Whereas the neurological effects of cocaine have been well documented, effects of acute cocaine consumption on genome-wide gene expression across the brain remain largely unexplored. This question cannot be readily addressed in humans but can be approached using the Drosophila melanogaster model, where gene expression in the entire brain can be surveyed at once. Flies exposed to cocaine show impaired locomotor activity, including climbing behavior and startle response (a measure of sensorimotor integration), and increased incidence of seizures and compulsive grooming. To identify specific cell populations that respond to acute cocaine exposure, we analyzed single-cell transcriptional responses in duplicate samples of flies that consumed fixed amounts of sucrose or sucrose supplemented with cocaine, in both sexes. Unsupervised clustering of the transcriptional profiles of a total of 86,224 cells yielded 36 distinct clusters. Annotation of clusters based on gene markers revealed that all major cell types (neuronal and glial) as well as neurotransmitter types from most brain regions were represented. The brain transcriptional responses to cocaine showed profound sexual dimorphism and were considerably more pronounced in males than females. Differential expression analysis within individual clusters indicated cluster-specific responses to cocaine. Clusters corresponding to Kenyon cells of the mushroom bodies and glia showed especially large transcriptional responses following cocaine exposure. Cluster specific coexpression networks and global interaction networks revealed a diverse array of cellular processes affected by acute cocaine exposure. These results provide an atlas of sexually dimorphic cocaine-modulated gene expression in a model brain.

/pdf/the-drosophila-brain-on-cocaine-at-single-cell-resolution-2da131ugcx.pdf

The Drosophila brain on cocaine at single-cell resolution.

The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immune-reactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos.

The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry

Propofol is a worldwide-used intravenous general anesthetic with ideal effects, but hedonic effects of propofol have been reported and cause addictive issue. There is little known about the neurobiological mechanism of hedonic effects of propofol. Increasing researches have shown that the dopaminergic nervous system of the ventral tegmental area (VTA) and the noradrenergic system of locus coeruleus (LC) play a crucial role in hedonic experiences, which are putative sites for mediating the hedonic effects of propofol. In the present study, rat hedonic response scale and place conditioning paradigm were employed to examine the euphoric effects of propofol. In vivo GCaMP-based (AVV-hSyn-GCaMP6s) fiber photometry calcium imaging was used to monitor the real-time neuronal activity in VTA and LC area in rats exhibiting propofol-induced euphoric behaviors. Then DREADDs (designer receptors exclusively activated by designer drugs) modulation using rAAV-hSyn-hM4D(Gi)-EGFP was performed to confirm the neuronal substrate that mediates the euphoric effects of propofol. The score of hedonic facial responses was significantly increased in the 4 mg/kg group compared with that of the 0 mg/kg group. The locomotor activity in the propofol-paired compartment was significantly increased at the 4 mg/kg dose compared with that of the saline-paired group. When compared with the 0 mg/kg group, the place preference increased in the 4 mg/kg group. Administration of 4 mg/kg of propofol triggers reliable increases in GcaMP fluorescence. However, in the VTA GcaMP-expressing rats, administration of 4 mg/kg of propofol did not induce any change of GcaMP signals. The facial score and the place preference, which increased by 4 mg/kg propofol were abolished by chemogenetic inhibition of the neuronal activity in the LC area. Our results suggest that LC noradrenergic neurons, not VTA dopaminergic neurons, are directly involved in the hedonic effects of sub-anesthetic dose of propofol.

/pdf/neurons-in-the-locus-coeruleus-modulate-the-hedonic-effects-2wfk9ggtik.pdf

Neurons in the Locus Coeruleus Modulate the Hedonic Effects of Sub-Anesthetic Dose of Propofol

A single dose of cocaine potentiates glutamatergic synaptic transmission onto locus coeruleus neurons

Introduction Cocaine use during pregnancy can affect fetal brain development. A fetal brain injury could happen from the direct effect of cocaine on the developing brain or from the reduction of placental perfusion from vasoconstriction, which may lead to hypoxia-ischemia. A potential mechanism for brain injury could be due to a neurotransmitter imbalance within the brain, especially glutamate. In an immature rat brain synaptosome model, we explored the additive effect of cocaine alone on glutamate release and the effect of cocaine combined with simulated hypoxic depolarization using potassium as a surrogate. Method Rat pups' brains were dissected and placed on a chilled petri dish. They then entered the experimental protocol. The suspended synaptosomes were divided equally into four experimental groups (control, high potassium "surrogate to hypoxic stimulation," cocaine, and cocaine + high K). Reversed-phase high-performance liquid chromatography analyzed glutamate with fluorescent detection Results The glutamate level was lowest in the cocaine-only group, with a level of 1.96 × 104, compared to the control and high potassium group. However, combining cocaine with high potassium seemed to generate a synergistic effect, achieving the highest glutamate level of all groups with a value of 5.31 × 104. Post hoc Conover's test for multiple pairwise-comparison between groups was done. In comparing various solutions to control, we did not find a statistically significant difference with the cocaine-only solution with a p-value of 0.074. Also, on comparing various other solutions to each other, there was no statistically significant difference between cocaine vs. cocaine + high potassium a p-value of 0.074. Conclusion Our data support the conclusion that cocaine alone does not induce glutamate release from fetal rat brain synaptosomes. Exposure to high potassium does lead to glutamate release. However, cocaine greatly enhances glutamate release in the presence of high potassium levels. This could explain how cocaine affects brain maturation during pregnancy with a low oxygen tension environment in the placenta. This hypothesis should be tested in vivo.

/pdf/effect-of-cocaine-on-potassium-evoked-release-of-glutamate-3obnowze.pdf

Effect of Cocaine on Potassium-Evoked Release of Glutamate From Fetal Rat Brain Synaptosomes

The locus coeruleus (LC) is an important brainstem area involved in cocaine addiction. However, evidence to elucidate how cocaine modulates the activity of LC neurons remains incomplete. Here, we performed whole recordings in brain slices to evaluate the effects of cocaine on the sodium (Na+), potassium (K+), calcium (Ca2+) channels, and glutamatergic synaptic transmission in the locus coeruleus neurons. Local application of cocaine significantly and reversibly reduced the spontaneous firing rate but did not affect action potential amplitude, rising time, decay time, or half width of noradrenergic locus coeruleus neurons. Moreover, cocaine attenuated the sodium current but did not affect potassium and calcium currents. The N-methyl-d-aspartate receptor mediated excitatory postsynaptic currents were reduced by neuropeptide galanin but not cocaine. All those data demonstrate that cocaine has inhibitory effect on the spontaneous activities and sodium current in locus coeruleus neurons. Therefore, neuromodulation of sodium channel in locus coeruleus neurons may play an important role in drug addiction.

Effect of Cocaine on Ion Channels and Glutamatergic EPSCs in Noradrenergic Locus Coeruleus Neurons

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Effect of Cocaine on Ion Channels and Glutamatergic EPSCs in Noradrenergic Locus Coeruleus Neurons