Faculty Bibliography

We used traditional volumetric regional analysis and a finer anterior-posterior (AP) profile volumetric analysis to examine the cerebral ventricular system in an all-male, demographically matched sample of schizophrenia patients (n = 73) and normal controls (n = 29) using 2.8-mm-thin coronal T1-weighted magnetic resonance images from a 1.5 tesla scanner. Traditional regional analysis was performed on various regions using absolute volumes after adjusting for intracranial volume (ICV) and age. The fine AP profile analysis was done by intrasubject 'stacking' of contiguous coronal cross-sectional volumes (adjusted for ICV and age) across the AP plane, intersubject AP alignment of all slices relative to the mammillary bodies, and plotting of slice volumes along the AP plane with 95 percent t-test-based confidence intervals. Schizophrenia subjects had mild to moderate multifocal ventricular enlargement (overall effect size d = 0.48), which was especially prominent in the right posterior temporal horn and, more generally, in the central to posterior portions of the lateral and third ventricles. Schizophrenia subjects also had milder enlargement in the left frontal horn, but no significant differences were found in the anterior temporal horns and the right frontal horn. Post hoc analyses of demographic, clinical, and neuropsychological variables did not account for much variance in the ventriculomegaly observed in the schizophrenia group. The lack of a single locus in the observed ventricular enlargement, the nonsignificant results from schizophrenia subtypes based on regional distributions, and the strong positive correlations among the ventricular regions for the schizophrenia group suggest that the ventriculomegaly seen in this chronic population reflects a single brainwide disease process leading to a multifocal or patchy loss of integrity in brain structure

Chronic food restriction (FR) augments the locomotor and rewarding effects of abused drugs (Cabeza de Vaca and Carr, J. Neurosci. 18:7502,1998). FR also augments the induction of c-fos by amphetamine in nucleus accumbens, central nucleus of the amygdala (CEA) and bed nucleus of the stria terminalis (BNST) (Carr and Kutchukhidze, Brain Res. 861:88, 2000). Because all drugs tested to date, whose rewarding effects are augmented by FR, directly or indirectly stimulate dopamine (DA) release, the c-fos findings suggest that FR may augment behavioral responses by enhancing DA releasability in one or more DA terminal regions. The purpose of this study was to test whether direct DA receptor agonists are exempt from the effect of FR. In Exp. 1, the D-2 agonist quinpirole (0.2 and 0.5 mg/kg, i.p.) produced a dramatic locomotor response in FR rats and no response in ad libitum fed controls. The D-1 agonist A77636 (1.0 and 2.5 mg/kg, i.p.) did not differentially affect the two groups. In Exp. 2, the rewarding effect of A77636 (1.0 and 2.5 mg/kg, i.p.), assessed in a self-stimulation rate-frequency paradigm, was greater in FR rats than controls. The rewarding effect of quinpirole (0.2 and 0.5 mg/kg, i.p.) displayed only a trend in that direction. In Exp. 3, quinpirole (0.5 mg/kg, i.p.) induced fos-like immunoreactivity (FLI) in globus pallidus, BNST, and CEA; the response in CEA was augmented by FR. The behavioral results indicate that augmentation of rewarding/stimulant drug effects by FR may be mediated, at least in part, by postsynaptic DA mechanisms. The immunohistochemical results suggest that augmented transsynaptic effects of quinpirole on cellular activity in CEA may be involved in the locomotor response to this drug in FR rats

BACKGROUND: Several short-term, controlled trials have documented the efficacy of vitamin E in treating tardive dyskinesia. However, the persistent nature of the disease prompted us to perform a multicenter, longer-term trial of vitamin E. METHODS: The study was a prospective, randomized, 9-site trial of up to 2 years of treatment with d-vitamin E (1600 IU/d) vs matching placebo. One hundred fifty-eight subjects with tardive dyskinesia who were receiving neuroleptic medications were enrolled. The blinded assessments performed were clinical (Abnormal Involuntary Movements Scale, Barnes Akathisia Scale, and Modified Simpson-Angus [for Extrapyramidal Symptoms] Scale) and electromechanical assessments of movement disorders, psychiatric status (Brief Psychiatric Rating Scale), and functioning (Global Assessment of Functioning). There were no significant differences in baseline demographic characteristics or in study assessments between the group that received vitamin E and the group that received placebo. RESULTS: Vitamin E was well tolerated and subject compliance with medication was good and similar between treatment groups. One hundred seven subjects (70% of those receiving vitamin E and 66% of subjects receiving placebo) completed at least 1 year of treatment. There were no significant effects of vitamin E on total scores or subscale scores for the AIMS, electromechanical measures of dyskinesia, or scores from the other 4 scales. CONCLUSION: This long-term, randomized trial of vitamin E vs placebo found no evidence for efficacy of vitamin E in the treatment of tardive dyskinesia

It was previously reported that systemic administration of the nonselective opioid antagonist, naltrexone, induces Fos-like immunoreactivity (FLI) within the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (lateral-dorsal division; BSTLD), nucleus accumbens shell (NACshell) and ventral tegmental area (VTA) of free-feeding rats. These findings suggest that cellular activity in these brain regions is subject to opioid-mediated inhibitory control under basal conditions. Considering the involvement of mesoaccumbens dopamine neurons and components of the 'extended amygdala' in motivated behavior and reward, it was hypothesized that the induction of c-Fos by naltrexone accounts for the motivational-affective consequences of opioid antagonism. In Experiment 1, naltrexone was administered intracerebroventricularly (i.c.v.; 100 microg) to determine whether results obtained in the prior immunohistochemical studies could be attributed to blockade of opioid receptors in brain as opposed to peripheral tissues that convey visceral sensory inputs to the CeA and BSTLD. Naltrexone produced a marked increase in FLI within the CeA and BSTLD, and a moderate increase in NACshell. In Experiment 2, the kappa opioid antagonist, nor-binaltorphimine (Nor-BNI; 20.0 microg, i.c.v.) reproduced the effect of naltrexone in BSTLD and CeA, suggesting that the induction of c-Fos in these two structures is a consequence of kappa receptor blockade. The selective mu antagonist, CTAP (2.0 microg, i.c.v.), reproduced the effect of naltrexone in NACshell, suggesting that the induction of c-Fos in this structure is a consequence of mu receptor blockade. The functional implications of these results are discussed in terms of the known functions of these brain regions and opioid receptor types, and the prior observation that chronic food restriction eliminates the FLI induced by naltrexone in CeA and BSTLD. It is suggested that tonic mu opioid-mediated inhibition in NACshell has a predisposing effect on goal-approach behavior in general while kappa opioid-mediated inhibition in CeA and BSTLD has a predisposing effect on palatability-driven feeding in particular. Finally, a possible relationship between food restriction-induced suppression of the kappa opioid mechanism in CeA/BSTLD, local CRH function, and sensitization of the neural substrate for incentive-motivating effects of abused drugs is discussed.

Activation of striatal dopamine (DA) neurons by neuroleptic treatment or by electrical stimulation of the nigrostriatal pathway increases the activity of tyrosine hydroxylase (TH). The increase is mediated by phosphorylation of the enzyme. However, abolition of DA neuronal activity [by gamma-butyrolactone (GBL) treatment or transection of the nigrostriatal pathway] also increases TH activity. Quantitative blot immunolabeling experiments using site- and phosphorylation state-specific antibodies to TH demonstrated that GBL treatment (750 mg/kg, 35 min) significantly increased phosphorylation at Ser19 (+40%) and Ser40 (+217%) without altering Ser31 phosphorylation. Concomitantly, GBL treatment [along with the 3,4-dihydroxyphenylalanine (dopa) decarboxylase inhibitor NSD-1015, 100 mg/kg, 30 min] increased in vivo striatal dopa accumulation and in vitro TH activity 3-fold. Likewise, cerebral hemitransection of the nigrostriatal pathway significantly increased phosphorylation of TH at Ser19 (+89%) and Ser40 (+158%) but not at Ser31; dopa levels were increased accordingly (+191%). Kinetic analysis of TH activity established that GBL treatment and hemitransection primarily decreased the Km for the cofactor tetrahydrobiopterin (3-fold). The effects of GBL and hemitransection were abolished or attenuated by pretreatment with the DA agonist R-(-)-N-n-propylnorapomorphine (NPA; 30 microgram/kg, 40 min), presumably via stimulation of inhibitory presynaptic DA autoreceptors. NPA dose-response curves for reversal of GBL-induced dopa accumulation and Ser40 phosphorylation were identical; however, only the highest dose of NPA reversed the small and variable increase in Ser19 phosphorylation. Thus, TH activity seems to be regulated by phosphorylation in both hyper- and hypoactive striatal DA neurons; in the latter case, activation seems to be caused by selective phosphorylation of Ser40

Comorbid substance use disorders occur frequently in schizophrenia with significant detrimental effects to clinical outcome. Unfortunately, attempts to identify factors associated with comorbid substance use disorders (beyond demographic characteristics such as gender) have not been successful. This study examined an affect regulation model of comorbid substance use in schizophrenia with a focus on personality traits and coping. It was hypothesized that maladaptive coping and the traits of negative affect (NA) and disinhibition (DIS), but not trait positive affect (PA), would be associated with greater substance use problems. Thirty-nine patients with schizophrenia or schizoaffective disorder completed measures of personality traits, coping, and negative consequences associated with substance use. Traits were differentially associated with coping in that NA and DIS, but not PA, were associated with maladaptive coping including the use of drugs and alcohol to cope with stress. Alternatively, PA, but not DIS or NA, was related to adaptive coping strategies. Individuals high in NA and endorsing the use of drugs and alcohol to cope reported the greatest number of negative consequences from substance use. This finding held after controlling for gender. These results are consistent with an affect regulation model of substance use and suggest the advantage of examining the role of affect, traits, and coping in understanding comorbid substance use in schizophrenia.

This study employed grade of membership (GoM) analysis in a clinical setting to determine if the DSM-III-R personality disorder (PD) diagnostic criteria cluster into recognizable disorders resembling the official axis II nosology. The GoM model, based on fuzzy-set theoretic concepts, explicitly examines medical diagnostic systems by quantitatively identifying and characterizing subpatterns of illness within a broad class. A semistructured assessment of 110 outpatients was performed for 12 PDs and their 112 diagnostic criteria. GoM analysis was performed using internal variables of the 112 PD criteria rated as present or absent. Demographic variables, axis I and II diagnosis (structured clinical Interview for DSM [SCID]), and treatment response (Global Adjustment Scale [GAS]) information were used as external validators. Four pure types (PT) provided the most satisfactory solution to the data. PT-I is characterized by marked maladaptive personality pathology, which is manipulative, egocentric, impulsive, and alloplastic. PT-II consists primarily of exaggerated socially anxious and detached traits. PT-III is sociably dependent and autoplastic. PT-IV is essentially asymptomatic. GoM provides a more parsimonious handling of the PD criteria than provided by classifying according to DSM categories. The analysis fails to confirm the natural occurrence of any single specific axis II PD or cluster.