Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon

Abstract

We previously reported that treatment and withdrawal from cocaine increases: (1) serotonin 2A (5-HT 2A ) receptor-mediated neuroendocrine responses, and (2) GÎ q and GÎ 11 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-HT 2A receptor supersensitivity is due to cocaine treatment or is induced during the withdrawal period. We report here increases in 5-HT 2A receptormediated neuroendocrine responses only 12 or 24 h post-treatment, but not during the initial 4 h withdrawal period. Levels of membrane-or cytosol-associated GÎ q or GÎ 11 proteins in PVN are not altered during the first 24 h of withdrawal. However, the density of 125 I-DOI-labeled high-affinity 5-HT 2A receptors in PVN increased 35% in rats withdrawn from cocaine for 24 h. These findings demonstrate that cocaine-induced increases in 5-HT 2A receptor function in PVN represents a withdrawal-induced phenomena that: (1) is likely attributed to increased G-protein coupled/highaffinity conformational state of the 5-HT 2A receptor, and (2) occurs in the absence of changes in the levels of associated G proteins during the first 24 h.

Cannabinoid-induced upregulation of serotonin 2A receptors in the hypothalamic paraventricular nucleus and anxiety-like behaviors in rats

“…Plasma prolactin and corticosterone concentrations were determined by radioimmunoassays as previously described [7]. …”

“…The pellet was incubated with extraction buffer II with protease inhibitor cocktail for 30 mins at 4°C under gentle agitation and centrifuged 16,000 × g for 15 mins at 4°C to isolate the membrane fraction contained in the supernatant. Expression of membrane-associated 5-HT 2A receptors in PVN was determined by Western blot as previously described [7]. Films were analyzed densitometrically using Scion Image software (Scion Corporation, Frederick, MD, USA) as previously described [7].…”

“…Expression of membrane-associated 5-HT 2A receptors in PVN was determined by Western blot as previously described [7]. Films were analyzed densitometrically using Scion Image software (Scion Corporation, Frederick, MD, USA) as previously described [7]. Each sample was measured on three independent gels.…”

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…2). Previous studies have suggested that withdrawal from cocaine sensitizes 5-HT 2A R Rothman, 1996, 1998;Carrasco et al, 2006;Carrasco and Battaglia, 2007), which may contribute to relapse, particularly as antagonists at 5-HT 2A R are able to block cue-and cocaine-primed reinstatement (Fletcher et al, 2002;Filip, 2005;Nic Dhonnchadha et al, 2009;Murnane et al, 2013b). It is important to note that the highest expression of 5-HT 2A R in the brain is on the dendrites of layer V cortical pyramidal glutamatergic cells (Cornea-Hebert et al, 1999;Jakab and Goldman-Rakic, 2000;Miner et al, 2003).…”

Monoamine Transporter Inhibitors and Substrates as Treatments for Stimulant Abuse

“…Cocaine exposure has also been reported to affect density and/or function of post-synaptic 5HT receptors, ranging from decreases in 5HT3 receptors in the nucleus accumbens shell of rats sensitized to cocaine (Ricci, Stellar & Todtenkopf, 2004) to reduced sensitivity of 5HT1A receptors (Baumann & Rothman, 1998). Cocaine exposure and withdrawal also have been reported to affect 5HT2A receptor expression and function, although no consensus has been reached as to the exact nature of these effects (Carrasco & Battaglia, 2007; Carrasco, Van de Kar, Sullivan, Landry, Garcia, Muma et al, 2006; Huang, Liang, Lee, Wu & Hsu, 2009). Overall, chronic cocaine clearly results in an altered state of the serotonin system, which could contribute to the development of cocaine dependence.…”