Effects of acute administration of nicotinic and muscarinic cholinergic agonists and antagonists on performance in different cost–benefit decision making tasks in rats

Rationale

Alterations in cost?Cbenefit decision making accompany numerous neuropsychiatric conditions, including schizophrenia, attention deficit hyperactivity disorder, and addiction. Central cholinergic systems have been linked to the etiology and/or treatment of many of these conditions, but little is known about the role of cholinergic signaling in cost?Cbenefit decision making.

Objectives

The goal of these experiments was to determine how cholinergic signaling is involved in cost?Cbenefit decision making, using a behavioral pharmacological approach.

Methods

Male Long-Evans rats were trained in either ??probability discounting?? or ??delay discounting?? tasks, in which rats made discrete-trial choices between a small food reward and a large food reward associated with either varying probabilities of omission or varying delays to delivery, respectively. The effects of acute administration of different doses of nicotinic and muscarinic acetylcholine receptor agonists and antagonists were assessed in each task.

Results

In the probability discounting task, acute nicotine administration (1.0?mg/kg) significantly increased choice of the large risky reward, and control experiments suggested that this was due to robust nicotine-induced impairments in behavioral flexibility. In the delay discounting task, the muscarinic antagonists scopolamine (0.03, 0.1, and 0.3?mg/kg) and atropine (0.3?mg/kg) both significantly increased choice of the small immediate reward. Neither mecamylamine nor oxotremorine produced reliable effects on either of the decision making tasks.

Conclusions

These data suggest that cholinergic receptors play multiple roles in decision making contexts which include consideration of reward delay or probability. These roles should be considered when targeting these receptors for therapeutic purposes.     

Role of nicotinic acetylcholine receptors in the effects of cocaine-paired contextual stimuli on impulsive decision making in rats

Rationale

Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine-paired conditioned stimuli on this behavior. Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon.

Methods

Rats were trained to achieve stable performance on a delay discounting task, which involved lever press-based choice between a single food pellet (small reward) available immediately and three food pellets (large reward) available after a 10-, 20-, 40-, or 60-s time delay. Rats then received Pavlovian context-cocaine (15?mg/kg, i.p.) and context-saline (1?ml/kg, i.p.) pairings in two other, distinct contexts. Subsequently, delay discounting task performance was assessed in the previously cocaine-paired or saline-paired context following pretreatment with saline or cocaine (15?mg/kg, Experiment 1) or with saline or the nAChR antagonist, mecamylamine (0.2 and 2?mg/kg, Experiment 2), using counterbalanced within-subjects testing designs.

Results

Independent of cocaine pretreatment, rats exhibited greater decrease in preference for the large reward as a function of delay duration in the cocaine-paired context, relative to the saline-paired context. Furthermore, systemic mecamylamine pretreatment dose-dependently attenuated the decrease in preference for the large reward in the cocaine-paired context, but not in the saline-paired context, as compared to saline.

Conclusion

Cocaine-paired contextual stimuli evoke a state of impulsive decision making, which requires nAChR stimulation. Drug context-induced impulsivity likely increases the propensity for drug relapse in cocaine users, making the nAChR an interesting target for drug relapse prevention.     

Effects of amphetamine and methylphenidate on delay discounting in rats: interactions with order of delay presentation

Rationale

Drug effects on delay discounting are thought to reflect changes in sensitivity to reinforcer delay, although other behavioral mechanisms might be involved. One strategy for revealing the influence of different behavioral mechanisms is to alter features of the procedures in which they are studied.

Objective

This experiment examined whether the order of delay presentation under within-session delay discounting procedures impacts drug effects on discounting.

Methods

Rats responded under a discrete-trial choice procedure in which responses on one lever delivered one food pellet immediately and responses on the other lever delivered three food pellets either immediately or after a delay. The delay to the larger reinforcer (0, 4, 8, 16, and 32 s) was varied within session and the order of delay presentation (ascending or descending) varied between groups.

Results

Amphetamine (0.1–1.78 mg/kg) and methylphenidate (1.0–17.8 mg/kg) shifted delay functions upward in the ascending group (increasing choice of the larger reinforcer) and downward in the descending group (decreasing choice of the larger reinforcer). Morphine (1.0–10.0 mg/kg) and delta-9-tetrahydrocannabinol (0.32–5.6 mg/kg) tended to shift the delay functions downward, regardless of order of delay presentation, thereby reducing choice of the larger reinforcer, even when both reinforcers were delivered immediately.

Conclusion

The effects of amphetamine and methylphenidate under delay discounting procedures differed depending on the order of delay presentation, indicating that drug-induced changes in discounting were due, in part, to mechanisms other than altered sensitivity to reinforcer delay. Instead, amphetamine and methylphenidate altered responding in a manner consistent with increased behavioral perseveration.     

Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task

Rationale

Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward.

Objectives

To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward.

Materials and methods

Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays.

Results

Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine.

Conclusions

The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity.     

Noradrenergic α2A-receptor stimulation in the ventral hippocampus reduces impulsive decision-making

Rationale

Guanfacine, an α_2A-adrenergic receptor agonist, is currently in use for treatment of a variety of psychiatric disorders that are associated with impulsive decision-making (e.g., attention-deficit hyperactivity disorder; ADHD). In animals and humans, the behavioral effects of adrenergic agents are presumed to involve neuromodulation of the prefrontal cortex, consistent with the demonstrated actions of dopaminergic agents. However, recent experimental work has shown that the ventral hippocampus (vHC) contributes to decision-making and impulse control, raising the possibility that the hippocampus may be an important site of action for these drugs.

Objective

The purpose of this study was to examine the effect of local vHC infusions of guanfacine and other neuropharmacological agents on behavioral decisions that involve a trade-off between reward size and delay.

Methods

Different cohorts of rats were implanted with bilateral guide cannulae targeting the vHC. We examined the animals’ behavior in a touchscreen version of a delay discounting task following intra-vHC infusions of: (a) guanfacine (α_2A-adrenergic receptor agonist), (b) SCH 23390 (dopamine D₁ receptor antagonist), and (c) muscimol/baclofen (GABA_A/B agonists).

Results

Guanfacine led to a dose-dependent reduction in impulsive decision-making, increasing the animals’ tolerance for delay in exchange for a larger reward. By contrast, infusion of SCH 23390 had no behavioral effects. Consistent with previous lesion studies, reversible pharmacological inactivation with muscimol/baclofen increased impulsive decision-making.

Conclusions

These data provide the first evidence that guanfacine, a commonly used treatment for ADHD, may derive its clinical benefits through hippocampal stimulation, via α_2A-adrenergic receptors.     

Delay Discounting of Oral Morphine and Sweetened Juice Rewards in Dependent and Non-Dependent Rats

Rationale

Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats

Methods

We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose.

Results

Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly.

Conclusions

These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.     

Simultaneous blockade of dopamine and noradrenaline reuptake promotes disadvantageous decision making in a rat gambling task

Rationale

The inability to make profitable long-term decisions has been implicated in several psychiatric disorders. There is emerging evidence to support a role for dopamine (DA) in decision making, but our understanding of the role of noradrenaline (NA) and serotonin (5-HT) in decision making, and of possible interactions between the three monoamines, is limited. Moreover, impulsivity has been associated with aberrant decision making, but the underlying mechanisms are incompletely understood.

Objective

The purpose of this study is to improve our understanding of the neuropharmacological mechanisms of decision making and impulse control.

Methods

We investigated the effects of amphetamine (0.25–1.0 mg/kg) and selective reuptake inhibitors of DA (GBR12909; 2.5–10 mg/kg), NA (atomoxetine; 0.3–3.0 mg/kg), and 5-HT (citalopram; 0.3–3.0 mg/kg) in a rat gambling task (rGT). Since the rGT allows for detection of impulsive action, i.e., premature responding, we also assessed the relationship between decision making and impulsivity.

Results

In the rGT, rats developed an optimal choice strategy from the first session onwards. Elevation of endogenous DA or NA levels increased and decreased impulsivity, respectively, but did not alter decision making. However, simultaneous blockade of DA and NA disrupted decision making, reflected by a relative decrease in choice for the advantageous choice options. Increasing 5-HT neurotransmission did not affect decision making or impulsivity.

Conclusions

These data suggest important but complementary or redundant roles of DA and NA neurotransmission in decision-making processes based on reward probability and punishment. Moreover, impulse control and decision making in the rGT rely on dissociable mechanisms.     

Impulsivity and cigarette smoking: discounting of monetary and consumable outcomes in current and non-smokers

Rationale

In delay discounting, temporally remote rewards have less value. Cigarette smoking is associated with steeper discounting of delayed money. The generality of this to nonmonetary outcomes, however, is unknown.

Objectives

We sought to determine whether cigarette smokers also show steep discounting of other delayed outcomes.

Methods

Sixty-five participants (32 smokers and 33 non-smokers) completed four delay-discounting tasks, each involving different hypothetical outcomes. In the monetary task, participants indicated their preference for a smaller amount of money available immediately (titrated across trials) and $100 awarded at delays ranging from 1 week to 25 years (tested in blocks). In the three other discounting tasks the larger-later reward was $100 worth of a favorite food, alcoholic drink, or a favorite form of entertainment. All other aspects of these discounting tasks were identical to the monetary discounting task.

Results

As previously shown, smokers discounted delayed money more steeply than non-smokers did. In addition, smokers discounted delayed food and entertainment rewards more steeply than did nonsmokers. A person’s discounting of one outcome was correlated with discounting of other outcomes. Non-smokers discounted money less steeply than all other outcomes; smokers discounted money significantly less than food.

Conclusions

When compared to nonsmokers, cigarette smokers more steeply discount several types of delayed outcomes. This result, together with the finding that cross-commodity discounting rates were correlated within subjects, suggests that delay discounting is a trait that extends across domains.     

Exogenous cortisol acutely influences motivated decision making in healthy young men

Background

The glucocorticoid (GC) hormone cortisol is the end product of the hypothalamic–pituitary–adrenal axis (HPA axis). Acute psychological stress increases HPA activity and GC release. In humans, chronic disturbances in HPA activity have been observed in affective disorders and in addictive behaviour. Recent research indicates that acute effects of GCs may be anxiolytic and increase reward sensitivity. Furthermore, cortisol acutely influences early cognitive processing of emotional stimuli.

Methods

In order to extend such findings to more complex emotional-cognitive behaviour, the present study tested acute effects of 40 mg cortisol on motivated decision making in 30 healthy young men.

Results

Results showed that cortisol indeed increased risky decision making, as predicted. This effect occurred for decisions where making a risky choice could potentially yield a big reward. These results are discussed with respect to currently proposed mechanisms for cortisol’s potential anxiolytic effect and GCs’ involvement in reward systems.     

The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats

Rationale

Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-d-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice.

Objectives

Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice.

Methods

Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755.

Results

Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition.

Conclusions

NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low-impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used.     

Adolescent Intermittent Ethanol Exposure Is Associated with Increased Risky Choice and Decreased Dopaminergic and Cholinergic Neuron Markers in Adult Rats

Background:

Binge drinking is prevalent during adolescence and may have effects on the adult brain and behavior. The present study investigated whether adolescent intermittent ethanol exposure alters adult risky choice and prefrontal dopaminergic and forebrain cholinergic neuronal marker levels in male Wistar rats.

Methods:

Adolescent (postnatal day 28–53) rats were administered 5g/kg of 25% (vol/vol) ethanol 3 times/d in a 2-days–on/2-days–off exposure pattern. In adulthood, risky choice was assessed in the probability discounting task with descending and ascending series of large reward probabilities and after acute ethanol challenge. Immunohistochemical analyses assessed tyrosine hydroxylase, a marker of dopamine and norepinephrine in the prelimbic and infralimbic cortices, and choline acetyltransferase, a marker of cholinergic neurons, in the basal forebrain.

Results:

All of the rats preferred the large reward when it was delivered with high probability. When the large reward became unlikely, control rats preferred the smaller, safe reward, whereas adolescent intermittent ethanol-exposed rats continued to prefer the risky alternative. Acute ethanol had no effect on risky choice in either group of rats. Tyrosine hydroxylase (prelimbic cortex only) and choline acetyltransferase immunoreactivity levels were decreased in adolescent intermittent ethanol-exposed rats compared with controls. Risky choice was negatively correlated with choline acetyltransferase, implicating decreased forebrain cholinergic activity in risky choice.

Conclusions:

The decreases in tyrosine hydroxylase and choline acetyltransferase immunoreactivity suggest that adolescent intermittent ethanol exposure has enduring neural effects that may lead to altered adult behaviors, such as increased risky decision making. In humans, increased risky decision making could lead to maladaptive, potentially harmful consequences.     

Curcumin,demethoxycurcumin and bisdemethoxycurcumin differentially inhibit morphine's rewarding effect in rats

Rationale

Recent animal studies reported that curcumin, the active constituent of Curcuma longa, has several central actions and may attenuate morphine tolerance.

Objectives

In the present study, we utilized the intracranial self-stimulation (ICSS) paradigm to examine the effects of the commercially available curcuminoid mixture and each one of its components, individually, on brain stimulation reward and on the reward-facilitating effect of morphine.

Methods

Male Sprague-Dawley rats were implanted with an electrode into the medial forebrain bundle and trained to respond for electrical stimulation using a rate-frequency paradigm. In the first study, rats were injected with graded doses either of the curcuminoid mixture, or curcumin I, or II, or III. In the second study, we examined whether a low dose of the curcuminoid mixture or each individual curcumin analogue composing it could counteract the reward-facilitating effect of morphine.

Results

At low doses, both the curcuminoid mixture and curcumin I did not affect brain stimulation reward, whereas, higher doses increased ICSS thresholds. Curcumin II and curcumin III did not affect brain stimulation reward at any doses. Subthreshold doses of the curcuminoid mixture and curcumin I inhibited the reward-facilitating effect of morphine.

Conclusion

Both the curcuminoid mixture and curcumin I lack hedonic properties and moderate the reward-facilitating effect of morphine. Our data suggest that curcumin interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids and provide evidence that curcumin may be a promising adjuvant for attenuating morphine’s rewarding effects in patients who are under long-term opioid therapy.     

Comparatively preserved impulse control in late-onset opiate users

Rationale

A substantial literature indicates that in alcohol addiction aspects of impulsive decision-making are typical of individuals with an early onset of addictive behaviour problems. It is not known whether the same applies to opiate addiction, and this insight has important theoretical and clinical implications.

Objectives

This study aims to examine the relationship between age at onset of addictive behaviour problems and decision-making in opiate addiction.

Methods

Ninety-three opiate-dependent, treatment-seeking individuals were divided in three groups, early, late and intermediate onset of problems, and completed impulsivity questionnaires and delay discounting and gambling tasks.

Results

Individuals with a late onset of opiate problems (25 years or above) had lower delay discounting rates than individuals with early (18 years or less) or intermediate onset. There were no differences in performance on the gambling tasks. Late-onset individuals were older and had shorter drug histories, but there was no relationship between either age or length of exposure to opiates and delay discounting rates.

Conclusions

In keeping with previous studies in alcohol addiction, these findings support the notion of at least two distinct subgroups of opiate-dependent individuals, characterised by a different onset of problems, different propensity to impulsive behaviour and perhaps distinct mechanisms leading to addiction.     

NMDA Receptor Blockade in the Prelimbic Cortex Activates the Mesolimbic System and Dopamine-Dependent Opiate Reward Signaling

Rationale

N-Methyl-d-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood.

Objective

This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA).

Methods

Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings.

Results

We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism.

Conclusions

These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.     

Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J Mice

Rationale

The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration.

Objective

To examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine.

Methods

Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward (BSR)). Mice received cocaine (n?=?11, 3.0–30.0 mg/kg, intraperitoneal (i.p.)) or the neuroactive steroid allopregnanolone (n?=?11, 3.0–17.0 mg/kg, i.p.). BSR thresholds (θ ₀) and maximum (MAX) operant response rates after drug treatments were compared to those after vehicle injections.

Results

Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 min following the 30 mg/kg dose, while allopregnanolone was maximally effective (30 % reduction) 15–45 min after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates.

Conclusions

The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol, suggesting that positive modulation of GABA_A receptors can facilitate reward-related behaviors in C57BL/6J mice.     

Altruism in time: social temporal discounting differentiates smokers from problem drinkers

Rationale

Recent studies on reinforcer valuation in social situations have informed research on mental illness. Social temporal discounting may be a way to examine effects of social context on the devaluation of delayed reinforcers. In prior research with non-drug-using groups, we demonstrated that individuals discount delayed rewards less rapidly (i.e., value the future more) for a group of which they are a member than they do for themselves alone.

Objectives

The current study examined how cigarette smoking and level of alcohol use relate to rates of delay and social temporal discounting.

Methods

In this study, we used crowd-sourcing technology to contact a large number of individuals (N?=?796). Some of these individuals were hazardous-to-harmful drinkers (n?=?269), whereas others were non-problem drinkers (n?=?523); some were smokers (n?=?182), whereas others were nonsmokers (n?=?614). Delay discounting questionnaires for individual rewards (me now, me later) and for group rewards (we now, we later; me now, we later) were used to measure individuals’ discounting rates across various social contexts.

Results

Our analyses found that smokers discounted delayed rewards more rapidly than controls under all conditions. However, hazardous-to-harmful drinkers discounted delayed rewards significantly more rapidly than the non-problem drinkers under the individual condition, but not under the social conditions.

Conclusions

This finding suggests that the use of different abused drugs may be associated with excessive discounting in the individual condition and has selective effects when discounting for a group in the social conditions.     

Opposing neural effects of naltrexone on food reward and aversion: implications for the treatment of obesity

Rationale

Opioid antagonism reduces the consumption of palatable foods in humans but the neural substrates implicated in these effects are less well understood.

Objectives

The aim of the present study was to examine the effects of the opioid antagonist, naltrexone, on neural response to rewarding and aversive sight and taste stimuli.

Methods

We used functional magnetic resonance imaging (fMRI) to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 20 healthy volunteers who received a single oral dose of naltrexone (50 mg) and placebo in a double-blind, repeated-measures cross-over, design.

Results

Relative to placebo, naltrexone decreased reward activation to chocolate in the dorsal anterior cingulate cortex and caudate, and increased aversive-related activation to unpleasant strawberry in the amygdala and anterior insula.

Conclusions

These findings suggest that modulation of key brain areas involved in reward processing, cognitive control and habit formation such as the dorsal anterior cingulate cortex (dACC) and caudate might underlie reduction in food intake with opioid antagonism. Furthermore we show for the first time that naltrexone can increase activations related to aversive food stimuli. These results support further investigation of opioid treatments in obesity.     

The effects of caffeine on option generation and subsequent choice

Rationale

Although the effects of caffeine on basic cognitive functions are well-known, its effects on more complex decision making, particularly on option generation, is yet to be explored.

Objective

We examined the effects of caffeine on option generation in decision making using everyday life decisional situations.

Methods

In a double-blind placebo-controlled experiment, participants (N?=?47) either received 300 mg of caffeine or a placebo. Participants had to generate choice options (things they could do) for a series of high and low familiar real-world scenarios and, subsequently, to decide among these options.

Results

Analyses revealed that participants in the caffeine condition generated significantly fewer options than participants in the placebo condition. Moreover, caffeine significantly reduced the option generation onset time, that is, participants in the caffeine condition generated their first option significantly faster than participants in the placebo condition. Regarding subsequent choice, we found evidence supporting the “take-the-first” heuristic, that is, the tendency to select the first generated option. This tendency was neither affected by caffeine nor by the familiarity of the scenarios.

Conclusions

Caffeine results in fewer options generated in unconstrained real-life decision-making situations and decreases generation onset times.     

Reduced Acute Recovery from Alcohol Impairment in Adults with ADHD

Rationale

Prior research has found that adults with attention-deficit/hyperactivity disorder (ADHD) show increased sensitivity to the impairing effects of alcohol (Weafer et al., Exp Clin Psychopharmacol 17: 113–121, 2009). However, these studies have focused exclusively on the ascending limb of the blood alcohol concentration (BAC) curve, and it is unclear whether these adults continue to show increased sensitivity during the later phase of the dose as BAC is declining.

Objective

This study tested the hypothesis that those with ADHD would display increased response to alcohol during the ascending limb of the BAC curve and less recovery from the impairing effects during the descending limb.

Methods

Adult social drinkers with ADHD and control adults completed measures of motor coordination, reaction time (RT), and subjective intoxication twice following 0.64 g/kg alcohol and placebo. The measures were administered during the ascending limb of the BAC curve and again during the descending limb.

Results

During the ascending limb, alcohol reduced motor coordination, slowed RT, and increased self-reports of subjective intoxication. Those with ADHD displayed greater impairment of motor coordination compared with controls. During the descending limb, controls reported diminished subjective intoxication and showed recovery from the impairing effects of alcohol on both their motor coordination and their RT. Those with ADHD showed reduced subjective intoxication and faster RT during this time, but they did not recover motor control.

Conclusions

The protracted time course of motor impairment in adults with ADHD despite reductions in subjective intoxication may contribute to poor decision making and diminished behavioral control in this group.     

Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

Rationale

Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.

Objectives

The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.

Methods

Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.

Results

Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.

Conclusions

These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse.