensory-processing deficits seen in this disease. Animal models of sensory deficits have been used to identify specific nicotinic receptor subunits that are involved in these brain pathways, indicating that the alpha 7 nicotinic receptor subunit may play a role. Genetic linkage in schizophrenic families also supports a role for the alpha 7 subunit with linkage at the alpha 7 locus on chromosome 15. Bipolar disorder has some phenotypes in common with schizophrenia and also exhibits genetic linkage to the alpha 7 locus, suggesting that these two disorders may share a gene defect. The alpha 7 receptor is decreased in expression in schizophrenia. [(3)H]-Nicotine binding studies in postmortem brain indicate that high-affinity nicotinic receptors may also be affected in schizophrenia.

Comparison of the regional expression of nicotinic acetylcholine receptor ?7 mRNA and [125I]-?-bungarotoxin binding in human postmortem brain

Neuronal nicotinic acetylcholine receptors are expressed in the human central nervous system. A specific subtype of this receptor family, the α7 nicotinic acetylcholine receptor, is thought to be the principal α‐bungarotoxin (αBTX)‐binding protein in mammalian brain. Although the expression of this receptor subtype has been characterized in rat, no study has specifically compared the expression of both the α7 gene and the localization of BTX binding sites in human brain. Expression of α7 mRNA and receptor protein in human postmortem brain tissue was examined by in situ hybridization and [125I]‐α‐bungarotoxin autoradiography, respectively, with particular emphasis on regions associated with sensory processing. Regions with high levels of both α7 gene expression and [125I]‐αBTX binding include the nucleus reticularis of the thalamus, the lateral and medial geniculate bodies, the basilar pontine nucleus, the horizontal limb of the diagonal band of Broca, the nucleus basalis of Meynert, and the inferior olivary nucleus. High‐to‐moderate levels of α7 probe hybridization were also seen in the hippocampus and the cerebral cortex; however, there was a reduced or variable degree of [125I]‐αBTX binding in these regions compared with the level of probe hybridization. In most brain regions, [125I]‐αBTX binding was localized to neuronal cell bodies similar in morphology to those that exhibited α7 hybridization, suggesting that the high‐affinity [125I]‐αBTX binding sites in the human brain are likely to be principally composed of α7 receptor subtypes. J. Comp. Neurol. 387:385–398, 1997.

Sensory Physiology and Catecholamines in Schizophrenia and Mania

Hypersensitivity to sensory stimulation is a prominent characteristic of both schizophrenia and mania. Neurophysiological recordings suggest a common deficit in a central neuronal sensory gating mechanism which regulates sensitivity to repeated auditory stimuli. Dopamine and norepinephrine are hypothesized to have major roles in these illnesses, but their role in aberrant sensory processing has not yet been proved. Presumptive evidence for effects of catecholamines on sensory processing comes from psychophysiological studies of normal subjects challenged with stimulants who show decreased sensory gating, and studies of psychotic patients treated with neuroleptics who show improved function. Studies of similar phenomena in animals show comparable effects of catecholamines on sensory processing, both behaviorally and at the single neuron level. In this study, gating of auditory evoked potentials (EPs) during treatment of both illnesses was compared with plasma dopamine and norepinephrine metabolites. Comparisons of medicated and unmedicated states showed that schizophrenic patients have a fixed deficit in sensory gating, which is a familial trait, unchanged by medication. During acute illness, they have an additional transient hypersensitivity to stimuli, manifested as smaller EPs, which seems to be mediated by dopamine. Manic patients have only the deficit in sensory gating, which is transient and seems to be mediated by norepinephrine. Thus, similar neurophysiological deficits in the two psychoses are associated with different biochemical abnormalities, which may explain similarities in acute symptoms and differences in other aspects of the illnesses, such as their response to treatment.

Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings

Schizophrenia may result from the concerted action of several pathophysiological factors. This pilot study compared the distribution of measurements of three such putative factors in 11 schizophrenics and their siblings: a neurophysiological deficit in auditory sensory gating, diminished hippocampal volume, and increased catecholamine metabolism. Abnormal auditory sensory gating was found in all schizophrenics in the 11 families studied and in 8 of their 20 siblings. Compared with the schizophrenics, the clinically unaffected siblings with abnormal auditory gating had larger hippocampal volume. There was no similar difference for the siblings with normal gating. The siblings with abnormal auditory gating also had lower homovanillic acid levels than the other siblings. The data suggest that a familial neuronal deficit, identified by diminished sensory gating, may be a necessary, but not sufficient factor in the pathogenesis of schizophrenia. Individuals with this deficit are generally clinically unaffected, except for schizophrenics, who also have other abnormalities, such as diminished hippocampal volume and increased catecholamine metabolism.

Sensory gating deficits in psychiatric impatients: Relation to catecholamine metabolites in different diagnostic groups

Acutely ill psychiatric inpatients were examined for a deficit in sensory gating, measured as failure to suppress the P50 wave of the auditory-evoked response to the second of paired stimuli. Previously, we had found that in mania, this sensory gating deficit is correlated with increased plasma-free levels of the noradrenergic metabolite 3-methoxy, 4-hydroxyphenylglycol (pMHPG), whereas in schizophrenia, there is no correlation with catecholamine metabolism. To assess the generalizability of these findings, we examined inpatients with a broader range of diagnoses, including those with multiple DSM III-R Axis I, II, and III diagnoses. The patients were grouped into three diagnostic spectra for analysis: schizophrenic, manic, and depressive. In the schizophrenic patients, there was no relationship between pMHPG or other catecholamine metabolites and the sensory gating deficit. In manic patients, however, a positive correlation between pMHPG level and the sensory gating deficit was again observed. This relationship did not extend to the depressive patients, who uniquely showed sensory gating deficits that correlated negatively with the severity of their illness. The data suggest that sensory gating deficits are common to these three diagnostic spectra, but the deficits in each group have different relationships to catecholamine metabolism and symptom severity that may reflect differences in the underlying neuronal pathophysiology of these illnesses.

Comparison of polymorphisms in the α7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects

The hypothesis that the 15q13‐15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The α7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first‐degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty‐one variants were found in the exons, but non‐synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal.

Auditory sensory gating and catecholamine metabolism in schizophrenic and normal subjects

Diminished neuronal response to repeated sensory input is a sensory-gating phenomenon that has been found to be deficient in schizophrenic patients. For example, schizophrenic patients fail to decrease the amplitude of the P50 wave of the auditory evoked potential to the second of paired click stimuli. In some studies, however, normal subjects have also failed to decrease their P50 responses. The aim of this study was to determine if accommodation to the recording situation over time would affect the gating of the P50 response. The gating of the P50 wave is measured as the ratio of the amplitude of the second response to the amplitude of the first. Three successive auditory evoked potentials were compiled, each from trains of 32 pairs of stimuli. Twelve normal subjects and 12 schizophrenic patients were studied. Unconjugated catecholamine metabolites were measured from venous samples drawn before and after the electrophysiological recording. Between the first and third trials, the normal subjects significantly increased their gating of P50. This increase in gating of P50 was related to decreased levels of the noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol. No similar phenomenon was observed in the schizophrenic patients, a number of whom had a further decrease in P50 gating over the three trials. Transient failure to observe gating of P50 in normal subjects may be related to increased state-dependent noradrenergic activity, which is known to disrupt sensory gating. This mechanism does not seem to account for the more persistent failure of sensory gating in schizophrenia.

Reproducibility of the measurement of plasma noradrenergic and dopaminergic metabolites in normal subjects

The object of this study was to determine the reproducibility of the measurement of plasma catecholamine metabolites in normal control subjects and to assess the influence of factors such as time of day, diet, activity, blood pressure, and mood on the variance of these measures. Plasma free homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA) were simultaneously measured by high performance liquid chromatography with electrochemical detection. Samples were collected from 15 doctors and nurses at 8 a.m. and at noon on 2 separate days. After the fasting 8 a.m. sample, the subjects ate a regular hospital breakfast. Activity in their usual tasks on an inpatient psychiatric unit was monitored electronically by an activity meter. Levels of each metabolite were not significantly different between days at the respective assay times and were highly correlated for individuals. MHPG showed a significant increase from morning to noon, while HVA showed a significant decrease. Activity, dietary intake of tyrosine and tyramine, blood pressure, pulse, scores on the Profile of Mood States, age, and sex were not related to plasma levels. The results demonstrate that measures of dopamine and norepinephrine metabolites have significant reliability in normal subjects in a setting used for research studies with psychiatric patients.

Uptake and Release of Dopamine from Rat Striatal Slices: Comparison of PCP, Amphetamine and Nomifensine

Phencyclidine (PCP) is an abused drug which produces untoward side-effects (violent behavior, hallucinations and paranoia) resembling certain forms of schizophrenia (Rawson et al., 1981). Understanding its mechanism of action may lead to the development of therapies to block its side-effects and may provide a basis for understanding the causes of schizophrenia.

Stability of plasma catecholamine metabolites in outpatient schizophrenics

for tardive dyskinesia vulnerability, we conducted a post hoc analysis of plasma AA levels and BPRS symptoms. Subjects were 53 randomly selected young male chronic schizophrenic inpatients having three to 20 years of neuroleptic treatment. Pearson correlation coefficients were calculated between LNAA levels and ratios as compared to BPRS individual item scores and BPRS factor scores. Most of the LNAAs were found to have significant positive correlations with psychotic symptoms. TYR had only positive correlations with depression and anxiety. The branched chain amino acids (valine, isoleucine, and leucine) also showed positive correlations with depressive symptoms. Though PHE, TYR, and TRP have been the primary focus of this line of research, fasting HIS (a precursor of histamine which is a probable neurotransmitter) was found to have significant negative correlations with the following BPRS items: mannerisms, conceptual disorganization, grandiosity, unusual thought content, disorientation, total BPRS score; and the factors of thought disorder, activation, and hostility/suspiciousness. A positive correlation was found for blunted affect. Postloading levels, however, did not show any significant associations. These preliminary findings suggest that future research in the AAs and mental illness should include a broader range of AAs such as HIS and their relationships to symptomatology .