SummaryElevation of the head as a common practice to reduce raised intracranial pressure (ICP) has been discussed controversially of late. Some investigators were able to show that besides lowering ICP head elevation may also reduce cerebral perfusion pressure (CPP). For a new evaluation of optimal head position in neurosurgical care it would be of importance to know the influence of body position on cerebral perfusion.We therefore employed continuous jugular venous oximetry, monitoring cerebral oxygenation, to study the effect of 0°, 15°, 30°, and 45° head elevation on ICP, CPP and jugular venous oxygen saturation (SJVOz) in 25 comatose patients with reduced intracranial compliance.As expected, head elevation significantly reduced ICP from 19.8 ± 1.3 mmHg at 0° to 10.2 ± 1.2mmHg at 45°. Already at 30°92% of the possible effect on ICP was detected. There was no statistically significant change in CPP and SJV02 associated with varying head position. Individual reactions of CPP to changes in head position, however, were quite unpredictable. The data suggest that an individual approach to head elevation is to be prefered. A moderate head evelation between 15° and 30° significantly reduces ICP and, in general, does not impair cerebral perfusion. Jugular venous oximetry may be used to optimize ICP, CPP and cerebral oxygenation.

Dopaminergic, serotonergic, and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D 2 receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D 2 receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D 2 receptors. In this study, we used functional assays for recombinant D 2 receptors and native 5-hydroxytryptamine 2A (5-HT 2A ), a 2C -adrenergic, and histamine H 1 receptors to compare the pharmacological properties of terguride and three of its halogenated derivatives (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL (hD 2S ) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D 2S receptor-mediated inhibition of cAMP accumulation to the same extent; intrinsic activity was half as high as that of terguride. All compounds tested behaved as antagonists at human D 2long /Ga o (hD 2L /Ga o ) receptors. Compared with aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT 2A receptors and a 2C -adrenoceptors and lower affinity at H 1 receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS.

RationaleRecently, we showed that 2-bromoterguride acted as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A and α2C-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy.ObjectiveTo extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT2A receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs).ResultsAcute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity.ConclusionsOur data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain.

Rationale2-Bromoterguride, a dopamine D2 receptor partial agonist with antagonist properties at serotonin 5-HT2A receptors and α2C-adrenoceptors, meets the prerequisites of a putative atypical antipsychotic drug (APD). We recently showed that 2-bromoterguride is effective in tests of positive symptoms of schizophrenia in rats without inducing extrapyramidal side effects or metabolic changes.ObjectiveIn continuation of our recent work, we now investigated the effect of 2-bromoterguride on apomorphine and phencyclidine (PCP)-induced disruptions of prepulse inhibition (PPI) of the acoustic startle response, a measure of sensory gating. In addition, we used subchronic PCP treatment to produce cognitive deficits and social aversion, and assessed the effect of 2-bromoterguride on the performance in the novel object recognition (NOR) task (model for studying cognitive deficit symptoms of schizophrenia) and the social interaction test (model for studying negative symptoms of schizophrenia). Finally, we extended the side effect profile of 2-bromoterguride by measuring the prolactin response to systemic administration of the drug in rats.ResultsTreatment with 2-bromoterguride (0.1 and 0.3 mg/kg) reversed PPI deficits induced by apomorphine and PCP, respectively. Subchronic PCP induced impairments in object memory and social interaction behavior which were ameliorated by 2-bromoterguride but not by clozapine and aripiprazole, respectively. Prolactin concentration in blood serum was not elevated at 1, 2, or 4 h post-2-bromoterguride treatment, which further supports the safe and effective use of this drug.ConclusionsOur data support 2-bromoterguride as a promising APD candidate due to its beneficial effect on cognitive impairments and negative symptoms of schizophrenia.

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