Enhanced Nicotinic Receptor Function and Drug Abuse Vulnerability

Abstract

In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display high activity levels in a novel environment are more likely to self-administer psychostimulant drugs, including nicotine, cocaine, amphetamine, and morphine. Recent reports from behavioral studies indicate that nicotinic acetylcholine receptor (nAChR) activity contributes to the rewarding effects of several different addictive drugs. Thus, we hypothesized that differences in nAChR activity may contribute to the predisposition to drug self-administration. After screening of adult rats (Ͼ60 d postnatal) for the behavioral response to a novel environment, electrophysiological measures of nAChR function were conducted in brain slices that included the mesoaccumbens dopamine neurons of the ventral tegmental area (VTA). We found a positive correlation between the response to novelty and nAChR function in each assay conducted, including nAChR modulation of glutamatergic and GABAergic synaptic inputs to VTA dopamine neurons, as well as somatic nAChR responses of VTA neurons. The response to novelty and sensitivity to addictive drugs are positively correlated with the hormonal response to stress. Consistent with this observation, we found enhanced nAChR responses in vitro after a 48 h corticosterone treatment and in vivo after 48 h of repeated stress. Each of these effects was inhibited by RU486 (11␤-[p-(dimethylamino)phenyl]-17␤-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) pretreatment, suggesting a steroid hormone receptor-dependent process. These findings suggest that differences in nAChR function within the mesoaccumbens dopamine system may contribute to individual differences in drug abuse vulnerability and that these are likely attributable to differences in stress hormone levels.

Presynaptic Opioid and Nicotinic Receptor Modulation of Dopamine Overflow in the Nucleus Accumbens

“…For investigating the electrophysiology of striatal cholinergic interneurons, young rats (P20 -P25) were used to optimize cell identification and viability of these cells. The rats were anesthetized with isoflurane (Abbott Laboratories, North Chicago, IL) and aortically perfused (Martin et al, 2006) with 25 ml of cold, sucrose-artificial CSF (ACSF) containing the following (in mM): 200 sucrose, 25 NaHCO 3 , 20 glucose, 10 ascorbic acid, 2.5 KCl, 2.5 CaCl 2 , 1 MgCl 2 , and 1 NaH 2 PO 4 , pH 7.4, saturated with 95% O 2 and 5% CO 2 (Fagen et al, 2007). They were then rapidly decapitated and their brains were removed into the same solution.…”

“…The brains were sliced into 300-m-thick coronal slices that included the shell region of the NAc on a vibratome (VT100S; Leica, Nussloch, Germany). Slices were incubated for at least 1 h in bath circulated at 20 ml/min with normal, 32°C ACSF containing (in mM) 125 NaCl, 25 NaHCO 3 , 20 glucose, 2.5 KCl, 2.5 CaCl 2 , 1 MgCl 2 , 1 NaH 2 PO 4 , and 1 ascorbic acid, pH 7.4, saturated with 95% O 2 and 5% CO 2 (Fagen et al, 2007). During recording, slices were superfused (2 ml/min) with this same ACSF at ϳ34°C, but without the ascorbic acid, because it oxidizes within the voltage range tested and interferes with the dopamine signal.…”

Long-Term Nicotine Treatment Differentially Regulates Striatal α6α4β2*and α6(Nonα4)β2*nAChR Expression and Function

“…In rats undergoing long-term nicotine treatment, competition analysis of E11A inhibition of 125 I-␣-CtxMII binding yielded a monophasic curve in four animals and a biphasic curve in two animals. This diversity between animals could relate to individual variations in outbred rats that influence the effect of nicotine treatment (Fagen et al, 2007). When all the data were pooled, a biphasic curve was obtained showing a preferential decrease in the very-high-affinity f1 fraction (control, f1 ϭ 74%; nicotine, f1 ϭ 26%) (Fig.…”

Poster Abstracts

“…Moreover, the modulation of nAchRs is of utmost importance for the pharmacological research mainly due to the implications of these receptors in a number of diseases and syndromes as Alzheimer's disease, Parkinson, schizophrenia, as well as target for the development of analgesics, anxiolytics, neuroprotectors, and smoking cessation molecules (Steinlein and Bertrand 2008;Rahman et al 2008). The role of nAChR in addiction symptoms of several abuse drugs, from tobacco to cocaine, has also been shown (Fagen et al 2007;Williams and Adinoff 2008). The interaction of BPP-10c with the allosteric site of nAchR enables this peptide to modulate receptor activity by protecting it from the inhibition induced by MK-801 (Nery et al 2008).…”