The β2 but not α7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice

Rationale Tobacco use is implicated in approximately 440,000 deaths per year, making it the leading cause of preventable death in the United States. Although it is generally recognized that tobacco use is correlated with a variety of health-related complications, many smokers are unsuccessful in their efforts to stop smoking using current cessation therapies. Objectives Given that nicotine is the addictive component of tobacco, successful smoking cessation therapies must address the various processes, including reward, which contribute to nicotine addiction. As such, determining the nicotinic receptor subtypes involved in nicotine reward is of utmost importance to understanding how nicotine addiction progresses. Methods Conditioned place preference (CPP) in three-chamber conditioning boxes was performed. For antagonist studies, drug was given on all conditioning sessions 10 min before nicotine or saline injection and placement in the boxes. Results We have demonstrated that a pretreatment with the α4β2 subunit of the nicotinic acetylcholine receptor (nAChR) antagonist dihydro-β-erythroidine (2.0 mg/kg, s.c.) blocked nicotine (0.5 mg/kg, s.c.) CPP in wild-type mice (C57BL/6 mice). In contrast, pretreatment with an antagonist of the α7 subunit of the nAChR, methyllycaconitine (MLA, 5.0 or 10.0 mg/kg, s.c.), had no effect on this behavior. Finally, we showed that mice lacking the β2 subunit of the nAChR did not exhibit nicotine CPP while α7 knock-out mice did. Conclusion Taken together, these data suggest that the β2 subunit of the nAChR is critically involved in nicotine reward as measured by CPP.     

Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit

Rationale The ionotropic NMDA glutamate receptor is composed of NR1 and NR2 (NR2A-D) subunits. While there is compelling evidence that NMDA receptors modulate behavioral effects of ethanol, there is little understanding of how the subunit composition of the NMDA receptor mediates these effects.Objectives In the current study, we assessed the relative roles of NMDA subunits via phenotypic assessment of ethanol-related behaviors in NR2A knockout (KO) mice.Results Results demonstrated that NR2A KO and heterozygous mice failed to show evidence of ethanol-induced conditioned place preference. As compared to wild-type (WT) controls, KO mice showed impaired motor coordination at baseline and, in some instances, following ethanol treatment on the accelerating rotarod, balance beam, and wire-hang tests. By contrast, open field locomotor-stimulant, sedative/hypnotic, and hypothermic responses to ethanol were not different between genotypes, nor was voluntary ethanol consumption and preference in a two-bottle choice paradigm. Blood ethanol concentrations were lower in KO than WT mice following intraperitoneal ethanol injection.Conclusions Results suggest that the loss of NR2A subunit-containing NMDA receptors impairs the ability to form or express learned reward-related responses to ethanol and causes deficits in motor coordination. However, the loss of NR2A does not alter other measures of acute ethanol intoxication or ethanol consumption, possibly implicating other NMDA subunits in these effects. These data provide novel insight into the role of NMDA receptors in modulating the behavioral effects of ethanol.Research supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program.     

Cocaine cue versus cocaine dosing in humans: evidence for distinct neurophysiological response profiles

Subjective, physiological and electroencephalographic (EEG) profiles were studied in cocaine dependent study participants in response to cocaine cue exposure or a dose of smoked cocaine. Both stimuli increased subjective ratings of cocaine high and craving, enhanced negative affect, and boosted plasma ACTH and skin conductance levels. However, cocaine dose produced a greater increase in high and a more prolonged increase in plasma ACTH, while cocaine cue produced a decline in skin temperature. Both stimuli produced increases in absolute theta, alpha and beta EEG power over the prefrontal cortex. However, interhemispheric EEG coherence over the prefrontal cortex decreased during cocaine cue exposure but increased following cocaine dose. Moreover, correlation analysis of subjective, physiological and EEG responding to cocaine cue and dose revealed distinct profiles. Delta and theta activity were associated with negative affect during cocaine cue exposure, but were associated with cocaine craving and reward following cocaine dosing. In both conditions, alpha activity was marker for anxiousness but not high. These data demonstrate similar subjective, physiological responding in clinical laboratory states of cocaine craving and reward. However, differences in EEG response profiles, and their relationship to function, indicate distinct neurophysiological mediators of cocaine craving and reward within the prefrontal cortex.     

Intracranial self-administration of MDMA into the ventral striatum of the rat: differential roles of the nucleus accumbens shell, core, and olfactory tubercle

Rationale Behavioral and anatomical data suggest that the ventral striatum, consisting of the nucleus accumbens and olfactory tubercle, is functionally heterogeneous. Cocaine and d-amphetamine appear to be more rewarding when administered into the medial olfactory tubercle or medial accumbens shell than into their lateral counterparts, including the accumbens core. Objectives We sought to determine whether rats self-administer the popular recreational drug (±)-3,4-methylenedioxymethamphetamine (MDMA) into ventrostriatal subregions and whether the medial olfactory tubercle and medial accumbens shell mediate MDMA’s positive reinforcing effects more effectively than their lateral counterparts. Results Rats receiving 30 mM MDMA into the medial olfactory tubercle, medial accumbens shell, or accumbens core, but not the lateral tubercle or lateral shell, showed higher self-administration rates than rats receiving vehicle. The medial shell supported more vigorous self-administration of MDMA at higher concentrations than the core or medial olfactory tubercle. In addition, intra-medial shell MDMA self-administration was disrupted by co-administration of the D1 or D2 receptor antagonists SCH 23390 (1–3 mM) or raclopride (3–10 mM). Conclusions Our data suggest that the ventral striatum is functionally heterogeneous. The medial accumbens shell appears to be more important than other ventrostriatal subregions in mediating the positive reinforcing effects of MDMA via both D1- and D2-type receptors. Together with previous data, our data also suggest that unidentified actions of MDMA interfere with the positive reinforcing effects of dopamine in the medial olfactory tubercle.     

Effects of fentanyl dose and exposure duration on the affective and somatic signs of fentanyl withdrawal in rats

Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of chronic pain. The aim of the present study was to investigate the effect of the dose of fentanyl and the exposure duration on the affective and somatic signs of fentanyl withdrawal in rats. Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function and somatic signs were recorded from a checklist of opioid abstinence signs. The opioid receptor antagonist naloxone elevated the brain reward thresholds of the rats chronically treated with high doses of fentanyl (0.3 and 0.6mg/kg/day), but not those of rats treated with low doses of fentanyl (0.006 and 0.06mg/kg/day). Fentanyl had a dose-dependent effect on the naloxone-induced elevations in brain reward thresholds. On a similar note, the discontinuation of the administration of high doses of fentanyl was associated with elevations in brain reward thresholds and the discontinuation of the administration of low doses of fentanyl did not lead to an elevation in brain reward thresholds. The results also demonstrated that the duration of fentanyl administration does not affect naloxone-induced elevation in brain reward thresholds. In contrast, the somatic withdrawal syndrome gradually developed over time; maximum somatic signs were observed 120h after pump implantation. These studies suggest that the magnitude and duration of the negative affective signs of fentanyl withdrawal depend on the dose of fentanyl administered and not on the duration of fentanyl administration.     

The role of dopamine in alcohol self-administration in humans: Individual differences

Objective: To clarify dopamine's role in alcohol self-administration in a heterogeneous sample of drinkers using acute phenylalanine/tyrosine depletion (APTD). Methods: Sixteen men with variable drinking histories were characterized on their ethanol-induced cardiac response, a marker previously proposed to index dopamine system reactivity and vulnerability to alcohol abuse. During separate sessions participants were administered (i) a nutritionally balanced (BAL) amino acid (AA) mixture, (ii) a mixture lacking the dopamine precursors, phenylalanine and tyrosine, and (iii) APTD followed by the dopamine precursor, l-DOPA. Five hours after AA administration, participants could earn units of alcohol using a progressive ratio breakpoint task. Results: Alcohol self-administration was reduced in the APTD and APTD + l-DOPA conditions relative to the BAL condition. In both cases the changes were predicted by ethanol-induced cardiac change. Conclusions: The motivation to drink is likely regulated by more than one neurobiological mechanism. Individual differences in cardiac responsivity to ethanol might provide a peripheral marker of responsiveness to pharmacological manipulations of dopamine.     

Enhanced vulnerability to the rewarding effects of nicotine during the adolescent period of development

This study compared the rewarding and aversive effects of nicotine in adolescent, adult, and adult rats pre-exposed to nicotine during adolescence. Prior to conditioning, the rats were tested for their initial preference for either of 2 distinct compartments. Adolescent and adult rats then received various nicotine doses in their initially non-preferred side on one day and saline in the other side on alternate days. This 2-day procedure was repeated over 8 consecutive days. Following conditioning, rats were re-tested for their preference. Another cohort of adolescent and adult rats were conditioned with various doses of d-amphetamine. Nicotine produced CPP in an inverted U-shaped manner in both age groups. However, adolescents displayed a larger upward shift in CPP that was significant across a wider dose range relative to adults. There were no developmental differences to CPP produced by d-amphetamine. In a final study, adolescents were prepared with pumps that delivered nicotine for 14 days. These rats were conditioned later as adults using the same procedures used previously. Pre-exposure to nicotine during adolescence diminished the aversive effects produced by the highest nicotine dose in naïve adults. Taken together, these studies provide a basis for enhanced vulnerability to nicotine during adolescence.     

Influence of substrate oxidation on the reward system, no role of dietary fibre

It has been suggested that a high intake of dietary fibre helps regulate energy intake and satiety. The present study aimed to examine whether dietary fibre influenced the liking and wanting components of the food reward system, the metabolic state or subsequent intake. Five sessions involving 32 normal-weight subjects (16 men and 16 women, 30.6 ± 7.6 year) were held. The sessions differed in the composition of the bread eaten during breakfasts (dietary fibre content varied from 2.4 to 12.8 g/100 g). Several factors such as the palatability, weight, volume, energy content and macronutrient composition of the breakfasts were adjusted. Energy expenditure, the respiratory quotient (R), olfactory liking for four foods, wanting for six other foods, and hunger sensations were evaluated before and after the breakfast, as well as before a morning snack. The results showed no significant differences after ingestion of the various breads. Interestingly, R correlated with olfactory liking and with wanting, which highlights in an original manner the influence of the metabolic state on hedonic sensations for food. In conclusion, dietary fibre was found to have no effect on olfactory liking and wanting, and had no detectable effect on satiety sensations or on subsequent energy intake.     

Prolonged nicotine exposure does not alter GABA(B) receptor-mediated regulation of brain reward function

Gamma-aminobutyric acid subtype B (GABA(B)) receptors play an important role in regulating brain reward function. Accumulating evidence suggests that chronic exposure to drugs of abuse may alter GABA(B) receptor function. The present studies investigated whether chronic nicotine administration, using a regimen that induces nicotine dependence, increased inhibitory regulation of brain reward function by GABA(B) receptors, as measured by intracranial self-stimulation (ICSS) thresholds in rats. Such an action of nicotine may contribute to the reward deficit observed during nicotine withdrawal. Nicotine-dependent and control rats received the GABA transaminase inhibitor gamma-vinyl-GABA or the GABA(B) receptor agonist CGP44532 according to a within-subjects Latin square design, and ICSS thresholds were assessed post-injection. Systemic administration of the lowest doses of GVG or CGP44532 did not alter reward thresholds in control or nicotine-treated rats, whereas the highest doses of each drug elevated thresholds similarly in both groups. Further, micro-infusion of CGP44532 directly into the ventral tegmental area elevated ICSS thresholds similarly in saline- and nicotine-treated rats. Overall, these data demonstrate that prolonged nicotine exposure did not alter GABA(B) receptor-mediated regulation of brain reward function, and suggest that alterations in GABA(B) receptor activity are unlikely to play a role in the brain reward deficits associated with spontaneous nicotine withdrawal.