Gerhard Gründer

Drug interactions at GABA(A) receptors.

Neurotransmitter receptor systems have been the focus of intensive pharmacological research for more than 20 years for basic and applied scientific reasons, but only recently has there been a better understanding of their key features. One of these systems includes the type A receptor for the gamma-aminobutyric acid (GABA), which forms an integral anion channel from a pentameric subunit assembly and mediates most of the fast inhibitory neurotransmission in the adult vertebrate central nervous system. Up to now, depending on the definition, 16-19 mammalian subunits have been cloned and localized on different genes. Their assembly into proteins in a poorly defined stoichiometry forms the basis of functional and pharmacological GABA(A) receptor diversity, i.e. the receptor subtypes. The latter has been well documented in autoradiographic studies using ligands that label some of the receptors various binding sites, corroborated by recombinant expression studies using the same tools. Significantly less heterogeneity has been found at the physiological level in native receptors, where the subunit combinations have been difficult to dissect. This review focuses on the characteristics, use and usefulness of various ligands and their binding sites to probe GABA(A) receptor properties and to gain insight into the biological function from fish to man and into evolutionary conserved GABA(A) receptor heterogeneity. We also summarize the properties of the novel mouse models created for the study of various brain functions and review the state-of-the-art imaging of brain GABA(A) receptors in various human neuropsychiatric conditions. The data indicate that the present ligands are only partly satisfactory tools and further ligands with subtype-selective properties are needed for imaging purposes and for confirming the behavioral and functional results of the studies presently carried out in gene-targeted mice with other species, including man.

Association of Low Striatal Dopamine D2 Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse

OBJECTIVEnAll drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers.nnnMETHODnIn vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation.nnnRESULTSnIndependent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex.nnnCONCLUSIONSnSimilar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.

Dopamine in amygdala gates limbic processing of aversive stimuli in humans

Dopamine is released under stress and modulates processing of aversive stimuli. We found that dopamine storage capacity in human amygdala, measured with 6-[18F]fluoro-L-DOPA positron emission tomography, was positively correlated with functional magnetic resonance imaging blood oxygen level–dependent signal changes in amygdala and dorsal anterior cingulate cortex that were evoked by aversive stimuli. Furthermore, functional connectivity between these two regions was inversely related to trait anxiety. Our results suggest that individual dopamine storage capacity in amygdala subserves modulation of emotional processing in amygdala and dorsal cingulate, thereby contributing to individual differences in anxious temperament.

The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans.

BACKGROUNDnPurpose of this study was to investigate the functional relationship between electroencephalographic (EEG) alpha power and cerebral glucose metabolism before and after pharmacological alpha suppression by lorazepam.nnnMETHODSnTen healthy male volunteers were examined undergoing two F18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) scans with simultaneous EEG recording: 1x placebo, 1x lorazepam. EEG power spectra were computed by means of Fourier analysis. The PET data were analyzed using SPM99, and the correlations between metabolism and alpha power were calculated for both conditions.nnnRESULTSnThe comparison lorazepam versus placebo revealed reduced glucose metabolism of the bilateral thalamus and adjacent subthalamic areas, the occipital cortex and temporo-insular areas (P < 0.001). EEG alpha power was reduced in all derivations (P < 0.001). Under placebo, there was a positive correlation between alpha power and metabolism of the bilateral thalamus and the occipital and adjacent parietal cortex (P < 0.001). Under lorazepam, the thalamic and parietal correlations were maintained, whereas the occipital correlation was no longer detectable (P < 0.001). The correlation analysis of the difference lorazepam-placebo showed the alpha power exclusively correlated with the thalamic activity (P < 0.0001).nnnCONCLUSIONSnThese results support the hypothesis of a close functional relationship between thalamic activity and alpha rhythm in humans mediated by corticothalamic loops which are independent of sensory afferences. The study paradigm could be a promising approach for the investigation of cortico-thalamo-cortical feedback loops in neuropsychiatric diseases.

Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology – a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist

Abstract The benzamide amisulpride (ASP) is a selective D2-like dopamine antagonist, while flupentixol (FPX), a thioxanthene, blocks D2-like, D1-like and 5-HT2 receptors. To evaluate efficacy and safety of ASP and to investigate the importance of an additional D1-like antagonism for antipsychotic effects and extrapyramidal tolerability, a randomized double-blind multi-center study versus FPX as reference drug was performed for 6 weeks in 132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (ASP: 1000u2008mg/day; FPX: 25u2008mg/day) but could be reduced by 40% in case of side effects (mean daily doses: ASP: 956u2008mg; FPX: 22.6u2008mg). Intention-to-treat evaluation demonstrated significant improvement under both medications. The difference between the mean BPRS decreases of both treatment groups was 5.6 points (95% CI: 0.55;u200810.65) in favour of ASP. According to CGI, 62% of patients in either drug group were treatment responders. ANCOVA analysis showed that reductions of BPRS (ASP: −42%; FPX: −32%) and SAPS (ASP: −78%; FPX: −65%) were more pronounced under ASP. Due to adverse events, significantly fewer ASP patients (6%) were withdrawn from the study (FPX: 18%). Extrapyramidal tolerability was better in the ASP group, as demonstrated by smaller increases in the Simpson-Angus Scale, the AIMS, and the Barnes Akathisia Scale in ANCOVA analyses with dosage as covariate. ASP appears to be as effective as FPX with regard to antipsychotic effects on positive schizophrenic symptomatology, while extrapyramidal tolerability is better. These conclusions have to be drawn cautiously, as dosage effects on outcome parameters cannot be entirely ruled out. The present results question the notion that additional blockade of D1-like receptors may be necessary to achieve sufficient antipsychotic effects or to improve extrapyramidal tolerability.

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long [18F]fluorodopa (FDOPA)/PET recordings from eight unmedicated patients with schizophrenia and 15 healthy age-matched control subjects, using new methods for the quantification of [18F]fluorodopamine steady-state kinetics. The fractional rate constant for the catabolism and elimination of [18F]fluorodopamine was elevated nearly twofold in striatum, the largest biochemical difference in brain of schizophrenics yet reported. The magnitude of the intrinsic blood–brain FDOPA clearance with correction for this loss of [18F]fluorodopamine metabolites was increased by 20% in caudate and putamen and by 50% in amygdala and midbrain of the patients. However, the magnitude of the steady-state storage of FDOPA and its decarboxylated metabolites (Vd) was reduced by one-third in the caudate nucleus and amygdala of the schizophrenic group. Thus, reduced steady-state storage of [18F]fluorodopamine occurs in the midst of accelerated synthesis in brain of untreated patients. Positive scores of the positive and negative syndrome scale correlated inversely with the magnitude of Vd in amygdala, suggesting an association between positive symptoms and impaired steady-state storage of FDOPA metabolites in that structure.

Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ 18 F]Fallypride PET Study

OBJECTIVEnAripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia.nnnMETHODnSixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole.nnnRESULTSnMean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142).nnnCONCLUSIONSnBecause of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

Therapeutic Monitoring of New Antipsychotic Drugs

Abstract: Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350–600 ng/mL), risperidone (20–60 ng/mL), and olanzapine (20–80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.

A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia

A double-blind, randomized, parallel study in 167 hospitalized patients with major depression and melancholia was conducted to determine if rapidly escalated doses of venlafaxine produced an earlier response, compared with rapidly escalated doses of imipramine. The daily dose of venlafaxine was rapidly increased to 375 mg/day over a five-day period, was maintained at this level for 10 days, and then was reduced to 150 mg/day for the remainder of the study. The imipramine dose was rapidly increased to 200 mg/day over five days and was maintained at this level to the end of the study. The primary efficacy variables were time to response and time to sustained response on the HAM-D and MADRS. No differences in the response rates on the HAM-D or MADRS were observed between treatments. However, among patients who demonstrated a response on the HAM-D, there was a significantly faster onset of response (p = 0.036) and sustained response (p = 0.018) in the venlafaxine group. The median time to response on the HAM-D among responders was 14 days with venlafaxine and 21 days with imipramine. However, no differences between treatments were observed among responders on the MADRS (median time to response: 15 days for venlafaxine, 18 days for imipramine). Study events were reported in 69% of venlafaxine-treated patients and 76% of imipramine-treated patients. In severely depressed patients with melancholia, a faster onset of response was observed with venlafaxine on the HAM-D, but not the MADRS, and maximal tolerated doses of venlafaxine and imipramine were comparable for overall efficacy. These results confirm and extend previous observations and suggest that venlafaxine may have an early onset of action and may produce a rapid response in hospitalized patients with severe depression complicated by melancholia.

Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo.

The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D2-like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesis capacity. Whereas the phenomenon of depolarization block is well established in animals, it is unknown if a similar phenomenon occurs in humans treated with neuroleptics. We hypothesized that haloperidol treatment should result in decreased DA synthesis capacity. We used 6-[18F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmental modeling to measure the relative activity of DOPA decarboxylase (DDC) (kD3, min−1) in the brain of nine unmedicated patients with schizophrenia, first in the untreated condition and again after treatment with haloperidol. Patients were administered psychometric rating scales at baseline and after treatment. Consistent with our hypothesis, there was a 25% decrease in the magnitude of kD3 in both caudate and putamen following 5 weeks of haloperidol therapy. In addition, the magnitudes of kD3 in cerebral cortex and thalamus were also decreased. Psychopathology as measured with standard rating scales improved significantly in all patients. The decrease of kD3 in the thalamus was highly significantly correlated with the improvement of negative symptoms. Subchronic treatment with haloperidol decreased the activity of DDC in the brain of patients with schizophrenia. This observation is consistent with the hypothesis that the antipsychotic effect of chronic neuroleptic treatment is associated with a decrease in DA synthesis, reflecting a depolarization block of presynaptic DA neurons. We link an alteration in cerebral catecholamine metabolism in human brain with the therapeutic action of neuroleptic medication.