mk-9470 and Disease-Models--Animal

Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [(18)F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) (4mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32-42 (adolescence) and in the same animals again at PNDs 75-79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p=0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p=0.034) and hypothalamus (p=0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies.

Topics: Age Factors; Animals; Body Weight; Brain; Brain Mapping; Disease Models, Animal; Female; Gene Expression Regulation, Developmental; Magnetic Resonance Imaging; Male; Poly I-C; Positron-Emission Tomography; Pregnancy; Prenatal Exposure Delayed Effects; Protein Binding; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Recent ex vivo and pharmacological evidence suggests involvement of the endocannabinoid system in the pathophysiology of stroke, but conflicting roles for type 1 and 2 cannabinoid receptors (CB(1) and CB(2)) have been suggested. The purpose of this study was to evaluate CB(1) and CB(2) receptor binding over time in vivo in a rat photothrombotic stroke model using PET.. CB(1) and CB(2) microPET imaging was performed at regular time-points up to 2 weeks after stroke using [(18)F]MK-9470 and [(11)C]NE40. Stroke size was measured using MRI at 9.4 T. Ex vivo validation was performed via immunostaining for CB(1) and CB(2). Immunofluorescent double stainings were also performed with markers for astrocytes (GFAP) and macrophages/microglia (CD68).. [(18)F]MK-9470 PET showed a strong increase in CB(1) binding 24 h and 72 h after stroke in the cortex surrounding the lesion, extending to the insular cortex 24 h after surgery. These alterations were consistently confirmed by CB(1) immunohistochemical staining. [(11)C]NE40 did not show any significant differences between stroke and sham-operated animals, although staining for CB(2) revealed minor immunoreactivity at 1 and 2 weeks after stroke in this model. Both CB (1) (+) and CB (2) (+) cells showed minor immunoreactivity for CD68.. Time-dependent and regionally strongly increased CB(1), but not CB(2), binding are early consequences of photothrombotic stroke. Pharmacological interventions should primarily aim at CB(1) signalling as the role of CB(2) seems minor in the acute and subacute phases of stroke.

Topics: Animals; Disease Models, Animal; Positron-Emission Tomography; Pyridines; Quinolines; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Stroke; Thrombosis

Type 1 cannabinoid (CB1) receptors are expressed in high concentrations in the central nervous system, including the basal ganglia, and could have direct or indirect effects on motor behavior through modulation of dopaminergic, glutamatergic and GABA-ergic neurotransmission. Using the CB1 receptor radioligand [(18)F]MK-9470 and small-animal PET, we investigated for the first time in vivo cerebral changes in [(18)F]MK-9470 binding in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), parallel to dopamine transporter (DAT) imaging, tyrosine hydroxylase (TH) staining, and behavioral measurements. In the 6-OHDA model, relative [(18)F]MK-9470 PET binding decreased in the contralateral cerebellum (-9%, p<0.0004) and caudate-putamen bilaterally (ipsilateral -8%, contralateral -7%; p=0.001 and p<0.0003, respectively). The number of TH(+) neurons in the substantia nigra was inversely correlated to CB1 receptor binding in the ipsilateral cerebellum (p=1.10(-6)). The behavioral outcome was positively related to regional CB1 receptor binding in the contralateral somatosensory cortex (p=4.10(-6)). In vivo [(18)F]MK-9470 PET imaging points to changes in endocannabinoid transmission, specifically for CB1 receptors in the 6-OHDA model of PD, with mainly involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum and somatosensory cortex.

Topics: Animals; Brain; Brain Mapping; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Female; Neurons; Neuropsychological Tests; Oxidopamine; Parkinsonian Disorders; Positron-Emission Tomography; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Severity of Illness Index; Tyrosine 3-Monooxygenase