Evidence for a role of dopamine in self-stimulation of the nucleus accumbens of the rat.

Investigated the effects of centrally administered spiroperidol, a dopamine receptor blocking agent, on self-stimulation of the nucleus accumbens and medial prefrontal cortex in the rat. Spiroperidol in a volume of 1 μl was microinjected into the region of the stimulating electrodes. Self-stimulation of the nucleus accumbens was significantly attenuated by .75, 1.0, and 2.0 μg spiroperidol. Control microinjections of the drug vehicle had no effect. Spiroperidol microinjected into the nucleus accumbens contralateral to the stimulating electrode, as a control for possible motor or nonspecific effects, did not attenuate self-stimulation. Microinjections of spiroperidol into the region of the stimulating electrodes in the prefrontal cortex had no consistent effect on self-stimulation with the two lower doses, but did result in attenuation at the 2.0 μg dose. Self-stimulation of the nucleus accumbens was not changed by microinjections of spiroperidol into the ipsilateral or contralateral prefrontal cortex. Similarly, self-stimulation of the prefrontal cortex was not altered by microinjections of spiroperidol into the nucleus accumbens. By controlling for nonspecific effects of spiroperidol, the results provide further evidence that dopaminergic neurons contribute to self-stimulation of the nucleus accumbens. (French summary) (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characterization of the role of medial prefrontal cortex dopamine receptors in cocaine-induced locomotor activity.

Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D?-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D? receptor agonist PD 168,077 or the selective D? receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D?, and D? receptors. These results suggest that D? receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and nucleus accumbens on the reaction to novelty: Implications for limbic—striatal interactions.

The effects of bilateral excitotoxic lesions of 3 major sources of afferents to the ventral striatum (nucleus accumbens) were compared on an open field test of food neophobia allowing the choice between familiar and novel food. Whereas lesions of the basolateral amygdala and ventral subiculum had qualitatively similar effects to reduce food neophobia (although not affecting the latency to eat), amygdala lesions increased and the ventral subiculum decreased locomotor activity. In contrast, damage to the ventromedial prelimbic prefrontal cortex only affected initial food choice and latency measures. By comparison, excitotoxic lesions of the nucleus accumbens itself and intra-accumbens infusion of the N-methyl-{d}-aspartate (NMDA) receptor antagonist AP5 increased activity and attenuated food neophobia. Results are discussed in terms of the role of limbic and prefrontal neuronal networks converging in the nucleus accumbens to control different aspects of the behavioral response to novelty. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of the medial prefrontal cortex in the play fighting of rats.

Although decorticated rats are able to engage in play, their play is abnormal in three ways. First, decorticates do not display the normal, age-related shifts in defensive strategies during development. Second, decorticates do not modify their defensive tactics in response to the social identity of their partners. Third, decorticates display a global shift in defensive tactics from more complex to less complex strategies. It has been shown that lesions of the motor cortex (MC) selectively produce the abnormal developmental effects on play, and that lesions of the orbitofrontal cortex (OFC) selectively produce the deficits in behavioral discrimination between social partners. In the current set of experiments, we demonstrate that lesions of the medial prefrontal cortex (mPFC) produce the shift from more complex to less complex defensive tactics, while leaving intact the age-related and partner-related modulation of defensive strategies. Thus, we have evidence for a triple dissociation of function between the MC, the OFC, and the mPFC with respect to social play behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Brain self-stimulation: direct evidence for the involvement of dopamine in the prefrontal cortex

Rats were trained to self-stimulate the medial prefrontal cortex, a region rich in dopaminergic terminals. After the region adjacent to the electrode site was labeled with [14C]dopamine, it was perfused repeatedly by means of push-pull cannulas. Electrical stimulation of this cortical area in six animals enhanced the release of dopamine and its associated metabolites in nine of 16 experiments. Thus in vivo evidence is provided that dopamine is involved in the brain self-stimulation mechanism within the frontal cortex.     

Fos expression in the prefrontal cortex and nucleus accumbens following exposure to retrospective timing tasks.

The dorsal striatum and prefrontal cortex have been implicated in interval timing. We examined whether performance of temporal discrimination tasks is associated with increased neuronal activation in these areas, as revealed by Fos expression, a marker for neuronal activation. In Experiment 1, rats were trained on a discrete-trials temporal discrimination task in which a light (22 cd/m2) was presented for a variable time, t (2.5–47.5 s), after which levers A and B were presented. A response on lever A was reinforced if t t > 25 s. A second group was trained on a light-intensity discrimination procedure, in which a light of variable intensity, i (3.6–128.5 cd/m2) was presented for 25 s. A response on lever A was reinforced if i i > 22 cd/m2. In Experiment 2, bisection procedures were used to assess temporal (200–800 ms, 22 cd/m2) and light-intensity (3.6–128.5 cd/m2, 400 ms) discrimination. The increase in proportional choice of lever B as a function of stimulus duration or intensity conformed to a two-parameter logistic equation. Fos expression in the prefrontal cortex and nucleus accumbens was higher in rats performing temporal discrimination tasks than in those performing light-intensity discrimination tasks, indicating greater neuronal activation in these areas during temporal discrimination tasks. Fos expression in the dorsal striatum did not differ between rats performing temporal and light-intensity discrimination tasks. These results suggest that the prefrontal cortex and nucleus accumbens are involved in temporal discrimination. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Electrical stimulation of the medial prefrontal cortex increases dopamine release in the striatum

Exogenous and endogenous glutamate has been shown to evoke dopamine (DA) release in the striatum using both in vitro and in vivo techniques. We hypothesized that stimulation of the prefrontal cortex (PFC) would phasically enhance striatal DA release via the glutamatergic corticostriatal pathway. To test this hypothesis, in vivo brain microdialysis was employed to measure extracellular concentrations of DA in the striatum during electrical stimulation of the PFC. Five rats were implanted with bilateral electrodes located in the medial PFC and dialysis probes in the dorsal striatum. Two days later the PFC of these awake, freely moving rats was stimulated first at 50 microA and then at 100 microA for 20 minutes at 2-hour intervals. Both currents significantly increased DA release. Extracellular DA rose rapidly during stimulation, peaked immediately afterward, and then slowly returned to baseline values. Dopamine reached 118% of baseline values with 50 microA stimulation and 138% with 100 microA stimulation. Histologic analysis using the fluorescent retrograde dye Fluoro Gold confirmed that cells projecting to the vicinity of the striatal dialysis probe originated in the vicinity of the PFC electrodes. These results provide direct evidence for phasic, excitatory modulation of striatal DA release by the PFC.     

Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat

Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus-footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus-footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.     

Electrical stimulation of the prefrontal cortex increases cholecystokinin, glutamate, and dopamine release in the nucleus accumbens: an in vivo microdialysis study in freely moving rats

In vivo microdialysis, radioimmunoassay, and HPLC with electrochemical or fluorometric detection were used to investigate the release of cholecystokinin (CCK), glutamate (Glu), and dopamine (DA) in nucleus accumbens septi (NAS) as a function of ipsilateral electrical stimulation of medial prefrontal cortex (mPFC). CCK was progressively elevated by mPFC stimulation at 50-200 Hz. Stimulation-induced CCK release was intensity-dependent at 250-700 microA. NAS Glu and DA levels were each elevated by stimulation at 25-400 Hz; the dopamine metabolites DOPAC and homovanillic acid were increased by stimulation at 100-400 Hz. When rats were trained to lever press for mPFC stimulation, the stimulation induced similar elevations of each of the three transmitters to those seen with experimenter-administered stimulation. Perfusion of 1 mM kynurenic acid (Kyn) into either the ventral tegmental area (VTA) or NAS blocked lever pressing for mPFC stimulation. VTA, but not NAS, perfusion of Kyn significantly attenuated the increases in NAS DA levels induced by mPFC stimulation. Kyn did not affect NAS CCK or Glu levels when perfused into either the VTA or NAS. The present results are consistent with histochemical evidence and provide the first in vivo evidence for the existence of a releasable pool of CCK in the NAS originating from the mPFC. Although dopamine is the transmitter most closely linked to reward function, it was CCK that showed frequency-dependent differences in release corresponding most closely to rewarding efficacy of the stimulation. Although not essential for the reward signal itself, coreleased CCK may modulate the impact of the glutamatergic action in this behavior.     

The dopaminergic and serotoninergic components of the self-stimulation reaction of the lateral hypothalamus in rats with disruption of the medial prefrontal cortex

The hospital in the future will be faced with the major problem of managing and optimizing the use of images provided from numerous sources examining both anatomy (MRI, CT-scan...) and function (gamma-camera, PET-scan...). One of the first to benefit from such rationalization will be the surgeon. After studying the results of the physical examination, the laboratory reports and the medical imaging, the surgeon will decide on the best curative measured and the best surgical route before operating. He thus needs a computer to assist him in integrating the multi-modal information available for his patient, in particular the imaging with automatic integration and visualisation in synoptic mode (perception step), showing the trajectory of possible access routes to the target organ, memorization of the chosen route (decision step) and real operation either using laser or a manuel tool, or with robot assistance under human control (action step). This close cooperation between surgery and computers is called computer-assisted surgery. A few examples of current uses an future perspectives of this new field of surgery are presented.     

Memory for duration: role of hippocampus and medial prefrontal cortex

In this task rats had to learn that a three-dimensional object stimulus (a rectangle) that was visible for 2 s would result in a positive (go) reinforcement for one object (a ball) and no reinforcement (no go) for a different object (a bottle). However, if the rectangle stimulus was visible for 8 s then there would be no reinforcement for the ball (no go), but a reinforcement for the bottle (go). After rats learned this conditional discrimination by responding differentially in terms of latency to approach the object, they received large (dorsal and ventral) lesions of the hippocampus, lesions of the medial prefrontal cortex (anterior cingulate and precentral cortex), lesions of the cortex dorsal to the dorsal hippocampus, or served as sham-operated controls. Following recovery from surgery they were retested. The results indicate that there were major impairments following hippocampal lesions, in contrast to cortical control and medial prefrontal cortex lesions, as indicated by smaller latency differences between positive and negative trials on postsurgery tests. In order to ensure that the deficits observed with hippocampal lesions were not due to a discrimination problem, new rats were trained in an object (gray cylinder) duration discrimination task. In this go/no go procedure, the rats were reinforced for a 2-s exposure (duration) of the gray cylinder, but not a 10-s duration, or vice versa. The results indicate that after hippocampal lesions, there was an initial deficit followed by complete recovery. There were no significant changes for the medial prefrontal, cortical control, or sham-operated animals. It appears that the hippocampus, but not the medial prefrontal cortex, is actively involved in representing in short-term memory temporal attribute information based on the use of markers for the beginning and end of the presence (duration) of a stimulus (object).     

Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats.

The emotional reactivity of rats with lesions of the dorsal portion of medial prefrontal cortex (mPFC) was examined using a classical fear conditioning paradigm. Conditioned fear behavior (freezing responses) was measured during both the acquisition and extinction phases of the task. Lesions enhanced fear reactivity to both the conditioned stimulus (CS) and contextual stimuli during both phases, suggesting that dorsal mPFC lesions produce a general increase in fear reactivity in response to fear conditioning. M. A. Morgan, L. M. Romanski, and J. E. LeDoux (1993) found that lesions just ventral to the present lesions had no effect during acquisition of the same task and prolonged the fear response to the CS (but not the context) during extinction. Thus, both dorsal and ventral regions of mPFC are involved in the fear system, but each modulates different aspects of fear responsivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociation of attention in learning and action: Effects of lesions of the amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex.

Many associative learning theories assert that the predictive accuracy of events affects the allocation of attention to them. More reliable predictors of future events are usually more likely to control action based on past learning, but less reliable predictors are often more likely to capture attention when new information is acquired. Previous studies showed that a circuit including the amygdala central nucleus (CEA) and the cholinergic substantia innominata/nucleus basalis magnocellularis (SI/nBM) is important for both sustained attention guiding action in a five-choice serial reaction time (5CSRT) task and for enhanced new learning about less predictive cues in a serial conditioning task. In this study, the authors found that lesions of the cholinergic afferents of the medial prefrontal cortex interfered with 5CSRT performance but not with surprise-induced enhancement of learning, whereas lesions of cholinergic afferents of posterior parietal cortex impaired the latter effects but did not affect 5CSRT performance. CEA lesions impaired performance in both tasks. These results are consistent with the view that CEA affects these distinct aspects of attention by influencing the activity of separate, specialized cortical regions via modulation of SI/nBM. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociable roles of dopamine within the core and medial shell of the nucleus accumbens in memory for objects and place.

There is increasing focus on the role of the nucleus accumbens (NAc) in learning and memory, but there is little consensus as to how the core and medial shell subregions of the NAc contribute to these processes. In the current experiments, we used spontaneous object recognition to test rats with 6-hydroxydopamine lesions targeted at the core or medial shell of the NAc on a familiarity discrimination task and a location discrimination task. In the object recognition variant, control animals were able to discriminate the novel object at both 24-hr and 5-min delay. However, in the lesion groups, performance was systematically related to dopamine (DA) levels in the core but not the shell. In the location recognition task, sham-operated animals readily detected the object displacement at test. In the lesion groups, performance impairment was systematically related to DA levels in the shell but not the core. These results suggest that dopamine function within distinct subregions of the NAc plays dissociable roles in the modulation of memory for objects and place. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

N-methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens

Systemic nicotine enhances burst firing of dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens, mainly via stimulation of nicotinic acetylcholine receptors in the ventral tegmental area. Given that both the neuronal activity of mesolimbic dopamine neurons and terminal dopamine release are regulated by excitatory amino acid inputs to the ventral tegmental area and that nicotine facilitates glutamatergic transmission in brain, we investigated the putative role of ionotropic glutamate receptors within the ventral tegmental area for the effects of nicotine on dopamine release in the nucleus accumbens using microdialysis, with one probe implanted in the ventral tegmental area for drug application and another in the ipsilateral nucleus accumbens for measuring dopamine, in awake rats. Systemic nicotine (0.5 mg/kg, s.c.) and infusion of nicotine (1.0 mM) into the ventral tegmental area increased dopamine output in the nucleus accumbens. Intrategmental infusion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (0.1 mM) or N-methyl-D-aspartate (0.3 mM) increased accumbal dopamine release; these effects were antagonized by concomitant infusion of a selective antagonist at N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid (0.3 mM), and non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (0.3 mM), respectively. Infusion of either antagonist (0.3 or 1.0 mM) into the ventral tegmental area did not affect basal dopamine levels, whereas infusion of 2-amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2,3-dione, starting 40 min before nicotine injection dose-dependently attenuated the nicotine-induced increase in accumbal dopamine release. Concurrent intrategmental infusion of 2-amino-5-phosphonopentanoic acid and nicotine decreased nicotine-induced dopamine release in the nucleus accumbens. These results indicate that the stimulatory action of nicotine on the mesolimbic dopamine system is to a considerable extent mediated via stimulation of N-methyl-D-aspartate receptors within the ventral tegmental area.     

The effects of D1 or D2 dopamine receptor antagonism in the medial preoptic area, ventral pallidum, or nucleus accumbens on the maternal retrieval response and other aspects of maternal behavior in rats.

The medial preoptic area (MPOA), ventral pallidum (VP), and nucleus accumbens (NA) receive dopaminergic afferents and are involved in maternal behavior. Experiments investigated whether dopamine (DA) receptor antagonism in NA disrupts maternal behavior, determined the type of DA receptor involved, and investigated the involvement of drug spread to VP or MPOA. Injection of SCH 23390 (D1 DA receptor antagonist) into NA of postpartum rats disrupted retrieving at dosage levels that were ineffective when injected into MPOA or VP. Motor impairment was not the cause of the deficit. Injection of eticlopride (D2 DA receptor antagonist) into NA or VP was without effect. Results emphasize the importance of DA action on D1 receptors in NA for retrieval behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of the rat medial prefrontal cortex in novelty detection.

The prefrontal cortex in humans has been implicated in processes that underlie novelty detection and attention. This study examined the contribution of the rat medial prefrontal cortex to novelty detection using the targeting, or orienting, response (OR) as a behavioral index. Lesions to the medial prefrontal cortex (specifically the prelimbic and infralimbic cortices) influenced neither the OR to a novel visual stimulus from a localized light source (V1), nor the change in this OR over the course of a series of exposures to V1. However, after exposure to V1, the OR to a 2nd visual stimulus from the same source, V2, was more pronounced in control rats than in lesioned rats. These results suggest that the medial prefrontal cortex in the rat contributes to the process of novelty detection. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Excitotoxic lesions of the prefrontal cortex reduce dopamine D1-like receptors in the ventral tegmental area

Ventral mesencephalic dopamine D1-like receptors were quantified in brains of male rats ten days after unilateral microinjections of ibotenic acid (2 or 10 microg/microl) or its vehicle into the medial prefrontal cortex. The density of dopamine D1-like receptors was reduced by more than 40% in the ipsilateral ventral tegmental area (both doses) and by 15% (low dose) and 44% (high dose) in the contralateral side; no significant reduction was observed in the substantia nigra. These results suggest that a significant number of ventral tegmental D1-like receptors are localized on afferent terminals from the medial prefrontal cortex.     

The role of the nucleus accumbens core in impulsive choice, timing, and reward processing.

The present series of experiments aimed to pinpoint the source of nucleus accumbens core (AcbC) effects on delay discounting. Rats were trained with an impulsive choice procedure between an adjusting smaller sooner reward and a fixed larger later reward. The AcbC-lesioned rats produced appropriate choice behavior when the reward magnitude was equal. An increase in reward magnitude resulted in a failure to increase preference for the larger later reward in the AcbC-lesioned rats, whereas a decrease in the larger later reward duration resulted in normal alterations in choice behavior in AcbC-lesioned rats. Subsequent experiments with a peak timing (Experiments 2 and 3) and a behavioral contrast (Experiment 4) indicated that the AcbC-lesioned rats suffered from decreased incentive motivation during changes in reward magnitude (Experiments 2 and 4) and when expected rewards were omitted (Experiments 2 and 3), but displayed intact anticipatory timing of reward delays (Experiments 2 and 3). The results indicate that the nucleus accumbens core is critical for determining the incentive value of rewards, but does not participate in the timing of reward delays. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

(R)-8-OH-DPAT preferentially increases dopamine release in rat medial prefrontal cortex

A case of isolated entrapment of the palmar cutaneous branch of the median nerve is presented. At operation, a ganglion compressing the nerve within its tunnel was found. Symptoms were relieved with no recurrence at 2 years after decompression and excision of the ganglion.