Highlights [ 18 F]DPA-714 PET showed an increased brain signal following peripheral LPS challenge. The cellular origin of TSPO signal appears to depend on the brain region examined. TSPO signal increase in the hippocampus arises from microglia and astrocytes. Microglia, macrophages and astrocytes are the main contributors in the substantia nigra. Macrophages and microglial cells expressing TSPO are distinguished by RNAscope.

Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABA A receptor (GABA A R) α subunits, including α5GABA A R. Positron emission tomography (PET) measures of GABA A R availability in schizophrenia, however, have not revealed consistent alterations in vivo . Animal studies using the GABA A R agonist [ 3 H]-muscimol provide evidence that antipsychotic drugs influence GABA A R availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABA A R radioligands. To address this, we combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed postmortem using the GABA A R subunit-selective radioligand [ 3 H]-Ro15-4513 and the non-subunit selective radioligand [ 3 H]-flumazenil. Chronic haloperidol exposure increased [ 3 H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus ( p <0.01; q <0.01; d =+1.3), which was not dose-dependent. [ 3 H]-flumazenil binding also increased in most rat brain regions ( p <0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABA A R radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABA A R-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABA A R in the context of schizophrenia.

Data from post-mortem studies suggest that schizophrenia is associated with abnormal expression of GABAA receptor (GABAAR) a subunits including a5GABAA. Positron emission tomography (PET) measures of GABAAR binding in schizophrenic patients, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [ 3 H]muscimol have provided evidence that antipsychotic drugs used in schizophrenia can influence GABAAR binding, in a region-specific manner, complicating the interpretation of the PET GABA signal in medicated patients. No binding data, however, are available for more subunit-selective ligands. To address this, we combined a rodent model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or vehicle were continuously administered to adult male Sprague-Dawley rats via osmotic pumps to maintain a clinically relevant, steady-state levels of drug exposure for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAA selective radioligand [ 3 H]Ro15-4513 and the non-subunit selective radioligand [ 3 H]flumazenil. Chronic haloperidol exposure increased [ 3 H]Ro15-4513 binding in the CA1 sub-field of the dorsal hippocampus (p<0.01; q<0.01). [ 3 H]flumazenil binding was also increased in most of the explored regions (p<0.05), independently of the dose of haloperidol used. This is the first study to demonstrate a region/dose-specific effect of haloperidol on [ 3 H]Ro15-4513 binding.Although caution needs to be exerted when extrapolating results from animals to patients, collectively these data confirm previous findings that antipsychotic treatment contributes to the heterogeneity observed in PET studies of GABAAR in schizophrenic patients, specifically at the a1/5GABAAR.

Conditional response probability (CRP) analyses applied to free recall data indicate that recall occurs for contiguous items with forward-directionality, thought to reflect the shared encoding context of nearby items. We hypothesized that a context disruption, produced by presenting infrequent oddballs, would modulate CRP curves, increasing the forward-flow of recall due to strong binding of items presented after these oddballs to the new encoding context. Seventy young, healthy male and female participants encoded word lists containing either emotional or perceptual oddballs at varying stimulus onset asynchronies (SOA) followed by free recall. Serial recall transitions from emotional, but not perceptual, oddballs were enhanced in the forward direction except at the shortest SOA (1s). The present results provide empirical evidence of CRP modulation selectively by emotional salience and suggest that recall patterns after presenting emotional and perceptual oddballs are mediated by different mechanisms.