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There is increasing interest in the use of cannabis and its major non-intoxicating component cannabidiol (CBD) as a treatment for mental health and neurodevelopmental disorders, such as autism spectrum disorder (ASD). However, before launching large-scale clinical trials, a better understanding of the effects of CBD on brain would be desirable. Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels, including in brain regions linked to ASD, such as the basal ganglia (BG) and the dorsomedial prefrontal cortex (DMPFC). However, differences in glutamate and GABA pathways in ASD mean that the response to CBD in people with and without ASD may be not be the same. To test whether CBD ‘shifts’ glutamate and GABA levels; and to examine potential differences in this response in ASD, we used magnetic resonance spectroscopy (MRS) to measure glutamate (Glx = glutamate + glutamine) and GABA+ (GABA + macromolecules) levels in 34 healthy men (17 neurotypicals, 17 ASD). Data acquisition commenced 2 h (peak plasma levels) after a single oral dose of 600 mg CBD or placebo. Test sessions were at least 13 days apart. Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant. Thus, CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD. Our results do not speak to the efficacy of CBD. Future studies should examine the effects of chronic administration on brain and behaviour, and whether acute brain changes predict longer-term response.

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies – including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites – markers of the brain’s primary excitatory and inhibitory system - in both the ‘typical’ and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the ‘shift’ in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous \"entourage\" compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain.

Prior studies have demonstrated that both nicotine administration and cigarette smoking lead to dopamine (DA) release in the ventral striatum/nucleus accumbens. In tobacco-dependent individuals, smoking denicotinized cigarettes leads to reduced craving, but less pleasure, than smoking regular cigarettes. Using denicotinized cigarettes and (11)C-raclopride positron emission tomography (PET) scanning, we sought to determine if nicotine is necessary for smoking-induced DA release. Sixty-two tobacco-dependent smokers underwent (11)C-raclopride PET scanning, during which they smoked either a regular or denicotinized cigarette (double-blind). Change in (11)C-raclopride binding potential (BP) in the ventral striatum from before to after smoking was determined as an indirect measure of DA release. Cigarette craving, anxiety, and mood were monitored during scanning. Smoking a regular cigarette resulted in a significantly greater mean reduction in ventral striatal (11)C-raclopride BP than smoking a denicotinized cigarette. Although both groups had reductions in craving and anxiety with smoking, the regular cigarette group had a greater improvement in mood. For the total group, change in BP correlated inversely with change in mood, indicating that greater smoking-induced DA release was associated with more smoking-related mood improvement. Thus, nicotine delivered through cigarette smoking appears to be important for ventral striatal DA release. Study findings also suggest that mood improvement from smoking is specifically related to ventral striatal DA release.

This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (<30 µm) DRG neurons from intact DRGs (ex-vivo whole ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold.

Rationale The basal ganglia play an important role in motor control, which is dependent on dopaminergic input. Preparation of a motor response has been associated with dopamine release in the basal ganglia, and response readiness may therefore serve as a pharmacodynamic marker of dopamine activity. Methods We measured response readiness using the amplitude of the contingent negative variation (CNV), a slow negative shift in the electroencephalogram. The CNV is evoked in a paradigm in which a warning stimulus (S1) signals the occurrence of the imperative stimulus (S2) 4 s later, to which the participant has to respond. CNV was assessed in healthy volunteers after administration of placebo or 10, 20 or 40 mg of methylphenidate, a catecholamine re-uptake blocker which primarily enhances the synaptic concentration of dopamine and to a lesser extent also noradrenaline. In addition, participants filled out two visual analogue scales measuring subjective ratings of mood and alertness: Profile of Mood States and Bond and Lader. Results Methylphenidate dose dependently increased CNV amplitude and decreased reaction times. Furthermore, participants reported improved mood, feeling more alert, vigorous and content and less angry and tired after methylphenidate. Conclusions These results indicate that dopamine availability increases response readiness as measured by the CNV paradigm. The CNV appears to be a good candidate biomarker for assessing changes in dopaminergic function by treatments that either directly or indirectly target the dopaminergic system.

Manipulation of neurotrophin (NT) signalling by administration or depletion of NTs, by transgenic overexpression or by deletion of genes coding for NTs and their receptors has demonstrated the importance of NT signalling for the survival and differentiation of neurons in sympathetic and dorsal root ganglia (DRG). Combination with mutation of the proapoptotic Bax gene allows the separation of survival and differentiation effects. These studies together with cell culture analysis suggest that NT signalling directly regulates the differentiation of neuron subpopulations and their integration into neural networks. The high-affinity NT receptors trkA, trkB and trkC are restricted to subpopulations of mature neurons, whereas their expression at early developmental stages largely overlaps. trkC is expressed throughout sympathetic ganglia and DRG early after ganglion formation but becomes restricted to small neuron subpopulations during embryogenesis when trkA is turned on. The temporal relationship between trkA and trkC expression is conserved between sympathetic ganglia and DRG. In DRG, NGF signalling is required not only for survival, but also for the differentiation of nociceptors. Expression of neuropeptides calcitonin gene-related peptide and substance P, which specify peptidergic nociceptors, depends on nerve growth factor (NGF) signalling. ret expression indicative of non-peptidergic nociceptors is also promoted by the NGF-signalling pathway. Regulation of TRP channels by NGF signalling might specify the temperature sensitivity of afferent neurons embryonically. The manipulation of NGF levels “tunes” heat sensitivity in nociceptors at postnatal and adult stages. Brain-derived neurotrophic factor signalling is required for subpopulations of DRG neurons that are not fully characterized; it affects mechanical sensitivity in slowly adapting, low-threshold mechanoreceptors and might involve the regulation of DEG/ENaC ion channels. NT3 signalling is required for the generation and survival of various DRG neuron classes, in particular proprioceptors. Its importance for peripheral projections and central connectivity of proprioceptors demonstrates the significance of NT signalling for integrating responsive neurons in neural networks. The molecular targets of NT3 signalling in proprioceptor differentiation remain to be characterized. In sympathetic ganglia, NGF signalling regulates dendritic development and axonal projections. Its role in the specification of other neuronal properties is less well analysed. In vitro analysis suggests the involvement of NT signalling in the choice between the noradrenergic and cholinergic transmitter phenotype, in the expression of various classes of ion channels and for target connectivity. In vivo analysis is required to show the degree to which NT signalling regulates these sympathetic neuron properties in developing embryos and postnatally.

Estrogen receptor-alpha immunoreactivity and mRNAs are present in neurons in locales that innervate genital organs, e.g., parasympathetic pelvic autonomic ganglia, sensory dorsal root and nodose ganglia, and autonomic areas of the lumbosacral spinal cord. With the availability of probes for the beta-isoform of the estrogen receptor, we studied this receptor in autonomic, sensory, and spinal cord neurons and compared it with the distribution of the alpha-receptor. Estrogen receptor-alpha and -beta immunoreactivity were located in the nuclei of neurons, were in subpopulations of parasympathetic neurons in pelvic ganglia, and sensory neurons of dorsal root and nodose ganglia. Both receptor subtypes were present in the lumbosacral spinal cord: in neurons of the outer laminae of the dorsal horn, lateral collateral and medial collateral pathways, sacral parasympathetic nucleus, dorsal intermediate gray, and lamina X. Similar numbers of spinal cord neurons were immunoreactive for estrogen receptor-beta and estrogen receptor-alpha. However, estrogen receptor-beta-immunoreactive neurons appeared less numerous in the outer dorsal horn, but more numerous in the deeper layers of the spinal cord than estrogen receptor-alpha neurons. Retrograde tracing from the uterus revealed \"uterine-related\" neurons in dorsal root and pelvic ganglia that contained estrogen receptor-alpha and -beta. In situ hybridization revealed both estrogen receptor-alpha and -beta mRNA transcripts in sensory neurons of the dorsal root and nodose ganglia, parasympathetic neurons of pelvic ganglia, and spinal cord neurons in the dorsal horn, sacral parasympathetic nucleus, and dorsal intermediate gray of L6-S1 segments. These studies show that both estrogen receptor-alpha and -beta are synthesized by autonomic and sensory neurons in parts of the nervous system that have connections with the female reproductive system. Such neurons contain neurotransmitters that have important functions in the female reproductive organs; thus, it is likely that estrogen can influence the activity of such neurons and consequently, through them, the activities of the reproductive organs.

Olanzapine is a neuroleptic drug widely prescribed to treat schizophrenia and bipolar disorder. Although it is long known that modulation of the dopamine system is a basic mechanism of action of neuroleptics, their impact on reward functions mediated by dopamine is still poorly understood. Using functional magnetic resonance imaging (fMRI), we intended to reveal the effects of a single dose of olanzapine on reward-related brain activation. Eight healthy subjects were each scanned twice, once 5 h after intake of 5 mg of olanzapine and once after intake of placebo in a double-blind cross-over design. Subjects performed a delayed incentive paradigm with monetary reward to investigate reward functions and a breath-holding task as a hypercapnic challenge to reveal unspecific drug effects on the fMRI signal. Reward-related brain activation in the ventral striatum, anterior cingulate and inferior frontal cortex was reduced on olanzapine compared to placebo. Only the differential effects (high>no reward) in the ventral striatum were independent of overall drug effects as measured with the breath-holding task. Parallel to the differential effects in the ventral striatum, the acceleration of reaction times in the trials with higher rewards was diminished in the olanzapine sessions. Our behavioural and fMRI results can be interpreted as first evidence from neuroimaging that olanzapine affects the assignment of incentive salience represented by differential activation in dopaminergic brain areas and acceleration of reaction times. This can help to better understand neuroleptic effects in psychiatric diseases. Furthermore, we demonstrate the value of a hypercapnic challenge in functional pharmaco-MRI.

The specific functions of sensory systems depend on the tissue-specific expression of genes that code for molecular sensor proteins that are necessary for stimulus detection and membrane signaling. Using the Next Generation Sequencing technique (RNA-Seq), we analyzed the complete transcriptome of the trigeminal ganglia (TG) and dorsal root ganglia (DRG) of adult mice. Focusing on genes with an expression level higher than 1 FPKM (fragments per kilobase of transcript per million mapped reads), we detected the expression of 12984 genes in the TG and 13195 in the DRG. To analyze the specific gene expression patterns of the peripheral neuronal tissues, we compared their gene expression profiles with that of the liver, brain, olfactory epithelium, and skeletal muscle. The transcriptome data of the TG and DRG were scanned for virtually all known G-protein-coupled receptors (GPCRs) as well as for ion channels. The expression profile was ranked with regard to the level and specificity for the TG. In total, we detected 106 non-olfactory GPCRs and 33 ion channels that had not been previously described as expressed in the TG. To validate the RNA-Seq data, in situ hybridization experiments were performed for several of the newly detected transcripts. To identify differences in expression profiles between the sensory ganglia, the RNA-Seq data of the TG and DRG were compared. Among the differentially expressed genes (> 1 FPKM), 65 and 117 were expressed at least 10-fold higher in the TG and DRG, respectively. Our transcriptome analysis allows a comprehensive overview of all ion channels and G protein-coupled receptors that are expressed in trigeminal ganglia and provides additional approaches for the investigation of trigeminal sensing as well as for the physiological and pathophysiological mechanisms of pain.