Search

The [A.sub.2A]R is largely coexpressed with [D.sub.2]Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the [A.sub.2A]R antagonizes [D.sub.2]R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct [A.sub.2A]R-[D.sub.2]R interaction. However, whether the [D.sub.2]R is required for the [A.sub.2A]R to exert its neural function is an open question. In this study, we examined the role of [D.sub.2]Rs in [A.sub.2A]R-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in [A.sub.2A]RS or [D.sub.2]Rs or both). Behavioral analysis shows that the [A.sub.2A]R agonist 2-4-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamineinduced locomotion in both [D.sub.2] KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the [A.sub.2A]R antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the [D.sub.2]R, although the stimulation was significantly attentuated. At the cellular level, [A.sub.2A]R inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by [D.sub.2]R deficiency. Consistent with the [D.sub.2] KO phenotype, [A.sub.2A]R inactivation partially reversed both acute [D.sub.2]R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that [A.sub.2A]RS elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of [D.sub.2]Rs. Thus, [A.sub.2A]R-mediated neural functions are partially independent of [D.sub.2]Rs. Moreover, endogenous adenosine acting at striatal [A.sub.2A]RS may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of [D.sub.2]R neurotransmission.

Typically the social-emotional development or mental health of under 5-year-old Children in Care (CiC) is not routinely assessed and there are few published data in the UK on the prevalence of difficulties for these children. Our hypothesis was that there could be a significant level of unidentified and unmet need within this group. A screening procedure was developed and piloted in a 12-month study assessing both child factors and the developing relationships between children and their caregivers. Previous screening studies have shown that recommendations for interventions are not reliably expedited. An intervention component was incorporated to address this and minimise delay in the children and their carers receiving support. Close inter-agency collaboration was integral to the establishment, implementation and high level of participation in the study. The screening proved acceptable to the majority of birth parents and caregivers, with 94% uptake of participants. In the year prior to screening only 10% of under-fives coming into care were identified as having difficulties in contrast to 67% of children in the screening cohort. The brief interventions offered were taken up in three-quarters of cases, leading to increased referrals on and access to mental health services for these children. [ABSTRACT FROM PUBLISHER]

The amphetamine challenge, in which positron emission tomography (PET) or single photon emission computed tomography radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [18F] fallypride is the first PET radioligand that allows measurement of the effects of amphetamine on D2/D3 ligand binding in striatum and extra-striatal brain regions in a single scanning session following amphetamine. We scanned 15 healthy volunteer subjects with [18F] fallypride at baseline and following amphetamine (0.3 mg/kg) using arterial plasma input-based modeling as well as reference region methods. We found that amphetamine effect was robustly detected in ventral striatum, globus pallidus, and posterior putamen, and with slightly higher variability in other striatal subregions. However, the observed effect sizes in striatum were less than those observed in previous studies in our laboratory using [11C] raclopride. Robust effect was also detected in limbic extra-striatal regions (hippocampus, amygdala) and substantia nigra, but the signal-to-noise ratio was too low to allow accurate measurement in cortical regions. We conclude that [18F] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but it is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum. Synapse 64:350-362, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) and the high affinity D2/3 radiotracer [18F]fallypride allow the assessment of D2/3 receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D2 agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6±5.5% at 2 mg/day to 96.8±5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D2 occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.Neuropsychopharmacology (2008) 33, 3111–3125; doi:10.1038/npp.2008.33; published online 16 April 2008 [ABSTRACT FROM AUTHOR]

Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A2A receptors in psychostimulant-induced locomotor sensitization using an A2A receptor knockout (A2A KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A2A KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D1 agonist SKF81297 (2.5 mg/kg) or the D2 agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A2A KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A2A KO and WT mice, suggesting normal D1 and D2 receptor responsiveness. Finally, at the cellular level A2A receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A2A KO mice suggests a critical role of the A2A receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A2A adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure. [ABSTRACT FROM AUTHOR]

Examines the role of the D[sub 2] dopamine receptors in A[sub 2A] adenosine receptor-induced behavioral and cellular responses. Effects of genetic inactivation of A[sub 2A] and D[sub 2] receptors on the expression of adenosine and dopamine receptors in striatum; Effects of D[sub 2]R inactivation on A[sub 2A] agonist-induced motor depression in mice.

Background: Serotonergic abnormalities are hypothesized to contribute to obsessive-compulsive disorder (OCD). This study used positron emission tomography with the radioligand [11C]MDL 100907 to examine whether the distribution of serotonin 2A (5-HT2A) receptors is altered in OCD. Methods: Nineteen OCD subjects, free of psychiatric medications and depression, and 19 matched healthy subjects underwent positron emission tomography scans following injection of [11C]MDL 100907. Total distribution volumes were derived by kinetic analysis using the arterial input function. Two measures of 5-HT2A availability were computed: the ratio at equilibrium of specifically bound radiotracer either to nondisplaceable radiotracer in tissue (BPND) or to unmetabolized tracer in arterial plasma (BPp). Groups were compared using a region of interest (ROI) analysis and voxelwise analysis of spatially normalized parametric maps. ROIs included cortical (orbitofrontal, dorsolateral prefrontal, medial prefrontal, anterior cingulate, temporal, parietal, occipital, and insular cortex) and limbic (entorhinal cortex, parahippocampal gyrus, and medial temporal lobe) regions. Results: No significant group differences were observed in [11C]MDL 100907 BPND or BPp in the ROIs or in the voxelwise analysis of BPND maps. There was a significant correlation in the orbitofrontal cortex between [11C]MDL 100907 binding and age of onset, with earlier age of onset associated with higher binding. Conclusions: Adults with OCD are not characterized as a group by major changes in 5-HT2A availability in cortical or limbic brain regions. Further research is warranted to examine potential differences in 5-HT2A availability between early- and late-onset OCD and to assess 5-HT2A function in relation to other neurotransmitter systems implicated in OCD. [ABSTRACT FROM AUTHOR]

Unlabelled: Whole-body radiation dosimetry of 11C-raclopride was performed in healthy human volunteers., Methods: Subjects (n = 6) were scanned with PET. Subjects received single-bolus injections of 11C-raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy-6-methoxybenzamide) (533 +/- 104 MBq) and were scanned for approximately 110 min with a 2-dimensional whole-body protocol. Regions of interest were placed over all visually identifiable organs and time-activity curves were generated. Residence times were computed as the area under the curve of the time-activity curves, normalized to injected activities and standard values of organ volumes. Absorbed doses were computed according to the MIRD schema with MIRDOSE3.1 software., Results: Organs with the highest radiation burden were gallbladder wall, small intestine, liver, and urinary bladder wall., Conclusion: On the basis of the estimated absorbed dose, the maximum allowable single study dose under U.S. federal regulations for studies performed under Radiation Drug Research Committee is 1.58 GBq (42.8 mCi). This is still considerably higher than the doses of 11C-raclopride commonly used in research PET (370-555 MBq).