Alcohol sales to pseudo-intoxicated bar patrons.

OBJECTIVES: Many establishments serve alcoholic beverages to obviously intoxicated patrons despite laws against such sales. To guide the development of interventions to reduce these illegal alcohol sales, this study used actors feigning intoxication to determine whether servers recognized obvious signs of intoxication and to assess the tactics servers used when dealing with intoxicated patrons. METHODS: Male actors ages 30 to 50 acted out signs of obvious intoxication as they attempted to purchase alcoholic beverages. If served during the first attempt, these pseudo-intoxicated buyers made second purchase attempts during the same visit. Observers accompanied the actors; after each visit, actors and observers recorded the servers' behavior and comments. RESULTS: Alcoholic beverages were served to actors portraying intoxicated patrons at 68% of first purchase attempts and 53% of second purchase attempts (62% of a total of 106 purchase attempts). The most common refusal technique was a direct refusal (68% of refusals), made with either no excuse or with reference to the actors' apparent intoxication level. Servers' second most commonly used refusal technique was offering alcohol-free beverages, such as coffee or water (18% of refusals). CONCLUSIONS: Further research is needed to determine why servers who recognize intoxication serve alcoholic beverages and what training, outlet policies, and external pressures are needed to reduce illegal alcohol sales to obviously intoxicated patrons.     

Urine colour as an index of hydration in critically ill patients

In order to test the hypothesis that urine colour can be used as an index of hydration in critically ill patients, we selected 40 intensive care and high-dependency patients and correlated urine colour (scored on an eight-point scale) with various indices of hydration: urine:plasma sodium, osmolality and urea ratios, urine output and central venous pressure. In addition, we compared the colour-chart score with scores made by intensive care nurses (without the benefit of a colour chart) in order to test subjective assessment of urine colour. There were weak but statistically significant correlations between urine colour and urine output (Spearman's r = - 0.555) and between urine colour and urine:plasma sodium ratio (Spearman's r = - 0.459). Subjective assessment of urine colour appeared to be reliable. Thus, although urine colour does vary with hydration in the critically ill, assessment of urine colour adds little to the overall assessment of hydration in this group of patients.     

Learning-related neuronal responses in prefrontal cortex studied with functional neuroimaging

We assessed time-dependent neuronal activity accompanying learning using functional magnetic resonance imaging (fMRI). An artificial grammar learning paradigm enabled us to dissociate activations associated with individual item learning from those involved in learning the underlying grammar system. We show that a localized region of right prefrontal cortex (PFC) is preferentially sensitive to individual item learning during the early stages of the experiment, while the left PFC region is sensitive to grammar learning which occurred across the entire course of the experiment. In addition to dissociating these two types of learning, we were able to characterize the effect of rule acquisition on neuronal responses associated with explicit learning of individual items. This effect was expressed as modulation of the time-dependent right PFC activations such that the early increase in activation associated with item learning was attenuated as the experiment progressed. In a further analysis we used structural equation modelling to explore time-dependent changes in inter-regional connectivity as a function of both item and grammar rule learning. Although there were no significant effects of item learning on the measured path strengths, rule learning was associated with a decrease in right fronto-parietal connectivity and an increase in connectivity between left and right PFC. Further fronto-parietal path strengths were observed to change, with an increase in left fronto-parietal and a decrease in right fronto-parietal connectivity path strength from right PFC to left parietal cortex. We interpret our findings in terms of a left frontal system mediating the semantic analysis of study items and directly influencing a right fronto-parietal system associated with episodic memory retrieval.     

Expression, distribution and ultrastructural localization of the synapse-organizing molecule agrin in the mature avian retina

At the vertebrate neuromuscular junction the extracellular matrix molecule agrin is responsible for the formation, maintenance and regeneration of most if not all postsynaptic specializations. Several agrin isoforms are generated by alternative splicing which differ in their function and which are all expressed in the CNS. To analyse the role of agrin in the CNS, we investigated the expression and ultrastructural localization of agrin in the posthatched chick retina. In situ hybridization revealed the presence of agrin mRNA in all cellular layers of the mature retina, indicating that most if not all major retinal cell types synthesize agrin. Pan-specific as well as isoform-specific antiagrin antisera stained the optic fibre layer and the outer plexiform layer. However, only the pan-specific antiserum additionally stained the inner limiting membrane. Immunoelectron microscopy showed that in the optic fibre layer agrin was associated with ganglion cell axons and that at least part of this agrin corresponds to a neuronal isoform of agrin. In the outer plexiform layer, agrin was localized in the cleft between the photoreceptor terminals and the invaginating horizontal and bipolar cell dendrites. In the synapse-containing inner plexiform layer both antisera revealed punctate immunoreactivity. This staining corresponded to agrin concentrated in the synaptic cleft of conventional synapses as determined by preembedding immunoelectron microscopy. Agrin is thus concentrated at mature interneuronal synapses as it is at the neuromuscular junction, consistent with a role of agrin during formation and/or maintenance of synapses in the CNS.     

Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction

Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5–1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes. Received: 5 May 1998/Final version: 7 July 1998     

Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward

Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect by investigating the effects of 5-HT agonists with differing affinities for 5-HT₁ and 5-HT₂ receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained to associate a light/tone stimulus (subsequently the CR) with water delivery. In a test phase, they were allowed access to a lever delivering the CR, and an inactive (NCR) lever. Responding on the CR lever was greater than responding on the NCR lever, indicating that the light/tone stimulus functioned as a CR. Responding for the CR was selectively potentiated by injections of d-amphetamine (10 μg) into the nucleus accumbens. This effect was reduced by injections into the nucleus accumbens of 5-CT (0.5 and 1 μg), RU24969 (10 μg), CP93,129 (1.25 and 2.5 μg) but not by DOI (10 μg) or 8-OH-DPAT (5 μg). The lower doses of 5-CT and CP93,129 did not reduce baseline responding for CR, or responding for water in a separate group of animals, indicating that the effects of these drugs were behaviourally selective. The higher doses abolished the CR effect, and in the case of 5-CT and RU24969 also reduced responding for water. All of the effective drugs share in common the ability to stimulate 5-HT_1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5-HT_1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the5-HT_1B/1D antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT_1B receptors within the nucleus accumbens attenuates the effects of a dopamine-dependent behaviour, and that activation of these receptors can oppose the behavioural effects of elevated mesolimbic dopamine transmission. Received: 22 April 1998/Final version: 28 July 1998     

Evidence that GABA(A) but not GABA(B) receptor activation in the dorsal raphe nucleus modulates ethanol intake in Wistar rats

Injection of the GABA(A) agonist muscimol into the dorsal raphe nucleus produces a marked and selective increase in voluntary ethanol intake. The purpose of the present study was threefold: first, to demonstrate that the effect of muscimol on ethanol consumption is mediated by GABA(A) receptors; secondly, to test the generalizability of this effect by examining the effects of another GABA(A) agonist, THIP, on ethanol drinking; and finally, to examine whether GABA(B) receptors within the dorsal raphe also play a role in modifying voluntary ethanol consumption under the same experimental conditions. Rats were trained to drink a 12% ethanol solution in a limited access paradigm with water concurrently available. Muscimol (50ng) injected into the dorsal raphe enhanced intake by at least 100%. Peripheral administration of the GABA(A) antagonist bicuculline (4mg/kg), but not the 5-HT(1A) antagonist (+)- WAY100135 (1 and 3mg/kg), antagonized the stimulatory effect of muscimol at a dose which, when administered alone, did not alter ethanol intake. This supports the suggestion that the effect of muscimol is mediated via GABA(A) receptors. This conclusion was further supported by the finding that another GABA(A) agonist, THIP (500ng), also selectively increased ethanol intake in this paradigm. Injection of bicuculline (60ng) into the dorsal raphe reduced ethanol intake, but also appeared to reduce water intake. Finally, intra-dorsal raphe injection of the GABA(B) agonist baclofen (62.5 and 125ng) did not produce any change in ethanol or water consumption. Together, these findings suggest that enhancement of GABAergic activity in the dorsal raphe increased voluntary ethanol intake via activation of GABA(A) but not GABA(B) receptors.