Improvement in tardive dyskinesia after muscimol therapy.

Muscimol, thought to be a agonist of gamma-aminobutyric acid (GABA), was administered to eight neuroleptic-free subjects with tardive dyskinesia. At oral dose levels from 5 to 9 mg, involuntary movements were consistently attenuated, usually in the absence of sedation. These results support the view that pharmacologic attempts to stimulate GABA-mediated synaptic transmission may afford symptomatic relief to patients with tardive dyskinesia.     

Effect of apomorphine on schizophrenic symptoms

Summary The effects of apomorphine on psychotic symptoms were evaluated in chronic schizophrenic patients using double-blind placebo controlled procedures. Although on the basis of dopamine theory of schizophrenia, apomorphine was expected to increase schizophrenic symptoms, in this study apomorphine substantially reduced psychotic symptoms in some chronic schizophrenic patients. No patient showed the substantial increase in psychotic symptoms previously demonstrated after the administration of IV methylphenidate. These clinical effects of apomorphine in schizophrenia may be relevant to recent pharmacological research which has indicated that apomorphine also has potent effects on presynaptic dopamine neurons, in addition to its previously described postsynaptic receptor stimulation.This work was begun when all authors were associated with the Illinois State Psychiatric Institute.     

Functional effects of single dose first- and second-generation antipsychotic administration in subjects with schizophrenia

Using PET with (15)O water, we characterized the time course of functional brain changes following the acute administration of a first- and a second-generation antipsychotic. Volunteers with schizophrenia were scanned while drug-free (baseline) and after single dose administration of haloperidol (n=6) or olanzapine (n=6) during a time course adapted to their plasma kinetics. To obtain brain location information, we contrasted each post-drug scan to baseline-acquired scans. We plotted the regional cerebral blood flow (rCBF) extracted in these locations and calculated the kinetic characteristics of the curves. Further, we compared and contrasted the rCBF changes induced by the drugs over the first 4 h post-drug administration. Dorsal and ventral striatum, thalamus and anterior cingulate cortex were activated with haloperidol, while frontal, temporal and cerebellum regions evidenced reduced flow. With olanzapine, ventral striatum, anterior cingulate and temporal cortices evidenced increases, and thalamus and lingual cortex decreases, in rCBF. Both drugs activated the caudate nucleus. Haloperidol induced greater activation of the dorsal striatum than did olanzapine. These data reveal important differences in patterns of brain activation between the drugs. Differences in the involvement in basal ganglia parallel known differences between the drugs in the emergence of acute EPS upon emergency administration.     

Ileal endogenous nitrogen recovery is increased and its amino acid pattern is altered in pigs fed quebracho extract

Ileal endogenous nitrogen recovery (ENR) in pigs (9 +/- 0.6 kg body weight) was estimated simultaneously using the (15)N-isotope dilution technique ((15)N-IDT) and the peptide alimentation ultrafiltration (UF) method. Diets were cornstarch, enzyme-hydrolyzed casein with no (control) or high (4%) content of quebracho extract (Schinopsis spp.) rich in condensed tannins. The amino acid (AA) pattern of the ENR was also determined. The ENR of pigs fed the quebracho diet was higher (P = 0.0001) than that of pigs fed the control diet [6.00 vs. 1.95 g/kg dry matter intake (DMI) for the (15)N-IDT and 5.18 vs. 1.49 g/kg DMI for the UF method, respectively]. With the (15)N-IDT, ENR values were 0.44-0.79 g/kg DMI (24%) higher (control P = 0.0032, quebracho P = 0.0002) than for the UF method. Apparent nitrogen digestibility depended on diet (69.0% quebracho vs. 86.0% control, P = 0.0001). Real nitrogen digestibility (RD-N) determined by the UF method was higher (P = 0.0001) for the control than for the quebracho diet (91.4 vs. 88.2%). Corresponding values for the (15)N-IDT did not differ (P = 0.0569) between diets (92.8 vs. 91.4%). The (15)N-IDT gave higher values for RD-N of both diets (control P = 0.0030, quebracho P = 0.0002) compared with the UF method. Endogenous AA recoveries (g/kg DMI) were increased 300% (P = 0.0001) and the AA-pattern of ENR was changed (P from 0.0001 to 0.7530 for different AA) by the quebracho diet. A constant AA-pattern of ENR cannot be assumed. Despite limitations of both techniques, the (15)N-IDT and the UF method gave similar results with respect to ENR.     

Treatment-refractory schizophrenia

Between one-third and one-half of the individuals who meet diagnostic criteria for schizophrenia remain actively ill despite optimal pharmacological treatment. These individuals tend to progressively deteriorate in terms of social and vocational functioning despite major public and private investments in their rehabilitation. For patients who do not respond to the first prescribed antipsychotic drug, current clinical practice is to switch to a second and a third drug, and eventually to clozapine, the only antipsychotic drug proven to be effective in treatment-refractory schizophrenia (TRS). Occasionally, two antipsychotics are given concomitantly or psychotropic drugs are added to antipsychotic drugs; however, very few empirical data exist to support this practice. Although there are many exceptions, patients who do not benefit from the first prescribed drug will not benefit from any pharmacological intervention. Therefore, efforts are under way to determine the reason for lack of response to available treatments and devise novel, more effective treatments. To be successful these efforts must result in a more specific definition of TRS, as well as in a better understanding of the illness pathophysiology and the mechanism of action of the drugs.     

Scopolamine fails to diminish chronic haloperidol-induced purposeless chewing in rats

Chronic haloperidol treatment for 4-12 months gradually induces spontaneous, irregular, purposeless oral chewing movements (CMs), apparently involuntary, in some but not all treated rats. Based on phenomenologic and pharmacologic similarities, this laboratory preparation has been used as an animal model of tardive dyskinesia (TD), which is the human hyperkinetic motor syndrome associated with chronic antipsychotic administration. This putative animal model has received the most severe challenge to its validity by claims that its oral movements can be suppressed by anticholinergic treatments, since resistance to anticholinergic suppression is an accepted pharmacologic feature of TD. In this experiment, we challenged a group of haloperidol-treated rats with CMs using three doses of scopolamine (0.1, 0.3, 1.0 mg/kg) and placebo and rated the change in dyskinetic movements. Each scopolamine dose reduced CMs by a similar magnitude, without any dose effect; the saline dose also reduced CMs to an equivalent degree. Therefore, we concluded that some component of the experiment, not the scopolamine, reduced the CMs. The handling component of the procedure was identified as a likely confound, and we tested this further. Rats with CMs were handled at several levels of "severity"; and the dyskinesias were rated at 1 and 3 h later. CMs were reduced by the experimental handling, in relation to the strength of the handling. Minimal handling produced modest CM reductions with quick recovery; whereas, the "strongest" handling plus the placebo injection produced the greatest CM reduction, evident over 3 h, resembling the CM reductions seen in the scopolamine and placebo experiment. Overall, these results suggest that anticholinergic drugs do not suppress chronic haloperidol-induced rat CMs. However, the movements are sensitive to stressful handling situations, and diminish with stress. In both of these characteristics, rat CMs resemble human TD, further supporting a role for this model in studies of human TD.     

Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia-thalamocortical neural pathways

The effects of three chronically administered antipsychotic drugs on selected neurochemical markers of dopaminergic and GABAergic transmission were compared within the cerebral regions making up the basal ganglia-thalamocortical parallel processing neuronal pathways. All three drugs reduce psychosis in humans, whereas only haloperidol, but not olanzapine or sertindole, induce purposeless oral chewing movements (CMs) in rats or cause high rates of parkinsonism or tardive dyskinesia in humans. Male Sprague Dawley rats were treated with haloperidol, sertindole, or olanzapine delivered in drinking water for 6 months at doses which produce drug plasma levels in rat in the human therapeutic range. Results show the expected dopamine D2 receptor upregulation in striatum predominantly with haloperidol, although mild D2 upregulation was apparent in striatum after olanzapine. GAD67 mRNA was increased in striatum and decreased in globus pallidus by haloperidol and sertindole, but not by olanzapine. In the substantia nigra pars reticulata (SNR), both olanzapine and sertindole failed to induce GABA(A) receptor upregulation or D1 receptor downregulation, but haloperidol did both, confirming a previous report. In thalamus, all three drugs increased GAD expression in the reticular nucleus, whereas only haloperidol decreased GABA(A) binding in the mediodorsal nucleus, actions consistent with a reduction in nigrothalamic, GABA-mediated neural transmission. These results are consistent with the idea that the two new antipsychotics tested have mild and regionally restricted actions within the basal ganglia nuclei and a common action on increasing GAD expression in the reticular nucleus of the thalamus (RtN). Haloperidol, in contrast, has a broad and potent action in basal ganglia, causing changes in SNR and in the mediodorsal nucleus, while also altering GAD mRNA in RtN, potentially reflective of its dyskinetic and antipsychotic actions.     

Probing the human hippocampus using rCBF: contrasts in schizophrenia.

Regional cerebral blood flow (rCBF) data from two PET-15O water schizophrenia studies were analyzed using individually placed, magnetic resonance (MR)-guided hippocampal volumes of interest (VOI). In one study, normal (N = 10) and schizophrenic (N = 18) volunteers performed an overlearned auditory discrimination task in rest, control, and decision conditions. In the other study, schizophrenic and normal volunteers received the noncompetitive NMDA receptor antagonist ketamine and placebo and had sequential rCBF evaluations. Moreover, the schizophrenic volunteers were off drug in one study and on antipsychotic drug in the second study, allowing an additional comparison of medication status. VOIs were placed on anterior, middle, and posterior hippocampal areas in each PET image from both studies, redirected from an MR scan, and individually adjusted. While no hippocampal activation was apparent in either the normal or schizophrenic group in the task vs. condition comparison, rCBF was higher in the schizophrenic than in the normal hippocampus in both task and control conditions, independently. In addition, at rest rCBF was significantly higher in the unmedicated group of schizophrenics than in the group of medicated patient volunteers and higher than in the normal comparison group. This suggests that schizophrenia is associated with elevated rCBF in the hippocampus, which "normalizes" with antipsychotic drug treatment. Ketamine, the noncompetitive NMDA receptor antagonist, was more potent in reducing rCBF in the schizophrenic group compared to the normal volunteer group. These data are consistent with a previous report from our laboratory of reduced NMDA receptor NR1 subunit expression and possible abnormal NMDA receptor composition in schizophrenia. These data show an abnormality of hippocampal function in schizophrenia and suggest that this abnormality may be associated with the pathophysiology of the illness.     

羟甲芬太尼立体异构体的晶体结构

对强效镇痛剂羟甲芬太尼的两个光学异构体体cis-(3R,4S,2′R)-羟甲芬太尼(I)和trans-(3R,4R,2′S)-羟甲芬太尼(Ⅱ)进行了X-射线衍射晶体结构分析。两个异构体均有一个sp³N(l)原子和一个sp²N(7)原子。哌啶环呈椅式构象,顺式异构体I的3-甲基处于直立键,4-N-苯基丙酰胺基处于平伏键;反式异构体II的3-甲基与4-N-苯基丙酰胺基均处于平伏键。在I分子中,C(4)原子与4-丙酰胺基组成的平面与N-苯环平面近似相互垂直,而在II中,两平面的二面角近似为100℃。两异构体分子中均存在分子内氢键O(1)一H…N(1),反式异构体II还存在分子间氢键O(1)一H(A)…O(2)(B)。