Investigating a race model account of executive control in rats with the countermanding paradigm.

The countermanding paradigm investigates the ability to withhold a response when a stop signal is presented occasionally. The race model (Logan and Cowan, 1984) was developed to account for performance in humans and to estimate the stop signal response time (SSRT). This model has yet to be fully validated for countermanding performance in rats. Furthermore, response adjustments observed in human performance of the task have not been examined in rodents. Male Wistar rats were trained to respond to a visual stimulus (go signal) by pressing a lever below that stimulus, but to countermand the lever press (25% of trials) subsequent to an auditory tone (stop signal) presented after a variable delay. We found decreased inhibitory success as stop signal delay (SSD) increased and estimated a SSRT of 157ms. As expected by the race model, response time (RT) of movements that escaped inhibition: (1) were faster than responses made in the absence of a stop signal; (2) lengthened with increasing SSD; and (3) were predictable by the race model. In addition, responses were slower after stop trial errors, suggestive of error monitoring. Amphetamine (AMPH) (0.25, 0.5mg/kg) resulted in faster go trial RTs, baseline-dependent changes in SSRT and attenuated response adjustments. These findings demonstrate that the race model of countermanding performance, applied successfully in human and nonhuman primate models, can be employed in the countermanding performance of rodents. This is the first study to reveal response adjustments and AMPH-induced alterations of response adjustments in rodent countermanding.

Double dissociation of the effects of haloperidol and the dopamine D3 receptor antagonist ABT-127 on acquisition vs. expression of cocaine-conditioned activity in rats.

Dopamine receptors play a critical role in reward-related learning, but receptor subtypes may be differentially involved. D2-preferring receptor antagonists, e.g., haloperidol, attenuate acquisition of cocaine-conditioned motor activity at doses that fail to block expression. We compared haloperidol [4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one] with the D3 receptor-preferring antagonist 2,3-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4] triazol-3-yisulfanyl)-propyl]-piperazin-1-y1}-pyrimidine hydrochloride (ABT-127), given at D3 receptor-selective doses [i.e., no displacement of [(3)H]3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide binding, no effects on γ-butyrolactone-induced striatal l-3,4-dihydroxyphenylalanine; haloperidol accumulation; no attenuation of apomorphine-induced stereotypy]. We hypothesized that haloperidol and ABT-127 will produce a doubly dissociable effect on acquisition versus expression of cocaine-conditioned activity. Rats received three 1-h habituation sessions to activity monitors followed by three 1-h cocaine (10 mg/kg) conditioning sessions. The expression phase (no cocaine injections) took place 48 h later. Haloperidol (50 µ/kg) given during the conditioning phase blocked the acquisition of conditioned activity but failed to block the expression of conditioning when given on the test day. In contrast, ABT-127 (1.0 mg/kg), when given during conditioning, failed to block the acquisition of conditioned activity but blocked the expression of conditioning when administered on the test day. Results suggest that D2 receptors are more critically involved in acquisition than initial expression and D3 receptors are more critically involved in expression than acquisition of conditioned activity based on cocaine.

Increased GABAergic activity in the region of the pedunculopontine and deep mesencephalic reticular nuclei reduces REM sleep and impairs learning in rats.

Newly formed memories are initially fragile and require consolidation to be transformed into an enduring state. Memory consolidation may occur during increased postlearning REM sleep. REM deprivation during these periods (termed REM sleep windows [RSWs]) impairs subsequent performance. The pedunculopontine nucleus (PPT) and adjacent deep mesencephalic reticular nuclei (DpMe) have been implicated in the generation of REM sleep. Following 24-hr baseline recording, rats were trained on the 2-way avoidance task for 50 trials/day over 2 days and retested on Day 3. EEG was recorded 22 hr after training on training Days 1 and 2. Rats were injected with the GABAB agonist baclofen or saline into the PPT/DpMe region at 0300 to coincide with the start of a known RSW. Based on shuttle performance, saline rats were assigned post hoc to a learning group (LG) that avoided the footshock at least 60% at retest or nonlearning group (NLG) that performed below this criterion. Baclofen-injected rats were not assigned post hoc into separate groups as all rats performed below the learning criterion. PPN/DpMe infusions of the inhibitory GABAB agonist baclofen decreased REM and impaired subsequent memory performance. Normal GABAergic transmission in the PPN/DpMe may be necessary for REM to occur and for the consolidation of incentive learning.

Too much of a good thing? Elevated baseline sleep spindles predict poor avoidance performance in rats.

Sleep spindles may be involved in synaptic plasticity. Learning-dependent increases in spindles have been observed in both humans and rats. In humans, the innate (i.e., baseline) number of spindles correlate with measures of academic potential such as Intelligence Quotient (IQ) tests. The present study investigated if spindles predict whether rats are able to learn to make avoidance responses in the two-way shuttle task. Baseline recordings were taken continuously for 24h prior to training on the two-way shuttle task for 50trials/day for two days followed by a 25 trial re-test on the third day. At re-test, rats were categorized into learners (n=16) or non-learners (n=21). Groups did not differ in baseline duration of rapid eye movement sleep, slow wave sleep, wake or spindle density. For combined groups, spindle density in the 21 to 24-hour period but not at any other period during baseline was negatively correlated with shuttle task performance at re-test. Conversely, the learning-related change in spindle density in the 21 to 24-hour period, but not at any other time after the first training session was positively correlated with shuttle task performance. Rats in the non-learning condition have a higher number of spindles at baseline, which is unaffected by training. On the other hand, learning rats have fewer spindles at baseline, but have a learning-related increase in spindles. Extreme spindle activity and high spindle density have been observed in humans with learning disabilities. Results suggest that while spindles may be involved in memory consolidation, in some cases, high levels of spindles prior to training may be maladaptive.

Focusing on symptoms rather than diagnoses in brain dysfunction: conscious and nonconscious expression in impulsiveness and decision-making.

Symptoms and syndromes in neuropathology, whether expressed in conscious or nonconscious behaviour, remain imbedded in often complex diagnostic categories. Symptom-based strategies for studying brain disease states are driven by assessments of presenting symptoms, signs, assay results, neuroimages and biomarkers. In the present account, symptom-based strategies are contrasted with existing diagnostic classifications. Topics include brain areas and regional circuitry underlying decision-making and impulsiveness, and motor and learned expressions of explicit and implicit processes. In three self-report studies on young adult and adolescent healthy individuals, it was observed that linear regression analyses between positive and negative affect, self-esteem, four different types of situational motivation: intrinsic, identified regulation, extrinsic regulation and amotivation, and impulsiveness predicted significant associations between impulsiveness with negative affect and lack of motivation (i.e., amotivation) and internal locus of control, on the one hand, and non-impulsiveness with positive affect, self-esteem, and high motivation (i.e., intrinsic motivation and identified regulation), on the other. Although presymptomatic, these cognitive-affective characterizations illustrate individuals' choice behaviour in appraisals of situations, events and proclivities essentially of distal perspective. Neuropathological expressions provide the proximal realities of symptoms and syndromes with underlying dysfunctionality of brain regions, circuits and molecular mechanisms.

Dopaminergic mechanism of reward-related incentive learning: focus on the dopamine D(3) receptor.

Dopamine D(3) receptors (Drd3) have been implicated in the control of responding by drug-related conditioned incentive stimuli. We review recent studies of the effects of Drd3 antagonists or partial agonists on the control of self-administration of intravenous (IV) cocaine, IV morphine and oral ethanol on reward-rich and lean schedules, in reinstatement tests, on second-order schedules and on the acquisition and expression of conditioned place preference (CPP) and conditioned motor activity. For comparison, related studies where conditioned stimuli are based on nutritional reward also are considered. When self-administration depends more heavily on conditioned cues for its maintenance, for example on second-order schedules or lean ratio schedules, Drd3 antagonists or partial agonists reduce responding. Although data are limited, similar effects may be seen for responding for cues based on drugs or nutritional rewards. Drd3 agents also block the ability of conditioned cues to reinstate responding for cocaine or food. Published results suggest that Drd3 plays a more important role in the expression than in the acquisition of a CPP or conditioned motor activity. The mechanism mediating the role of Drd3 in the control of responding by conditioned incentive stimuli remains unknown but it has been found that Drd3 receptors increase in number in the nucleus accumbens during conditioning. Perhaps Drd3 participates in the molecular mechanisms underlying the role of dopamine and of dopamine receptor subtypes in reward-related incentive learning.

Movement disorders: neurodevelopment and neurobehavioural expression.

Braak and co-workers have recently shown that movement disorders such as Parkinson's disease develop progressively over years with early neuronal losses in brainstem regions caudal to the substantia nigra. The relevance of this finding to notions of comorbidity between movement disorders and psychiatric symptoms was recognised at the recent meeting concerning, "Implications of Comorbidity for the Etiology and Treatment of Neuropsychiatric Disorders" held in Oct. 2005 in Mazagon, Spain. The identification of stages in the early development of neurodegenerative disorders appeared to unify multiple, diverse findings. These included: novel therapeutic innovations for Parkinson's disease, Alzheimer's disease and depression in the aged; the neurochemical ontogeny of drug-induced oral dyskinesias; the types of chemical agents abused in neuropsychiatric states; postnatal iron overload effects upon the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expression of movement disorders; and the spectrum of motor symptoms expressed in schizophrenia and attention deficit hyperactivity disorder and the eventual treatment of these disorders. A continued focus on a number of neuropsychiatric diseases as progressive disorders may lead to further advances in understanding their etiology and in developing better therapeutics.

Behavioural sensitization in addiction, schizophrenia, Parkinson's disease and dyskinesia.

Incentive learning takes place when dopaminergic neurons are activated, usually by rewards. As a result, previously neutral stimuli associated with reward acquire incentive salience and thus the ability to elicit approach or other responses in the future. Incentive learning is assumed to underlie psychostimulant-induced context-dependent sensitization that may play a prominent role in the development of addiction, in dyskinesia, and in amphetamine-induced psychosis. Assuming that these pathological states are due to the gradual process of sensitization, the effects of therapeutics might be manifested as a gradual desensitization. This assumption could explain the delay between onset of cellular effects of drugs (e.g., dopamine receptor blockade) and the improvement in symptoms (e.g., decreases in psychotic symptoms). Reduced dopamine activity results in behavioural changes that are opposite to psychostimulant-induced sensitization, i.e., rewarded behaviours decline in an extinction-like fashion despite the presence and consumption of rewards. We show here that also non reward-related behaviour, i.e., motor activity and catalepsy, follows the same rules: motility is not switched off by dopamine receptor blockade or by 6-hydroxydopamine lesions, but shows a test-to-test extinction-like decline. Thus, psychostimulant-induced sensitization and dopamine-deficiency induced decline of behaviour follows similar rules but in opposite directions.

The dopamine D(3) receptor-preferring partial agonist BP 897 dose-dependently attenuates the expression of amphetamine-conditioned place preference in rats.

Previously we reported that systemic administration of the dopamine D3 receptor-preferring partial agonist BP 897 blocked the expression, but not the acquisition, of amphetamine-conditioned activity. This suggested the hypothesis that BP 897 would block the expression, but not the acquisition, of amphetamine-conditioned place preference (CPP). Thus, during preconditioning rats had access to two chambers connected by a tunnel for three 15-min sessions. During eight conditioning days with the tunnel blocked, one chamber was paired with drug administration for four 30-min sessions, alternating with pairing of the other chamber with saline administration. In a drug-free test session, time on the drug-paired side was compared to time spent there in preconditioning; a significant increase was defined as a place preference. Systemic amphetamine (2.0 mg/kg) or amphetamine+BP 897 (1.0, 2.0 mg/kg) during conditioning produced a significant place preference, while administration of BP 897 (1.0 or 2.0 but not 0.5 mg/kg) during the test blocked the amphetamine-CPP. There was no evidence that BP 897 produced a conditioned aversion. Results supported the hypothesis that BP 897 would block expression, but not acquisition, of amphetamine-CPP.

Gene-environment interplay in alcoholism and other substance abuse disorders: expressions of heritability and factors influencing vulnerability.

Factors that confer predisposition and vulnerability for alcoholism and other substance abuse disorders may be described usefully within the gene-environment interplay framework. Thus, it is postulated that heritability provides a major contribution not only to alcohol but also to other substances of abuse. Studies of evoked potential amplitude reduction have provided a highly suitable and testable method for the assessment of both environmentally-determined and heritable characteristics pertaining to substance use and dependence. The different personal attributes that may co-exist with parental influence or exist in a shared, monozygotic relationship contribute to the final expression of addiction. In this connection, it appears that personality disorders are highly prevalent co-morbid conditions among addicted individuals, and, this co-morbidity is likely to be accounted for by multiple complex etiological relationships, not least in adolescent individuals. Co-morbidity associated with deficient executive functioning may be observed too in alcohol-related aggressiveness and crimes of violence. The successful intervention into alcohol dependence and craving brought about by baclofen in both human and animal studies elucidates glutamatergic mechanisms in alcoholism whereas the role of the dopamine transporter, in conjunction with both the noradrenergic and serotonergic transporters, are implicated in cocaine dependence and craving. The role of the cannabinoids in ontogeny through an influence upon the expression of key genes for the development of neurotransmitter systems must be considered. Finally, the particular form of behaviour/characteristic outcome due to childhood circumstance may lie with biological, gene-based determinants, for example individual characteristics of monoamine oxidase (MAO) activity levels, thereby rendering simple predictive measures both redundant and misguiding.

Gene-environment interplay in affect and dementia: emotional modulation of cognitive expression in personal outcomes.

A multitude of factors, that either singly, interactively, or sequentially influence the gene-environment interplay in affective and dementia states, include several phases of neurodevelopmental liability in both humans and laboratory animals. Genetic vulnerability for both affective disorders and dementia describes a scenario distinguished by progressive need for concern, particularly in view of the interplay between these areas of ill-health. The contribution of emotional and cognitive expression to personal outcomes, e.g., as a function of affective personality type, a state-dependent analysis of personality characteristics, appears to pervade both the individual's experience of social and physical environments and the performance of cognitive tasks. The role of the endocannabinoids in mental health may offer insights for the psychopharmacology of both cognition and affect. Maladaptive emotional reactions and a defective cognitive ability will contribution to unsatisfactory/maladaptive coping strategies, in turn, leading to further complications of an affective and dysfunctional nature, eventually with a clinical psychopathological outcome. These considerations impinge upon critical issues concerning predisposition and vulnerability. Classical eye-blink conditioning provides a highly established procedure for assessment of defective physiology in models of Alzheimer's dementia. In order to develop a consideration of the array of situations presenting the variation of outcome due to type of affective personality, the role of fear and anxiety and stress in affective states influencing cognition are examined and the critical role of brain circuits mediating emotions influencing cognitive outcomes is discussed.

Brain sites of movement disorder: genetic and environmental agents in neurodevelopmental perturbations.

In assessing and assimilating the neurodevelopmental basis of the so-called movement disorders it is probably useful to establish certain concepts that will modulate both the variation and selection of affliction, mechanisms-processes and diversity of disease states. Both genetic, developmental and degenerative aberrations are to be encompassed within such an approach, as well as all deviations from the necessary components of behaviour that are generally understood to incorporate "normal" functioning. In the present treatise, both conditions of hyperactivity/hypoactivity, akinesia and bradykinesia together with a constellation of other symptoms and syndromes are considered in conjunction with the neuropharmacological and brain morphological alterations that may or may not accompany them, e.g. following neonatal denervation. As a case in point, the neuroanatomical and neurochemical points of interaction in Attention Deficit and Hyperactivity disorder (ADHD) are examined with reference to both the perinatal metallic and organic environment and genetic backgrounds. The role of apoptosis, as opposed to necrosis, in cell death during brain development necessitates careful considerations of the current explosion of evidence for brain nerve growth factors, neurotrophins and cytokines, and the processes regulating their appearance, release and fate. Some of these processes may possess putative inherited characteristics, like alpha-synuclein, others may to greater or lesser extents be endogenous or semi-endogenous (in food), like the tetrahydroisoquinolines, others exogenous until inhaled or injested through environmental accident, like heavy metals, e.g. mercury. Another central concept of neurodevelopment is cellular plasticity, thereby underlining the essential involvement of glutamate systems and N-methyl-D-aspartate receptor configurations. Finally, an essential assimilation of brain development in disease must delineate the relative merits of inherited as opposed to environmental risks not only for the commonly-regarded movement disorders, like Parkinson's disease, Huntington's disease and epilepsy, but also for afflictions bearing strong elements of psychosocial tragedy, like ADHD, autism and Savantism.

Neurosteroids and glutamate toxicity in fibroblasts expressing human NMDA receptors.

We characterized glutamate receptor-mediated toxicity in mouse fibroblasts expressing the human NR1a/2A or NR1a/2B NMDA receptor. After induction of NMDA receptors, cells in both lines died over a 24 h time period. This toxicity was associated with a progressive increase in the glutamate content of the media. Cell death could be prevented by including either the non-competitive NMDA receptor antagonist ketamine or the competitive antagonist D,L-AP5. Cells expressing NR1a/2A receptors were maximally protected by 0.5 mM D,L -AP-5, while those expressing NR1a/2B receptors required 2 mM D,L -AP-5 for maximal protection. The neurosteroid pregnenolone sulfate, which negatively modulates NMDA receptor function, partially protected fibroblasts containing NR1a/2A or NR1a/2B NMDA receptor constructs. However, the neurosteroid pregnenolone sulfate, which has been reported to act as a positive allosteric modulator of the NMDA receptor, had no effect on the toxicity caused by endogenous glutamate. Our results on cells expressing human NMDA receptors suggest that certain neurosteroids may protect against NMDA induced toxicity while having low neurotoxic liabilities of their own.

Neonatal exposure to the glutamate receptor antagonist MK-801: effects on locomotor activity and pre-pulse inhibition before and after sexual maturity in rats.

Neonatal lesions of the ventral hippocampus in rats lead to post- but not pre-pubertal behavioral changes suggesting adolescent onset of dopaminergic hypersensitivity and providing an animal model of schizophrenia. Neonatal exposure to glutamate receptor antagonists produces accelerated apoptosis leading to neuronal loss in central nervous system structures including the hippocampus. This suggested that neonatal MK-801 might lead to behavioural changes like those reported following ventral hippocampal lesions. Thus, rats received MK-801 (0, 0.5, 1.0 mg/kg ip) on postnatal day 3 (P3) and were tested pre- (P35) and post-pubertally (P56). MK-801 produced an increase in TUNEL staining in the hippocampus and other forebrain structures, confirming the induction of apoptosis. Results showed little difference in locomotor activity between neonatal saline- and MK-801-treated groups during habituation or following saline injection but increased activity was seen in the 0.5 mg/kg MK-801 group following amphetamine (1.5 mg/kg i.p.) at P35 but not P56. In tests of pre-pulse inhibition (PPI), neonatal saline and MK-801 groups showed stable startle amplitudes, minimal responding to the pre-pulse stimuli alone, an increase in PPI with increases in pre-pulse intensity, and reduced PPI with apomorphine (0.1 mg/kg s.c.). At P56, neonatal MK-801 groups tested following vehicle showed less sensitivity to changes in pre-pulse intensity. It was concluded that neonatal MK-801 increases apoptotic cell loss in the hippocampus but does not produce behavioural effects like those seen after neonatal ventral hippocampal lesions. However, neonatal MK-801 did lead to increases in locomotor activity in juveniles but not adults and reduced sensitivity to pre-pulse intensity in PPI tests in adulthood.

Biphasic effects of 7-OH-DPAT on the acquisition of responding for conditioned reward in rats.

Previous studies have shown that dopamine (DA) receptor subtype-specific agonists differentially affect responding for conditioned reward D1-like agonists impair, whereas D2-like agonists enhance responding. The present study compared the effects of the D2-like agonists bromocriptine and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT). Food-deprived rats (N=159) were preexposed to a chamber with two levers, one producing a tone (3 s) and the other turning the house lights off (3 s), for five 40-min sessions. In four subsequent 65-min conditioning sessions with the levers removed, the lights-off stimulus was paired with food (80 presentations per session). During two 40-min test sessions, the lights-off (CR) and tone (NCR) levers were replaced and responses at each lever were recorded. Confirming previous results, bromocriptine (0.50-5.0 mg/kg) dose-dependently enhanced responding on the lever producing conditioned reward. In contrast, 7-OH-DPAT had a biphasic effect on responding for conditioned reward. Low doses (0.10-0.25 mg/kg) reduced CR lever responding, whereas a higher dose of 1.0 mg/kg enhanced such responding. An intermediate dose of 0.50 mg/kg neither impaired nor enhanced CR lever responding. The biphasic profile of 7-OH-DPAT may arise through differential actions at D3 vs. D2 receptors or presynaptic vs. postsynaptic DA receptors at low and high doses, respectively.

Pimozide, like extinction, devalues stimuli associated with sucrose taking.

Conditioned stimuli (CS) can be devalued by exposure to those stimuli in the absence of primary reward. We tested the hypothesis that dopamine (DA) mediates the control of behavior by conditioned appetitive stimuli. Long-Evans rats were trained to respond for sucrose under a heterogeneous chain schedule in which seeking responses (lever press) turned on a houselight [variable interval (VI)-120 s]; taking responses (wheel turn or chain pull) in the presence of the houselight were reinforced [fixed ratio (FR)-1] by a sucrose pellet. When responding on this schedule was stable, the levers were retracted and subjects had access to the sucrose-taking manipulandum only. Sucrose-taking responses were either extinguished or reinforced under the influence of the DA antagonist, pimozide. Control groups were also reinforced for sucrose-taking responses but received no injection or a vehicle injection prior to each session. Responses of extinction and pimozide-treated groups declined over sessions. Sucrose-seeking responses were measured in a later test when subjects had no access to the sucrose-taking manipulandum or to the reinforcer. Both extinction and pimozide manipulations reduced seeking responses, relative to the respective control groups. Pimozide injections in the home cage had no effect. These data support the idea that DA mediates the conditioned reinforcing properties provided by access to the taking link of the chain.

Cognitive effects of neurotoxic lesions of the nucleus basalis magnocellularis in rats: differential roles for corticopetal versus amygdalopetal projections.

The cholinergic hypothesis states that cholinergic neurons of the basal forebrain nucleus basalis magnocellularis (nbm) that project to cortical and amygdalar targets play an important role in memory. Biochemical studies have shown that these target areas are differentially sensitive to different excitotoxins (e.g., ibotenate vs. quisqualate). This observation might explain the finding from many behavioural studies of memory that different excitotoxins affect memory differentially even though they produce about the same level of depletion of cholinergic markers in the cortex and similar cortical electrophysiological effects. Thus, the magnitude of mnemonic impairment might be related to the extent of damage to cholinergic projections to the amygdala more than to the extent of damage to corticopetal cholinergic projections. This explanation might similarly apply to the observation that the immunotoxin 192 IgG-saporin produces mild effects on memory when injected into the nbm. This is because it damages cholinergic neurons projecting to the cortex but not those projecting to the amygdala. Studies comparing the effects on memory of ibotenic acid vs. quisqualic acid lesions of the nbm are reviewed as are studies of the mnemonic effects of 192 IgG-saporin. Results support the cholinergic hypothesis and suggest that amygdalopetal cholinergic neurons of the nbm play an important role in the control of memory.

Hippocampal-prefrontocortical circuits: PKA inhibition in the prefrontal cortex impairs delayed nonmatching in the radial maze in rats.

Recent findings implicate the prefrontal cortex (PFC) and, in particular, frontocortical dopamine acting at D1-like receptors, in working memory. However, the mechanisms underlying this function of dopamine remain unknown. The present studies evaluated the hypothesis that dopamine contributes to working memory through its action on the 2nd messenger cyclic 3',5'-adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA). Thus, rats were trained to perform random foraging or delayed (30 min) nonmatching-to-position (delayed win-shift) tasks on the radial maze. With hippocampal output to the frontal cortex disconnected by injecting lidocaine (20 microg/0.5 microl) unilaterally into the ventral subiculum, contralateral frontocortical injections of lidocaine (20 microg/0.5 microl) or the D1-like dopamine receptor antagonist SCH 23390 (0.5 microg/0.5 microl) impaired delayed win-shift but not random foraging, replicating previous findings. In similarly disconnected rats, frontocortical injections of the PKA inhibitor Rp-cAMPS (5.0 and 10.0, but not 1.0, microg/0.5 microl) selectively impaired delayed nonmatching-to-position. Results suggest that activation of the cAMP-PKA pathway by dopamine acting at D1-like receptors in the frontal cortex is necessary for working memory.

Neurosteroids and reward: allopregnanolone produces a conditioned place aversion in rats.

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) has been reported to have rewarding properties in mice tested for place conditioning. Another study found that allopregnanolone reduced dopamine (DA) output in the nucleus accumbens (NAc) of rats. As many rewarding stimuli increase accumbens DA, these results may appear contradictory. Thus, the present study examined the rewarding properties of allopregnanolone in rats tested for place conditioning using an unbiased conditioning procedure. In control studies, a place preference was observed following conditioning with intraperitoneal (2.0 mg/kg) or intracerebroventricular (i.c.v.) (100 microg/0.5 microl) amphetamine. Conditioning with i.c.v. allopregnanolone produced a significant aversion at a dose of 5.0 microg (in 5.0 microl) and a near aversion at 25.0 microg (in 8.3 microl); doses of 0 microg (i.e., vehicle alone, in 10 microl) or 30.0 microg (in 10 microl) produced little effect on place preference. During conditioning, locomotor activity was stimulated by amphetamine using either route of administration, but allopregnanolone had no significant main effect on locomotor activity. Thus, there was a dissociation between the effects of drugs on locomotor activity vs. place conditioning. Results show that i.c.v. amphetamine produces a place preference, whereas allopregnanolone produces either no effect or an aversion, depending on the dose.

Conditioned locomotion in rats following amphetamine infusion into the nucleus accumbens: blockade by coincident inhibition of protein kinase A.

Recent studies demonstrate a role for cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) in the nucleus accumbens (NAc) in reward-related learning. To clarify this role, we assessed the effect of PKA inhibition on the unconditioned and conditioned locomotor activating properties of intra-NAc amphetamine. Rats underwent three 60 min conditioning sessions, pairing a test environment with bilateral co-infusions of amphetamine (25 microg/side) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (0, 2.5, 250, 500 ng, 1, 10 or 20 microg/side). Two additional groups - receiving amphetamine explicitly unpaired with the environment or saline/environment pairings - served as controls. In a subsequent drug-free 60 min session, animals that received amphetamine/environment pairings demonstrated conditioned locomotion relative to controls. Rp-cAMPS co-treatment during pairing sessions differentially affected conditioned and unconditioned locomotor activation. Amphetamine-induced unconditioned activity was significantly enhanced by 500 ng and 1 microg Rp-cAMPS, locomotor sensitization was enhanced by 250 ng-1 microg Rp-cAMPS, and conditioned activity was attenuated by 1 microg Rp-cAMPS and blocked by 10 and 20 microg Rp-cAMPS. Thus, unconditioned activity and locomotor sensitization were enhanced at doses (250 ng-1 microg) that did not affect or attenuated conditioned activity, while conditioned activity was reduced or blocked at doses (1-20 microg) that enhanced or did not affect overall unconditioned activity. These results demonstrate that the activation of PKA plays a critical role in the process by which properties of drugs become associated with environmental stimuli.