Faculty Bibliography

BACKGROUND: Studies of cocaine-dependent subjects have shown that re-exposure to environmental cues previously associated with cocaine use produces a strong conditioned response characterised by autonomic hyperarousal and increases in subjective measures of cocaine craving. METHODS: To evaluate the role of dopamine release by such cues, 20 cocaine-dependent inpatients were randomised in a single-dose, crossover, placebo-controlled design, to haloperidol (4 mg by mouth) and placebo. Plasma homovanillic acid (HVA, a dopamine metabolite), adrenocorticotropic hormone (ACTH), and cortisol were assayed before and after cue exposure. Craving and anxiety were measured before and after cues with visual analogue scales for desire to use cocaine now and for mood changes. FINDINGS: Cocaine cues significantly increased anxiety, ACTH, cortisol, and HVA. Increases in anxiety and craving resulting from cue exposure were significantly antagonised by pretreatment with haloperidol. INTERPRETATION: It has long been hypothesised that increases in extracellular concentrations of dopamine mediate the acute reinforcing effects of cocaine. Our data suggest that dopamine release may also mediate some of the conditioned responses to cocaine cues

Using quantitative autoradiography, it was previously observed that chronic food restriction alters mu and kappa receptor binding in several regions of the rat forebrain. The present autoradiographic study was designed to investigate whether food restriction affects regional mu and kappa binding in the brainstem. [3H]DAGO (mu) and-mu/delta blocked [3H]BMZ (kappa) binding were analyzed in 21 brainstem regions. A significant decrease in mu binding was observed in the external lateral and external medial subnuclei of the parabrachial nucleus while a significant increase in kappa binding was observed in the external lateral subnucleus. The possible functional significance of these changes is discussed

The purpose of this study was to assess further the effect of amphetamine on negative symptoms of schizophrenia. Thirty-seven schizophrenic males meeting DSM-III criteria were rated with the Brief Psychiatric Rating Scale, the Abrams and Taylor Scale, and the Abnormal Involuntary Movements Scale before and after double-blind administration of either amphetamine (n = 26) or placebo (n = 11). Our results indicated that amphetamine administration generally did not improve negative symptoms, even when accounting for changes in positive symptoms. However, greater baseline negative symptoms were associated with a modest diminution after amphetamine treatment. Therefore, amphetamine may modestly improve negative symptoms in those schizophrenics in whom this symptomatology is more severe

Chronic food restriction lowers the threshold for lateral hypothalamic electrical self-stimulation (LHSS). This effect has previously been interpreted to reflect a sensitization of reward. In the present study a curve-shift method was used to explicitly differentiate effects of food restriction on brain stimulation rewarding efficacy and performance. Food restriction consistently shifted rate-frequency curves to the left, lowering the M-50 and Theta-0 parameters of rewarding efficacy. Asymptotic rates of reinforcement and slopes of rate-frequency functions were unaffected, confirming that food restriction does not facilitate LHSS by enhancing performance. In this and previous studies, LHSS in food-restricted rats was measured in the period immediately preceding the daily meal when hunger (i.e., period since last meal) and plasma corticosterone are at peak levels. In the light of evidence that corticosterone may regulate sensitivity of the mesolimbic dopamine pathway and account for the sensitizing effect of stress on psychomotor effects of opiates and stimulants, LHSS and corticosterone were measured in the immediate pre-and post-meal periods. While all food-restricted rats displayed elevated corticosterone levels in the pre-meal period and generally displayed a decline to control levels in the post-meal period, the sensitization of reward was not reversed in the post-meal period. These results indicate that chronic food restriction produces a sensitization of reward that does not depend upon the acute state of hunger that precedes the daily meal and does not vary with dynamic changes in plasma corticosterone level

This study tests the hypothesis that the dopaminergic system mediates a restitutive response by decreasing its own activity in the face of events like persistent inescapable stress that threaten to interrupt organized mental activity. It is well established that neuroleptic drugs inhibit the conditioned avoidance response (CAR), but not the escape response, probably via a reduction in subcortical dopaminergic activity. We trained rats to perform the CAR and then subjected them to acute and chronic stress to determine whether this would result in inhibition of the CAR. Rats subjected to twice daily tailshock stress for 8 days showed inhibition of the CAR and a reduction in dopamine (DA) utilization in the nucleus accumbens. These findings are compatible with the hypothesis that an endogenous DA-dependent mechanism exists that mimics neuroleptic effects in the face of repeated stress. In humans this response may serve as a protection against psychotic decompensation from chronic endogenous or exogenous insult

Pharmacological studies suggest that diabetes produces changes in the brain opioid system, affecting several behavioral functions including analgesia, feeding and self-stimulation. Previous investigations of opioid receptor binding have failed to explain the unusual opioid pharmacology of the diabetic animal. In the present study, the effects of streptozotocin-induced diabetes on levels of three immunoreactive (ir)-prodynorphin-derived peptides, ir-dynorphin A1-17 (A1-17), ir-dynorphin A1-8 (A1-8) and ir-dynorphin B1-13 (B1-13), were determined in eleven brain regions known to be involved in appetite, taste and reward. Diabetes was found to increase levels of A1-17 in the ventromedial and dorsomedial hypothalamic nuclei (+60% and +25%, respectively) and levels of A1-8 in the dorsomedial and lateral hypothalamus (+45% and +35%, respectively). The possible significance of these results is discussed in relation to (i) diabetic hyperphagia, (ii) medial hypothalamic transduction of circulating insulin levels, and (iii) the potentiation of reward by metabolic need states