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PubMed1992

Localization of drug reward mechanisms by intracranial injections.

Intracranial drug injections are useful in localizing brain areas where drugs of abuse initiate their habit-forming actions. However, serious methodological problems accompany such studies. Pharmacological controls are necessary to assess non-receptor-mediated local actions of the drug, anatomical controls are necessary to rule out drug efflux to distal sites of action, and behavioral controls are necessary to separate rewarding from general activating effects of drugs. Five brain sites have been advanced as sites of rewarding opiate actions: the ventral tegmental area (VTA), nucleus accumbens septi (NAS), lateral hypothalamus, periaqueductal gray, and hippocampus. Current evidence appears to confirm two of these--VTA and NAS; evidence is currently incomplete in the case of the hippocampus and is conflicting in the case of the lateral hypothalamus and periaqueductal gray. Two sites have been advanced as sites of rewarding psychomotor stimulant actions: NAS and the frontal cortex; each site seems implicated, but puzzling differences between amphetamine and cocaine findings remain to be resolved. Each of the clearly implicated sites is local to dopamine cell bodies or dopamine terminals that have been implicated in the rewarding effects of brain stimulation, food, and sex.

Animals↗
PubMed2001

Only self-paced mating is rewarding in rats of both sexes.

When rats are mated in a traditional mating chamber (with one male and one female) in which the male dictates the pace of the copulatory sequence, males develop a reward state as evaluated by conditioned place preference (CPP). In this mating situation no reward state is induced in females. However, when female rats are able to control (pace) the rate of sexual stimulation, thereby reducing the aversive consequences associated with mating, a clear CPP is observed. In the present study the CPP paradigm was used to determine whether if the reinforced state induced by coital interactions in male rats can be maintained when females pace the sexual interaction. Adult male and female rats were mated in one of two different conditions: (1) where subjects were able to pace their coital interactions or (2) where subjects were not able to pace their sexual contacts. The results showed that when males had control over the sexual interaction they developed a clear place preference while males that mated with females that paced their coital contacts did not develop CPP. Similarly, only females that were able to pace their sexual contacts developed place preference. These results suggest that coital interactions in males, as well as in females, can induce a reward state only when they are able to control the sexual interaction. Under seminatural conditions sexual behavior in rats is highly promiscuous, they mate in groups and repeatedly change partners in the middle of copulation. This behavioral sequence allows both, male and female to control the rate of sexual interaction, assuring the induction of a reward state outlasting the actual performance of coital responses.

Animals↗
PubMed2002

The amygdala but not the hippocampus is involved in pattern separation based on reward value.

A total of 32 male Long-Evans rats were tested on a modified version of Flaherty, Turovsky, and Krauss's (1994) anticipatory contrast paradigm to assess pattern separation for reward value. Prior to testing, each rat received either a control, a hippocampal, or an amygdala lesion. In the home cage, each rat was allowed to drink a water solution containing 2% sucrose for 3 min followed by a water solution containing 32% sucrose for 3 min. Across 10 days of testing, the rats in each lesion group showed significantly increased anticipatory discriminability as a function of days. To assess the operation of a pattern separation mechanism, each rat was then tested using the same procedure except the 2% solution was followed by a 16% solution for 10 days and then by an 8% solution for 10 days. Control and hippocampal-lesioned rats continued to show high discriminability when the 2% solution was followed by a 16% solution; however, the amygdala-lesioned rats showed low anticipatory discriminability. On trials where the 2% sucrose solution was followed by an 8% sucrose solution, all groups showed low discriminability scores, suggesting that when two reward values are very similar even control animals are not able to separate the reward values in memory. However, the results of a preference task revealed that all groups can perceptually discriminate between a 2% and an 8% sucrose solution. The data suggest that the amygdala but not the hippocampus is involved in the separation of patterns based on reward value.

Amygdala↗
PubMed2002

Reward-based planning of motor selection in the rostral cingulate motor area.

The cingulate motor areas, located in the banks of the cingulate sulcus, constitute a portion of the cingulate cortex of primates. We here present experimental evidence showing that the rostral cingulate motor area (CMAr), but not the caudal one (CMAc) is crucial for the selection of future movements based on reward information. After muscimol injection into the CMAr, monkeys were impaired in selecting movements appropriately on the basis of the amount of reward obtained by performing correct movements. Furthermore, four types of cells in the CMAr were found to reflect a process intervening between detection of reward alteration and selection of a future movement. Each type of cell seems to be involved in responding to the quality of the reward, and to relay that information to change planned movements, and prepare a new movement.

Animals↗
PubMed1994

Reward and its control by dynorphin peptides.

Reward is a strong behavioral cue. It is argued that a sense of reward must be strictly controlled in time and magnitude to be functional. Central to the reward system is the mesolimbic dopamine pathway which is titillated by addictive drugs and alcohol. Rat lines or strains that voluntarily drink alcohol have lower dynorphin levels in relevant brain areas than those which avoid alcohol. Reward control may be a protective factor against addiction.

Alcohol Drinking↗
PubMed1990

Reward dominance and passive avoidance learning in adolescent psychopaths.

This study tests predictions that adolescent psychopaths are hyperresponsive to rewards (Quay, 1988) and deficient in passive avoidance learning (Newman & Kosson, 1986). Forty male adolescent juvenile offenders were divided into psychopaths and nonpsychopaths using cluster analysis. Subjects were administered a passive avoidance learning task which required learning when to respond to cards associated with either reward or punishment. Results showed a greater responsivity to reward in psychopaths, with no group differences in passive avoidance errors. Results lend support to the view that psychopaths tend to focus on the prospect of reward under conditions of mixed incentives and, when sufficiently motivated, are capable of improved performance. Together with findings of recent psychophysiological studies, these results suggest that adolescent psychopaths may have latent abilities which could have treatment implications.

Adolescent↗
PubMed1988

A community program to reward children's use of seat belts.

This paper reports on a community-wide effort to increase elementary school children's use of seat belts. Twenty-five schools serving over 9,000 children participated in a program of rewards (stickers, bumper strips, and chances on pizza dinners) administered by parent-teacher organization volunteers. Comprehensive observations were made at three representative schools. Categorization of compliance with safety rules required all passengers to be buckled into safety devices before the children received the rewards. The rewards, on average across schools, increased compliance from baseline of 18.1% to 62.4% during the interventions. Withdrawal of the rewards resulted in a decrease to 49% compliance, but this rate remained above baseline. The involvement of community groups and institutions in this safety program is highlighted.

Accidents, Traffic↗
PubMed1990

Acute morphine lowers brain stimulation reward thresholds in rats with depressed or elevated response rates.

The positively-reinforcing effect of acute morphine sulfate (MS) administration was assessed by concurrent rate-dependent and rate-independent measures of brain stimulation reward in male rats. An acute 4 mg/kg MS injection produced a rapid, statistically-significant decrease in reward threshold of 28.5%, when compared with saline control values, 45 min after injection. Response rates for brain stimulation delivery decreased by 60.6%, when compared with saline values during the period of maximum threshold change. Other animals, injected with an acute 1 mg/kg MS dose, exhibited significant threshold decreases (21.5%), relative to changes in saline values that occurred in a prior session, and response-rate increases of 23.1%, relative to saline-session changes, when the data were recorded 40 min after injection. The findings reported here demonstrate that the decreases in reward threshold produced by acute morphine administration are independent of the response-rate changes that occur and also support the idea that morphine's rewarding effect may be independent of the behavioral inhibition or activation that can result from the effects of different morphine doses.

Animals↗
PubMed1990

Increased sensitivity to amphetamine and reward-related stimuli following social isolation in rats: possible disruption of dopamine-dependent mechanisms of the nucleus accumbens.

These experiments compared isolation-reared and socially-reared rats in two complementary paradigms for measuring responding to signals of reward, both undrugged and following either systemic or intraaccumbens d-amphetamine (AMPH). In experiment 1, locomotor activity conditioned to food presentation was measured in rats exposed to a restricted feeding schedule. The interaction between this conditioned activity, AMPH administration (0.5, 2.0, 3.5, 5.0 mg/kg IP) and motivational state was measured. In experiment 2, hungry rats were trained to associate a compound light/noise stimulus with sucrose reward and were then implanted with guide cannulae in the nucleus accumbens. In the test phase, responding on one of two novel levers produced the compound stimulus (conditioned reinforcer; CR). Responses on the other lever had no effect. Each rat received four counterbalanced intra-accumbens infusions of AMPH (0, 3, 10, 20 micrograms). In both experiments, isolated rats responded more with stimuli associated with reward and this differential rearing effect was further exaggerated by AMPH. The isolation-induced sensitivity to these stimuli and to AMPH was critically dependent on motivational variables. Thus, in experiment 1 there were no differences between the groups when sated or during extinction and in experiment 2 the increased responding was restricted to the lever providing CR. Measurements of the locomotor response to intra-accumbens AMPH (0, 3, 10 micrograms) also revealed that isolated rats were more sensitive to a low dose of the drug when tested food-deprived in a relatively novel environment. These results suggest that the experience of isolation-rearing interacts either directly or indirectly with dopamine-dependent mechanisms of the nucleus accumbens to enhance the effects of reward-related stimuli.

Animals↗
PubMed2003

Cannabinoids: reward, dependence, and underlying neurochemical mechanisms--a review of recent preclinical data.

BACKGROUND AND RATIONALE: Starting with the discovery of an endogenous brain cannabinoid system with specific receptors and endogenous ligands, research in the cannabinoid field has accelerated dramatically over the last 15 years. Cannabis is the most used illicit psychotropic substance in the world but only recently have reliable preclinical models become available for investigating the rewarding and dependence-producing actions of its psychoactive constituent, delta9-tetrahydrocannabinol (THC). OBJECTIVES: The goal of this review is to examine the various animal models currently available that are being used to facilitate our understanding of the rewarding and dependence-producing actions of cannabinoids, which are central to their abuse liability, and of the neurochemical mechanisms that may underlie these actions of cannabinoids. RESULTS AND CONCLUSIONS: Recent demonstrations that strong and persistent intravenous self-administration behavior can be obtained in squirrel monkeys using a range of THC doses that are in agreement with the total intake and the single doses of THC normally self-administered by humans smoking marijuana cigarettes provides a reliable and direct tool for assessing the reinforcing effects of THC that are central to its abuse liability. In addition, recent demonstrations of persistent intravenous self-administration of synthetic cannabinoid CB1 receptor agonists by rats and mice and the development of genetically modified mice lacking specific cannabinoid receptors provide convenient rodent models for exploring underlying neurochemical mechanisms. Repeated demonstrations in rats that THC and synthetic CB1 agonists can induce conditioned place preferences or aversions, depending on details of dose and spacing, can reduce the threshold for intracranial self-stimulation behavior under certain conditions, and can serve as effective discriminative stimuli for operant behavior provide less direct, but more rapidly established, measures for investigating the rewarding effects of cannabinoids. Finally, there have been numerous recent reports of major functional interactions between endogenous cannabinoid, opioid, and dopaminergic neurotransmitter systems in areas such as analgesia, physical dependence and tolerance development, and drug reinforcement or reward. This provides an opportunity to search for drugs with the beneficial therapeutic effects of currently available cannabinoids or opioids but without undesirable adverse effects such as abuse liability.

Animals↗
PubMed2004

Inhibition of the morphine-induced rewarding effect by direct activation of spinal protein kinase C in mice.

RATIONALE: We previously demonstrated that the morphine-induced rewarding effect was attenuated under a neuropathic pain-like state following partial sciatic nerve ligation in rodents. Furthermore, the up-regulation of protein kinase C (PKC) activity in the spinal cord is considered to be the key factor for induction of hyperalgesia following sciatic nerve ligation. However, little direct evidence is available for the involvement of activated PKC in the spinal cord in reduction of rewarding effects induced by morphine under chronic pain-like state. OBJECTIVE: The present study was to investigate whether direct activation of spinal PKC by intrathecal (IT) administration of a specific PKC activator, phorbol 12,13-dibutyrate (PDBu) could produce hyperalgesia and suppress the place preference induced by morphine in mice. METHOD: The morphine-induced rewarding effect was investigated using the conditioned place preference method. Conditioning sessions (three for morphine, three for saline) were started 24 h after IT injection of PDBu or saline and conducted once daily for 6 days. On the day after the final conditioning session, a post-conditioning test was performed. RESULTS: IT-administered PDBu produced a long-lasting thermal hyperalgesia. Under these conditions, the place preference induced by morphine was abolished by a single IT pretreatment with PDBu. The effect was reversed by concomitant IT treatment with the specific PKC inhibitor Ro-32-0432. In contrast, IT-administered PDBu failed to affect the hyperlocomotion and supraspinal antinociception induced by morphine. CONCLUSION: The present findings suggest that activated PKC in the spinal cord with chronic pain-like hyperalgesia may play a substantial role in the suppression of the morphine-induced rewarding effect in mice with chronic pain-like hyperalgesia.

Animals↗
PubMed2005

Facilitation of brain stimulation reward by MK-801 (dizocilpine) may be independent of D2-like dopamine receptor stimulation in rats.

RATIONALE: Dopamine (DA) and glutamate (Glu) interactions in the mesocorticolimbic pathway may regulate motivation and reward and contribute to schizophrenia and drug abuse. We have recently demonstrated synergistic effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor blockade and D(2/3) DA receptor stimulation in brain stimulation reward (BSR). OBJECTIVES: This study was conducted to explore interactions between DA and Glu systems in BSR using the NMDA receptor antagonist MK-801 and the DA receptor agonists 7-OH-DPAT and apomorphine. METHODS: Systemic effects of these compounds were measured in male Sprague-Dawley rats using rate-frequency threshold analysis of ventral tegmental area (VTA) BSR (n=27). Effects of bilateral applications of MK-801 and 7-OH-DPAT into the nucleus accumbens (NAS) shell subregion were also investigated (n=10). RESULTS: MK-801 (0.03 or 0.13 mg kg(-1) i.p. or 0.66 mug intra-NAS) reduced reward thresholds while 7-OH-DPAT (0.03 mg kg(-1) s.c. or 5.0 microg intra-NAS) or apomorphine (0.05 mg kg(-1), s.c.) increased this measure. MK-801 combined with apomorphine or with 7-OH-DPAT, systemically or in the NAS shell, induced additive effects. CONCLUSIONS: Lack of interaction between DA agonists and MK-801 in this study contrasts with our previous work showing synergistic reward-decreased effects of AMPA/kainate receptor blockade and D(2/3) DA receptor stimulation in the NAS shell, and indicates possible independence of DA and N-methyl-D-aspartate (NMDA) receptor effects in VTA electrical self-stimulation.

Animals↗
PubMed2005

Sex differences in the influence of nicotine dose instructions on the reinforcing and self-reported rewarding effects of smoking.

RATIONALE: Compared to men, the smoking behavior of women may be less responsive to nicotine and more responsive to nonpharmacological factors, perhaps including verbal information (e.g., dose instructions). OBJECTIVE: This study compared the influence of the presence vs absence of dose instructions on the subjective and reinforcing effects of nicotine via cigarette smoking in men and women. METHODS: Subjects (n=120) abstained overnight from smoking and were randomly assigned to one of four groups. Half of the subjects received nicotine cigarettes (Quest 1, yield of 0.6 mg), and the other half received denicotinized cigarettes ("denic"; Quest 3, yield of 0.05 mg). Furthermore, half of each subsample was accurately instructed they were receiving a "normal nicotine" or a "no nicotine" cigarette, while the other half received no instructions. Subjects completed baseline measures of craving and mood (positive and negative affect), took two puffs from the cigarette after receiving dose instructions or no instructions, and then rated the cigarette's "reward" value (liking, satisfying) and other characteristics. They also repeated the craving and mood measures. Subjects then smoked more of that same brand ad libitum over the next 30 min to measure reinforcement (puff number and latency to first puff). RESULTS: Overall, nicotine increased reward, other cigarette ratings, and positive affect, but did not affect craving or smoking behavior. However, results varied by sex. Dose instructions enhanced the effects of nicotine on smoking reward and reinforcement in women, while instructions tended to dampen or even reverse these effects of nicotine in men (i.e., interaction of sex x nicotine x instructions). CONCLUSIONS: In women but not in men, the influence of nicotine on smoking reward and reinforcement is enhanced by accurate verbal information about the cigarette's nicotine dose. These results are consistent with the notion that the smoking behavior of women, relative to men, may be more responsive to nonpharmacological factors.

Adult↗
PubMed2006

Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine.

RATIONALE: Initiation of tobacco use typically begins during adolescence, and the nature of these first experiences with nicotine may affect the probability of continued use. In rodents, a number of studies suggest that periadolescents are more responsive to the rewarding effects of nicotine compared to adults. OBJECTIVES: This study was designed to determine if there are age differences in the rewarding and aversive effects of nicotine by using the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. We also examined age differences in locomotor responses to nicotine. METHODS: In the CPP paradigm, male periadolescent and adult Wistar rats received nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle prior to place conditioning trials. In the CTA paradigm, in separate groups of rats, periadolescents and adults were exposed to a 0.1% saccharin solution, followed by the administration of nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle. Four saccharin-nicotine pairings were followed by a preference test and three extinction sessions. RESULTS: In the CPP paradigm, nicotine produced a dose-dependent place preference in periadolescent, but not in adult, rats. In the CTA paradigm, adult rats expressed a dose-dependent avoidance of saccharin after pairings with nicotine, whereas periadolescents were resistant to CTA formation. With regard to locomotor activity, adults and periadolescents showed comparable locomotor responses to nicotine. CONCLUSIONS: These results suggest that periadolescent rats find nicotine more rewarding and less aversive, compared to adult rats. This shift in the balance between the rewarding and aversive effects of nicotine may make adolescents more susceptible to continued nicotine use.

Aging↗
PubMed2006

Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics.

RATIONALE: Clinical studies in patients with schizophrenia suggest that atypical neuroleptics are more effective than typical neuroleptics in reducing negative symptoms including apathy and anhedonia. Dysfunction of the dopaminergic reward system may contribute to negative symptoms in schizophrenia. OBJECTIVE: We used functional magnetic resonance imaging to assess the blood oxygen level dependency response in the ventral striatum of medicated schizophrenics and healthy control subjects during reward anticipation. METHODS: Twenty schizophrenics [ten medicated with typical (e.g., haloperidol) and ten with atypical (e.g., olanzapine and risperidone) neuroleptics] and ten age-matched healthy volunteers participated in an incentive monetary delay task in which visual cues predicted that a rapid response to a subsequent target stimulus would result either in monetary gain or no consequence. RESULTS: Healthy volunteers and schizophrenics treated with atypical neuroleptics showed ventral striatal activation in response to reward-indicating cues, but schizophrenics treated with typical neuroleptics did not. In patients treated with typical neuroleptics, decrease in activation of the left ventral striatum was correlated with the severity of negative symptoms. CONCLUSIONS: Failure to activate the ventral striatum during reward anticipation was previously associated with the severity of negative symptoms in schizophrenia and was also found in schizophrenics treated with typical neuroleptics in this study. Significant blunting of ventral striatal activation was not observed in patients treated with atypical neuroleptics, which may reflect the improved efficacy of these drugs in treating negative symptoms.

Adult↗
PubMed2006

Effects of aripiprazole on operant responding for a natural reward after psychostimulant withdrawal in rats.

RATIONALE: Withdrawal from repeated amphetamine administration has been shown to decrease the motivation to work for a natural reward in rats, a phenomenon thought to be associated with hypofunction of the mesolimbic dopamine system. OBJECTIVES: We tested whether aripiprazole, a partial dopamine receptor agonist, can restore the animals' responding for reward pellets after amphetamine withdrawal. MATERIALS AND METHODS: Rats were trained to lever-press for food pellets under a progressive ratio-schedule of reinforcement. After reaching a stable breakpoint, i.e., the highest ratio completed, one group was injected ten times with increasing doses of amphetamine (1 to 10 mg/kg, three times a day for 4 days), while the other group received vehicle injections. The rats were again tested for their breakpoint 24 h after the last amphetamine injection under 0.0, 0.25, 0.75, and 2.5 mg/kg aripiprazole. RESULTS: Withdrawal from repeated amphetamine injection reduced the breakpoint while low doses of aripiprazole (0.25 and 0.75 mg/kg) prevented this effect. In addition, the rats needed a longer time for the first 20 pellets (fixed ratio-schedule training before starting the progressive ratio-schedule) after amphetamine withdrawal but not after subsequent injection with aripiprazole. It is notable that the injection of 2.5 mg/kg aripiprazole reduced responding for reward pellets and prolonged the duration for the first 20 pellets irrespective of previous amphetamine or vehicle treatment. However, withdrawal from repeated administration of 0.25 and 2.5 mg/kg aripiprazole did not reduce responding for reward pellets. CONCLUSIONS: These results suggest that aripiprazole may have potential use as a treatment for the motivational effects of the acute withdrawal stage of the psychostimulant addiction cycle.

Amphetamine↗
PubMed2000

Effects of methyllycaconitine (MLA), an alpha 7 nicotinic receptor antagonist, on nicotine- and cocaine-induced potentiation of brain stimulation reward.

It has been shown that nicotine facilitates intracranial self-stimulation (ICSS) reward and that nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) are of primary importance for its reinforcing and dependence-producing actions. Recently, we have shown that alpha 7 nicotinic receptors in the VTA contribute to both the acute effects of nicotine on the mesolimbic dopamine system, as well as to nicotine withdrawal reactions. However, it is not yet known whether the same receptor conformation is directly involved in the reinforcing actions of nicotine. Here, using the curve-shift method we studied the effects of methyllycaconitine (MLA), a selective alpha 7 receptor antagonist, microinjected (graded doses: 1, 3, 9 micrograms/microliter per side) into the VTA on the rewarding efficacy of lateral hypothalamic self-stimulation and on the systemic nicotine-induced potentiation of brain stimulation reward. MLA did not affect baseline self-stimulation. Nicotine produced a significant reduction in ICSS threshold, without altering maximal rates of responding, while MLA attenuated the effect of nicotine at the two lower doses. Given the reported interaction between nicotine and cocaine at both the neuronal and the behavioral level, we also examined whether alpha 7 receptor antagonism within the VTA can affect the reinforcing action of cocaine, as measured with ICSS. Interestingly, MLA attenuated the reinforcing effect of cocaine in all doses tested, without altering the maximal rate of responding, i.e. the performance of the animals. These results suggest that alpha 7 nAChRs in the VTA are involved in mediating the reinforcing actions of drugs of abuse, such as nicotine and cocaine, and provide evidence that alpha 7 nAChR antagonists may be clinically useful in attenuating the rewarding effects of addictive drugs.

Aconitine↗
PubMed2000

Anatomical and pharmacological specificity of the rewarding effect elicited by microinjections of morphine into the nucleus accumbens of mice.

RATIONALE: The involvement of nucleus accumbens (NAc) in initiating opiate-induced reward has been difficult to demonstrate in rats, and has not been studied in mice. OBJECTIVES: To determine whether a reward-sensitive strain of mice (BALB/c) would self-administer morphine directly into the NAc or sub-regions of the dorsal striatum. METHODS: BALB/c mice were unilaterally implanted with a guide-cannula above either the NAc, the anterior caudate putamen, or the posterior caudate putamen. On each experimental day, a stainless-steel injection cannula was inserted into the guide cannula to test the capacity for morphine self-administration (6.5 pmol or 65 pmol/50 nl) using a spatial discrimination task in a Y maze. RESULTS: Only the ventro-medial NAc group discriminated between the arm enabling a microinjection of morphine and the neutral arm. Once self-administration had been acquired, the effects of a pretreatment with two doses of the opiate antagonist naloxone (0.4 mg/kg or 4 mg/kg) were tested. Both doses slightly disrupted self-administration on the first 2 days. Only subjects receiving the 4-mg/kg dose exhibited an extinction of self-administration, related to an increasing number of jump attempts; none of the other opiate withdrawal-associated signs were observed. Self-administration was reinstated when naloxone was replaced with saline. CONCLUSIONS: (1) Medio-ventral NAc is involved in acute rewarding effects of opiates in mice. (2) Neither anterior nor posterior dorsal striatum seem to participate in these effects. (3) NAc is involved in jumping caused by naloxone-induced extinction, a behavior presumably revealing an aversive state associated with the unexpected suppression of reward.

Animals↗