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PubMed2005

Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome.

In this review, we described the neural substrates underlying Reward Deficiency syndrome which, in turn, is posited to underlie alcohol dependency. Alcoholism is a complex, multifactorial disorder that results from the interplay between genetic and environmental factors. The D(2) dopamine receptor (DRD(2)) has been associated with pleasure, and the DRD(2) A1 allele has been referred to as a reward gene. Evidence suggests that there is a tripartite interaction involving dopamine receptor deficiency, a propensity to abuse alcohol, and reduced sensitivity to rewards. This interaction relies heavily on genetic characteristics of the individual, with certain ethnic groups having a greater tendency toward alcoholism than others. The DRD(2) has been one of the most widely studied in neuropsychiatric disorders in general, and in alcoholism and other addictions in particular. The dopamine D2 (DRD2) gene, and especially its allele TaqI A1 allele and its receptor, also may be involved in comorbid antisocial personality disorder symptoms, high novelty seeking, and related traits. The mesocorticolimbic dopaminergic pathway system plays an especially important role in mediating reinforcement by abused drugs, and it may be a common denominator for addictions such as alcoholism. When the mesocorticolimbic dopamine reward system dysfunctions (perhaps caused by certain genetic variants), the end result is Reward Deficiency syndrome and subsequent drug-seeking behaviors. Reward Deficiency syndrome refers to the breakdown of the reward cascade, and resultant aberrant conduct, due to genetic and environmental influences. Alcohol and other drugs of abuse, as well as most positive reinforcers, cause activation and neuronal release of brain dopamine, which can decrease negative feelings and satisfy abnormal cravings. A deficiency or absence of DRD(2) receptors then predisposes individuals to a high risk for multiple addictive, impulsive, and compulsive behaviors. Although other neurotransmitters (e.g., glutamate, gamma-aminobutyric acid (GABA), and serotonin) may be important in determining the rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and for reinstating drug use during protracted abstinence. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

Alcoholism↗
PubMed1996

Peripheral post-training administration of 4-OH amphetamine enhances retention of a reduction in reward magnitude.

This experiment examined the effect of post-training systemic (sc) injections of 4-OH amphetamine on memory for a reduction in reward. Rats were trained to run in a straight alley (six trials per day, 30-s intertrial interval) and received either 1 or 10 45-mg sucrose pellets on each trial. On Day 8, rats receiving 10 pellets were shifted to the 1-pellet reward. Shifted rats displayed a characteristic increase in response latencies typically attributed to an aversive emotional response to reward reduction. Immediately after the reward shift, all rats received an injection of either 2 mg/kg of 4-OH amphetamine or the equivalent volume of physiological saline. The rats were then returned to their home cages for 6 days without further training. On Day 15 the rats were returned to training, all with 1 sucrose pellet as reward. The performance of unshifted rats was comparable to that on Day 8 and the first trial performance of shifted rats given post-training saline was not significantly different from that of unshifted rats. Further, the shifted saline group's mean latencies for the entire training block on Day 15 were comparable to their mean latencies on Day 8. These findings suggest that the shifted saline rats did not remember the prior reward reduction on Day 8. In contrast, the shifted rats given post-training 4-OH amphetamine displayed first trial latencies that were longer than those of all other groups on Day 15. Additionally, on the entire training block on Day 15 the latencies of the shifted 4-OH amphetamine group were longer than those recorded on Day 8, indicating that shifted 4-OH amphetamine rates retained memory of the prior reward reduction. These findings suggest that post-training activation of peripheral adrenergic systems by 4-OH amphetamine enhances the retention for aversive emotional consequences elicited by reward reduction.

Amphetamine↗
PubMed1996

Feeding, drug abuse, and the sensitization of reward by metabolic need.

The incentive-motivating effects of external stimuli are dependent, in part, upon the internal need state of the organism. The increased rewarding efficacy of food as a function of energy deficit, for example, has obvious adaptive value. The enhancement of food reward extends, however, to drugs of abuse and electrical brain stimulation, probably due to a shared neural substrate. Research reviewed in this paper uses lateral hypothalamic electrical stimulation to probe the sensitivity of the brain reward system and investigate mechanisms through which metabolic need, induced by chronic food restriction and streptozotocin-induced diabetes, sensitizes this system. Results indicate that sensitivity to rewarding brain stimulation varies inversely with declining body weight. The effect is not mimicked by pharmacological glucoprivation or lipoprivation in ad libitum fed animals; sensitization appears to depend on persistent metabolic need or adipose depletion. While the literature suggests elevated plasma corticosterone as a peripheral trigger of reward sensitization, sensitization was not reversed by meal-induced or pharmacological suppression of plasma corticosterone. Centrally, reward sensitization is mediated by opioid receptors, since the effect is reversed by intracerebroventricular (i.c.v.) infusion of naltrexone, TCTAP (mu antagonist) and nor-binaltorphimine (kappa antagonist). The fact that these same treatments, as well as i.c.v. infusion of dynorphin A antiserum, block the feeding response to lateral hypothalamic stimulation suggests that feeding and reward sensitization are mediated by a common opioid mechanism. Using in vitro autoradiography, radioimmunoassays and a solution hybridization mRNA assay, brain regional mu and kappa opioid receptor binding, levels of prodynorphin-derived peptides, and prodynorphin mRNA, respectively, were measured in food-restricted and diabetic rats. Changes that could plausibly be involved in reward sensitization are discussed, with emphasis on the increased dynorphin A1-3 and prodynorphin mRNA levels in lateral hypothalamic neurons that innervate the pontine parabrachial nucleus, where mu binding decreased and kappa binding increased. Finally, the possible linkage between metabolic need and activation of a brain opioid mechanism is discussed, as is evidence supporting the relevance of these findings to drug abuse.

Animals↗
PubMed2004

A progressive ratio schedule of self-stimulation testing in rats reveals profound augmentation of d-amphetamine reward by food restriction but no effect of a "sensitizing" regimen of d-amphetamine.

RATIONALE: Prior research indicates that psychostimulant-induced sensitization is not expressed in lateral hypothalamic electrical self-stimulation (LHSS)-based measures of drug reward, although the augmenting effect of chronic food restriction is. Neuroadaptations within the brain dopamine system have been identified in both psychostimulant-sensitized and food-restricted animals. Consequently, a variant of the LHSS paradigm in which responding is particularly sensitive to changes in dopaminergic tone may be best suited to detect and compare effects of chronic d-amphetamine and food restriction. Instrumental responding on a progressive ratio (PR) schedule is more sensitive to dopaminergic manipulations than is responding on a continuous reinforcement (CRF) schedule, but has not previously been used to examine chronic psychostimulant and food restriction effects on LHSS-based measures of drug reward. OBJECTIVE: The first aim of this study was to determine whether a regimen of d-amphetamine treatment, that produces locomotor sensitization (5 mg/kg per day x5 days), increases the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The second aim, was to determine whether chronic food restriction produces a marked increase in the reward-potentiating effect of d-amphetamine in the PR LHSS protocol and, if so, whether it is reversible in parallel with body weight recovery when free feeding is restored. METHOD: Reward-potentiating effects of a challenge dose of d-amphetamine (0.25 mg/kg, IP) were measured in terms of the break point of LHSS responding on a PR schedule of reinforcement, in ad libitum fed and food-restricted rats. RESULTS: A regimen of d-amphetamine treatment that produced locomotor sensitization did not increase the break point for LHSS in the presence or absence of d-amphetamine. Chronic food restriction produced a marked increase in the break point-increasing effect of d-amphetamine (3-fold), which returned to baseline in parallel with body weight recovery over a 4-week period of restored free-feeding. CONCLUSIONS: A locomotor-sensitizing regimen of d-amphetamine treatment does not increase the rewarding effect of LH electrical stimulation or the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The augmenting effect of chronic food restriction on drug reward is mechanistically and functionally different from psychostimulant sensitization and may be controlled by signals associated with adipose depletion and repletion.

Animals↗
PubMed2004

Changes in food reward following smoking cessation: a pharmacogenetic investigation.

RATIONALE: Despite the high prevalence and public health significance of weight gain following smoking cessation, little is known about the underlying bio-behavioral mechanisms or effective therapies. OBJECTIVES: We evaluated the effects of bupropion on food reward following smoking abstinence and the moderating influence of genotype. METHODS: Seventy-one smokers of European ancestry were genotyped for the dopamine D2 receptor ( DRD2) Taq1 polymorphism and randomized to treatment with bupropion (300 mg) or placebo for smoking cessation. Subjects participated in two behavioral laboratory sessions during which the rewarding value of food was assessed using a behavioral economics measure: session 1 occurred prior to medication and before cessation of smoking; session 2 occurred following 3 weeks of medication and 1 week of sustained abstinence. RESULTS: Carriers of the DRD2 A1 minor allele exhibited significant increases in the rewarding value of food following abstinence from smoking, and these effects were attenuated by bupropion treatment ( P=0.03 for medication by genotype interaction). Further, higher levels of food reward at session 2 (post-quit) predicted a significant increase in weight by 6-month follow-up in the placebo group, but not in the bupropion-treated group ( P=0.006 for medication by food reward interaction). CONCLUSIONS: These results provide new evidence that the increase in body weight that occurs following smoking cessation is related to increases in food reward, and that food reward is partly determined by genetic factors. Bupropion's efficacy in attenuating abstinence-induced weight gain may be attributable, in part, to decreasing food reward.

Adult↗
PubMed2004

Paroxetine combined with a 5-HT(1A) receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats.

RATIONALE: "Diminished interest or pleasure" in rewarding stimuli is an affective symptom of amphetamine withdrawal and a core symptom of depression. An operational measure of this symptom is elevation of brain stimulation reward thresholds during drug withdrawal. Data indicated that increasing serotonin neurotransmission by co-administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the serotonin-1A receptor antagonist p-MPPI reversed reward deficits observed during drug withdrawal (Harrison et al. 2001). OBJECTIVES: We tested the hypothesis that increased serotonergic and noradrenergic neurotransmission, using the SSRI paroxetine which also inhibits noradrenaline reuptake, would alleviate affective aspects of amphetamine withdrawal. METHODS: A discrete-trial, current-threshold, self-stimulation procedure was used to assess brain reward function. The effects of paroxetine and p-MPPI alone and in combination were assessed in non-drug-withdrawing animals. We assessed also the effects of paroxetine and p-MPPI alone and in combination on reward deficits associated with amphetamine withdrawal. RESULTS: Paroxetine or p-MPPI alone had no effect on thresholds, while the co-administration of p-MPPI (3 mg/kg) and paroxetine (1.25 mg/kg) elevated thresholds in non-withdrawing rats. Amphetamine withdrawal resulted in threshold elevations. The co-administration of p-MPPI and paroxetine reduced the duration of amphetamine-withdrawal-induced reward deficits. CONCLUSIONS: Increased serotonergic and noradrenergic neurotransmission decreased reward function in non-withdrawing rats, while the same treatment reversed reward deficits associated with amphetamine withdrawal. Considering that paroxetine acts on both the serotonin and noradrenaline transporter, these results indicate that the affective symptoms of amphetamine withdrawal, similar to non-drug-induced depressions, may be, in part, mediated through reduced serotonergic and noradrenergic neurotransmission.

Affective Symptoms↗
PubMed2005

Roles of pedunculopontine tegmental cholinergic receptors in brain stimulation reward in the rat.

RATIONALE: The brainstem pedunculopontine tegmental nucleus (PPTg) is proposed to mediate hypothalamic self-stimulation reward via cholinergic activation of the ventral tegmental area (VTA). However, to date there is little direct evidence to support this hypothesis. OBJECTIVES: To further study the role of PPTg in hypothalamic self-stimulation reward. METHODS: By using in vivo microdialysis, the levels of extracellular acetylcholine (ACh) in the PPTg and VTA were detected during lateral hypothalamic (LH) self-stimulation in rats. Rate-frequency curve shift procedure was used to evaluate the effects of nonselective muscarinic antagonist scopolamine (1 approximately 100 microg/microl) and nicotinic antagonist mecamylamine (5 approximately 100 microg/microl) microinjected into the PPTg on the rewarding efficacy of LH self-stimulation. Subsequently, the drugs were injected into the PPTg, and the extracellular ACh in the VTA was measured. RESULTS: LH self-stimulation produced a concurrent ACh release in the PPTg and VTA. Intra-PPTg injection of scopolamine (100 microg/microl) significantly reduced the frequency threshold for LH self-stimulation reward, but nicotinic antagonist mecamylamine did not shift the threshold. However, mecamylamine (10, 25 microg/microl) injected into the PPTg robustly diminished the nicotine-potentiated LH self-stimulation reward. The extracellular ACh in the VTA was dramatically increased by intra-PPTg scopolamine (10, 100 microg/microl), but not by mecamylamine. CONCLUSIONS: Results confirm that PPTg plays an important role in brain stimulation reward by modulating the cholinergic activity of the VTA. The PPTg muscarinic receptors contribute to an inhibitory modulation of reward effects by self-stimulation, whereas nicotinic receptors seem to be more involved in nicotine potentiation of brain stimulation reward.

Acetylcholine↗
PubMed2006

The debate over dopamine's role in reward: the case for incentive salience.

INTRODUCTION: Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward. There are three competing explanatory categories: 'liking', learning, and 'wanting'. Does dopamine mostly mediate the hedonic impact of reward ('liking')? Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli ('wanting')? Each hypothesis is evaluated here, and it is suggested that the incentive salience or 'wanting' hypothesis of dopamine function may be consistent with more evidence than either learning or 'liking'. In brief, recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic 'liking' for sensory pleasures. Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal 'wanting', and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. That interaction sets the stage to cause compulsive 'wanting' in addiction, but also provides opportunities for experiments to disentangle 'wanting', 'liking', and learning hypotheses. Results from studies that exploited those opportunities are described here. CONCLUSION: In short, dopamine's contribution appears to be chiefly to cause 'wanting' for hedonic rewards, more than 'liking' or learning for those rewards.

Animals↗
PubMed1998

Ethanol induces impulsive-like responding in a delay-of-reward operant choice procedure: impulsivity predicts autoshaping.

Autoshaping conditioned responses (CRs) are reflexive and targeted motor responses expressed as a result of experience with reward. To evaluate the hypothesis that autoshaping may be a form of impulsive responding, within-subjects correlations between performance on autoshaping and impulsivity tasks were assessed in 15 Long-Evans hooded rats. Autoshaping procedures [insertion of retractable lever conditioned stimulus (CS) followed by the response-independent delivery of food (US)] were followed by testing for impulsive-like responding in a two-choice lever-press operant delay-of-reward procedure (immediate small food reward versus delayed large food reward). Delay-of-reward functions revealed two distinct subject populations. Subjects in the Sensitive group (n=7) were more impulsive-like, increasing immediate reward choices at longer delays for large reward, while those in the Insensitive group (n=8) responded predominantly on only one lever. During the prior autoshaping phase, the Sensitive group had performed more autoshaping CRs, and correlations revealed that impulsive subjects acquired the autoshaping CR in fewer trials. In the Sensitive group, acute injections of ethanol (0, 0.25, 0.50, 1.00, 1.50 g/kg) given immediately before delay-of-reward sessions yielded an inverted U-shaped dose-response curve with increased impulsivity induced by the 0.25, 0.50, and 1.00 g/kg doses of ethanol, while choice strategy of the Insensitive group was not influenced by ethanol dose. Ethanol induced impulsive-like responding only in rats that were flexible in their response strategy (Sensitive group), and this group also performed more autoshaping CRs. Data support the hypothesis that autoshaping and impulsivity are linked.

Animals↗
PubMed1981

Effects of GABAergic drugs on brain stimulation reward as assessed by a 'threshold' method.

Rats were trained in a two-lever intracranial self-stimulation (ICSS) paradigm. Responses at the first lever delivered brain stimulation which was decreased in magnitude after every 5 responses. Responses at the second re-set the available current to its original value. The current level at which the re-set responses occurred was defined as the 'reward threshold'. The rate of responding at each current level during the stimulate-re-set sequence was also determined. This paradigm, therefore, allowed simultaneous rate-independent and rate-dependent assessment of ICSS. Decreased reward, as demonstrated by an elevated 'reward threshold', was produced in a dose-related manner by the GABA antagonist picrotoxin. Similar effects could be produced by making each stimulation train less rewarding, i.e. by reducing the amount of charge delivered per stimulation. Conversely, increased reward, as indicated by a lower 'reward threshold', was produced in a dose-related manner by the GABA-mimetic muscimol, or by increasing the amount of charge delivered by each stimulation. Response rats were not significantly changed at any stimulation intensity following treatment with either drug. These data suggest that the effects of picrotoxin and muscimol on ICSS are due to changed perception of reward and not to altered performance of the lever pressing task. An important role for GABA in the mediation of reward needs, therefore, to be considered.

Animals↗
PubMed1994

The effects of systemic and intracerebral injections of D1 and D2 agonists on brain stimulation reward.

That dopamine (DA) plays a role in reward-related learning is well documented but the mechanisms through which it acts are not well understood. The present set of experiments investigated the role of DA receptor subtypes within DA-innervated forebrain regions in brain stimulation reward (BSR). Thirty-two rats were implanted with electrodes in the ventral tegmental area (VTA) and cannulae aimed at the caudal nucleus accumbens (NAcc), the caudate-putamen (CP) or cortex. Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding (thresholds). After BSR thresholds stabilized rats received treatments with DA agonists and their effects on thresholds were analyzed. Systemic treatments consisted of injections of (+)-amphetamine (1.0 mg/kg, i.p., 10 min before testing), the D2 agonist quinpirole (1.0 mg/kg, i.p., 10 min before testing), the novel D1 agonist A-77636 (3.0 mg/kg, s.c., 90 min before testing) or their vehicle (distilled H(2)0). Central treatments consisted of microinjections of quinpirole (0.3-10.0 micrograms/0.5 microliter) directly into the caudal NAcc, CP or cortex or A-77636 (30 micrograms/0.5 microliter) into the caudal NAcc or CP. Results showed that all three agonists, when injected systemically, significantly reduced the threshold frequency required for VTA BSR, indicating a potentiative effect on reward. Central injections of quinpirole in the caudal NAcc, CP or cortex produced significant increases in BSR thresholds indicative of reduced rewarding efficacy of stimulation. Central injections of A-77636 into the caudal NAcc, but not the CP, were associated with a reduction in VTA BSR thresholds, suggesting an increase in reward. These results suggest that stimulation of D1 or D2 receptors enhances the rewarding effect of brain stimulation. In the case of the systemic quinpirole enhancement of reward, the present results suggest that this may not occur in the caudal NAcc, CP or cortex. Finally, the present results suggest that D1 receptor stimulation in the caudal NAcc can facilitate reward-related learning.

Adamantane↗
PubMed1982

Dopaminergic and noradrenergic inhibition of hypothalamic self-stimulation: differentiation of reward and performance effects.

Dopaminergic and noradrenergic inhibition of lateral hypothalamic self-stimulation was investigated in a new signalled, discrete-trials shuttle-box paradigm. The differential inhibitory effects of drugs and stimulation frequency reductions within small blocks of trials differentiate reward inhibition from a variety of performance deficits. They further differentiate among the deficits produced by fatigue, sedation, dyskinesias, akinesia and sensory disruption. Pimozide's selective inhibition of the first response within each block of trials shows that its inhibition of self-stimulation is not due to either an inhibition of reward or to a general performance deficit. Instead, it suggests that pimozide specifically inhibits the initiation of motor responding. Pimozide-induced akinesia appears to be partly reversible by hypothalamic stimulation. Thus the pimozide data do not support a role for dopamine in mediating brain-stimulation reward. Since the inhibitory effects of clonidine were very similar to those of pimozide, it is suggested that clonidine also produces a stimulation-reversible akinesia. Thus the clonidine data do not support a role for noradrenaline in mediating brain-stimulation reward. LU 5-003, which selectively inhibits the presynaptic reuptake of noradrenaline, inhibited self-stimulation in almost exactly the same way as did reducing reward by reducing stimulation frequency. These data do support a primary role for noradrenaline in mediating brain-stimulation reward. However, it is suggested that LU 5-003 inhibits self-stimulation, not by inhibiting reward, but by enhancing reward and making the electrical stimulation superfluous.

Animals↗
PubMed1992

Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations.

A discrete-trial current-threshold intracranial self-stimulation (ICSS) paradigm has been used extensively to examine the effects of drugs on reward thresholds. However, there is little work to date validating that this specific procedure measures reward. The purpose of the present study was to establish the construct validity of this procedure by testing the procedure's ability to measure reward effects and to discriminate these reward effects from performance effects. The discrete-trial ICSS procedure provides four measures: current thresholds, response latency, extra responses and time-out responses. The effects of a performance manipulation (variations in the force required to operate the manipulandum) and of a reward manipulation (variations in the train duration of the electrical stimulation) were evaluated on the four measures. Reward effects were reflected primarily in changes in thresholds, with no effect on any of the other three measures. Conversely, performance effects were reflected primarily in changes in response latency, extra responses and time-out responses, with only a small effect on thresholds. Finally, the paradigm's potential as a useful tool in the elucidation of the neurobiological basis of reward was demonstrated by investigating the effects of two pharmacological agents, cocaine and curare, on the four measures derived from the discrete-trial current-threshold ICSS procedure. The results suggest that the discrete-trial current-threshold procedure can readily discriminate reward from performance treatments.

Animals↗
PubMed1981

The effects of pimozide and of reward omission on fixed-interval behavior of rats maintained by food and electrical brain stimulation.

Pimozide (0.125 to 2.0 mg/kg) was administered to rats whose behavior was maintained by a fixed-interval schedule in which the reward was either food (Experiment 1) or electrical stimulation of the brain (Experiment 2). The effects of the drug were compared with the effects of withholding reward (i.e., extinction) in both experiments. Reward omission and administration of pimozide both resulted in decreases in overall rates of responding and increases in the time taken by the subjects to complete a specified number of fixed-intervals. The typical patterning of responding during the sessions of reward omission was also characteristic of the effects of pimozide with food reward but not with brain stimulation reward. The duration of trains of brain stimulation which was under the control of the subjects in Experiment 2, was not altered by administration of pimozide. The differences between the effects of pimozide on behavior maintained by intermittent food reward or by intermittent brain stimulation reward limits a global interpretation of the effects of neuroleptics.

Animals↗
PubMed1991

Marijuana's interaction with brain reward systems: update 1991.

The most pervasive commonality amongst noncannabinoid drugs of abuse is that they enhance electrical brain stimulation reward and act as direct or indirect dopamine agonists in the reward relevant dopaminergic projections of the medial forebrain bundle (MFB). These dopaminergic projections constitute a crucial drug sensitive link in the brain's reward circuitry, and abused drugs derive significant abuse liability from enhancing these circuits. Marijuana and other cannabinoids were long considered "anomalous" drugs of abuse, lacking pharmacological interaction with these brain reward substrates. It is now clear, however, that delta 9-tetrahydrocannabinol (delta 9-THC), marijuana's principal psychoactive constituent, acts on these brain reward substrates in strikingly similar fashion to noncannabinoid drugs of abuse. Specifically, delta 9-THC enhances MFB electrical brain stimulation reward, and enhances both basal and stimulated dopamine release in reward relevant MFB projection loci. Furthermore, delta 9-THC's actions on these mechanisms is naloxone blockable, and delta 9-THC modulates brain mu and delta opioid receptors. This paper reviews these data, suggests that marijuana's interaction with brain reward systems is fundamentally similar to that of other abused drugs, and proposes a specific neural model of that interaction.

Animals↗
PubMed1994

Nitric oxide synthesis inhibition does not affect brain stimulation reward.

The effect of nitric oxide synthesis inhibition on brain stimulation reward was examined. A wide range of doses of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 30-300 mg/kg IP) failed to affect frequency thresholds for brain stimulation reward. The effect of L-NAME on cocaine's facilitation of brain stimulation reward was also examined. Nitric oxide synthesis inhibition had no effect on cocaine's ability to lower reward thresholds for electrical brain stimulation. Despite reports that nitric oxide may modulate dopamine release, these data suggest that nitric oxide is not involved in the dopamine-dependent rewarding effect of electrical brain stimulation or the reward facilitation produced by cocaine's enhancement of dopaminergic activity. Because L-NAME potently decreases cerebral blood flow, its lack of effect on cocaine-enhanced brain stimulation reward has additional significance. The failure of a moderate dose of L-NAME (30 mg/kg IP) to attenuate cocaine's lowering of reward thresholds argues against pharmacokinetic explanations of L-NAME's effect on other cocaine-induced behaviors.

Animals↗
PubMed2005

Partial deletion of glial cell line-derived neurotrophic factor (GDNF) in mice: Effects on sucrose reward and striatal GDNF concentrations.

Glial cell line derived neurotrophic factor (GDNF) has been reported to alter the reward value of abused substances such as alcohol and cocaine as well as neural circuitry underlying reward. The role of GDNF in reward was further characterized in the present study using operant procedures to determine the value of a natural reward, sucrose, in GDNF heterozygous (GDNF+/-) mice versus wild-type (WT) mice. Female mice were tested for 2 h daily for 10 days in operant chambers with 2 levers. Responses on the correct lever allowed 5-s access to a dipper cup containing 15% sucrose. GDNF+/- and WT mice did not differ with acquisition or accuracy of responding. GDNF+/- mice emitted more responses than WT mice for sucrose, suggesting enhanced reward value of sucrose in these mice. In a separate experiment, concentrations of GDNF protein in striatal tissue were determined at 4, 8, and 12 months of age and found to be 38%-68% lower in GDNF+/- than WT mice at all three ages. Together, the results are consistent with an emerging literature indicating that reduced GDNF levels augment reward and increased GDNF levels attenuate reward, suggesting that GDNF plays an important role in neural systems mediating reward.

Aging↗
PubMed2006

Effects of central leptin infusion on the reward-potentiating effect of D-amphetamine.

It was previously reported that chronic food restriction and maintenance of rats at 75-80% of initial body weight enhanced the reward-potentiating effect of D-amphetamine in the lateral hypothalamic self-stimulation (LHSS) paradigm. Moreover, the enhancement reversed in parallel with body weight recovery when ad libitum access to food was reinstated. The present study tested the hypothesis that hypoleptinemia during food restriction is necessary for expression of enhanced drug reward. In Experiment 1, intracerebroventricular (i.c.v.) infusion of leptin (0.5 microg/0.5 microl/hr for 8 days) in food-restricted rats did not alter the rewarding effect of D-amphetamine (0.5 mg/kg, i.p.). Considering that i.c.v. leptin may not diffuse into deep brain regions where direct effects on drug reward sensitivity may be exerted, effects of acute bilateral microinjection of leptin (0.5 microg) in ventral tegmental area and nucleus accumbens were tested in Experiment 2 and found to have no effect. In Experiment 3, chronic i.c.v. leptin infusion in ad libitum fed rats decreased food intake and body weight and enhanced the rewarding effect of D-amphetamine. Sensitivity to D-amphetamine returned to normal as body weight recovered following cessation of leptin infusion. This result suggests that weight loss, whether from hormone-induced appetite suppression or experimenter-imposed food restriction, is sufficient to enhance drug reward sensitivity. Experiment 4 tested whether food restriction in the absence of body weight loss alters drug reward sensitivity. Rats received chronic i.c.v. infusion of the orexigenic melanocortin receptor antagonist, SHU9119 (0.02 microg/0.5 microl/hr for 12 days), and a subset were pair-fed to vehicle-infused controls. Although these subjects ingested approximately 50% of the amount of food ingested by free-feeding SHU9119-infused rats, they displayed no weight loss and no change in sensitivity to D-amphetamine. Together, results of this study support the importance of weight loss, but not leptin, in the enhancement of drug reward sensitivity.

Animals↗