Alterations in cost–benefit 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–benefit decision making.
The goal of these experiments was to determine how cholinergic signaling is involved in cost–benefit decision making, using a behavioral pharmacological approach.
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.
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.
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.
Cholinergic; Nicotinic; Muscarinic; Delay discounting; Probability discounting; Impulsivity; Risk; Perseveration
Rationale and objectives
Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial pre-frontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence.
We trained rats to self-administer heroin or saline for 9–10 days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone’s (0–1.0 mg/kg) effect on extinction responding after 1 and 15 days.
Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day 11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day 1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1 day.
Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving.
BDNF; Extinction; MeCP2; μ opioid receptor; Heroin self-administration; Relapse; Withdrawal; Incubation of drug craving; Naloxone
Alcohol tolerance is observed as a diminished response to a given dose as a function of repeated administrations of the drug. Research has consistently shown that heavier drinkers display reduced reactions to alcohol (i.e., tolerance) compared with lighter drinkers. However, the majority of this work has focused primarily on measures of motor performance, whereas the development of tolerance to alcohol’s impairing effects on cognitive processes, such as inhibitory mechanisms of behavioral control, remains relatively unexplored.
The purpose of the present study was to examine the relationship between drinking habits and the degree to which alcohol affects drinkers’ inhibitory control and motor coordination.
Fifty-two non-dependent drinkers reported their recent drinking patterns. Their inhibitory control and motor coordination were measured in response to placebo and 0.65 g/kg alcohol.
Alcohol significantly impaired inhibitory control and motor coordination compared with placebo. Moreover, greater quantity and frequency of recent consumption predicted less alcohol impairment of motor coordination. However, there was no relationship between recent drinking habits and the degree of impairment of inhibitory control.
These findings suggest that tolerance to the disinhibiting effects of alcohol might not readily develop as a result of recent, heavy drinking.
Alcohol; Tolerance; Inhibitory control; Motor coordination
Galantamine (GAL), a reversible and competitive inhibitor of acetylcholinesterase, is used clinically in the treatment of Alzheimer’s dementia. Some preclinical and clinical studies support the potential efficacy of cholinesterase inhibitors for smoking cessation, although their effects on the behavioral and physiological responses to nicotine have not been examined. The goal of this study was to characterize GAL’s actions on multiple outcomes including withdrawal severity and cognitive performance, as well as subjective and physiological responses to nicotine administered intravenously.
A total of 12 smokers participated in a double-blind, placebo-controlled, crossover study. Smokers had two 4-day treatment periods, assigned in random sequence, to GAL (8 mg/day) or placebo treatment. On day 4 of each treatment phase, smokers had an experimental session in which they received an intravenous (IV) dose of saline or 1 mg/70 kg nicotine, one hour apart, in a random order.
GAL attenuated the self-reported rating of “craving for cigarettes” and prevented decrements in performance in a Go/No-Go task. In response to IV nicotine, GAL treatment attenuated the self-report ratings of “like the drug effects,” “good drug effects,” “bad drug effects,” and “stimulated.”
These findings support the potential utility of GAL as a treatment for smoking cessation.
galantamine; nicotine dependence; intravenous nicotine; nicotine abstinence
Oxytocin is a neuropeptide that is associated with increases in social affiliative behaviors, particularly toward infants. However, no previous study has investigated healthy adults’ responses to infant faces following oxytocin administration. In addition, given that preliminary evidence suggests that a single nucleotide polymorphism (SNP) of the oxytocin receptor (OXTR) gene, rs53576, may influence behaviors associated with parental sensitivity, we assessed whether such responses vary according to OXTR rs53576 genotype.
The present study assessed the effects of intranasally administered oxytocin and OXTR genotype on human adults’ preferences for infant faces.
A double-blind, between-groups design was used, with 57 genotyped volunteers randomly assigned to receive intranasally administered oxytocin or placebo. Fifty minutes following the administration of oxytocin or placebo, participants viewed infants’ and adults’ faces showing neutral expressions and assessed how appealing they found each face.
Infants’ faces were more strongly preferred following oxytocin inhalation relative to placebo. When participants were separated according to genotype, this effect was only observed for participants homozygous for the rs53576G allele. Parallel effects were not seen for adults’ faces.
The present results are consistent with the hypothesis that acute oxytocin administration increases sensitivity to reward-relevant features of infants and/or reduces sensitivity to their aversive properties. The results also are consistent with suggestions of more efficient oxytocinergic function in rs53576G homozygotes.
Oxytocin; OXTR; parental; faces; affiliation
One possible basis for the proclivity of ethanol and nicotine co-abuse is an interaction between the discriminative stimulus (SD) effects of each drug.
The current work sought to assess the discriminative control of ethanol and nicotine cues in mice trained with drug mixtures and to determine whether interactive mechanisms of overshadowing and potentiation occur.
Male C57BL/6J mice were trained to discriminate ethanol (1.5 g/kg) alone or ethanol plus nicotine (0.4, 0.8 or 1.2 mg/kg base) in experiment 1, and nicotine (0.8 mg/kg) alone or nicotine plus ethanol (0.5, 1.0 or 2.0 g/kg) in experiment 2. Stimulus generalization of the training mixtures to ethanol, nicotine and the drug combination were assessed.
Ethanol (1.5 g/kg) retained discriminative control despite the inclusion of a progressively larger nicotine dose within the training mixtures in experiment 1. Although the nicotine SD was overshadowed by ethanol training doses > 0.5 g/kg in experiment 2, nicotine did potentiate the effects of low dose ethanol.
These findings are suggestive of dual mechanisms whereby ethanol (>0.5 g/kg) overshadows the SD effects of nicotine, and at lower doses (< 1 g/kg) the salience of ethanol’s SD effects is potentiated by nicotine. These mechanisms may contribute to the escalation of concurrent drinking and smoking in a binge-like fashion.
Drug discrimination; Discriminative stimulus; Ethanol; Alcohol; Nicotine; Overshadowing; Potentiation; Mice
Marijuana is believed to increase impulsivity and risk taking, but the processes whereby it affects such behaviors are not understood. Indeed, either the pharmacologic effect of delta-9-tetrahydrocannabinol (THC) or the expectancy of receiving it may lead to deficits in cognitive processing and increases in risk taking.
Objectives and methods
We examined the relative effects of expecting to receive active marijuana and the pharmacological drug effects using a balanced placebo design. Young adult regular marijuana users (N=136) were randomly assigned into one of four groups in a two × two instructional set (Told THC vs. Told no THC) by drug administration (smoked marijuana with 2.8 % THC vs. placebo) design. Dependent measures included subjective intoxication, behavioral impulsivity, and decision-making related to risky behaviors.
Active THC, regardless of expectancy, impaired inhibition on the Stop Signal and Stroop Color-Word tasks. Expectancy of having smoked THC, regardless of active drug, decreased impulsive decision-making on a delay discounting task among participants reporting no deception and increased perception of sexual risk among women, consistent with a compensatory effect. Expectancy of smoking THC in combination with active THC increased negative perceptions from risky alcohol use. Active drug and expectancy independently increased subjective intoxication.
Results highlight the importance of marijuana expectancy effects as users believing they are smoking marijuana may compensate for expected intoxication effects when engaged in deliberate decision-making by making less impulsive and risky decisions. Effects of marijuana on impulsive disinhibition, by contrast, reflect direct pharmacologic effects for which participants did not compensate.
THC; Cannabis; Expectancy; Impulsivity; Inhibition; Risk taking; Sexual risk
Social environment influences alcohol consumption in humans, however, animal models have only begun to address biological underpinnings of these effects.
We investigated whether social influences on alcohol drinking in the prairie vole are specific to the sex of the social partner.
In Experiment 1, control, sham, and gonadectomized voles were placed either in mesh-divided housing with a same-sex sibling or isolation with access to ethanol. In Experiment 2 animals were given an elevated plus maze test (EPM) and then females were paired with a castrated male followed by isolation or mesh-divided housing with access to ethanol. In Experiment 3, subjects categorized as low or high drinkers based on initial ethanol intake were placed in mesh-divided housing with an opposite-sex partner of the same or opposite drinking group and ethanol access. Subjects were then moved back to isolation for a final ethanol access period.
Same-sex pairs showed social facilitation of drinking similar to previous reports. Gonadectomy did not affect alcohol drinking. Opposite-sex paired animals in Experiment 2 did not differ in alcohol drinking based on social housing. EPM measures suggested a relationship between anxiety-like behaviors and drinking that depended on social environment. Experiment 3 identified moderate changes in alcohol preference based on social housing, but these effects were influenced by the animal’s own drinking behavior and were independent of their partner’s drinking.
Social influences on alcohol self-administration in prairie voles differ based on the sex of a social partner, consistent with human drinking behavior.
Prairie voles; social behavior; alcohol self-administration; social influence
Dopamine receptors are divided into two families: D1 including D1 and D5 receptors and D2 including D2, D3 and D4 receptors. The role of dopamine D3 receptors in the brain remains controversial. We found that highly selective D3 antagonists induced positive cerebral blood volume (CBV) changes whereas D3 agonism using 7-OH-DPAT induced negative CBV changes in brain regions including nucleus accumbens, antero-medial striatum, cingulate cortex, thalamus, interpeduncular region and hypothalamus. There was pronounced activation in the hippocampus restricted to the subiculum – the output from the infralimbic cortex and dentate gyrus. At higher doses of D3 agonist, functional changes were differentiated across cortical lamina, with layer V–VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are consistent with differential D1 and D3 innervation in these layers respectively and provide evidence of D1–D3 receptor interactions. Further, the use of MRI provides a new tool for testing the in vivo selectivity of novel dopaminergic ligands where radiolabels are not available - as in the case of D3 receptors.
Several studies suggest that repeated nicotine administration causes alterations in glutaminergic transmission that may play an important role in developing and maintaining nicotine addiction. Chronic nicotine administration in rats decreases the expression of the glutamate transporter-1 (GLT-1) and cysteine–glutamate exchanger (system xC−) in the nucleus accumbens. We hypothesized that ceftriaxone, a GLT-1 and system xC− activator, would decrease murine behavioral aspects of nicotine dependence.
This study aimed to investigate the effect of repeated ceftriaxone administration on the behavioral effects of nicotine using mouse models of conditioned reward and withdrawal.
Using male ICR mice, the ability of repeated ceftriaxone injections to modulate the development and reinstatement of a nicotine-conditioned place preference (CPP) was evaluated. Additionally, nicotine withdrawal-associated signs were assessed. These included both physical (somatic signs and hyperalgesia) and affective (anxiety-related behaviors) withdrawal signs in mice. Finally, the effects of ceftriaxone on nicotine-induced antinociception and hypothermia after acute nicotine injection were measured.
Ceftriaxone had no effect on the development of nicotine preference but significantly attenuated nicotine-induced reinstatement of CPP. Furthermore, ceftriaxone reversed all nicotine withdrawal signs measured in mice.
Altogether, these findings show that a β-lactam antibiotic reduces nicotine withdrawal and nicotine-seeking behavior. Our results suggest that the documented efficacy of ceftriaxone against cocaine and morphine dependence-related behaviors effects extends to nicotine.
Ceftriaxone; GLT-1; Conditioned place preference; Nicotine; Reward; Withdrawal; Reinstatement
Several studies implicate stress as a risk factor for the development and maintenance of drug addictive behaviors and drug relapse. Kappa opioid receptor (KOR) antagonists have been shown to attenuate behavioral responses to stress and stress-induced reinstatement of cocaine and ethanol seeking and preference.
In the current study, we determined whether the selective KOR antagonist, norbinaltorphimine (nor-BNI), would block stress-induced reinstatement of nicotine preference.
Adult Institute of Cancer Research mice were conditioned with 0.5 mg/kg nicotine, injected subcutaneously (s.c.) for 3 days and tested in the nicotine-conditioned place preference (CPP) model. After 3 days extinction, nor-BNI (10 mg/kg, s.c.) was administered 16 h prior to a priming dose of nicotine (0.1 mg/kg, s.c.), and mice were tested in the CPP model for nicotine-induced reinstatement of CPP. A separate group of mice was subjected to a 2-day modified forced swim test (FST) paradigm to induce stress after 3 days extinction from CPP. Mice were given vehicle or nor-BNI (10 mg/kg, s.c.) 16 h prior to each FST session.
Nor-BNI pretreatment significantly attenuated stress-induced reinstatement of nicotine-CPP, but had no effect on nicotine-primed reinstatement.
Blockade of KORs by selective antagonists attenuates stress-induced reinstatement of nicotine-CPP. Overall, the kappa opioid system may serve as a therapeutic target for suppressing multiple signaling processes which contribute to maintenance of smoking, smoking relapse, and drug abuse in general.
Nicotine; Kappa opioid receptors; Nor-BNI; Drug reinstatement; Forced swim test; Nicotine-CPP
Studies in laboratory animals have demonstrated an influence of environmentally derived stress and enrichment on the reinforcing effects of stimulants.
To characterize the effects of acute exposure to ethologically valid environmental stimuli on the reinforcing strength of cocaine relative to food in socially housed monkeys.
Materials and Methods
Choice between cocaine and food was assessed in subsets of sixteen socially housed (4/pen) male cynomolgus monkeys immediately after the following manipulations: (1) treats placed in homecage; (2) a 10-minute exposure to a rubber snake or (3) three to seven days of living in a larger environment without cage mates.
Placing treats in the homecage shifted the cocaine dose-response curve to the left in 5 monkeys tested and to the right in 4 of 12 animals. The rubber snake significantly shifted the cocaine choice curve to the left in dominant monkeys. Exposure to an enlarged environment decreased cocaine choice in 9 of 15 monkeys; this effect was transient and not related to social rank. Repeated testing did not affect cocaine choice.
Brief exposure to environmental events hypothesized to be stressors or enrichment altered cocaine choice, although not all individuals were affected and the effects were transient. Importantly, the data suggest that implementing positive changes in the environment produced effects that are clinically desirable. The behavioral and neurobiological mechanisms mediating sensitivity to environmental events in socially housed animals will lead to better treatment strategies for drug addiction.
social rank; environmental enrichment; vulnerability; nonhuman primates; drug self-administration
Although cocaine is often abused in social situations, very few animal studies examine the effects of cocaine in the context of social behavior.
This review highlights studies investigating the behavioral effects of cocaine in the context of social housing conditions using nonhuman primates. In addition, this review presents recent findings examining the effects of self-administering cocaine on social behavior and the effects of manipulations hypothesized to be stressful or enriching on the interactions between cocaine reinforcement and social rank. The following dependent variables are examined: 1) cocaine-induced changes in social behavior and 2) cocaine self-administration in cynomolgus monkeys of varying social ranks. The independent variables examined include several environmental and pharmacological manipulations.
The studies reviewed here indicate that several variables can differentially affect cocaine self-administration when studied in a social context, rather than in individually housed animals. These variables include the social rank and sex of the individual, drug history, the nature of the “fear”-inducing manipulation, and the reliability of cortisol as an appropriate measure of “stress.” While the inclusion of socially housed animals necessitates larger sample sizes, animal models incorporating social behavior are more homologous to the human condition and should be implemented when possible.
aggression; submission; social interactions; social consequences; social rank; cocaine self-administration; nonhuman primates
Love has long been referred to as an addiction in literature and poetry. Scientists have often made comparisons between social attachment processes and drug addiction, and it has been suggested that the two may share a common neurobiological mechanism. Brain systems that evolved to govern attachments between parents and children, and between monogamous partners, may be the targets of drugs of abuse and serve as the basis for addiction processes.
Here, we review research on drug addiction in parallel with research on social attachments, including parent-offspring attachments and social bonds between mating partners. This review focuses on the brain regions and neurochemicals with the greatest overlap between addiction and attachment, and in particular the mesolimbic dopamine pathway.
Significant overlap exists between these two behavioral processes. In addition to conceptual overlap in symptomatology, there is a strong commonality between the two domains regarding the roles and sites of action of dopamine, opioids, and corticotrophin-releasing factor (CRF). The neuropeptides oxytocin and vasopressin are hypothesized to integrate social information into attachment processes that is not present in drug addiction.
Social attachment may be understood as a behavioral addiction, whereby the subject becomes addicted to another individual and the cues that predict social reward. Understandings from both fields may enlighten future research on addiction and attachment processes.
social attachment; loved; addiction; substance dependence; dopamine; opioids; CRF; oxytocin; vasopressin; pair bond
Ecstasy (MDMA) is used predominately by adolescents and young adults. Young MDMA users are more likely than non-users to use other drugs, including cocaine. The response to stimulant drugs can be affected by environmental factors; however, little information exists about the role that housing plays in mediating effects of MDMA in adolescence.
The present experiment examined whether social and environmental factors alter effects of MDMA on activity and cocaine reward.
Male adolescent rats were housed on PND 23. Isolated rats were housed alone (1 rat/cage) in an impoverished environment with no toys (II) or enriched with toys (IE). Social rats were housed three/cage with (SE3) or without (SI3) toys. Starting on PND 29, 5 mg/kg MDMA or saline was injected and activity was measured for 60 min once daily for five consecutive days. On PND 36–40, cocaine CPP was conducted.
Saline vehicle-induced activity of II rats was higher than other groups, and all groups became sensitized to the locomotor-stimulant effects of MDMA. In II rats, maximal CPP was increased after MDMA pre-exposure compared to vehicle. Environmental enrichment blocked this; however, dose–effect curves for cocaine CPP shifted to the left in both IE and SE3 rats. In rats with just social enrichment, there were no effects of MDMA on cocaine CPP.
Drug prevention and treatment strategies should take into account different environments in which adolescents live. These findings show that MDMA increases cocaine reward in male adolescents, and social enrichment diminishes, while environmental enrichment enhances this.
MDMA; Ecstasy; Cocaine; Adolescent; Enrichment; Reward
Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activation, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-hour “binge” in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected.
This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited access self-administration “binge.”
Long-Evans rats underwent episodic social defeat and were assessed ten days later for either (1)behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, ip), (2)neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3)intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited access “binge.”
Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer “binge” in both sexes, females had a significantly longer “binge” duration than males.
These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization.
social stress; sex differences; cocaine; dopamine; behavioral sensitization; neural sensitization; self-administration; microdialysis
Memantine is a potential treatment for alcoholic patients, yet few studies investigate the effect of concurrent treatment with memantine and ethanol on aggression. We evaluated aggressive behavior following ethanol consumption and treatment with glutamatergic drugs to characterize interactions between these compounds.
To use rodent models of aggression to examine interactions between glutamatergic compounds and ethanol.
Materials and Methods
Once male CFW mice reliably self-administered 1 g/kg ethanol or water, they were assessed for aggression in resident-intruder confrontations. Alternatively, aggression was evaluated following a social-instigation procedure. Animals were then injected with memantine, ketamine, neramexane, MTEP or LY379268 before aggressive confrontations. Effects of the pharmacological manipulations on salient aggressive and non-aggressive behaviors were analyzed.
Moderate doses of memantine, neramexane and MTEP interacted with ethanol to increase the frequency of attack bites while ketamine did not. The highest dose of LY379268, an mGluR2/3 agonist, reduced both aggressive and non-aggressive behaviors after water and ethanol self-administration. Attack bites increased with social instigation and decreased with administration of high doses of MTEP and LY379268. Memantine and MTEP both reduced attack bite frequency in the instigation condition without reducing locomotor behavior.
Memantine and neramexane interacted with ethanol to heighten aggression. The binding characteristics of these compounds allow for ‘partial trapping’ by which some NMDARs are unblocked between depolarizations. We propose that this feature may contribute to the differential aggression-heightening interactions between these compounds and ethanol. MTEP also interacted with ethanol to escalate aggression, possibly through inhibition of mGluR5 modulation of NMDARs.
Aggression; Glutamate Receptor; NMDA; mGluR; Dorsal Raphe; Ventral Tegmental Area
Pharmacological activation of GABAB receptors in the dorsal raphé nucleus (DRN) can escalate territorial aggression in male mice.
We characterized this escalated aggression in terms of its behavioral and environmental determinants.
Aggressive behavior of resident male (CFW or ICR mouse) was assessed in confrontations with a group-housed intruder. Either baclofen (0.06 nmol/0.2 μl) or vehicle (saline) was microinjected into the DRN ten minutes before the confrontation. We examined baclofen-heightened aggression in five situations: aggression in a neutral arena and after social instigation (experiment 1), aggression during the light phase of the cycle (experiment 2), aggression without prior fighting experience (experiment 3), aggression toward a female (experiment 4), and aggression after defeat experiences (experiment 5). In addition, we examined the body targets towards which bites are directed and the duration of aggressive bursts after baclofen treatment.
Regardless of the past social experience, baclofen escalated aggressive behaviors. Even in the neutral arena and after defeat experiences, where aggressive behaviors were inhibited, baclofen significantly increased aggression. Baclofen increased attack bites directed at vulnerable body areas of male intruders but not toward a female and only in the dark. Also, baclofen prolonged the duration of aggressive bursts.
For baclofen to escalate aggression, specific stimulation (male intruder) and tonic level of serotonin (dark cycle) are required. Once aggressive behavior is triggered, intra-DRN baclofen escalates the level of aggression to abnormal levels and renders it difficult to terminate. Also, baclofen counteracts the effects of novelty or past experiences of defeat.
Dorsal raphé nucleus (DRN); GABAB receptor; serotonin (5-HT); escalated aggression; winning; defeat; light/dark period; female intruder; vulnerable targets; termination of aggressive behavior
To address the public health problems caused by smoking, researchers have suggested a gradual reduction in the nicotine content of cigarettes. There remain concerns, however, about the potential for smokers to compensate for reductions in nicotine content by altering their smoking behavior. Such compensatory behaviors may negate any potential cessation and/or harm reduction benefits.
The purpose of this study was to quantify smoking behavior (e.g., puff number, volume, duration, inter-puff interval, and peak flow) in response to cigarettes varying only in nicotine content, administered repeatedly.
Sixty-seven dependent smokers participated in this two session, within-subject study. Moderate nicotine content and placebo cigarettes (Quest© brand) were administered in a double-blind and counterbalanced manner. Each session required 12-hours of tobacco abstinence, and included four ad lib smoking bouts of the condition-assigned cigarette with 40 minutes separating each bout.
Placebo cigarettes produced increases in total puff volume and duration and decreases in total inter-puff interval relative to cigarettes with moderate nicotine content. Differences in total puff volume and duration generally dissipated across smoking bouts, with differences in total puff volume non-existent by the 3rd and 4th bouts.
Placebo cigarettes produce compensatory smoking during initial exposures; however, these effects appear to be short lived. These findings are consistent with previous work where smoking compensation has been observed in response to a single cigarette but not over several days of smoking.
Smoking; topography; compensation; nicotine; extinction
Repeated injections of cocaine cause blunted responses to acute cocaine challenge-induced increases in the expression of immediate early genes (IEGs).
The aim of this study was to test if chronic methamphetamine (METH) exposure might cause similar blunting of acute METH-induced increases in IEG expression.
Repeated saline or METH injections were given to rats over 14 days. After one day of withdrawal, they received a single injection of saline or METH (5 mg/kg). Acute injection of METH increased c-fos, fosB, fra2, junB, Egr1-3, Nr4a1 (Nur77), and Nr4a3 (Nor-1) mRNA levels in the striatum of saline-pretreated rats. Chronic METH treatment alone reduced the expression of AP1, Erg1-3, and Nr4a1 transcription factors below control levels. Acute METH challenge normalized these values in METH-pretreated rats. Unexpectedly, acute METH challenge to METH-pretreated animals caused further decreases in Nr4a2 (Nurr1) mRNA levels. In contrast, the METH challenge caused significant but blunted increases in Nr4a3 and Arc expression in METH-pretreated rats. There were also chronic METH-associated decreases in the expression of cAMP responsive element binding protein (CREB) which modulates IEG expression via activation of the cAMP/PKA/CREB signal transduction pathway. Chronic METH exposure also caused significant decreases in preprotachykinin, but not in prodynorphin, mRNA levels.
These results support the accumulated evidence that chronic administration of psychostimulants is associated with blunting of their acute stimulatory effects on IEG expression. The METH-induced renormalization of the expression of several IEGs in rats chronically exposed to METH hints to a potential molecular explanation for the recurrent self-administration of the drug by human addicts.
Addiction; Arc; Preprotachykinin; Dynorphin; Molecular neuroadaptations
Dopamine D2-like agonists maintain responding when substituted for cocaine in laboratory animals. However, these effects appear to be mediated by an interaction with stimuli that were previously paired with cocaine reinforcement (CS).
To evaluate the extent to which the pramipexole-maintained and -induced responding are influenced by cocaine-paired stimuli.
Rats were trained to nosepoke for cocaine under fixed ratio 1 (FR1) or progressive ratio (PR) schedules of reinforcement. In FR1-trained rats, pramipexole was substituted for cocaine with injections either paired with CSs, or delivered in their absence. The capacity of experimenter-administered pramipexole to induce FR1 and PR responding for CS presentation was evaluated. The effects of altering stimulus conditions, as well as pretreatments with D2- (L-741,626) and D3-preferring (PG01037) antagonists on pramipexole-induced PR responding were also evaluated.
When substituted for cocaine, pramipexole maintained responding at high rates when injections were paired with CSs, but low rates when CSs were omitted. Similarly, experimenter-administered pramipexole induced dose-dependent increases in FR1 or PR responding, with high rates of responding observed when the CS was presented, and low rates of responding when CS presentation was omitted. D2 and D3 antagonists differentially affected pramipexole-induced PR responding, with L-741,626 and PG01037 producing rightward, and downward shifts in the dose-response curve for CS-maintained responding, respectively.
These data indicate that pramipexole is capable of enhancing the reinforcing effectiveness of conditioned stimuli, and raise the possibility that similar mechanisms are responsible for the increased occurrence of impulse control disorders in patients being treated with pramipexole.
Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral Pattern Monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAOA inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses.
The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a reduction in the rate of 5-MeO-DMT metabolism. This hypothesis was tested using a deuterated derivative of 5-MeO-DMT (α,α,β,β-tetradeutero-5-MeO-DMT) that is resistant to metabolism by MAO.
Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses greater than 1.0 mg/kg, produced only reductions in locomotor activity. Although low doses of α,α,β,β-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites.
The finding with α,α,β,β-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metabolism of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations.
Ayahuasca; hallucinogen; kinetic isotope effect; locomotor activity; 5-methoxy-N,N-dimethyltryptamine; monoamine oxidase; deutero-5-MeO-DMT
18-Methoxycoronaridine (18-MC), a selective antagonist of α3β4 nicotinic receptors, has been previously shown, in rats, to reduce the self-administration of several drugs of abuse, reduce operant responding for sucrose, and prevent the development of sucrose-induced obesity. It has become increasingly apparent that there is a significant overlap between the systems regulating drug reward and food intake, therefore, we investigated whether 18-MC might modulate the effects of ghrelin, one of several orexigenic peptides recently implicated in both feeding and drug reward.
In female Sprague–Dawley rats, we determined whether acute 18-MC treatment would reduce both ghrelin-induced increases in sucrose intake and ghrelin-elicited increases in accumbal dopamine levels.
Pretreatment with 18-MC (20 mg/kg, i.p.), given prior to the administration of ghrelin (1 µg, lateral ventricle), blocked ghrelin-induced increases in sucrose (5%) intake in a two-bottle open access paradigm. Using in vivo microdialysis, 18-MC (both 20 and 40 mg/kg) prevented ghrelin (2 µg, intraventral tegmental area)-induced increases in extracellular dopamine in the nucleus accumbens. 18-MC had no effect on deposition of fat or on serum levels of glucose, triglycerides, and cholesterol in ghrelin-treated rats.
The present results suggest that one potential mechanism by which 18-MC exerts its effects on palatable food consumption is via modulation of ghrelin’s effects.
Sucrose; Obesity; Nicotinic receptors; Ghrelin; 18-Methoxycoronaridine
Tobacco and alcohol are frequently used together, and this may be partly explained by a distinct profile of subjective effects associated with co-administration. Ecological Momentary Assessment studies have examined effects of naturally occurring co-use, but, to date, have not assessed differing effects as alcohol levels rise and fall.
To describe subjective states and appraisals of cigarette and alcohol effects reported during the entirety of real-world drinking episodes.
Currently-smoking frequent drinkers (N = 255) carried electronic diaries for 21 days. Analyses focused on reports made during 2,046 drinking episodes. Signaled prompts intensively oversampled moments in the hours following consumption of the first drink in an episode. Multilevel regression analyses were used to predict ratings of buzz, dizziness, excitement, and sluggishness as a function of person-level and contextual covariates, estimated blood alcohol concentration (eBAC) level, ascending vs. descending eBAC, smoking, and their interactions. Appraisals of cigarette and alcohol effects were also examined within this framework.
Buzz, excitement, and pleasure from alcohol and cigarettes were prominent features of real-world drinking episodes. Smoking was associated with enhanced buzz and excitement when eBAC was high and descending. Smoking slightly accentuated the relation between eBAC and ratings of drinking pleasure among women, but this relation was somewhat weakened by smoking among men.
Smoking during drinking episodes may be partly be explained by a persistence of stimulant alcohol effects beyond the BAC peak. Acute effects of nicotine and tobacco use on the descending limb deserve further scrutiny in experimental alcohol challenge research.
smoking; tobacco; alcohol; craving; reinforcement; subjective states; Ecological Momentary Assessment
Repeated exposure to psychostimulants alters behavioral responses to reward-related cues; however, the motivational underpinnings of this effect have not been fully characterized.
The following study was designed to examine how amphetamine sensitization affects performance in rats on a series of Pavlovian and operant tasks that distinguish between general-incentive and outcome-selective forms of conditioned responses.
Adult male rats underwent Pavlovian and instrumental training for food pellet rewards. Following training, rats were sensitized to d-amphetamine (2 mg/kg for 7 days). Rats were subsequently tested on an outcome-selective Pavlovian-instrumental transfer (PIT) task, an outcome-reinstatement task, and an outcome devaluation task. Additionally, in a separate experiment PIT was assessed in amphetamine-sensitized and control rats using a Pavlovian backward-conditioned stimulus.
Repeated amphetamine exposure sensitized locomotor activity to acute amphetamine challenge. Amphetamine altered responses to CS presentations by increasing conditioned approach. During tests of PIT amphetamine-treated rats showed no outcome-selectivity in their responding, responding to a CS whether or not it shared a common outcome with the instrumental response. No effect of amphetamine sensitization was observed on tests of outcome-selective reinstatement by outcome delivery, or action selection based on outcome value. Amphetamine-sensitized rats showed impaired outcome-selective PIT to a backward CS but were unaltered in conditioned approach.
Amphetamine sensitization prevents outcome-selective responding during PIT, which is dissociable from amphetamine’s effects on conditioned approach. These data suggest fundamental alterations in how stimuli motivate action in addiction.
Sensitization; incentive; devaluation; reinstatement; operant