Dopamine receptor mechanisms are thought to play a role in the reinforcing effects of cocaine and other abused drugs. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D3-preferring agonists, a D2-preferring agonist, and a D4 agonist. The D2-preferring agonist did not maintain responding in any monkeys, and the D4 agonist was self-administered at low rates, just above those maintained by saline in one monkey. The D3-preferring agonists were self-administered by approximately half of the animals, although at lower rates than cocaine. These results indicate the apparent limited reinforcing effectiveness of D2-like agonists requires activity at D3 receptors. Previous data from this laboratory and others also suggest that these drugs may not serve as reinforcers directly; the behavior may be maintained by response-contingent delivery of stimuli previously paired with cocaine. The ability of drug-related stimuli to maintain responding apparently differs among monkeys and other organisms, and may be related to individual differences in drug-taking behavior in humans.
D2-like agonists; reinforcing effects; rhesus monkeys; self-administration
Impulsivity is widely regarded as a multidimensional trait that encompasses two or more distinct patterns of behavior, and dopaminergic systems are implicated in the expression of impulsive behavior in both humans and animals. Impulsive choice, or the tendency to choose rewards associated with relatively little or no delay, has been extensively studied in humans and animals using delay discounting tasks. Here, delay discounting procedures were used to assess the effects of receptor-selective dopaminergic agonists, antagonists, and dopamine transporter ligands on choices of immediate versus delayed sucrose pellets. The effects of d-amphetamine, GBR 12909, apomorphine, SKF 81297, sumanirole, pramipexole, ABT-724, SCH 23390, L-741,626, PG01037, and L-745,870 were assessed in 24 Sprague Dawley rats. The only drugs to affect impulsive choice selectively without altering undelayed choice were the D1-like antagonist SCH 23390 (0.01 mg/kg) and the D4 partial agonist ABT-724 (3.2 mg/kg), which both increased impulsive choice. The shared effects of these compounds may be explained by their localization within the prefrontal cortex on different groups of neurons. None of the selective agonists and antagonists tested reduced impulsive choice, so further research is needed to determine if direct dopaminergic agonists or antagonists may be therapeutically useful in the treatment of impulse-control disorders.
Delay discounting; inter-temporal choice; impulsive choice; impulsivity; self control; dopamine; SCH 23390; ABT-724; rat
Addiction science would benefit from the identification of a behavioral
marker. A behavioral marker could reflect the projected clinical course of the
disorder, function as a surrogate measure of clinical outcome, and/or may be
related to biological components that underlie the disorder. In this paper we
review relevant literature, made possible with the early and sustained support
by NIDA, to determine whether temporal discounting, a neurobehavioral process
derived from behavioral economics and further explored through neuroeconomics,
may function as a behavioral marker. Our review suggests that temporal
discounting 1) identifies individuals who are drug-dependent, 2) identifies
those at risk of developing drug dependence, 3) acts as a gauge of addiction
severity, 4) correlates with all stages of addiction development, 5) changes
with effective treatment, and 6) may be related to the biological and genetic
processes that underlie addiction. Thus, initial evidence supports temporal
discounting as a candidate behavioral marker. Additional studies will be
required in several areas for a more conclusive determination. Confirmation that
temporal discounting functions as a behavioral marker for addiction could lead
to 1) a screen for new treatments, 2) personalization of prevention and
treatment interventions, and 3) the extension of temporal discounting as a
behavioral marker for other etiologically similar disorders.
Increased signal-detection accuracy on the 5-choice serial reaction time (5-CSRT) task has been shown with drugs that are useful clinically in treating attention deficit hyperactivity disorder (ADHD), but these increases are often small and/or unreliable. By reducing the reinforcer frequency, it may be possible to increase the sensitivity of this task to pharmacologically-induced improvements in accuracy.
Rats were trained to respond on the 5-CSRT task on a fixed ratio (FR) 1, FR 3, or FR 10 schedule of reinforcement. Drugs that were and were not expected to enhance performance were then administered before experimental sessions.
Significant increases in accuracy of signal detection were not typically obtained under the FR 1 schedule with any drug. However, d-amphetamine, methylphenidate, and nicotine typically increased accuracy under the FR 3 and FR 10 schedules.
Increasing the FR requirement in the 5-CSRT task increases the likelihood of a positive result with clinically effective drugs, and may more closely resemble conditions in children with attention deficits.
5-choice serial reaction time task; sustained attention; attention deficit hyperactivity disorder; fixed ratio; psychostimulants; rats
The generalized matching law provides precise descriptions of choice, but has not been used to characterize choice between different doses of drugs or different classes of drugs. The current study examined rhesus monkeys' drug self-administration choices between identical drug doses, different doses, different drugs (cocaine, remifentanil, and methohexital), and between drug and drug-paired stimuli. The bias parameter of the generalized matching law was used to quantify preference for one reinforcer over another. Choice between identical drug doses yielded undermatching. Choices between 0.3 µg/kg/injection remifentanil and either 0.1 µg/kg/injection remifentanil or saline plus drug-paired stimuli revealed bias for the 0.3 µg/kg/injection dose. Choice was relatively insensitive to differences in random interval schedule value when one reinforcer was replaced with drug-paired stimulus presentations. Bias for 0.3 µg/kg/injection remifentanil over 10 µg/kg/injection cocaine was seen in one subject, and indifference was generally observed between 0.1 µg/kg/injection remifentanil and 56 µg/kg/injection cocaine and between 30 µg/kg/injection cocaine and 320 µg/kg/injection methohexital. These findings suggest the bias parameter may be useful in quantitatively measuring level of preference, which would be an advantage over concurrent FR procedures that often result in exclusive choice.
matching law; self-administration; remifentanil; cocaine; methohexital; lever press; rhesus monkeys
Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs)
who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that
CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC.
Excessively devaluing delayed reinforcers co-occurs with a wide variety of clinical conditions such as drug dependence, obesity, and excessive gambling. If excessive delay discounting is a trans-disease process that underlies the choice behavior leading to these and other negative health conditions, efforts to change an individual’s discount rate are arguably important. Although discount rate is often regarded as a relatively stable trait, descriptions of interventions and environmental manipulations that successfully alter discount rate have begun to appear in the literature. In this review, we compare published examples of procedures that change discount rate and classify them into categories of procedures, including therapeutic interventions, direct manipulation of the executive decision-making system, framing effects, physiological state effects, and acute drug effects. These changes in discount rate are interpreted from the perspective of the competing neurobehavioral decision systems theory, which describes a combination of neurological and behavioral processes that account for delay discounting. We also suggest future directions that researchers could take to identify the mechanistic processes that allow for changes in discount rate and to test whether the competing neurobehavioral decision systems view of delay discounting is correct.
delay discounting; behavioral neuroscience; impulsivity; executive function; human
Substance abusers, including cocaine abusers, discount delayed rewards to a greater extent than do matched controls. In the current experiment, individual differences in discounting of delayed rewards in rats (choice of one immediate over three delayed sucrose pellets) were assessed for associations with demand for either sucrose pellets or an i.v. dose of 0.1 mg/kg/infusion cocaine. Twenty-four male Sprague Dawley rats were split into three groups based on sensitivity to delay to reinforcement. Then, demand for sucrose pellets and cocaine was determined across a range of fixed-ratio (FR) values. Delay discounting was then reassessed to determine the stability of this measure over the course of the experiment. Individual differences in impulsive choice were positively associated with elasticity of demand for cocaine, a measure of reinforcer value, indicating that rats having higher discount rates also valued cocaine more. Impulsive choice was not associated with level of cocaine consumption as price approached 0, or any parameter associated with demand for sucrose. Individual sensitivity to delay was correlated with the initial assessment when reassessed at the end of the experiment, although impulsive choice increased for this cohort of rats as a whole. These findings suggest that impulsive choice in rats is positively associated with valuation of cocaine, but not sucrose.
Behavioral economics; cocaine demand; delay discounting; impulsive choice; impulsivity; Sprague Dawley rats
Delay discounting describes the devaluation of a reinforcer as a function of the delay until its receipt. Although all people discount delayed reinforcers, one consistent finding is that substance-dependent individuals tend to discount delayed reinforcers more rapidly than do healthy controls. Moreover, these higher-than-normal discounting rates have been observed in individuals with other behavioral maladies such as pathological gambling, poor health behavior, and overeating. This suggests that high rates of delay discounting may be a trans-disease process (i.e., a process that occurs across a range of disorders, making findings from one disorder relevant to other disorders). In this paper, we argue that delay discounting is a trans-disease process, undergirded by an imbalance between two competing neurobehavioral decision systems. Implications for our understanding of, and treatment for, this trans-disease process are discussed.
Delay discounting; trans-disease process; neuroscience; addiction; gambling; obesity; health behaviors
Aims: To assess the efficacy of the Therapeutic Workplace, a substance abuse intervention that promotes abstinence while simultaneously addressing the issues of poverty and lack of job skills, in promoting abstinence from alcohol among homeless alcoholics. Methods: Participants (n = 124) were randomly assigned to conditions either requiring abstinence from alcohol to engage in paid job skills training (Contingent Paid Training group), offering paid job skills training with no abstinence contingencies (Paid Training group) or offering unpaid job skill training with no abstinence contingencies (Unpaid Training group). Results: Participants in the Contingent Paid Training group had significantly fewer positive (blood alcohol level ≥ 0.004 g/dl) breath samples than the Paid Training group in both randomly scheduled breath samples collected in the community and breath samples collected during monthly assessments. The breath sample results from the Unpaid Training group were similar in absolute terms to the Contingent Paid Training group, which may have been influenced by a lower breath sample collection rate in this group and fewer reported drinks per day consumed at intake. Conclusion: Overall, the results support the utility of the Therapeutic Workplace intervention to promote abstinence from alcohol among homeless alcoholics, and support paid training as a way of increasing engagement in training programs.
Naltrexone can be used to treat opioid dependence, but patients refuse to take it. Extended-release depot formulations may improve adherence, but long-term adherence rates to depot naltrexone are not known. This study determined long-term rates of adherence to depot naltrexone and whether employment-based reinforcement can improve adherence.
Participants who were inducted onto oral naltrexone were randomly assigned to Contingency (n=18) or Prescription (n=17) groups. Participants were offered six depot naltrexone injections and invited to work at the therapeutic workplace weekdays for 26 weeks where they earned stipends for participating in job skills training. Contingency participants were required to accept naltrexone injections to maintain workplace access and to maintain maximum pay. Prescription participants could work independent of whether they accepted injections.
The therapeutic workplace, a model employment-based intervention for drug addiction and unemployment.
Opioid-dependent unemployed adults.
Depot naltrexone injections accepted and opiate-negative urine samples.
Contingency participants accepted significantly more naltrexone injections than Prescription participants (81% versus 42%), and were more likely to accept all injections (66% versus 35%). At monthly assessments (with missing urine samples imputed as positive), the groups provided similar percentages of samples negative for opiates (74% versus 62%) and for cocaine (56% versus 54%). Opiate positive samples were more likely when samples were also positive for cocaine.
Employment-based reinforcement can maintain adherence to depot naltrexone. Future research should determine whether persistent cocaine use compromises naltrexone's effect on opiate use. Workplaces may be useful for promoting sustained adherence to depot naltrexone.
depot naltrexone; contingency management; heroin; substance abuse; employment-based reinforcement
Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors.
The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists.
Materials and methods
Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole.
Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group.
Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role.
Drug discrimination; Either/or discrimination; D2; D3; Dopamine; Pramipexole; Sumanirole; Rat