Elevations In Reward Thresholds Research Articles

Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis.

The extra medical use of, and addiction to, prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self-stimulation (ICSS) reward and oxycodone intravenous self-administration (IVSA) models. Male Wistar rats were given access to oxycodone IVSA (0.15 mg·kg-1 per infusion, i.v.) in short-access (ShA; 1 h) or long-access (LgA; 12 h) sessions for five sessions per week followed by intermittent 60-h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. Separate groups were first trained in the ICSS procedure and then in oxycodone IVSA in 11-h LgA sessions. Rats given LgA to oxycodone escalated their responding more than ShA rats, with further significant increases observed following each 60-h discontinuation. Presession brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1-h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60-h weekend abstinence. The increase in ICSS thresholds was attenuated in a group treated with the long-acting κ-opioid antagonist norbinaltorphimine prior to IVSA training. Changes in brain reward function during escalation of oxycodone self-administration are driven by an interplay between κ-opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.

Effects of adolescent alcohol exposure on stress-induced reward deficits, brain CRF, monoamines and glutamate in adult rats.

Adolescent alcohol exposure may increase depression vulnerability in adulthood by increasing the anhedonic response to stress. Male Wistar rats (postnatal days 28-53) were exposed to binge-like adolescent intermittent ethanol (AIE) or water. In adulthood, rats were exposed to social defeat, consisting of daily confrontations with an aggressive conspecific, followed by testing of brain reward function in a discrete-trial current-intensity intracranial self-stimulation procedure for 10 consecutive days. Neurochemistry and corticotropin-releasing factor (CRF) and CRF receptor 1 (CRFR1) mRNA levels were assessed in corticolimbic brain areas on day 11 of social defeat stress. Social defeat elevated reward thresholds in both AIE- and water-exposed rats indicating stress-induced anhedonia. However, AIE-exposed rats were more likely to show threshold elevations after repeated stress compared to water-exposed rats. AIE exposure decreased CRF mRNA levels in the nucleus accumbens and increased CRFR1 mRNA levels in the prefrontal cortex, while stress increased CRF mRNA levels in the central amygdala. In the caudate putamen, AIE exposure decreased dopamine turnover, while stress increased glutamate and serotonin metabolism and turnover. These results demonstrate increased risk of repeated stress-induced anhedonia after AIE exposure, an effect that may be due to alterations in brain CRF and dopamine systems. These results suggest that the increased rates of depression reported in people with a history of adolescent alcohol exposure may be related to alterations in brain reward and stress systems that may contribute to increased stress-induced anhedonia.

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An animal model can be viewed as an experimental paradigm developed for the purpose of studying a given phenomenon found in humans. Although there are no complete animal models of depression, anxiety, schizophrenia, or addiction, animal models do exist for many elements of the syndrome. Animal models for antidepressant medications include a number of tests with good predictive validity, but limited construct validity, and include the forced swim test, modified swim test, learned helplessness, olfactory bulbectomy, differential reinforcement of low rates of responding, maternal deprivation, neonatal clomipramine treatment, social stress in shrews, chronic mild stress, agonistic behavior, and Flinders sensitive rats. Animal models of depression that have face validity and construct validity for a key element of depression are reward deficits measured by brain stimulation reward and progressive-ratio responding for a natural reward. Widely used animal models of generalized anxiety include the operant conflict test, elevated plus maze, defensive withdrawal, defensive burying, and social interaction, all of which have face and predictive validity. Animal models for individual types of anxiety disorder remain a challenge, with some advances in posttraumatic stress disorder, which includes models of repeated shock stressors, repeated social stressors, and a single prolonged stress paradigm. Animal models of schizophrenia are limited by the limited knowledge of the pathophysiology of the disease but include pharmacological, developmental, and genetic models combined with behavioral tests with some face and contruct validity, such as locomotor activity (positive symptoms), prepulse inhibition of the startle response (attention), latent inhibition (attention), social withdrawal (negative symptoms), and measures of executive function. Animal models of addiction can be organized within the stages of the addiction cycle, including: binge/intoxication (drug or alcohol self-administration, conditioned place preference, brain stimulation reward thresholds), withdrawal/negative affect (anxiety-like responses, conditioned place aversion, elevated reward thresholds, withdrawal-induced increases in drug self-administration), and preoccupation/anticipation (drug-induced reinstatement, cue-induced reinstatement, stress-induced reinstatement). These models have excellent face and construct validity and have led to major insights into the neurobiological mechanisms of addiction. Animal models remain a key heuristic approach to elucidation of the pathophysiology and treatment of psychiatric disorders.

Chronic bupropion attenuated the anhedonic component of nicotine withdrawal in rats via inhibition of dopamine reuptake in the nucleus accumbens shell

Bupropion, a dopamine reuptake inhibitor, is an effective therapy for smoking cessation, but the behavioral and neurochemical mechanisms mediating its antismoking properties are relatively unknown. To explore the hypothesis that bupropion ameliorates nicotine withdrawal partly by a dopamine-dependent mechanism, we investigated the effects of chronic bupropion on potassium-stimulated dopamine overflow in the nucleus accumbens shell in nicotine-withdrawing rats. We also assessed the effects of chronic bupropion on behavioral aspects of nicotine withdrawal measured by elevations in brain reward thresholds and somatic signs of withdrawal. Rats were treated with nicotine or saline for 7 days and then coadministration of bupropion or saline was initiated. After 14 days of coadministration of bupropion/saline and nicotine/saline, nicotine/saline administration was terminated, whereas bupropion/saline administration continued. These conditions mimic bupropion administration in human smokers. Cessation of nicotine administration in non-bupropion-treated rats elevated reward thresholds reflecting a reward deficit, increased somatic signs and diminished potassium-evoked dopamine overflow in the nucleus accumbens shell. Chronic bupropion lowered reward thresholds and increased potassium-evoked dopamine release regardless of previous nicotine exposure, possibly by inhibition of dopamine reuptake, and thus attenuated the anhedonic and neurochemical effects of nicotine withdrawal. Chronic bupropion blocked withdrawal-associated increased somatic signs. Finally, acute experimenter-administered nicotine enhanced brain reward function equally in all groups, indicating that bupropion does not alter the reward-facilitating effects of experimenter-administered nicotine. In conclusion, the bupropion-induced increase in extracellular dopamine in the nucleus accumbens shell may ameliorate the anhedonia associated with nicotine withdrawal, which in turn may facilitate smoking cessation.

Conditioned nicotine withdrawal profoundly decreases the activity of brain reward systems.

Withdrawal from nicotine decreases the activity of brain reward systems, measured in rats by elevations of intracranial self-stimulation (ICSS) thresholds. This reward deficit is hypothesized to contribute to the persistence of the tobacco habit in tobacco smokers. Accumulating evidence suggests that aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via pavlovian conditioning processes. Here we investigated whether hedonically neutral stimuli repeatedly paired with nicotine withdrawal gained "affective valence" such that withdrawal-associated conditioned stimuli alone decreased brain reward function. Nicotine-dependent rats were presented with a light/tone conditioned stimulus and injected with the nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE; 3 mg/kg) for 4 d consecutively; ICSS thresholds were assessed before and immediately after DHbetaE injection. On the test day, the rats were presented with the conditioned stimulus and injected with saline; next, ICSS thresholds were assessed. During conditioning sessions, DHbetaE elevated reward thresholds, and the magnitude by which thresholds were elevated increased during successive conditioning sessions. These data suggest that withdrawal-associated conditioned stimuli potentiated the magnitude of nicotine withdrawal as their motivational significance increased. Most importantly, on the test day, the conditioned stimulus alone elevated reward thresholds. Similarly, in a separate experiment, withdrawal-associated cues elevated reward thresholds in morphine-dependent rats. These data provide the first empirical verification that conditioned nicotine withdrawal may occur after exposure to withdrawal-paired cues. Moreover, these data demonstrate that withdrawal-paired conditioned stimuli attain negative affective valence and can decrease the activity of brain reward systems, mimicking the reward deficit observed during withdrawal from nicotine and other addictive drugs.

Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function.

Phencyclidine (PCP) is a drug of abuse that has rewarding and dysphoric effects in humans. The complex actions of PCP, and PCP withdrawal in particular, on brain reward function remain unclear. The purpose of the present study was to characterize the effects of withdrawal from acute and chronic PCP treatment on brain reward function in rats. A brain stimulation reward procedure was used to evaluate the effects of acute PCP injection (0, 5, or 10 mg/kg) or chronic PCP treatment (0, 10, 15, or 20 mg/kg/day for 14 days delivered via subcutaneous osmotic minipumps) on brain reward function. Withdrawal from acute administration of 5 and 10 mg/kg PCP produced a decrease in brain reward function as indicated by a sustained elevation in brain reward thresholds. When administered chronically, 10, 15, or 20 mg/kg/day PCP induced a progressive dose-dependent potentiation of brain stimulation reward, while cessation of the treatment resulted in significant elevations in reward thresholds reflecting diminished reward. Specifically, withdrawal from 15 or 20 mg/kg/day PCP induced a depression in brain reward function that lasted for the entire month of observation. These results indicate that prolonged continuous administration of high PCP doses facilitates brain stimulation reward, while withdrawal from acute high PCP doses or chronic PCP treatment results in a protracted depression of brain reward function that may be analogous to the dysphoric and anhedonic symptoms observed in PCP dependence, depression, and schizophrenia.

Both GABA B receptor agonist and antagonists decreased brain stimulation reward in the rat

The present experiments were designed to determine the role of GABA(B) receptor function on brain stimulation reward. Using a discrete-trial current-intensity threshold procedure, dose-effect functions were generated for the GABA(B) receptor agonist CGP 44532 (0-1.0 mg/kg, s.c.) and the GABA(B) receptor antagonists CGP 56433A (0-10.0 mg/kg, s.c.) and CGP 51176 (0-300.0 mg/kg, s.c.) on brain reward thresholds in rats. The GABA(B) receptor antagonists CGP 56433A and CGP 51176 were used also to examine interaction effects with the GABA(B) receptor agonist CGP 44532 on reward thresholds. Administration of the highest doses of both the GABA(B) receptor agonist and antagonists elevated reward thresholds. Thus, both the agonist and antagonists used induced a reward decrement when administered separately. In addition, the co-administration of either of the two receptor antagonists with the agonist induced an additive effect on thresholds, rather than blocking the agonist-induced threshold elevations. These results suggest that activation of GABA(B) receptors modulates intracranial self-stimulation behavior in a complex fashion, possibly through differential effects of GABA(B) agonists and antagonists on pre- and post-synaptic GABA(B) receptors.

Role of Adenosine A2 Receptors in Brain Stimulation Reward under Baseline Conditions and during Cocaine Withdrawal in Rats

The present experiments tested the hypothesis that adenosine A2 receptors are involved in central reward function. Adenosine receptor agonists or antagonists were administered to animals that had been trained to self-stimulate in a rate-free brain stimulation reward (BSR) task that provides current thresholds as a measure of reward. The adenosine A(2A) receptor-selective agonists 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680) (0.1-1.0 mg/kg) and 2-[(2-aminoethylamino)carbonylethyl phenylethylamino]-5'-N-ethylcarboxamido adenosine (APEC) (0.003-0.03 mg/kg) elevated reward thresholds without increasing response latencies, a measure of performance. Specifically, CGS 21680 had no effect on response latency, whereas APEC shortened latencies. Bilateral infusion of CGS 21680 (3, 10, and 30 ng/side), directly into the nucleus accumbens, elevated thresholds but shortened latencies. The highly selective A(2A) antagonist 8-(3-chlorostyryl)caffeine (0.01-10.0 mg/kg) and the A2-preferring antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (0.3-10.0 mg/kg) did not alter thresholds or latencies, but DMPX (1.0, 10.0 mg/kg) blocked the threshold-elevating effect of APEC (0.03 mg/kg). In another study, repeated administration of cocaine (eight cocaine injections of 15 mg/kg, i.p., administered over 9 hr) produced elevations in thresholds at 4, 8, and 12 hr after cocaine. DMPX (3 and 10 mg/kg), administered before both the 8 and 12 hr post-cocaine self-stimulation tests, reversed the threshold elevation produced by cocaine withdrawal. These results indicate that stimulating adenosine A(2A) receptors diminishes BSR without producing performance deficits, whereas blocking adenosine receptors reverses the reward impairment produced by cocaine withdrawal or by an A(2A) agonist. These findings indicate that adenosine, via A(2A) receptors, may inhibit central reward processes, particularly during the neuroadaptations associated with chronic drug-induced neuronal activation.

Neuronal nicotinic receptor agonists as potential therapeutic agents for Alzheimer's disease

The effects of the high-efficacy D1 receptor agonist SKF 81297 and the D2/3 receptor agonist 7-OH-DPAT on brain stimulation reward thresholds and on response latencies in responding for the stimulation, were compared to the effects of subtype-selective receptor antagonists and a dopamine uptake blocker. SKF 81297 produced dose-dependent elevations in reward thresholds but did not alter response latencies. In contrast, 7-OH-DPAT produced inconsistent reward threshold elevations, yet dose dependently increased response latencies. Both the dopamine D1 receptor antagonist SCH 23390 and the D2 antagonist raclopride elevated reward thresholds, but only raclopride significantly increased response latencies. The dopamine uptake inhibitor GBR 12909 lowered reward thresholds and did not influence response latencies. The present results provide a clear demonstration that a selective, high-efficacy D1 receptor agonist elevates brain stimulation reward thresholds without producing performance deficits. Furthermore, it was observed that the effects upon reward measures of D1-selective compounds, but not D2/D3-selective compounds, are dissociable from their effects upon response latency in this task. These results are discussed with regard to a distinction between the effects of indirect and direct dopamine agonists on reward thresholds, a distinction that does not depend upon the subtype-selectivity of the direct agonists tested.

A Dopamine D 1 Agonist Elevates Self-Stimulation Thresholds : Comparison to Other Dopamine-Selective Drugs

The effects of the high-efficacy D1 receptor agonist SKF 81297 and the D2/3 receptor agonist 7-OH-DPAT on brain stimulation reward thresholds and on response latencies in responding for the stimulation, were compared to the effects of subtype-selective receptor antagonists and a dopamine uptake blocker. SKF 81297 produced dose-dependent elevations in reward thresholds but did not alter response latencies. In contrast, 7-OH-DPAT produced inconsistent reward threshold elevations, yet dose dependently increased response latencies. Both the dopamine D1 receptor antagonist SCH 23390 and the D2 antagonist raclopride elevated reward thresholds, but only raclopride significantly increased response latencies. The dopamine uptake inhibitor GBR 12909 lowered reward thresholds and did not influence response latencies. The present results provide a clear demonstration that a selective, high-efficacy D1 receptor agonist elevates brain stimulation reward thresholds without producing performance deficits. Furthermore, it was observed that the effects upon reward measures of D1-selective compounds, but not D2/D3-selective compounds, are dissociable from their effects upon response latency in this task. These results are discussed with regard to a distinction between the effects of indirect and direct dopamine agonists on reward thresholds, a distinction that does not depend upon the subtype-selectivity of the direct agonists tested.

Decreased brain reward produced by ethanol withdrawal.

Abstinence from chronic administration of various drugs of abuse such as ethanol, opiates, and psychostimulants results in withdrawal syndromes largely unique to each drug class. However, one symptom that appears common to these withdrawal syndromes in humans is a negative affective/motivational state. Prior work in rodents has shown that elevations in intracranial self-stimulation (ICSS) reward thresholds provide a quantitative index that serves as a model for the negative affective state during withdrawal from psychostimulants and opiates. The current study sought to determine whether ICSS threshold elevations also accompany abstinence from chronic ethanol exposure sufficient to induce physical dependence. Rats prepared with stimulating electrodes in the lateral hypothalamus were trained in a discrete-trial current-intensity ICSS threshold procedure; subsequently they were subjected to chronic ethanol administration in ethanol vapor chambers (average blood alcohol level of 197 mg/dl). A time-dependent elevation in ICSS thresholds was observed following removal from the ethanol, but not the control, chambers. Thresholds were significantly elevated for 48 hr after cessation of ethanol exposure, with peak elevations observed at 6-8 hr. Blood alcohol levels were directly correlated with the magnitude of peak threshold elevation. Ratings of traditional overt signs of withdrawal showed a similar time course of expression and resolution. The results suggest that decreased function of reward systems (elevations in reward thresholds) is a common element of withdrawal from chronic administration of several diverse classes of abused drugs.