Effects of 8-OH-DPAT, 5-CT and muscimol on behaviour maintained by a DRL20 schedule of reinforcement, following microinjection into the dorsal or median raphe nuclei

Experiments were performed to investigate the effects of microinjections of the 5-HT(1A) agonist 8- hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), the non-selective 5-HT(1) agonist 5-carboxamidotryptamine (5-CT) and the GABA(A) agonist muscimol into the midbrain raphe nuclei, on behaviour maintained by a differential reinforcement of low rate (DRL) 20 schedule of food reinforcement. Following acquisition of responding under the DRL20 schedule, in which responses were reinforced only if they occurred at least 20s after the previous response, two groups of rats were prepared with a stainless steel guide cannula aimed at either the dorsal raphe nucleus or the median raphe nucleus. Injections of 8-OH-DPAT and 5-CT into the median raphe dose-dependently increased responding and reduced the number of reinforcers earned, leading to a net reduction in response efficiency from 45% to approximately 27% (5μg 8-OH-DPAT) and 22% (375ng 5-CT). Both drugs appeared to shift the frequency distribution of inter-response times (IRTs) towards shorter IRTs, and lowered the mean IRT. These effects were not observed after dorsal raphe injections of either drug. This pattern of results, together with results obtained in other paradigms measuring response inhibition, suggests that suppression of the activity of median raphe 5-HT neurones induces deficits in the ability to withhold responding. Muscimol increased responding, decreased the number of reinforcers earned and reduced response efficiency after both dorsal raphe and median raphe injections. These effects were more pronounced following median raphe injections, and were of considerably greater magnitude than those observed following treatment with the 5-HT agonists. Muscimol injected into the median raphe lowered the mean IRT, and increased the frequency of short duration IRTs. Thus, stimulation of GABA(A) receptors within the median raphe induces a pattern of behavioural disruption in the DRL task, that is more severe than that resulting from selective inhibition of 5-HT neural activity. The effects of muscimol probably arise from a general behavioural activation, rather than a specific deficit in the ability to withhold responding.     

Quality-of-life instruments in hypertension

This review considers the choice of dimensions to be assessed and the practical problems of measuring quality of life in hypertensive patients. The dimensions of symptomatic well-being, psychological well-being, sleep, sexual function and cognitive function should be assessed. Symptomatic well-being may be measured by many different instruments, and that devised by the authors has been used extensively. The results in different trials may therefore be examined for consistency and sensitivity. Psychological well-being has been assessed by the Psychological General Well-Being Index, the Symptom Rating Test and the Profile of Mood States. The response of these instruments is discussed. The assessment of sleep, sexual function and cognitive function is also described. It is recommended that quality-of-life instruments to be employed in trials of antihypertensive drugs are known to be sensitive to the effects of such drugs.     

Predicting posttreatment cocaine abstinence for first-time admissions and treatment repeaters

OBJECTIVES: This study examined client and program characteristics that predict posttreatment cocaine abstinence among cocaine abusers with different treatment histories. METHODS: Cocaine abusers (n = 507) treated in 18 residential programs were interviewed at intake and 1-year follow-up as part of the nationwide Drug Abuse Treatment Outcome Study (DATOS). Program directors provided the program-level data in a mail survey. We applied the hierarchical linear modeling approach for the analysis. RESULTS: No prior treatment and longer retention in DATOS programs were positive predictors of posttreatment abstinence. The interactive effect of these 2 variables was also significantly positive. Program that offered legal services and included recovering staff increased their clients' likelihood of cocaine abstinence. Crack use at both the client and program level predicted negative impact. None of the program variables assessed differentially affected the outcomes of first-timers and repeaters. CONCLUSIONS: Although treatment repeaters were relatively difficult to treat, their likelihood of achieving abstinence was similar to that of first-timers if they were retained in treatment for a sufficient time. First-timers and repeaters responded similarly to the treatment program characteristics examined. The treatment and policy implications of these findings are discussed.     

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.