PMID- 34975428
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231215
IS  - 1662-5153 (Print)
IS  - 1662-5153 (Electronic)
IS  - 1662-5153 (Linking)
VI  - 15
DP  - 2021
TI  - Self-Administration of Entactogen Psychostimulants Dysregulates 
      Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central 
      Nucleus of the Amygdala of Female Wistar Rats.
PG  - 780500
LID - 10.3389/fnbeh.2021.780500 [doi]
LID - 780500
AB  - Male rats escalate intravenous self-administration of entactogen 
      psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 
      3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as 
      with typical psychostimulants. Here, we investigated whether female rats escalate 
      self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and 
      MDMA and then studied consequences of MDMA and pentylone self-administration on 
      GABA(A) receptor and kappa opioid receptor (KOR) signaling in the central nucleus 
      of the amygdala (CeA), a brain area critically dysregulated by extended access 
      self-administration of alcohol or cocaine. Adult female Wistar rats were trained 
      to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or 
      saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions 
      (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The 
      effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission 
      (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of 
      KOR at CeA GABAergic synapses were determined in acute brain slices using 
      whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated 
      their drug intake (both obtained more infusions compared to MDMA-LgA rats), 
      however, pentylone-LgA rats reached higher breakpoints in PR tests. At the 
      cellular level, baseline CeA GABA transmission was markedly elevated in 
      pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, 
      pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) 
      and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes 
      (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In 
      addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such 
      as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) 
      decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling 
      pathways. This study confirms escalated self-administration of entactogen 
      psychostimulants under LgA conditions in female rats which is accompanied by 
      increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our 
      study suggests that CeA GABA and KOR mechanisms play a critical role in 
      entactogen self-administration like those observed with escalation of alcohol or 
      cocaine self-administration.
CI  - Copyright (c) 2021 Khom, Nguyen, Vandewater, Grant, Roberto and Taffe.
FAU - Khom, Sophia
AU  - Khom S
AD  - Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 
      United States.
AD  - Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.
FAU - Nguyen, Jacques D
AU  - Nguyen JD
AD  - Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United 
      States.
AD  - Department of Psychiatry, University of California San Diego, La Jolla, CA, 
      United States.
FAU - Vandewater, Sophia A
AU  - Vandewater SA
AD  - Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United 
      States.
FAU - Grant, Yanabel
AU  - Grant Y
AD  - Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United 
      States.
AD  - Department of Psychiatry, University of California San Diego, La Jolla, CA, 
      United States.
FAU - Roberto, Marisa
AU  - Roberto M
AD  - Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 
      United States.
FAU - Taffe, Michael A
AU  - Taffe MA
AD  - Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United 
      States.
AD  - Department of Psychiatry, University of California San Diego, La Jolla, CA, 
      United States.
LA  - eng
GR  - K99 DA047413/DA/NIDA NIH HHS/United States
GR  - R01 DA024705/DA/NIDA NIH HHS/United States
GR  - R01 DA042211/DA/NIDA NIH HHS/United States
GR  - R00 DA047413/DA/NIDA NIH HHS/United States
GR  - R01 DA024105/DA/NIDA NIH HHS/United States
PT  - Journal Article
DEP - 20211216
PL  - Switzerland
TA  - Front Behav Neurosci
JT  - Frontiers in behavioral neuroscience
JID - 101477952
PMC - PMC8716434
OTO - NOTNLM
OT  - MDMA
OT  - central amygdala
OT  - electrophysiology
OT  - inhibitory synaptic transmission
OT  - intravenous self-administration
OT  - methylone
OT  - pentylone
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/01/04 06:00
MHDA- 2022/01/04 06:01
PMCR- 2021/01/01
CRDT- 2022/01/03 05:35
PHST- 2021/09/21 00:00 [received]
PHST- 2021/11/08 00:00 [accepted]
PHST- 2022/01/03 05:35 [entrez]
PHST- 2022/01/04 06:00 [pubmed]
PHST- 2022/01/04 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fnbeh.2021.780500 [doi]
PST - epublish
SO  - Front Behav Neurosci. 2021 Dec 16;15:780500. doi: 10.3389/fnbeh.2021.780500. 
      eCollection 2021.