Biomedical subjects

Richard J Beninger

Publications and source records attributed to Richard J Beninger.

At least 19 recordsLinked to original sources

PubMed2006

Nucleus accumbens PKA inhibition blocks acquisition but enhances expression of amphetamine-produced conditioned activity in rats.

RATIONALE: The nucleus accumbens (NAc) plays a central role in dopamine-produced reward-related learning. In previous studies, the cyclic adenosine monophosphate-dependent protein kinase (PKA) inhibitor Rp-Cyclic 3',5'-hydrogen phosphorothioate adenosine triethylammonium salt (Rp-cAMPS) blocked the acquisition but not expression of NAc reward-related learning for natural rewards and the acquisition of psychostimulant drug conditioning. OBJECTIVES: The current study assessed the role of PKA in the expression of NAc amphetamine (amph)-produced conditioning using conditioned activity (CA). MATERIALS AND METHODS: After 5 days of habituation, a test environment was paired with bilateral NAc injections of amph (0.0 or 25.0 micro g) and the PKA inhibitor Rp-cAMPS (0.0, 5.0, 10.0, or 20.0 micro g) over three 60-min conditioning sessions separated by 48 h. To test for effects on expression, some groups received vehicle or amph alone before conditioning sessions and were injected with 0.0, 0.25, 5.0, or 20.0 mug of Rp-cAMPS before the single 60-min test session. RESULTS: Amph produced acute increases in locomotion and robust CA. Rp-cAMPS impaired the acquisition of amph-produced CA but not its expression; in fact, it enhanced expression. CONCLUSIONS: Results show that PKA inhibition blocks the acquisition but not the expression of amph-produced conditioning.

Amphetamine↗

PubMed2006

Place preference induced by nucleus accumbens amphetamine is impaired by local blockade of Group II metabotropic glutamate receptors in rats.

BACKGROUND: The nucleus accumbens (NAc) plays a critical role in amphetamine-produced conditioned place preference (CPP). In previous studies, NAc basal and amphetamine-produced DA transmission was altered by Group II mGluR agents. We tested whether NAc amphetamine CPP depends on Group II mGluR transmission. RESULTS: NAc injections (0.5 microl/side) of the Group II mGluR antagonist (2 S)-a-ethylglutamic acid (EGLU: 0.01-0.8 microg but not 0.001 microg) impaired CPP. The drug did not block the acute locomotor effect of amphetamine. CONCLUSION: Results suggest that Group II mGluRs may be necessary for the establishment of NAc amphetamine-produced CPP. These receptors may also mediate other forms of reward-related learning dependent on this structure.

Amphetamine↗

PubMed2006

Animal behaviour: chimpanzee choice and prosociality.

Silk et al. report that adult chimpanzees show no difference in their choices in a situation where one choice benefits a familiar conspecific and the other does not. From this, they conclude that chimpanzees are indifferent to the welfare of unrelated group members. But without additional data confirming that chimpanzees do choose differently in circumstances in which a difference would be expected, the authors cannot conclude that there is no difference in their scenario. How chimpanzees react to the welfare of unrelated group members remains an open question.

Aging↗

PubMed2006

Post-training intra-striatal scopolamine or flupenthixol impairs radial maze learning in rats.

Systemic treatments with acetylcholine (ACh) or dopamine (DA) receptor antagonists during hours 0-4 but not during hours 5-8 following training on a radial arm maze (RAM) or lesions of the dorsal striata impair learning. This suggested that intra-striatal infusions of ACh or DA receptor antagonists during hours 0-4 following training may impair learning. Rats were randomly assigned to groups (ns=5-11) receiving dorsal striatal infusions of the ACh receptor antagonist scopolamine (0-18 microg/microL at 0 and 2h or at 4 and 6h after training), the DA receptor antagonist cis-flupenthixol (0-25 microg/microL at 0, 4 or 12h after training) or the inactive isomer trans-flupenthixol (6 microg/microL at 0 h after training). Scopolamine and cis-flupenthixol impaired the habit-learning version of the task. Given after hours 0-4 following training, the effects of scopolamine were diminished but those of cis-flupenthixol were not. Trans-flupenthixol produced less impairment than cis-flupenthixol. Results suggest that ACh and DA receptors in the dorsal striatum during hours 0-4 following training play a role in habit learning.

Acetylcholine↗

PubMed2006

Dopamine and incentive learning: a framework for considering antipsychotic medication effects.

Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-fos, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-fos expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia.

Antipsychotic Agents↗

PubMed2005

Effects of Parkinson disease on two putative nondeclarative learning tasks: probabilistic classification and gambling.

OBJECTIVE: To assess performance on two nondeclarative (implicit) memory tasks of Parkinson disease (PD) patients without dementia in the earlier or later stages of the disease (Hoehn and Yahr Scale scores of 1-2.5 or 3-4, respectively). BACKGROUND: Different subtypes of nondeclarative memory appear to depend on different components of frontostriatal circuitry. Performance on a probabilistic classification learning (PCL) task was impaired by striatal damage (eg, in PD or Huntington disease) but not by circumscribed frontal lobe damage. On the other hand, performance on the Iowa Gambling Task (IGT) was impaired by damage to the prefrontal cortex. METHOD AND RESULTS: On the PCL, the learning of the control (age- and education-matched) group (n = 19) and the early PD group (n = 16) was comparable with each other, and both groups showed better performance than the later PD group (n = 16). On the IGT, the control group learned better than both of the PD groups. The control and early PD groups were similar on measures from the Wisconsin Card Sorting Test, Stroop Test, Mini-Mental State Examination, and Beck Depression Inventory II. CONCLUSIONS: The PCL and IGT tasks appear to rely on different parts of the frontostriatal circuitry in patients with early PD. The current finding that IGT performance was impaired in early PD implies ventromedial prefrontal cortical dysfunction early in the disease.

Aged↗

PubMed2005

Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine-produced conditioned place preference in rats.

The nucleus accumbens (NAc) plays a critical role in amphetamine-produced conditioned place preference (CPP). In previous studies inhibition or activation of cyclic adenosine monophosphate-dependent protein kinase (PKA) blocked NAc amphetamine-produced CPP. PKA activation unrelated to ongoing DA transmission may disrupt reward-related learning. Calcineurin (CN) down-regulates downstream PKA targets. Unlike PKA activation, CN inhibition may preserve and enhance reward-related learning. The PKA signalling cascade is negatively regulated by calcineurin (CN). We tested the hypothesis that post-training CN inhibition in NAc will enhance NAc amphetamine-produced CPP and that PKA activation will block CPP. Eight but not four or two 30-min conditioning sessions were sufficient to establish significant CPP. Immediate post-training, NAc injection of the calcineurin inhibitor FK506 (5.0 but not 1.0 microg in 0.5 microL per side) led to a significant amphetamine CPP in rats receiving four but not two training sessions; the 5.0-microg dose had no effect on rats trained with eight sessions. Injections of the PKA activator Sp-cAMPS (2.5 or 10.0 microg in 0.5 microL per side) failed to affect CPP following two or four training sessions and blocked CPP produced by a standard 8-day conditioning schedule. Results suggest that CN acts as a negative regulator in the establishment of NAc amphetamine-produced CPP, a form of reward-related learning.

Amphetamine↗

PubMed2004

Gene-environment interplay in neurogenesis and neurodegeneration.

Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for so-called genetic disorders, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in either knock-in or knock-out mice. However, there are similarly, many identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. Constituent cellular defense mechanisms responsive to the challenge of increased reactive oxygen species represent only one crossroad whereby environment can influence genetic predisposition. In this paper we highlight some of the major neurodegenerative disorders and discuss possible links of gene-environment interplay. The process of adult neurogenesis in brain is also presented as an additional element that influences gene-environment interplay. And the so-called priming processes (i.e., production of receptor supersensitization by repeated drug dosing), is introduced as yet another process that influences how genes and environment ultimately and co-dependently govern behavioral ontogeny and outcome. In studies attributing the influence of genetic alteration on behavioral phenotypy, it is essential to carefully control environmental influences.

Alzheimer Disease↗

PubMed2004

The role of signaling molecules in reward-related incentive learning.

Reward-related incentive learning involves the acquisition by neutral stimuli of an enhanced ability to elicit approach and other responses. Previous studies have shown that both dopamine (DA) and glutamate (Glu) play critical roles in this type of learning. Signaling molecules are intracellular messengers that participate in the influence of transmitter-receptor events on intracellular function including transcription in the nucleus. In recent years studies have begun to implicate signaling molecules in incentive learning. Thus, inhibition of cyclic adenosine monophosphate-dependent protein kinase (PKA) in the nucleus accumbens (NAc), that is activated by DA acting at D1-like receptors, blocks the acquisition of conditioned approach responses, lever pressing for food, conditioned place preference (CPP) based on NAc injections of amphetamine or cocaine, and conditioned activity based on NAc injections of amphetamine. Similar effects have been observed with PKA inhibition in the basolateral amygdala or medial prefrontal cortex. If animals were trained prior to testing with PKA inhibitors in NAc, no effect was seen suggesting that PKA is more important for acquisition than expression of incentive learning. Inhibition of calcium-dependent protein kinase or mitogen-activated protein kinases in NAc similarly has been shown to block the acquisition of incentive learning. Results support a model of DA-Glu synaptic interactions that form the basis of incentive learning.

Animals↗

PubMed2004

Scopolamine during the paradoxical sleep window impairs radial arm maze learning in rats.

It has been proposed that there are paradoxical sleep windows (PSW) during which REM sleep is required for effective learning. Thus, rats deprived of REM sleep during 0-4 (but not 5-8) h after training show impaired learning of a radial maze task. As cholinergic (ACh) systems are active during REM sleep and may be involved in learning, this experiment investigated the effects on learning of pharmacological manipulation of the cholinergic system during the period identified as the PSW. Sprague-Dawley rats were randomly assigned to groups that were physically deprived of REM for 4 h either immediately after training or beginning 4 h after training or treated with the ACh receptor antagonist scopolamine (0-0.4 mg/kg at 0 and 2 h after training or 0.006 mg/kg at 4 and 6 h after training) on each of 9 days of radial maze training. Post-training REM deprivation (0-4 h but not 5-8 h after training) and scopolamine dose-dependently impaired learning. Results suggest that REM sleep and intact ACh neurotransmission are required during the PSW for rats to learn the radial maze task.

Animals↗

PubMed2004

Place preference induced by nucleus accumbens amphetamine is impaired by antagonists of ERK or p38 MAP kinases in rats.

The nucleus accumbens (NAc) plays a role in conditioned place preference (CPP). The authors tested the hypothesis that inhibition of mitogen-activated protein kinases (MAPKs) would inhibit NAc-amphetamine-produced CPP. Results confirmed that NAc amphetamine increased levels of the MAPK extracellular signal-regulated kinase (ERK). In CPP studies, NAc injections (0.5 microl per side) of the ERK inhibitor PD98059 (1.0-2.5 microg) or the p38 kinase inhibitor SB203580 (15-500 ng) dose dependently impaired CPP. The c-Jun-N-terminal kinase (JNK) inhibitor SP600125 (1.0-2.5 microg) failed to block the CPP effect. The drugs did not block amphetamine-induced motor activity. Results suggest that ERK and p38, but not JNK, MAPKs may be necessary for the establishment of NAc amphetamine-produced CPP and may also mediate other forms of reward-related learning dependent on NAc.

Amphetamine↗

PubMed2004

Intra-BLA or intra-NAc infusions of the dopamine D3 receptor partial agonist, BP 897, block intra-NAc amphetamine conditioned activity.

Recent studies have shown that both systemic and intra-nucleus accumbens (NAc) or intra-amygdala administration of dopamine D3 receptor ligands modulate reward-related learning. A previous study (H. Aujla, H. Sokoloff, & R. J. Beninger. 2002) showed that systemic administration of the partial dopamine D3 receptor agonist BP 897 selectively blocked the expression, but not the acquisition, of amphetamine-conditioned activity. This suggested the hypothesis that intra-NAc or intra-basolateral amygdala (BLA) BP 897 would attenuate the expression, but not the acquisition, of amphetamine-conditioned activity. Rats were habituated to activity-monitoring chambers for 5 days, for 1 hr each day. Conditioning occurred on the next 3 days, followed by a single 1-hr test session. Intra-NAc or intra-BLA infusions of BP 897 during test, but not during conditioning, attenuated intra-NAc amphetamine conditioned activity. Results indicate that the ability of BP 897 to attenuate the expression of conditioned activity is mediated in part by the NAc and BLA.

Amphetamine↗

PubMed2003

Intra-accumbens protein kinase C inhibitor NPC 15437 blocks amphetamine-produced conditioned place preference in rats.

In a previous study, intracerebroventricular calcium-dependent protein kinase (PKC) inhibition attenuated cocaine place conditioning. This suggested the hypothesis that intra-nucleus accumbens (NAc) injections of the PKC inhibitor NPC 15437 may block place conditioning produced by NAc injections of amphetamine. An unbiased conditioned place preference paradigm was employed to evaluate the present hypothesis. Thus, during pre-conditioning rats had access to an apparatus consisting of two chambers connected by a tunnel for three 15-min sessions. During 8 conditioning days with the tunnel blocked, one chamber was paired with NAc injections of drug for four 30-min sessions alternating with pairing of the other chamber with NAc injections of saline. Time spent on the drug-paired side was assessed in a final drug-free test session and compared to the amount of time spent there in pre-conditioning; a significant increase was defined as a place preference. Intra-NAc amphetamine (20.0 microg/0.5 microl/side) produced a place preference. This effect was blocked dose dependently by NPC 15437 (0.1, 0.5 and 1.0 microg/0.5 microl/side). NPC 15437 (1.0 microg) alone did not produce a place preference or aversion. None of the doses of NPC 15437 affected the locomotor stimulant effect of intra-NAc amphetamine during conditioning revealing a dissociation between the locomotor stimulating and rewarding effects of intra-NAc amphetamine. Results implicate PKC in the NAc in reward-related learning. More work is needed to elucidate the signaling pathways involved in this type of learning.

Amphetamine↗

PubMed2003

Typical and atypical antipsychotic medications differentially affect two nondeclarative memory tasks in schizophrenic patients: a double dissociation.

Nondeclarative memory (NDM) has subtypes associated with different brain regions; learning of a probabilistic classification task is impaired by striatal damage and learning of a gambling task is impaired by ventromedial prefrontocortical damage. Typical and atypical antipsychotic medications differentially affect immediate early gene expression in the striatum and frontal cortex in normal rats. This suggested the hypothesis that schizophrenic patients treated with typical antipsychotics will have impaired probabilistic classification learning (PCL) and that similar patients treated with atypical antipsychotics will have impaired learning of the gambling task. Groups of schizophrenia patients treated with typical or atypical antipsychotics did not differ from each other on the Brief Psychiatric Rating Scale (BPRS), Mini Mental State Exam (MMSE) or a number of indexes of the Wisconsin Card Sorting Task (WCST) but performed worse than normal controls on these instruments. In the first study, patients treated with typicals (n=20) but not atypicals (n=20) or normal controls (n=32) were impaired in probabilistic classification. In the second study, those treated with atypicals (n=18) but not typicals (n=18) or normal controls (n=18) were impaired in the gambling task. Results suggest that typical and atypical antipsychotics differentially affect nondeclarative memory mediated by different brain regions.

Adult↗

PubMed2003

cAMP-dependent protein kinase and reward-related learning: intra-accumbens Rp-cAMPS blocks amphetamine-produced place conditioning in rats.

RATIONALE: Dopamine may produce reward-related learning by activating D(1)-like receptors in the nucleus accumbens (NAc) and stimulating the formation of cyclic adenosine monophosphate (cAMP) and the activation of cAMP-dependent protein kinase (PKA). OBJECTIVES: This hypothesis was tested using the conditioned place preference (CPP) based on NAc injections of amphetamine (amph) and evaluating the effects of PKA inhibition with Rp-cAMPS. METHODS: The CPP procedure consisted of three phases: pre-exposure (three 15-min sessions in a chamber consisting of two distinct compartments connected by a tunnel), conditioning (four 30-min placements into one compartment with the tunnel blocked following drug injection into the NAc alternating with four similar placements into the other side following NAc injection of saline), and test (one 15-min session with the tunnel open). A CPP was defined as an increase in time spent on the drug-paired side from mean pre-exposure to test. RESULTS: Dose-response experiments showed that 15.0 or 20.0 but not 5.0 or 10.0 micro g/0.5 micro l per side of amph produced a CPP. The amph (20.0 micro g) CPP was blocked by Rp-cAMPS co-injections of 25.0 and 250 but not 2.5 ng/0.5 micro l per side. Rp-cAMPS or the PKA activator Sp-cAMPS (50.0, 250, 500, 600 ng/0.5 micro l per side) alone had no effect on side preference. Co-injection of 10.0 micro g amph+Sp-cAMPS (25.0, 50.0, 250, 500 ng) did not result in a CPP but co-injection of 20.0 micro g amph+Sp-cAMPS (250 ng) led to a loss of the CPP normally seen with that dose of amph. Doses of Rp-cAMPS that blocked CPP did not block the locomotor stimulatory effect of amph during conditioning sessions. CONCLUSIONS: Results supported the hypothesis that PKA activation in NAc is necessary for reward-related learning.

Amphetamine↗

PubMed2003

Dimenhydrinate produces a conditioned place preference in rats.

Dimenhydrinate (DMH; trade names Gravol and Dramamine) is a compound of diphenhydramine (DP) and 8-chlorotheophylline in equimolar ratios. DMH has been reported to be abused by humans for its euphoric and hallucinogenic properties but few studies have evaluated its reinforcing effects in animals. To evaluate the hypothesis that DMH and its constituents DP and 8-chlorotheophylline are rewarding in animals, rats were tested for conditioned place preference (CPP). The paradigm consisted of pre-exposure (three 15-min sessions of access to both sides of the chamber), conditioning [eight 30-min pairings of one side with drug (four sessions) and, on alternate days, the other side with vehicle (four sessions)] and test phases (three 15-min sessions of access to both sides of the chamber). Significant preferences for the drug-paired location were found on test session one after conditioning with 60.0, but not 25.0, 40.0 or 50.0 mg/kg of DMH, and after conditioning with 37.8 but not 27.0 or 32.4 mg/kg of DP. No preference was found after conditioning with 23.0, 27.6 or 32.2 mg/kg of 8-chlorotheophylline. All three drugs stimulated locomotor activity during conditioning sessions and DMH and DP showed sensitization over conditioning sessions. DMH doses that showed sensitization (25.0 and 40.0 mg/kg) were lower than the dose (60.0 mg/kg) that produced a CPP revealing a dissociation of locomotor stimulating versus rewarding effects. Results reveal that DMH and DP have rewarding properties, although the molar equivalent dose-response curve for DP appeared to be further to the right than that for DMH. Future investigations into the neurotransmitter systems modulating this effect are awaited.

Animals↗

PubMed2002

Water maze versus radial maze: differential performance of rats in a spatial delayed match-to-position task and response to scopolamine.

Studies rarely assess treatment effects across tasks; the present experiments addressed this issue. In Experiments 1 and 2, rats (n=12) were trained and then tested with variable delays on a spatial match-to-position task sequentially in the water and radial mazes (in counterbalanced order). Experiment 1 compared the effect of 0-, 60- and 1440-min delays on performance in both mazes. Rats required fewer (P<0.05) mean (+/-S.E.M.) sessions to reach criterion performance in the water (11.0+/-1.0) versus radial maze (19.3+/-2.2). In test sessions, performance was impaired delay-dependently when scores were averaged across the two tasks (P<0.05) but no significant effect of task or task x delay interaction was found. In the second experiment, the same rats were retrained and tested with 0-, 1-, 3- and 5-min delays in both mazes and testing followed the administration of scopolamine (0, 0.1, 0.4 and 0.8 mg/kg). The mean (+/-S.E.M.) number of acquisition sessions was similar in the radial (6.33+/-0.34) and water maze (6.08+/-0.46). On the sample portion of trials, performance was impaired at the 0.8 mg/kg dose of scopolamine (P<0.02) in the radial maze only. On the recognition portion of trials in the radial maze, the 0.4 and 0.8 mg/kg doses of scopolamine impaired performance whereas in the water maze task the 0.8 mg/kg dose impaired performance. The pattern of results may reflect different natural tendencies of rats to alternate (win-shift) versus not alternate (win-stay) in dry land versus swim tasks.

Animals↗

PubMed2002

A dopamine D3 receptor partial agonist blocks the expression of conditioned activity.

The partial dopamine D3 receptor agonist BP 897 attenuates cocaine seeking suggesting that BP 897 will attenuate conditioned activity to environmental stimuli paired with amphetamine. During conditioning, amphetamine (2.0 mg/kg) stimulated activity and co-treatment with BP 897 (1.0 mg/kg) had no effect. In the saline test, groups conditioned with amphetamine or amphetamine plus BP 897 showed conditioned activity. Treatment with BP 897 in the test following conditioning with saline produced no significant effect but following conditioning with amphetamine BP 897 blocked conditioned activity. Results extend previous findings that BP 897 attenuates responding for cocaine-paired stimuli to amphetamine-paired stimuli in a different paradigm and support the potential of BP 897 as a therapeutic agent for the prevention of drug seeking.

Amphetamine↗