Biomedical subjects

C A Tamminga

Publications and source records attributed to C A Tamminga.

At least 19 recordsLinked to original sources

PubMed2002

Partial dopamine agonists in the treatment of psychosis.

The discovery and characterization of dopamine in the mammalian brain earned Dr. Arvid Carlsson the Nobel Prize in 2000. Along with his many insights about dopamine pharmacology, came his proposal of the existence and critical role of dopamine autoreceptors in the overall regulation of dopamine-mediated neurotransmission. In this paper, the rationale, the putative mechanisms, and pertinent clinical data are reviewed to support the idea of the clinical relevance of dopamine agonists, especially partial agonists, in the treatment of psychosis. Evidence was gathered for the usefulness of this strategy in schizophrenia in early trials with apomorphine and N-propylnoraporphine (NPA). But clinical relevance was not a reality before the application of (-)-3PPP. These clinical results are presented. Moreover, now a partial dopamine agonist, aripiprazole, has been developed and will likely be marketed by BMS and Otsuka for the treatment of psychosis and will be the first drug in this class to be commercially available. Partial dopamine agonists represent the next new class of antipsychotic drugs, effective in treating schizophrenia.

Animals↗

PubMed2001

Increased cortical kynurenate content in schizophrenia.

BACKGROUND: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of the key metabolites in this pathway, kynurenine, is either transaminated to form the glutamate receptor antagonist, kynurenate, or hydroxylated to 3-hydroxykynurenine, which in turn is further degraded to the excitotoxic N-methyl-D-aspartate receptor agonist quinolinate. Because a hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. METHODS: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. RESULTS: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 +/- 2.2 vs. 1.9 +/- 1.3 pmol/mg protein, p <.05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 +/- 28.0 vs. 22.4 +/- 14.3 pmol/mg protein; p <.05) and 19 (40.3 +/- 23.4 vs. 30.9 +/- 10.8; p <.05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p <.05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p >.05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation observed in schizophrenia is not due to antipsychotic medication. CONCLUSIONS: The data demonstrate an impairment of brain kynurenine pathway metabolism in schizophrenia, resulting in elevated kynurenate levels and suggesting a possible concomitant reduction in glutamate receptor function.

Adult↗

PubMed2001

Long-term outcome of patients who receive ketamine during research.

BACKGROUND: To comprehend the pathophysiology of schizophrenia and to facilitate drug discovery, animal and human models of schizophrenia are necessary. Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has been used to probe glutamatergic function in normal and schizophrenic volunteers. These studies and others have provided data consistent with a putative involvement of a glutamatergic dysfunction in the pathophysiology of schizophrenia; however, these studies have also raised concerns about the distress inflicted on patients, the potential for adverse events, and the serious long-term effects that could possibly be induced by symptom-simulating action. METHODS: For all patient volunteers (n = 30) who participated in these studies, we reviewed the acute safety during and in the immediate postketamine administration. Patients available for long-term follow-up (n = 25) were matched to a group of patients (n = 25) who participated in research but did not receive ketamine. We compared their long-term outcome in terms of psychopathology, the need for psychiatric care, and the amount of antipsychotic medication required for optimal therapeutic response. RESULTS: There were no serious adverse events in more than 90 ketamine interviews. Distress to patients was minimal, which is shown by the lack of anxiety ratings. Over a mean follow-up period of 8 months, we found no differences between patients who did and did not receive ketamine on any measures of psychopathology, psychiatric care, or the amount of antipsychotic medication. CONCLUSIONS: In a controlled environment and paying close attention to subject safety features, administering subanesthetic doses of ketamine causes no adverse events and little distress to schizophrenic volunteers. This study strongly indicates that administering ketamine does not change any aspect of the course of schizophrenic illness.

Adult↗

PubMed2001

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.

Animals↗

PubMed2001

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.

Animals↗

PubMed2001

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.

Acoustic Stimulation↗

PubMed2001

Sequential regional cerebral blood flow brain scans using PET with H2(15)O demonstrate ketamine actions in CNS dynamically.

The aim of this study was to examine the potential of serial rCBF studies to directly characterize the regional effects and dynamic time course of the centrally active drug ketamine. The value of a broader application of this technique to other neurally active drugs to characterize the pharmacodynamics of CNS compounds is suggested by these data. Thirteen normal subjects received a 0.3 mg/kg intravenous dose of ketamine over 60 seconds; ten other individuals received placebo in the same manner. For each subject, three baseline PET rCBF scans and seven sequential post-ketamine scans at 10-minute intervals were obtained using H(2)(15)O water. SPM techniques were employed to identify the maxima of any cluster significant by spatial extent analysis at any post-ketamine time point between 0 and 36 min. These extremes from the ketamine group, were identified in placebo scans similarly and grown to a 6x6x12 mm voxel set. The average rCBF values of the ketamine-defined clusters were determined in the drug and placebo conditions at all time points. rCBF across time was plotted for each cluster and compared between drug and placebo. Area under the curve (AUC) was calculated between baseline and 36 minutes. The kinetic characteristics of the ketamine-induced rCBF curves were compared to induced behaviors in each maxima. Ketamine produced distinct patterns of rCBF change over time in different brain regions; maxima within an anatomically defined region responded similarly. Ketamine induced rCBF activations in anterior cingulate, medial frontal and inferior frontal cortices. All maxima with a relative flow reduction with ketamine were in the cerebellum. The pattern of all activations and suppressions was monophasic with the peak changes at 6-16 minutes. In preliminary analysis, individual C(max) and AUC of maxima in the anterior cingulate/medial frontal region tended to correlate with the mild psychotomimetic action of ketamine; whereas, there was no tendency toward correlation with this psychological change in cerebellar maxima. The direct action of a centrally active drug can be assessed regionally and dynamically in brain using rCBF and a scan sequence optimally timed to complement the drug's time course. Ketamine pharmacodynamic response can be related to concurrent behavioral changes, tending to link the behavior with a brain region. This experimental design provides direct characterization of drug action in the CNS in ways heretofore unavailable.

Adult↗

PubMed2001

Effects of ketamine in normal and schizophrenic volunteers.

This study evaluates the effects of ketamine on healthy and schizophrenic volunteers (SVs) in an effort to define the detailed behavioral effects of the drug in a psychosis model. We compared the effects of ketamine on normal and SVs to establish the comparability of their responses and the extent to which normal subjects might be used experimentally as a model. Eighteen normal volunteers (NVs) and 17 SVs participated in ketamine interviews. Some (n = 7 NVs; n = 9 SVs) had four sessions with a 0.1-0.5 mg/kg of ketamine and a placebo; others (n = 11 NVs; n = 8 SVs) had two sessions with one dose of ketamine (0.3 mg/kg) and a placebo. Experienced research clinicians used the BPRS to assess any change in mental status over time and documented the specifics in a timely way. In both volunteer groups, ketamine induced a dose-related, short (<30 min) increase in psychotic symptoms. The scores of NVs increased on both the Brief Psychiatric Rating Scale (BPRS) psychosis subscale (p =.0001) and the BPRS withdrawal subscale (p =.0001), whereas SVs experienced an increase only in positive symptoms (p =.0001). Seventy percent of the patients reported an increase (i.e., exacerbation) of previously experienced positive symptoms. Normal and schizophrenic groups differed only on the BPRS withdrawal score. The magnitude of ketamine-induced changes in positive symptoms was similar, although the psychosis baseline differed, and the dose-response profiles over time were superimposable across the two populations. The similarity between ketamine-induced symptoms in SVs and their own positive symptoms suggests that ketamine provides a unique model of psychosis in human volunteers. The data suggest that the phencyclidine (PCP) model of schizophrenia maybe a more valid human psychosis/schizophrenia drug model than the amphetamine model, with a broader range of psychotic symptoms. This study indicates that NVs could be used for many informative experimental psychosis studies involving ketamine interviews.

Adult↗

PubMed2001

Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects.

The extracellular regulated kinases (ERK) 1 and ERK2 are members of mitogen-activated protein (MAP) kinase family that play an important role in transducing extracellular signals to the nucleus and have been implicated in a broad spectrum of biological responses. To test the hypothesis that MAP kinases may be involved in depression, we examined the activation of p44/42 MAP kinase and expression of ERK1 and ERK2 in the post-mortem brain tissue obtained from non-psychiatric control subjects (n = 11) and age- and the post-mortem interval-matched depressed suicide subjects (n = 11). We observed that p44/42 MAP kinase activity was significantly decreased in the prefrontal cortical areas (Brodmann's areas 8, 9 and 10) and the hippocampus of depressed suicide subjects without any change in the cerebellum. This decrease was associated with a decrease in mRNA and protein levels of ERK1 and ERK2. In addition, the expression of MAP kinase phosphatase (MKP)2, a 'dual function' ERK1/2 phosphatase, was increased in the prefrontal cortex and hippocampus. These studies suggest that p44/42 MAP kinases are less activated in the post-mortem brain of depressed suicide subjects and this may be because of reduced expression of ERK1/2 and increased expression of MKP2. Given the role of MAP kinases in various physiological functions and gene expression, alterations in p44/42 MAP kinase activation and expression of ERK1/2 may contribute significantly to the pathophysiology of depressive disorders.

Adult↗

PubMed2001

Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task.

OBJECTIVE: Using functional brain imaging, the authors sought to replicate their earlier finding of low metabolism in the middle frontal and inferior parietal cortices of schizophrenic patients with primary negative symptoms. METHOD: According to the presence or absence of enduring negative symptoms, patients with schizophrenia were classified as having deficit or nondeficit schizophrenia, respectively. Twelve normal volunteers and 18 drug-free schizophrenic volunteers (deficit, N=8; nondeficit, N=10) were trained in a tone discrimination task. They were trained to perform with 70%-80% accuracy and were then scanned with positron emission tomography with [(15)O]H(2)O during three conditions: rest, sensory-motor control task, and decision task. RESULTS: Levels of performance of the auditory recognition task were similar in the three groups. An initial hypothesis-driven analysis revealed that across tasks the deficit group failed to show significant activation in the middle frontal cortex. This was in contrast to both the normal volunteers and nondeficit patients. When the patient groups were contrasted, the deficit patients showed significantly less activation in the middle frontal cortex bilaterally during the control task and in the right middle frontal cortex and inferior parietal cortex during the decision task. An exploratory analysis contrasting deficit and nondeficit patients across conditions did not reveal further differences between groups. CONCLUSIONS: This study replicated the finding of low activation in the middle frontal cortex and inferior parietal cortex in deficit schizophrenia. This deficit was observed without performance confound and may provide a marker of primary negative symptoms and a target for new therapies.

Adult↗

PubMed2001