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)     

Topographic organization of medial pulvinar connections with the prefrontal cortex in the rhesus monkey

The medial nucleus of the pulvinar complex (PM) has widespread connections with association cortex. We investigated the connections of the PM with the prefrontal cortex (PFC) in macaque monkeys, with tracers placed into the PM and the PFC, respectively. Injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) placed into the PM resulted in widespread anterograde terminal labeling in layers III and IV, and retrograde cellular labeling in layer VI of the PFC. Injections of tracers centered on the central/lateral PM resulted in labeling of dorsolateral and orbital regions, whereas injections centered on caudal, medial PM resulted in labeling of dorsomedial and medial PFC. Since injections of the PM included neighboring thalamic nuclei, retrograde tracers were placed into distinct cytoarchitectonic regions of the PFC and retrogradely labeled cells in the posterior thalamus were charted. The results of this series of tracer injections confirmed the results of thalamic injections. Injections placed into areas 8a, 12 (lateral and orbital), 45, 46 and 11, retrogradely labeled neurons in the central/lateral PM, while tracer injections placed into areas 9, 12 (lateral), 10 and 24, labeled medial PM. The connections of the PM with temporal, parietal, insular, and cingulate cortices were also examined. The central/lateral PM has reciprocal connections with posterior parietal areas 7a, 7ip, and 7b, insular cortex, caudal superior temporal sulcus (STS), caudal superior temporal gyrus (STG), and posterior cingulate, whereas medial PM is connected mainly with the anterior STS and STG, as well as the cingulate cortex and the amygdala. These connectional studies suggest that the central/ lateral and medial PM have divergent connections which may be the substrate for distinct functional circuits.     

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats

Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex.     

Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability.

The authors examined set-shifting abilities in rats injected with antagonists of N-methyl-D-aspartate (NMDA) receptors (MK801) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (LY293558) into the medial prefrontal cortex (mPFC). Set-shifting was assessed with a maze-based task requiring a switch between brightness and texture discrimination strategies. Intra-mPFC injection of MK801 prior to training on the 2nd discrimination impaired discrimination strategy acquisition. The MK801-induced deficit was due to increased perseverative responding. AMPA receptor blockade also impaired acquisition of the 2nd discrimination, these impairments were due to more general cognitive deficits. Results suggest that, within the mPFC, both AMPA and NMDA receptors are necessary for set-shifting, and that NNMA receptor hypofunction impairs the capacity to modify existing knowledge or to inhibit responses that are no longer appropriate. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropeptide FF potentiates the behavioral sensitization to amphetamine and alters the levels of neurotransmitters in the medial prefrontal cortex

We have demonstrated that chronic administration of neuropeptide FF (NPFF) into the lateral ventricle potentiated the behavioral sensitization to amphetamine. Further, the treatment with NPFF decreased the levels of serotonin, and increased the glutamate and GABA content in the medial prefrontal cortex of amphetamine-sensitized rats. The results suggest that NPFF may modulate the neuronal process of amphetamine addiction.     

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).     

Psychomotor stimulant effects of cocaine in rats and 15 mouse strains.

Relative to intravenous drug self-administration, locomotor activity is easier to measure with high throughput, particularly in mice. Therefore its potential to predict differences in self-administration between genotypes (e.g., targeted mutations, recombinant inbred strains) is appealing, but such predictive value is unverified. The main goal of this study was to evaluate the utility of the locomotor assay for accurately predicting differences in cocaine self-administration. A second goal was to evaluate any correlation between activity in a novel environment, and cocaine-induced hyperactivity, between strains. We evaluated locomotor activity in male and female Sprague–Dawley rats and 15 mouse strains (129S1/SvImJ, 129S6/SvEvTac, 129X1/SvJ, A/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, SJL/J, SPRET/EiJ, and outbred Swiss Webster and CD-1/ICR), as well as cocaine self-administration in BALB substrains. All but BALB/cJ mice showed locomotor habituation and significant cocaine-induced hyperactivity. BALB/cJ mice also failed to self-administer cocaine. BALB/cByJ mice showed modest locomotor habituation, cocaine-induced locomotion, and cocaine self-administration. As previously reported, female rats showed greater cocaine-induced locomotion than males, but this was only observed in one of 15 mouse strains (FVB/NJ), and the reverse was observed in two strains (129X1/SvJ, BALB/cByJ). The intriguing phenotype of the BALB/cJ strain may indicate some correlation between all-or-none locomotion in a novel environment, and stimulant and reinforcing effects of cocaine. However, neither novelty- nor cocaine-induced activity offered a clear prediction of relative reinforcing effects among strains. Additionally, these results should aid in selecting mouse strains for future studies in which relative locomotor responsiveness to psychostimulants is a necessary consideration. (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.     

Functional modularity of the medial prefrontal cortex: Involvement in human empathy.

To investigate medial frontal lobe mediation of human empathy, the authors analyzed the activation areas in statistical parametric maps of 80 studies reporting neural correlates of empathic processing. The meta-analysis revealed 6 spatially distinct activation clusters in the medial part of the frontal lobe dorsal to the intercommissural plane. The most dorsal cluster coincided with the left supplementary motor area (SMA). Rostrally adjacent was a cluster that overlapped with the right pre-SMA. In addition, there were 3 left-hemispheric and 1 right-hemispheric clusters located at the border between the superior frontal and anterior cingulate gyrus. A broad spectrum of cognitive functions were associated with these clusters, including attention to one's own action, which was related to activations in the SMA, and valuation of other people's behavior and ethical categories, which was related to activations in the most rostroventral cluster. These data complement the consistent observation that lesions of the medial prefrontal cortex interfere with a patient's perception of own bodily state, emotional judgments, and spontaneous behavior. The results of the current meta-analysis suggest the medial prefrontal cortex mediates human empathy by virtue of a number of distinctive processing nodes. In this way, the authors' findings suggest differentiated aspects of self-control of behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine sensitization can accelerate the onset of peak cocaine behavioral effects

The development of sensitization to the behavioral effects of cocaine occurs with repeated intermittent usage. In the present study rats were given five daily i.p. injections of cocaine (10 mg/kg) immediately prior to placement in an open-field environment for 20 min to induce cocaine sensitization. Control groups received saline injections or cocaine injections (10 mg/kg) 30 min after testing in the home cage. One week later the animals were given a challenge test with 10 mg/kg cocaine. The animals that had received cocaine in the test environment exhibited a more rapid onset of cocaine-induced behavioral effects than either animals previously treated with saline or animals that had received cocaine in the home cage. In a second experiment, the same sensitization protocol was followed except that during the interval between the end of the cocaine/saline treatments and the challenge test, the animals were given six daily 20-min saline tests to assess the contribution of differential habituation and/or Pavlovian conditioning to the sensitization effect. Neither habituation or Pavlovian conditioning altered the more rapid onset of cocaine stimulant effects induced by repeated cocaine treatments. It is suggested that the faster onset of cocaine effects is another way in which cocaine sensitization contributes to cocaine abuse liability.     

Neuronal activity in the medial prefrontal cortex during Pavlovian eyeblink and nictitating membrane conditioning

The present study assessed Pavlovian eyeblink (EB) conditioning, using tones and periorbital shock as the conditioned and unconditioned stimuli (CS and US), and nictitating membrane (NM) conditioning, using tones and airpuffs as the CS and US. During each experiment, CS-evoked changes in multiple-unit activity (MUA) in the medial prefrontal cortex (mPFC) were recorded. Concomitant heart rate (HR) conditioned responses (CRs) were also recorded. A nonassociative control group received explicitly unpaired presentations of the CS and US in each experiment. Increases in both NM and EB CRs occurred over sessions in the paired, but not the unpaired, groups. Decelerative HR CRs also occurred in the eyeshock, but not the airpuff, group. Although tone-evoked increases in neuronal activity were obtained during 10 initial tone-alone presentations in all groups, this activity habituated over trials. CS-evoked increases in neuronal activity also occurred, but this activity was considerably greater in the group that received periorbital shock as the US. During subsequent extinction trials, decreases in tone-evoked neuronal activity occurred in this group, compared with the previous CS/US paired trials. CS-evoked MUA increases were minimal during all except the pretraining phase of the study in the CS/US unpaired control groups and in the paired airpuff group. These findings show that neuronal activity during associative learning occurs in the mPFC during Pavlovian EB, as well as HR conditioning, but this activity apparently reflects an affective component to learning that is only indirectly related to skeletal conditioning.     

Functional connections between medial prefrontal cortex and caudate-putamen in brain-stimulation reward of rats.

Rats were trained to self-stimulate for trains of cathodal pulses delivered via electrodes placed in the medial prefrontal cortex (MPFC) and caudate-putamen (CPu). When the pulses were delivered via 9 ipsilateral MPFC and CPu sites alternately, summation varied from 13% to 40%. However, the overall summation for 2 contralateral MPFC-CPu pairs was 5%, thus indicating a greater integration of ipsilateral than contralateral reward signals. When the interval between alternate pulses decreased in 4 of the 9 ipsilateral pairs, the summation also decreased, an outcome consistent with collision of action potentials passing between the MPFC and CPu sites. The size of the collision effect ranged from 15% to 33%. Estimates of conduction velocity varied between 0.4 to 5.4 m/sec, with a 1.7 m/sec average. According to these values, the neurons connecting the MPFC and CPu self-stimulation sites appear to be slower than the ones that have been shown to link reward fibers that course between posterior brain regions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of the medial prefrontal cortex in acquired distinctiveness and equivalence of cues.

In the present study, the authors examined the role of the medial prefrontal cortex in acquired equivalence and distinctiveness of cues. Rats were placed in 4 experimental contexts (A, B, C, and D) where they received presentations of 2 auditory stimuli (X and Y). In Contexts A and B, X was paired with food and Y was not, whereas in Contexts C and D, Y was paired with food and X was not. Rats that received sham lesions and those with lesions of the medial prefrontal cortex acquired this configural discrimination equally readily. Rats then received many pellets in A but not in C. After this training, sham-lesion rats exhibited more magazine activity in B than in D (an acquired distinctiveness/acquired equivalence effect), whereas those with medial prefrontal cortex lesions did not. These results indicate that the medial prefrontal cortex is involved in the process by which experience with stimuli influences the degree of generalization between them. (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)     

Involvement of subdivisions of the medial prefrontal cortex in learned cardiac adjustments in rabbits.

Electrical stimulation of area 24 and area 32 of the medial prefrontal cortex (mPFC) in rabbits elicited increases in respiration rate and decreases in heart rate (HR) and blood pressure. However, stimulation in area 25 elicited pressor responses and a biphasic HR response consisting of an initial HR increase followed by an HR decrease. Administration of an α-adrenergic receptor antagonist eliminated the pressor response and bradycardiac response produced by area 25 stimulation, but it had no effect on the bradycardia elicited by stimulation of area 24 or area 32. Lesions centered on area 32 of the mPFC greatly attenuated the conditioned bradycardiac response elicited by paired tone and paraorbital shock presentations. Lesions of area 24 produced a decrease in discrimination between a reinforced CS and a nonreinforced CS but had no effect on the magnitude of the CR. Area 25 lesions had no effect on any aspect of conditioned responding. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dexamethasone pretreatment reduces the psychomotor stimulant effects induced by cocaine and amphetamine in mice

1. The present study examined a comparison of the effect of DEX on psychomotor stimulant effects of cocaine and amphetamine in mice by using the locomotor activity test. 2. Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX per se (0.1-1.0-10 mg/kg/i.p.) did not modify the activity of control mice. 3. DEX pretreatment decreased the stimulating effects induced both by cocaine and amphetamine but no consistent dose-related effects were observed. 4. The results suggest that DEX may play an important role on the stimulating effects of cocaine and amphetamine and that it may be of some utility in the clinical management of psychostimulants abuse.     

Performance-related activity in medial rostral prefrontal cortex (area 10) during low-demand tasks.

Neuroimaging studies have frequently observed relatively high activity in medial rostral prefrontal cortex (PFC) during rest or baseline conditions. Some accounts have attributed this high activity to the occurrence of unconstrained stimulus-independent and task-unrelated thought processes during baseline conditions. Here, the authors investigated the alternative possibility that medial rostral PFC supports attention toward the external environment during low-demand conditions. Participants performed a baseline simple reaction time (RT) task, along with 3 other tasks that differed in the requirement to attend to external stimuli versus stimulus-independent thought. Medial rostral PFC activation was observed in the baseline task and in a condition requiring strong engagement with external stimuli, relative to 2 conditions with a greater requirement for stimulus-independent thought. An important finding was that activity in this region was associated with faster RTs in the baseline task, ruling out an explanation in terms of task-unrelated thought processes during this condition. Thus, at least under certain circumstances, medial rostral PFC appears to support attention toward the external environment, facilitating performance in situations that do not require extensive processing of experimental stimuli. (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)     

(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.     

Cocaine use is associated with increased craving in outpatient cocaine abusers

Continuous treatment with transdermal nitroglycerin leads to tolerance development within the first day of application. Effective long-term therapy can be provided by interval treatment with nightly patch removal, but even during the hours of intermittent patch application there is rapid attenuation of initial effects. To assess whether an unattenuated antiischemic and antianginal efficacy during the hours of intermittent dosing can be maintained, a modified drug-release profile with increasing plasma concentrations was evaluated using a double-blind, placebo-controlled crossover protocol. Eleven patients with documented coronary artery disease received, in a randomized order, a total of four low-dose nitroglycerin patches (5 mg/24 h each) or placebo, respectively, at intervals of 3 hours. After a treatment interval of 12 hours, all patches were removed for an equally long patch-free interval prior to renewed application of one patch the next morning. At a comparable workload, reductions of ST-segment depression of 65%, 63%, and 56% were found at 2.5 hours, 8 hours, and 12 hours after application of the first patch on day 1, respectively (all significant vs. placebo; 2.5 hours vs. 12 hours, n.s.). On day 2, the comparable reduction of 63% at 2.5 hours after renewed application indicates prevention of tolerance development during subchronic treatment. Effects on exercise capacity and angina pectoris paralleled those on exercise-induced ST-segment depression. Plasma concentrations of nitroglycerin increased from 223 pg/mL to 558 and 803 pg/mL on day 1 and amounted to 205 ng/mL at 2.5 hours on day 2. Thus, interval therapy with increasing nitroglycerin concentrations provides unattenuated antiischemic and antianginal efficacy during the hours of treatment and circumvention of early tolerance during subchronic application. This modified pharmacokinetic profile can be regarded as a model for an improved dosage regimen in nitrate interval therapy.