Nonspecific Sedation Research Articles

Antipsychotic Drugs: A Concise Review of History, Classification, Indications, Mechanism, Efficacy, Side Effects, Dosing, and Clinical Application.

The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis.

Chemical composition, antinociceptive and anti-inflammatory activities of the curzerene type essential oil of Eugenia uniflora from Brazil

Ethnopharmacological relevanceThe Eugenia uniflora leaf infusion is widely used in folk medicine to treat gastroenteritis, fever, hypertension, inflammatory and diuretic diseases. Aim of the studyThis work evaluated the acute oral toxic, antinociceptive, and anti-inflammatory activities of the curzerene chemotype of Eugenia uniflora essential oil (EuEO). Material and methodsEuEO was obtained by hydrodistillation and analyzed by GC and GC-MS. The antinociceptive action in mice was evaluated for the peripheral and central analgesic activity using abdominal contortion and hot plate tests (50, 100, and 200 mg/kg); xylene-induced ear swelling was carried out for the nociception test, and carrageenan-induced cell migration test. Spontaneous locomotor activity was assessed in the open field test to rule out any nonspecific sedative or muscle relaxant effects of EuEO. ResultsThe EuEO displayed a yield of 2.6 ± 0.7%. The major compounds classes were oxygenated sesquiterpenoids (57.3 ± 0.2%), followed by sesquiterpene hydrocarbons (16.4 ± 2.6). The chemical constituents with the highest concentrations were curzerene (33.4 ± 8.5%), caryophyllene oxide (7.6 ± 2.8%), β-elemene (6.5 ± 1.8%), and E-caryophyllene (4.1 ± 0.3%). Oral treatment with EuEO, at doses of 50, 300, and 2000 mg/kg, did not change the behavior patterns or mortality of the animals. EuEO (300 mg/kg) did not cause a reduction in the number of crossings in the open field compared to the vehicle group. The aspartate aminotransferase (AST) level was higher in EuEO-treated groups (50 and 2000 mg/kg) when compared to the control group (p < 0.05). EuEO, at doses of 50, 100, and 200 mg/kg, reduced the number of abdominal writhings by 61.66%, 38.33%, and 33.33%. EuEO did not show increased hot plate test time latency in any of the intervals analyzed. At 200 mg/kg, EuEO decreased paw licking time, with inhibition of 63.43%. In formalin-induced acute pain, EuEO decreased paw licking time at doses of 50, 100, and 200 mg/kg in the first phase, with inhibition of 30.54%, 55.02%, and 80.87%. The groups treated with EuEO at doses of 50, 100, and 200 mg/kg showed ear edema reduction of 50.26%, 55.17%, and 51.31%, respectively. Moreover, EuEO inhibited leukocyte recruitment only at a dose of 200 mg/kg. The inhibitory values of leukocyte recruitment after 4 h of carrageenan application were 4.86%, 4.93%, and 47.25% for 50, 100, and 200 mg/kg of essential oil, respectively. ConclusionThe EuEO, curzerene chemotype, has significant antinociceptive and anti-inflammatory activities and low acute oral toxicity. This work confirms the antinociceptive and anti-inflammatory of this species as the traditional use.

5‑Hydroxytryptamine 2A receptor inverse agonist pimavanserin impairs maternal behavior in postpartum female rats

Maternal behavior is a highly motivated and well-organized social behavior. Although previous studies have shown that 5‑hydroxytryptamine 2A/2C (5-HT2A/2C) receptors play an important role in mediating the expression of normal maternal behavior, the role of 5-HT2A receptors in maternal behavior remains unclear. In the present study, the homecage maternal behavior test paradigm was used to investigate whether the low or constitutive (i.e., intrinsic or basal) activity of 5-HT2A receptors influences the expression of normal maternal behavior. The inverse agonist pimavanserin (3, 6, and 12 mg/kg) and neural antagonist ketanserin (2.5 and 5 mg/kg) were used to induce the low or constitutive activity of 5-HT2A receptors, respectively. The results showed that inverse agonism of 5-HT2A receptors by pimavanserin slightly impaired maternal behavior in postpartum female rats, reflected by less time spent on nest building, and that ketanserin did not impair major components of maternal behavior. Furthermore, neither pimavanserin nor ketanserin impaired spontaneous locomotion. These data indicate that the reduced activity of 5-HT2A receptors may impair the expression of normal maternal behavior and this effect is not due to a nonspecific sedative effect. Nevertheless, the constitutive activity of 5-HT2A receptors in the absence of an endogenous agonist (i.e., serotonin) may be involved in the expression of normal maternal behavior.

Anticonvulsants lamotrigine and riluzole disrupt maternal behavior in postpartum female rats

Maternal behavior is a highly motivated and well-organized social behavior. Previous studies have reported that anticonvulsants are frequently used in postpartum bipolar disorder. However, the maternal disruptive effect of the anticonvulsants has not been explored. The purpose of the present study was to examine the effect of anticonvulsants lamotrigine and riluzole on maternal behavior in postpartum female rats. On postpartum Day 3, Sprague-Dawley mother rats were given a single intraperitoneal injection of vehicle, lamotrigine (15, 25, 35 mg/kg), or riluzole (2, 4, 8 mg/kg). Maternal behavior was tested 30 min before and after injection. Animals treated with lamotrigine or riluzole had a longer pup retrieval latency, retrieved fewer pups into the nest, spent less time on nursing pups, as well as on building the disturbed nest, and animals treated with riluzole spent less time on pup licking. Whereas, the drugs in the tested doses did not shorten the total duration of behavior unrelated to maternal behavior. Overall, these data indicate that lamotrigine and riluzole disrupt major components of maternal behavior in postpartum female rats, but do not inhibit the behaviors unrelated to maternal behavior, which indicates that the maternal disruptive effect is not due to nonspecific sedative effect.

Mild Sedation Exacerbates or Unmasks Focal Neurologic Dysfunction in Neurosurgical Patients with Supratentorial Brain Mass Lesions in a Drug-specific Manner.

Sedation is commonly used in neurosurgical patients but has been reported to produce transient focal neurologic dysfunction. The authors hypothesized that in patients with frontal-parietal-temporal brain tumors, focal neurologic deficits are unmasked or exacerbated by nonspecific sedation independent of the drug used. This was a prospective, randomized, single-blind, self-controlled design with parallel arms. With institutional approval, patients were randomly assigned to one of the four groups: "propofol," "midazolam," "fentanyl," and "dexmedetomidine." The sedatives were titrated by ladder administration to mild sedation but fully cooperative, equivalent to Observer's Assessment of Alertness and Sedation score = 4. National Institutes of Health Stroke Scale (NIHSS) was used to evaluate the neurologic function before and after sedation. The study's primary outcome was the proportion of NIHSS-positive change in patients after sedation to Observer's Assessment of Alertness and Sedation = 4. One hundred twenty-four patients were included. Ninety had no neurologic deficits at baseline. The proportion of NIHSS-positive change was midazolam 72%, propofol 52%, fentanyl 27%, and dexmedetomidine 23% (P less than 0.001 among groups). No statistical difference existed between propofol and midazolam groups (P = 0.108) or between fentanyl and dexmedetomidine groups (P = 0.542). Midazolam and propofol produced more sedative-induced focal neurologic deficits compared with fentanyl and dexmedetomidine. The neurologic function deficits were mainly limb motor weakness and ataxia. Patients with high-grade gliomas were more susceptible to the induced neurologic dysfunction regardless of the sedative. Midazolam and propofol augmented or revealed neurologic dysfunction more frequently than fentanyl and dexmedetomidine at equivalent sedation levels. Patients with high-grade gliomas were more susceptible than those with low-grade gliomas.

Analgesia enhancement and prevention of tolerance to morphine: beneficial effects of combined therapy with omega-3 fatty acids.

Recent evidence associates omega-3 fatty acids (O3) with pain reduction. The aim of this work was to evaluate the antinociceptive effect of O3, either alone or in combination with morphine after acute and chronic administration in rats. As well, a new pharmaceutical mixture that allows the concomitant administration of O3 and morphine as an oral solution was developed. Animals were fed on a control or an experimental diet supplemented with O3. They were subjected to the hot-plate test to assess analgesic effect and tolerance to the analgesic effect of morphine. The open-field test was carried out to determine if the differences in the response latency can be related to non-specific sedative effects. O3 dietary supplementation increased the response latency compared with the control group. Acute treatment with morphine in these groups resulted in an additive antinociceptive effect not related to locomotor activity. Chronic coadministration of morphine with O3 attenuated the development of tolerance. Oral administration of the new pharmaceutical mixture showed analgesic activity with a subtherapeutic dose of morphine. This finding suggests a role for O3 as adjuncts to opioids in pain therapy and might contribute to the reduction of the occurrence of morphine side-effects.

CS06-02 - How fast antipsychotics work – implications for theory and practise

It has been traditionally accepted that antipsychotics have a 'delayed onset' of action with various authors claiming 2–3 weeks of delay. Data from the previous few years has contradicted this notion.The talk will review this data, identify its theoretical implications and implications for practise. In an initial meta-analysis of over 8,000 patient data it was shown that antipsychotic action is not delayed at all but evident in teh first week, this change is not non-specific sedation but a specific anti-'psychotic' effect, and is seen with all evaluated antipsychotics. In more recent studies we have been able to show that this effect is even discernable in the first 24 hours, is related to dopmaine D2 occupancy achieved early on, and early non-response is a very strong predictor of subsequent non-response.This early onset is not only an isolated improvement in psychosis-but, can also be seen on quality of life and social functionign indicators. These data raise interesting questions regarding the mechanism of improvement: they question the standard 'depolarisation block' hypothesis of antispychotic action-and suggest a simpler dopamine occupancy hypothesis instead; since change occurs early it is possible to map different trajectories and our most recent findigns show that drug-treated patients show a distinct trajectory from those observed in placebo-treated patients. Finally, these findings have implications for the design of clinical trials and clinical practise. In clinical trials it is possible to use early-response to devise adpative or enriched designs that are more clinically relevant - example of a recent such application will be discussed and at a clinical level it may be possible to reconsider the standard notion that an antipsychotic must be tried for 6 weeks before considering an alterative option.

Intramuscular Aripiprazole in the Control of Agitation

To evaluate response to intramuscular (IM) aripiprazole injections using secondary analyses from clinical trials. Data from one trial in patients with bipolar I disorder and two trials in patients with schizophrenia were assembled and used for three secondary analyses. Analysis 1 looked at data from "nonsedated" patients (i.e., patients with scores < 8 [deep sleep] or 9 [unarousable] on the Agitation-Calmness Evaluation Scale [ACES]). In analysis 2, patients were subdivided into "higher" and "lower" agitation groups according to a median split on the baseline score for the Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) (median = 18). Analysis 3 looked at the patients who received a second injection within the 24-hour study period. In each analysis, the mean change from baseline in PEC scores was re-evaluated. Analysis 1 found that nonsedated patients with bipolar I disorder and schizophrenia showed significant decreases in PEC scores following treatment with aripiprazole IM (p < 0.005). Analysis 2 found that aripiprazole IM significantly reduced agitation compared with placebo in patients with bipolar I disorder who had lower baseline agitation (p < 0.01), while patients with bipolar I disorder who had higher baseline agitation showed similarly large PEC decreases with aripiprazole (-9.9) and placebo (-7.9). Patients with schizophrenia showed significant reductions in PEC scores compared with placebo regardless of baseline level of agitation (p < 0.01). Analysis 3 found that a second injection of aripiprazole IM significantly reduced agitation in patients with bipolar I disorder or schizophrenia (p < 0.05); repeated injections were safe and well tolerated. Improvements with aripiprazole IM appeared to be specific to core agitation symptoms, as opposed to nonspecific sedation, and to be independent of baseline level of agitation. Furthermore, patients benefited from a repeated aripiprazole injection when clinically warranted. These results address important clinical issues regarding use of aripiprazole IM in treating agitation.

The Treatment of Acute Agitation in Schizophrenia

AbstractAcute agitation is a nonspecific term applied to an array of syndromes and behaviors. It is frequently defined as an increase in psychomotor activity, aggression, disinhibition/impulsivity, and irritable or labile mood. Etiologies of acute agitation include medical disorders, delirium, substance intoxication or withdrawal, psychiatric disorders, and medication side effects. Treatment of acute agitation requires both environmental and pharmacologic intervention. Patients should be calmed with sedating agents early in the course of treatment, allowing for diagnostic tests to take place. Failure to correctly diagnose causes of agitation may lead to delayed treatment for serious conditions, and can even exacerbate agitation.The most common cause of agitation in patients with schizophrenia is psychotic relapse due to medication nonadherence. Pharmacologic treatment options for these patients include lorazepam and antipsychotic agents. Lorazepam causes nonspecific sedation and treats some substance withdrawal, but has little effect on psychosis. First-generation antipsychotics treat psychosis and, at high enough doses, cause sedation, but may induce extrapyramidal side effects (EPS). Some second-generation antipsychotics have been approved for the treatment of agitation in schizophrenia. These agents treat psychosis with a favorable EPS profile, but are comparatively expensive and cause risks such as hypotension. However, avoiding EPS may reduce patients' resistance to antipsychotic treatment.In this expert roundtable supplement, Joseph Battaglia, MD, provides an overview of the definition of acute agitation. Next, Delbert, G. Robinson, MD, outlines evaluation methods for actue agitation. Finally, Leslie Citrome, MD, MPH, reviews interventions for acute and ongoing management of agitation.

Depression: epidemic or pseudo-epidemic?

Depression: epidemic or pseudo-epidemic?

The involvement of norepinephrine and microglia in hypothalamic and splenic IL-1β responses to stress

The noradrenergic system plays an integral role in the stress response and modulates expression of proinflammatory cytokines. Recent work from our laboratory and others has shown that certain stressors increase the expression of the proinflammatory cytokine interleukin-1β (IL-1β) in the hypothalamus and spleen. One goal of the following studies was to assess the role of norepinephrine in stress-elicited increases in IL-1β. To do this, adult male Sprague–Dawley rats were injected with propranolol (20 mg/kg i.p.) or desipramine (20 mg/kg s.c.) and exposed to 80 inescapable footshocks (2.0 mA, 90 s variable ITI, 5 s each). We found that propranolol blocked the IL-1β response to footshock in both the hypothalamus and the spleen, while the noradrenergic reuptake inhibitor desipramine significantly augmented the footshock-induced IL-1β response in both of these sites. Our second goal was to determine whether these effects would also be blocked by administration of a putative microglial inhibitor (minocycline). Minocycline (40 mg/kg i.p.) completely reversed the footshock-induced increase in hypothalamic IL-1β but had no effect on the IL-1β response in the spleen. Moreover, lack of an effect of minocycline on conditioned fear responding suggests that the effect of this drug cannot be explained by nonspecific sedative properties produced by the drug. Together, these data suggest that NE powerfully modulates the hypothalamic and splenic IL-1β response to stress, and that microglia may be a primary cellular source of central IL-1β in response to footshock.

Risperidone reduction of amphetamine-induced self-injurious behavior in mice

The behavioral and neurochemical effects of high doses of amphetamine administered to BALB/c mice were examined in the presence and absence of co-administered haloperidol (a D 2 antagonist), SCH 23390 (a D 1 antagonist) and risperidone (a mixed 5-HT 2/D 2 antagonist). It was observed that mice displayed a dose-dependent increase in stereotypic behavior, oral dyskinesia, and self-injurious behavior (SIB) in response to amphetamine treatment. Furthermore, agents that blocked the SIB reversed the amphetamine-induced release of serotonin. This effect was unrelated to hyperthermia or non-specific sedation (as assessed by measurement of motor activity). These data are interpreted in the context of the underlying basis of murine SIB involving both dopaminergic and serotonergic activation and demonstrate the efficacy of risperidone in treating these behaviors.

Calming versus sedative effects of intramuscular olanzapine in agitated patients

Distinct calming rather than nonspecific sedation is desirable for the treatment of acute agitation. In 3 double-blind studies, acutely agitated patients with schizophrenia (N = 311), bipolar mania (N = 201), or dementia (N = 206) were treated with intramuscular (1–3 injections/24 hrs) olanzapine (2.5–10.0 mg), haloperidol (7.5 mg), lorazepam (2.0 mg), or placebo. The Agitation-Calmness Evaluation Scale (ACES; Eli Lilly and Co.) and treatment-emergent adverse events assessed sedation. Across all studies, 1 patient (lorazepam-treated, bipolar) became unarousable. There were no significant between-group differences in ACES scores of deep sleep or unarousable at any time across. Excluding asleep patients, agitation remained significantly more reduced with olanzapine than placebo ( P < .05). The incidences of adverse events indicative of sedation were not significantly different with olanzapine versus comparators. For the treatment of acute agitation associated with schizophrenia, bipolar mania, or dementia, intramuscular olanzapine-treated patients experienced no more sedation than haloperidol- or lorazepam-treated patients and experienced distinct calming rather than nonspecific sedation.

The effect of sleep deprivation on memory and psychomotor function in healthy volunteers.

Benzodiazepines and other psychotropic drugs have been implicated in the production of memory deficits. The mechanism is unclear, but both a distinct pharmacological action and a non-specific sedative effect have been suggested as being causal or contributory. These two postulated mechanisms of action may be examined separately by using sleep deprivation as a method of non-pharmacological sedation. We measured psychomotor and memory functions in eight sleep-deprived healthy volunteers and eight controls. There was both subjective and objective evidence of sedation, but memory function was not affected. These findings support the view that the effect on memory of psychotropic drugs is principally caused by a direct amnestic effect rather than by drug-induced sedation. Copyright 2000 John Wiley & Sons, Ltd.

Neuroleptics and the neuroleptic-induced deficit syndrome.

The first central pharmacodynamic action of chlorpromazine to be described was sedation without narcosis. The antipsychotic action and extrapyramidal symptoms were observed later. Sedation can be separated into nonspecific sedation (drowsiness, somnolence) and specific sedation (psychomotor inhibition and psychic indifference). Both types are parts of the clinical profiles of classical neuroleptics. The sedative properties of neuroleptics may contribute to the overall efficacy in the treatment of psychotic patients, depending on the clinical situation. In most patients, however, sedation is only needed for a short period, or not at all. The drug induced sedation may adversely affect the patients' well-being and functional capabilities. The term neuroleptic-induced deficit syndrome (NIDS) has been coined to focus attention on the adverse mental effects of neuroleptics. NIDS still needs to be properly defined and to be differentiated from the deficit syndrome of schizophrenia and postpsychotic depression. Assessment methods are needed to establish the incidence and prevalence of NIDS, to evaluate the importance of NIDS in the overall treatment outcome in psychoses and to facilitate development of better antipsychotic agents.

Effects of serotonergic agents on apomorphine-induced locomotor activity

The interactions of serotonin 5-HT1A, 5-HT1C/2 and 5-HT3 receptor subtypes with apomorphine-induced locomotor activity (AILA) were investigated in Sprague-Dawley rats. The 5-HT3 antagonists ondansetron and ICS 205-930 had no significant effects on AILA. The 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) produced an increase in locomotor activity that was independent of DA neurotransmission. The locomotor activity induced by co-administration of apomorphine (APO; 0.25 mg/kg) and 8-OH-DPAT (0.25-1.0 mg/kg) was not significantly higher than those induced by APO alone during the peak period of APO stimulation of locomotor activity, nor were they higher than activity induced by 8-OH-DPAT alone during the same time intervals. The 5-HT1 antagonist (1)-propranolol had a depressant effect on AILA, but only at high doses. Coadministration of (1)-propranolol (5 mg/kg) and 8-OH-DPAT (1.0 mg/kg) elevated spontaneous locomotor activity for the first 10 min of the session when compared to 8-OH-DPAT (1.0 mg/kg) alone. The 5-HT2 antagonist ketanserin along with moderate and high doses of mesulergine depressed AILA, effects which may be mediated by the 5-HT2 antagonist properties of these drugs, by nonspecific sedation or by direct effects of these compounds on DA D2 receptors. In contrast to the high-dose mesulergine depression of AILA, a low dose (0.1 mg/kg) of mesulergine elevated AILA, an effect which was blocked by the 5-HT1C/2 agonist 1-(2,-5-dimethoxy-4-iodophenyl) -2-aminopropane (DOI; 1 mg/kg). Neither of these compounds at the doses tested had significant effects on spontaneous locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioural analysis of the anorectic effects of fluoxetine and fenfluramine

Two sets of experiments were carried out to compare the effects of fenfluramine and fluoxetine on consummatory and operant behaviour. In food-deprived rats allowed access to a 35% sucrose solution, an initial period of sucrose consumption was followed by a short period of grooming and exploratory behaviour, later superceded by resting. This "behavioural satiety sequence" was advanced by fluoxetine, but disrupted by dl-fenfluramine, which suppressed post-prandial resting, even at sub-anorectic doses. Fluoxetine also elicited resting behaviour following water drinking. However, this did not appear to be a non-specific sedative effect, since fluoxetine increased post-prandial grooming. In rats performing on random interval schedules of food reinforcement, fluoxetine caused proportionally greater decreases in responding on a reinforcement-lean schedule (RI-300s), as compared to a reinforcement-rich schedule (RI-7.5s); this effect is similar to that of a reduction in level of food deprivation. By contrast, fenfluramine reduced responding equally on both schedules. In both paradigms, the effects of fluoxetine were compatible with an increase in postprandial satiety, but the effects of fenfluramine were not.

Behavioral and physiologic effects of CRH administered to infant primates undergoing maternal separation

Infant rhesus monkeys briefly separated from their mothers emit frequent distress vocalizations and alter their activity levels. These behavioral alterations are accompanied by physiologic changes and activation of the hypothalamic-pituitary-adrenal axis. Because corticotropin-releasing hormone (CRH) is a major regulator of the pituitary-adrenal system and has been implicated as a mediator of other aspects of the stress response, we examined the effects of centrally and peripherally administered CRH on the infant monkey's separation response. Intracerebroventricular (ICV) doses less than 10 micrograms did not alter behavior; 10-micrograms doses inhibited behavior without affecting distress vocalizations. The behavioral inhibition did not appear to be due to nonspecific sedation and may be related to increased fearfulness. It was accompanied by increases in adrenocorticotropic hormone (ACTH) and cortisol and small but significant decreases in body temperature and mean arterial pressure. Within an individual animal, no relationship was seen between ICV CRH's effects on physiologic parameters and its effects on behavior. ICV CRH produced significant increases in plasma concentrations of CRH, suggesting the possibility that the effects of CRH were mediated through peripheral mechanisms. However, 10 micrograms of CRH administered intravenously (IV) had no effect on behavior, blood pressure, or body temperature, nor did it increase plasma concentrations of ACTH or cortisol beyond the expected separation-induced elevation. This is interesting because plasma levels of CRH after IV CRH were much greater than after ICV CRH. Our findings suggest that in infant rhesus monkeys undergoing maternal separation, brain CRH systems mediate behavioral inhibition and pituitary-adrenal activation.

Reduced urinary serotonin excretion after intake of high doses of hypoxanthine.

Two healthy volunteers were treated with hypoxanthine 3 x 1 g and allopurinol 3 x 100 mg daily for 1 week. During this treatment serum oxypurine concentration and urinary oxypurine excretion increased as expected. No side effects were observed except for some mild daytime drowsiness and lethargy. Measurements of urinary serotonin (5-HT) excretion showed decreases to as much as 60% below initial values. Decreased urinary 5-HT excretion was also found in a patient with incomplete Lesch-Nyhan syndrome during treatment with high doses of hypoxanthine. His neurological symptoms improved slightly. The results suggest that high doses of hypoxanthine exert a nonspecific sedative effect on both patients with Lesch-Nyhan syndrome and healthy controls. The cause is probably a reduced synthesis or release of 5-HT.

Effects of clonidine and propranolol on separation-induced distress in infant rhesus monkeys

In primates, separation of an infant from its mother is a naturally occurring stressor resulting in activation of behavioral, endocrine, and autonomic systems. When separated from their mothers, infant rhesus monkeys emit frequent species-typical distress vocalizations (‘coos’). In earlier work we demonstrated that opiate and benzodiazepine systems influence the frequency of coos induced by separation in infant rhesus monkeys. The present studies assessed the role of α 2- and β-adrenergic systems in mediating distress vocalizations. We found that the α 2 agonist, clonidine (33 and 67 μg/kg), reduced activity levels without affecting separation-induced coos. Only at 100 μg/kg were distress vocalizations reduced, and this was associated with behavioral sedation. In the same animals, morphine (0.1 and 0.25 mg/kg) selectively reduced distress vocalizations without affecting activity. Thus, the effects of clonidine, 100 μg/kg, appear to be due to non-specific sedation. We next assessed whether antagonism of β-adrenergic receptors reduces separation distress. We administered propranolol over a wide dosage range to a different group of animals and found that a high dose (20 mg/kg) increased separation-induced coos while decreasing the activity levels. That such a high dose was necessary to affect coo vocalizations suggests that effects on vocalizations are due to non-specific effects of the drug. Unlike propranolol, morphine administered to these animals did not affect activity levels but did selectively reduce distress vocalizations. These findings suggest that α 2- and β-adrenergic systems do not specifically mediate separation-induced coos in infant rhesus monkeys. However, as demonstrated in an earlier study, opiate systems have a prominent role.