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Nature Jun 2024Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which...
Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs. Among the opioid receptors, µ-opioid receptors have a key role, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.
Topics: Animals; Female; Male; Mice; Analgesics, Opioid; Central Amygdaloid Nucleus; Dopamine; Dopaminergic Neurons; Fentanyl; Mice, Inbred C57BL; Nucleus Accumbens; Opioid-Related Disorders; Optogenetics; Receptors, Opioid, mu; Reinforcement, Psychology; Substance Withdrawal Syndrome; Ventral Tegmental Area
PubMed: 38778097
DOI: 10.1038/s41586-024-07440-x -
Behavioural Brain Research Jul 2024Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or...
Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HTR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HTR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[I]iodophenyl)-nortropane ([I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HTR inhibition and 5-HTR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.
Topics: Animals; Dopamine Plasma Membrane Transport Proteins; Male; Recognition, Psychology; Exploratory Behavior; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Motor Activity; Brain; Emotions; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Rats, Wistar
PubMed: 38777263
DOI: 10.1016/j.bbr.2024.115051 -
Neural Regeneration Research Jan 2025Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response. Recent studies have shown that brain-derived...
Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response. Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region-specific, particularly involving the corticolimbic system, including the ventral tegmental area, nucleus accumbens, prefrontal cortex, amygdala, and hippocampus. Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology. In this review, we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression. We focused on associated molecular pathways and neural circuits, with special attention to the brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling pathway and the ventral tegmental area-nucleus accumbens dopamine circuit. We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature, severity, and duration of stress, especially in the above-mentioned brain regions of the corticolimbic system. Therefore, BDNF might be a biological indicator regulating stress-related processes in various brain regions.
PubMed: 38767484
DOI: 10.4103/NRR.NRR-D-23-01419 -
Gene & Protein in Disease Mar 2024The D2 dopamine receptor () gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its...
The D2 dopamine receptor () gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."
PubMed: 38766604
DOI: 10.36922/gpd.1966 -
BioRxiv : the Preprint Server For... May 2024Midbrain dopamine neurons (DNs) respond to a first exposure to addictive drugs and play key roles in chronic drug usage. As the synaptic and transcriptional changes that...
Midbrain dopamine neurons (DNs) respond to a first exposure to addictive drugs and play key roles in chronic drug usage. As the synaptic and transcriptional changes that follow an acute cocaine exposure are mostly resolved within a few days, the molecular changes that encode the long-term cellular memory of the exposure within DNs remain unknown. To investigate whether a single cocaine exposure induces long-term changes in the 3D genome structure of DNs, we applied Genome Architecture Mapping and single nucleus transcriptomic analyses in the mouse midbrain. We found extensive rewiring of 3D genome architecture at 24 hours past exposure which remains or worsens by 14 days, outlasting transcriptional responses. The cocaine-induced chromatin rewiring occurs at all genomic scales and affects genes with major roles in cocaine-induced synaptic changes. A single cocaine exposure triggers extensive long-lasting changes in chromatin condensation in post-synaptic and post-transcriptional regulatory genes, for example the unfolding of which becomes most prominent 14 days post exposure. Finally, structurally remodeled genes are most expressed in a specific DN sub-type characterized by low expression of the dopamine auto-receptor , a key feature of highly cocaine-sensitive cells. These results reveal an important role for long-lasting 3D genome remodelling in the cellular memory of a single cocaine exposure, providing new hypotheses for understanding the inception of drug addiction and 3D genome plasticity.
PubMed: 38766140
DOI: 10.1101/2024.05.10.593308 -
BioRxiv : the Preprint Server For... Apr 2024Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to...
Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184's effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.
PubMed: 38766079
DOI: 10.1101/2024.04.02.585967 -
BioRxiv : the Preprint Server For... May 2024Extinction learning is an essential form of cognitive flexibility, which enables obsolete reward associations to be discarded. Its downregulation can lead to...
Extinction learning is an essential form of cognitive flexibility, which enables obsolete reward associations to be discarded. Its downregulation can lead to perseveration, a symptom seen in several neuropsychiatric disorders. This balance is regulated by dopamine from VTA (ventral tegmental area dopamine) neurons, which in turn are largely controlled by GABA (gamma amino-butyric acid) synapses. However, the causal relationship of these circuit elements to extinction and perseveration remain incompletely understood. Here, we employ an innovative drug-targeting technology, DART (drug acutely restricted by tethering), to selectively block GABA receptors on VTA neurons as mice engage in Pavlovian learning. DART eliminated GABA -mediated pauses-brief decrements in VTA activity canonically thought to drive extinction learning. However, contrary to the hypothesis that blocking VTA pauses should eliminate extinction learning, we observed the opposite-accelerated extinction learning. Specifically, DART eliminated the naturally occurring perseveration seen in half of control mice. We saw no impact on Pavlovian conditioning, nor on other aspects of VTA neural firing. These findings challenge canonical theories, recasting GABA -mediated VTA pauses from presumed facilitators of extinction to drivers of perseveration. More broadly, this study showcases the merits of targeted synaptic pharmacology, while hinting at circuit interventions for pathological perseveration.
PubMed: 38766037
DOI: 10.1101/2024.05.09.593320 -
BioRxiv : the Preprint Server For... May 2024Striatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear....
BACKGROUND
Striatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear. CIN express D2 and D5 receptors suggesting repeated activation of these receptors in response to L-Dopa could promote LID. While the role of D5 in this process has recently been probed, little is known about the role of D2.
METHOD
Mice with CIN-specific D2 ablation (D2 KO) underwent unilateral 6-OHDA lesion and chronic L-Dopa dosing, throughout which LID severity was quantified. The effect of D2 KO on histological markers of LID severity and CIN activity were also quantified postmortem.
RESULTS
D2 KO attenuated LID across L-Dopa doses, reduced expression of histological LID marker p-ERK, and prevented L-Dopa-induced increases in CIN activity marker p-rpS6 in the dorsolateral striatum.
CONCLUSION
The activation of D2 specifically on CIN is a key driver of LID.
PubMed: 38765986
DOI: 10.1101/2024.05.10.593604 -
Frontiers in Neuroanatomy 2024The striatal D dopamine receptor (DR) and A adenosine receptor (AR) signaling pathways play important roles in drug-related behaviors. These receptors activate the G...
The striatal D dopamine receptor (DR) and A adenosine receptor (AR) signaling pathways play important roles in drug-related behaviors. These receptors activate the G protein comprised of a specific combination of αβγ subunits. During assembly, the γ subunit sets the cellular level of the G protein. In turn, the amount of G protein determines the collective output from both DR and AR signaling pathways. This study shows the gene encodes multiple γ transcripts differing only in their non-coding regions. In striatum, Transcript 1 is the predominant isoform. Preferentially expressed in the neuropil, Transcript 1 is localized in dendrites where it undergoes post-transcriptional regulation mediated by regulatory elements in its 3' untranslated region that contribute to translational suppression of the γ protein. Earlier studies on gene-targeted mice demonstrated loss of γ protein disrupts assembly of the G protein. In the current study, morphological analysis reveals the loss of the G protein is associated with altered dendritic morphology of medium spiny neurons. Finally, behavioral analysis of conditional knockout mice with cell-specific deletion of the γ protein in distinct populations of medium spiny neurons reveals differential roles of the G protein in mediating behavioral responses to cocaine. Altogether, these findings provide a better understanding of the regulation of γ protein expression, its impact on G function, and point to a new potential target and mechanisms for treating addiction and related disorders.
PubMed: 38764487
DOI: 10.3389/fnana.2024.1394659 -
Cell Reports May 2024Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the...
Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Utilizing mice with a D1-SPN-specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell-type-specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis implicates genes involved in autism risk, electrophysiological properties, and neuronal development and function. Viral-mediated re-expression of Foxp1 into the double knockouts is sufficient to restore electrophysiological and behavioral deficits. These data indicate complementary roles between Foxp1 and Foxp2 in the D1-SPNs.
Topics: Animals; Forkhead Transcription Factors; Mice; Corpus Striatum; Repressor Proteins; Mice, Knockout; Receptors, Dopamine D1; Male; Neurons; Mice, Inbred C57BL; Social Behavior
PubMed: 38761373
DOI: 10.1016/j.celrep.2024.114257