Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor. It has recently been found to have antidepressant effects and is a drug of abuse, suggesting it may have dopaminergic effects. To examine the effect of ketamine on the dopamine systems, we carried out a systematic review and meta-analysis of dopamine measures in the rodent, human and primate brain following acute and chronic ketamine administration relative to a drug-free baseline or control condition. Systematic search of PubMed and PsychInfo electronic databases yielded 40 original peer-reviewed studies. There were sufficient rodent studies of the acute effects of ketamine at sub-anaesthetic doses for meta-analysis. Acute ketamine administration in rodents is associated with significantly increased dopamine levels in the cortex (Hedge’s g= 1.33, P<0.01), striatum (Hedge’s g=0.57, P<0.05) and the nucleus accumbens (Hedge’s g=1.30, P<0.05) compared to control conditions, and 62–180% increases in dopamine neuron population activity. Sub-analysis indicated elevations were more marked in in vivo (g=1.93) than ex vivo (g=0.50) studies. There were not enough studies for meta-analysis in other brain regions studied (hippocampus, ventral pallidum and cerebellum), or of the effects of chronic ketamine administration, although consistent increases in cortical dopamine levels (from 88 to 180%) were reported in the latter studies. In contrast, no study showed an effect of anaesthetic doses (>100 mg kg−1) of ketamine on dopamine levels ex vivo, although this remains to be tested in vivo. Findings in non-human primates and in human studies using positron emission tomography were not consistent. The studies reviewed here provide evidence that acute ketamine administration leads to dopamine release in the rodent brain. We discuss the inter-species variation in the ketamine induced dopamine release as well as the implications for understanding psychiatric disorders, in particular substance abuse, schizophrenia, and the potential antidepressant properties of ketamine, and comparisons with stimulants and other NMDA antagonists. Finally we identify future research needs.

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen's d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in prelimbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT 1A receptors but no appreciable action at dopamine D 2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT 1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.

Salt intake is an essential dietary requirement, but excessive consumption is implicated in hypertension and associated conditions. Little is known about the neural circuit mechanisms that control motivation to consume salt, although the midbrain dopamine system, which plays a key role in other reward-related behaviors, has been implicated. We, therefore, examined the effects on salt consumption of either optogenetic excitation or chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons in male mice. Strikingly, optogenetic excitation of dopamine neurons decreased salt intake in a rapid and reversible manner, despite a strong salt appetite. Importantly, optogenetic excitation was not aversive, did not induce hyperactivity, and did not alter salt concentration preferences in a need-free state. In addition, we found that chemogenetic inhibition of dopamine neurons had no effect on salt intake. Lastly, optogenetic excitation of dopamine neurons reduced consumption of sucrose following an overnight fast, suggesting a more general role of VTA dopamine neuron excitation in organizing motivated behaviors.

Cocaine is a recreational drug of abuse that binds to the dopamine transporter (DAT), preventing reuptake of dopamine into presynaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and postsynaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on presynaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography (PET) have revealed impaired presynaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use μ-PET imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of presynaptic dopamine function. We show that a dose of 20mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p<0.001). However, dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment (KiCer: 0.0097 min-1 vs. 0.0112 min-1 in vehicle controls, p>0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p>0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to presynaptic dopaminergic neurons are not initiated following a single exposure to the drug.

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Plasma and cerebrospinal fluid ABeta42 for the di erential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting.

Background Objectives Search methods Selection criteria Data collection and analysis Main results Authors' conclusions Plain language summary DTA 18 Plasma and Cerebrospinal fluid (CSF) Abeta42 for the differential diagnosis of Alzheimer's disease dementia in... Positron emission tomography F-2-fluoro-2-deoxy-D-glucose (18 F-FDG-PET); Positron emission tomography Pittsburg Compound-C (11 C-PIB-PE); Structural magnetic resonance imaging (sMRI); Neuropsychological tests (e.g. Mini-mental state examination (MMSE); Mini-cognitive assessment (MiniCOG); Montreal Cognitive Assessment (MoCA)) Informant interviews (e.g. Informant Questionnaire on Cognitive Decline in the Elderly(IQCODE); The Washington University Dementia Screening Test, "Eight-item Interview to Differentiate Aging and Dementia" (AD8)) APOE e4 (Apolipoprotein E e4 variant) DTA 18 Plasma and Cerebrospinal fluid (CSF) Abeta42 for the differential diagnosis of Alzheimer's disease dementia in...

BackgroundSchizophrenia is a chronic debilitating disorder which affects about 21 million people worldwide (WHO 2017). Elevated pre-synaptic striatal dopamine synthesis capacity is a robust neurochemical alteration seen in patients with schizophrenia compared to controls, with a large effect size Cohen’s d=0.79 (Howes et al., 2012). Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist induces psychotomimetic effects in healthy human (Krystal et al., 1994, Stone et al., 2007) and exacerbates psychotic symptoms in patients with schizophrenia (Lahti et al., 1991). For these reasons, it has been used to model the neurochemical alterations seen in schizophrenia such as dopaminergic overactivity (Usun et al., 2013, Kokkinou et al., 2017). However, the effect of sub-chronic ketamine on dopamine synthesis capacity in vivo is not known. Here we investigated the effect of sub-chronic ketamine on striatal dopamine synthesis capacity in vivo using Positron Emission Tomography (PET) imaging and on locomotor activity in the mouse. Moreover, via a chemogenetics approach (Roth 2016) we explored the role of midbrain dopamine neuron activity in mediating ketamine-induced effects.MethodsAll procedures were conducted under licence in accordance with the UK Animals (Scientific Procedures) Act of 1986. Mice received a sub-anaesthetic dose of ketamine or an equivalent volume of saline for five consecutive days. Locomotor activity was assessed in the open field test. Moreover, mice received a dynamic 3,4-dihydroxy-6-[(18)F]-fluoro-L-phenylalanine Positron Emission Tomography (PET) scan to assess striatal dopamine synthesis capacity in vivo. Data were analysed using an extended Patlak graphical analysis approach (Walker et al., 2013). Further midbrain dopamine neurons were transduced with an adeno-associated virus vector expressing Gi-coupled (hM4Di) inhibitory receptors under the control of the dopamine transporter (DAT) promoter in DATCre positive mice. Standard immunohistochemistry was used to label dopamine neurons and mCherry expression in dopamine neurons was confirmed using confocal microscopy. Two weeks following the stereotaxic injection of the viral construct, mice received clozapine N-oxide (CNO) to study the effects of inhibiting dopamine neuron firing on locomotor activity and striatal dopamine synthesis capacity in the sub-chronic ketamine model. Data were analysed by two-tailed independent samples t-tests, one-way ANOVA and repeated measures two-way ANOVA followed by Bonferroni post hoc tests where appropriate. p<0.05 was considered statistically significant.ResultsSub-chronic ketamine treatment significantly increased striatal dopamine synthesis capacity (p<0.05, effect size=1.2) and induced locomotor sensitization (p<0.01). hM4Di-mCherry viral construct was successfully transduced in midbrain dopamine neurons with over 98% specificity. Chemogenetic inhibition of midbrain dopamine neurons prevented the ketamine-induced elevation in striatal dopamine synthesis capacity (p<0.05, effect size= ...