Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon.
We previously reported that treatment and withdrawal from cocaine increases: (1) 5-HT2A receptor-mediated neuroendocrine responses, and (2) Galphaq and Galpha11 G-protein levels in the hypothalamic paraventricular nucleus (PVN) at 48 h post-treatment. This study investigates changes in the initial 24 h of withdrawal to discern whether 5-HT2A receptor supersensitivity is due to cocaine treatment or is induced during the withdrawal period. We report here increases in 5-HT2A receptor-mediated neuroendocrine responses only 12 or 24 h post-treatment, but not during the initial 4 h withdrawal period. Levels of membrane- or cytosol-associated Galphaq or Galpha11 proteins in PVN are not altered during the first 24 h of withdrawal. However, the density of 125I-(-)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI)-labeled high-affinity 5-HT2A receptors in PVN increased 35% in rats withdrawn from cocaine for 24 h. These findings demonstrate that cocaine-induced increases in 5-HT2A receptor function in PVN represents a withdrawal-induced phenomena that: (1) is likely attributed to increased G-protein coupled/high-affinity conformational state of the 5-HT2A receptor, and (2) occurs in the absence of changes in the levels of associated G proteins during the first 24 h.
Carrasco
G A
GA
Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
Van de Kar
L D
LD
Sullivan
N R
NR
Landry
M
M
Garcia
F
F
Muma
N A
NA
Battaglia
G
G
D000662:Amphetamines / Q000493:pharmacokinetics; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D003042:Cocaine / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013997:Time Factors
D000662:Amphetamines; D018765:Dopamine Uptake Inhibitors; D044385:GTP-Binding Protein alpha Subunits; D007456:Iodine Isotopes; D044402:Receptor, Serotonin, 5-HT2A; D017366:Serotonin Receptor Agonists; D003042:Cocaine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003345:Corticosterone