Dopamine depletion in the medial prefrontal cortex induces sensitized-like behavioral and neurochemical responses to cocaine

It has been postulated that behavioral sensitization to cocaine is associated with an attenuation of cocaine-induced dopamine (DA) transmission in the medial prefrontal cortex (mPFC). Hence, experiments were designed to examine the effects of chemically-induced cortical DA depletion on the acute behavioral and neurochemical responses to cocaine. One week following two bilateral 6-hydroxydopamine (6-OHDA) injections into the mPFC, animals received injections of cocaine (7.5, 15 or 30 mg/kg, i.p.) or saline (1 ml/kg, i.p.) in a randomized fashion with a minimum 3 day intertrial interval. Cocaine produced a dose-dependent increase in motor activity which was significantly enhanced in animals depleted (mean of 76%) of dopamine in the mPFC. Likewise, 6-OHDA lesions of the mPFC produced a significant enhancement of cocaine-induced DA transmission in the nucleus accumbens (NAC) as estimated by in vivo microdialysis. These data indicate a permissive involvement of cortical DA in mediating behavioral and neurochemical responses to cocaine, as well as confirm the ability of the mPFC to influence subcortical structures in response to an acute injection of cocaine. Collectively, the present findings suggest that alterations in cortical DA transmission may be a neural substrate mediating the development of sensitization to cocaine, and thus, may contribute to the addictive properties of cocaine.     

Contrasting effects of stress on medial and sulcal prefrontal cortex self-stimulation

Male Wistar rats were subjected to either 25 controllable or uncontrollable footshocks and then tested for changes in fixed-interval 5-second (FI-5) self-stimulation of the medial prefrontal cortex (MPC), sulcal prefrontal cortex (SPC) or nucleus accumbens (NAS). Controllable footshock caused a moderate facilitation of MPC self-stimulation (30% above baseline rates) but inhibited SPC self-stimulation (32% below baseline rates). Uncontrollable footshock had no effect on MPC self-stimulation but inhibited SPC self-stimulation (52% below baseline rates). An inhibition of SPC self-stimulation was also evident 24 hours following controllable or uncontrollable footshock. NAS self-stimulation was unaffected by footshock. Changes in locomotor activity were not consistently related to changes in self-stimulation following footshock. These results are discussed in terms of the different effects of mild stress on the release of reward-relevant neurotransmitters in the MPC, SPC and NAS. The possible role of stress-induced hypoalgesia in determining the stress-induced facilitation of MPC self-stimulation is also discussed.     

Physostigmine antagonizes ketamine-induced noradrenaline release from the medial prefrontal cortex in rats

Physostigmine is known to antagonize ketamine anesthesia. In this study, effects of physostigmine (0.1 mg kg⁻¹ i.p.) on ketamine (100 mg kg⁻¹ i.p.)-induced anesthesia time and noradrenaline release from the medial prefrontal cortex in rats were examined. Ketamine produced anesthesia for 27±1 min and increased noradrenaline release to 405% of the basal. Physostigmine significantly reduced anesthesia time to 23±1 min (p<0.05), and noradrenaline to 248% (p<0.05). Therefore, noradrenaline release may play an important role in ketamine anesthesia.     

Effect of adrenalectomy on cocaine facilitation of medial prefrontal cortex self-stimulation

Adrenalectomy (ADX) is known to block the acquisition of intravenous cocaine self-administration. A previous study therefore examined whether ADX decreases sensitivity of the `brain reward system' in general, or its response to cocaine in particular, by measuring thresholds for intracranial self-stimulation with and without concurrent cocaine administration. ADX had no effect on thresholds for lateral hypothalamic self-stimulation (LHSS) and did not alter the cocaine dose–response curve for lowering the LHSS threshold. This result suggested that ADX does not affect sensitivity of the brain reward system. However, medial prefrontal cortex (MPFC) appears to be an important site in the mediation of cocaine reinforcing effects, and MPFC self-stimulation (MPFCSS) is mediated by a neural substrate that is largely independent of that which mediates LHSS. The present study therefore assessed whether ADX diminishes cocaine facilitation of MPFCSS. It was found that the threshold-lowering effect of cocaine (5.0, 10.0 and 20.0 mg/kg, i.p.) did not differ between ADX rats maintained on 0.7% saline, ADX rats maintained on corticosterone (50 μg/ml) in 0.7% saline, and sham-operated controls. However, there was a trend toward desensitization of MPFCSS, itself, following ADX in the group that did not receive corticosterone supplementation. Based on this observation, and the similar responses of MPFCSS and cocaine self-administration to noncontingent priming stimulation, stress, and NMDA receptor antagonism, it is speculated that acquisition of MPFCSS and cocaine self-administration may be dependent upon a common sensitization process that is regulated by corticosterone.     

Supersensitivity to the reinforcing effects of cocaine following 6-hydroxydopamine lesions to the medial prefrontal cortex in rats

The effects of neurotoxic lesions to the medial prefrontal cortex on both the acquisition and maintenance of intravenous cocaine self-administration were examined. In one experiment, acquisition of intravenous cocaine self-administration (0.25, 0.5 or 1.0 mg/kg/infusion) was measured in separate groups of rats 14 days following either a sham or 6-hydroxydopamine lesion to the medial prefrontal cortex. For sham rats, the 1.0 and 0.5 mg/kg dose supported reliable self-administration as indicated by discriminative responding. These rats reliably chose a lever that resulted in the delivery of these doses of cocaine over an inactive lever. Reinforced response rates were reduced when 0.25 mg/kg was the available dose and there was a loss of discriminative responding for some of the rats suggesting that it was close to threshold for self-administration. For rats that sustained a 70% depletion of dopamine in the medial prefrontal cortex, the dose-response curve was an inverse function across the entire dose range tested. In contrast to the data from the control rats, lesioned rats had a high rate of reinforced responses and demonstrated good discrimination for all doses including 0.25 mg/kg/infusion, suggesting a supersensitive response to the initial reward effect of cocaine. Another group of rats was first screened for reliable cocaine self-administration (0.5 mg/kg/infusion) and then subjected to either the prefrontal cortical 6-hydroxydopamine or sham lesion. Dose-response curves for cocaine self-administration were compared 14 days following the infusions. The lesioned rats responded reliably for low doses of cocaine that were unable to maintain responding in sham rats. These data support the hypothesis that the medial prefrontal cortex plays an important role in cocaine self-administration.     

Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats

The effects of daily administration of haloperidol for 16 weeks on the structure of layer VI in medial prefrontal cortex of rat was performed at the light and electron microscopic levels. At the light microscopic level, no difference in either the size or the density of neurons was observed. At the electron microscopic level, the mean dendritic calibre of haloperidol-treated rats was twice that observed in control animals, but this was due to a selective loss of small-calibre dendritic profiles. Rats treated with neuroleptic also showed a reduction in axon terminals with asymmetric postsynaptic membrane specializations, which, in control animals, were preferentially associated with small-calibre dendritic profiles. These small-calibre dendritic profiles were found to be spines rather than small terminal dendritic shafts. An increase in axon terminals showing no membrane specialization on larger dendritic profiles also occurred in rats treated daily with the neuroleptic. The data suggest the possibility that haloperidol may have induced a relocation of asymmetric terminals from resorbed spinous processes to larger dendritic branches with the concomitant loss of their postsynaptic membrane specialization.     

Divergent responses of inflammatory mediators within the amygdala and medial prefrontal cortex to acute psychological stress

There is now a growing body of literature that indicates that stress can initiate inflammatory processes, both in the periphery and brain; however, the spatiotemporal nature of this response is not well characterized. The aim of this study was to examine the effects of an acute psychological stress on changes in mRNA and protein levels of a wide range of inflammatory mediators across a broad temporal range, in key corticolimbic brain regions involved in the regulation of the stress response (amygdala, hippocampus, hypothalamus, medial prefrontal cortex). mRNA levels of inflammatory mediators were analyzed immediately following 30 min or 120 min of acute restraint stress and protein levels were examined 0 h through 24 h post-termination of 120 min of acute restraint stress using both multiplex and ELISA methods. Our data demonstrate, for the first time, that exposure to acute psychological stress results in an increase in the protein level of several inflammatory mediators in the amygdala while concomitantly producing a decrease in the protein level of multiple inflammatory mediators within the medial prefrontal cortex. This pattern of changes seemed largely restricted to the amygdala and medial prefrontal cortex, with stress producing few changes in the mRNA or protein levels of inflammatory mediators within the hippocampus or hypothalamus. Consistent with previous research, stress resulted in a general elevation in multiple inflammatory mediators within the circulation. These data indicate that neuroinflammatory responses to stress do not appear to be generalized across brain structures and exhibit a high degree of spatiotemporal specificity. Given the impact of inflammatory signaling on neural excitability and emotional behavior, these data may provide a platform with which to explore the importance of inflammatory signaling within the prefrontocortical-amygdala circuit in the regulation of the neurobehavioral responses to stress.     

Age-related valence-based reversal in recruitment of medial prefrontal cortex on a visual search task

Previous behavioral research has revealed a positivity effect that occurs with aging, with older adults focusing more on positive information and less on negative emotional stimuli as compared to young adults. Questions have been raised as to whether this effect exists in the rapid detection of information or whether it operates only at later stages of processing. In the present study, we used eye-tracking and neuroimaging methodologies to examine whether the two age groups accomplished the detection of emotional information on a visual search task using the same mechanisms. Eye-tracking results revealed no significant age differences in detection or viewing time of emotional targets as a function of valence. Despite their general similarity in task performance, neuroimaging results revealed an age-related valence-based reversal in medial prefrontal cortex (MPFC) activity, with detection of negative compared to positive targets activating the MPFC more for younger adults, and detection of positive compared to negative targets activating the MPFC more for older adults. These results suggest that age-related valence reversals in neural activity can exist even on tasks that require only relatively automatic processing of emotional information.     

Preferential responses to faces in superior temporal and medial prefrontal cortex in three-year-old children

Perceiving faces and understanding emotions are key components of human social cognition. Prior research with adults and infants suggests that these social cognitive functions are supported by superior temporal cortex (STC) and medial prefrontal cortex (MPFC). We used functional near-infrared spectroscopy (fNIRS) to characterize functional responses in these cortical regions to faces in early childhood. Three-year-old children (n = 88, M(SD) = 3.15(.16) years) passively viewed faces that varied in emotional content and valence (happy, angry, fearful, neutral) and, for fearful and angry faces, intensity (100%, 40%), while undergoing fNIRS. Bilateral STC and MPFC showed greater oxygenated hemoglobin concentration values to all faces relative to objects. MPFC additionally responded preferentially to happy faces relative to neutral faces. We did not detect preferential responses to angry or fearful faces, or overall differences in response magnitude by emotional valence (100% happy vs. fearful and angry) or intensity (100% vs. 40% fearful and angry). In exploratory analyses, preferential responses to faces in MPFC were not robustly correlated with performance on tasks of early social cognition. These results link and extend adult and infant research on functional responses to faces in STC and MPFC and contribute to the characterization of the neural correlates of early social cognition.     

Ibotenic acid lesions of the medial prefrontal cortex block the development and expression of 3,4-methylenedioxymethamphetamine-induced behavioral sensitization in rats

There is ample evidence that plastic changes in the nervous system require the excitatory amino acid transmission. This appears to be also the case for psychostimulant-induced behavioral sensitization. More specifically the glutamatergic input from the medial prefrontal cortex (mPFC) to the VTA and the NAc appears to be involved in behavioral sensitization processes. However, dissociations regarding the role of the mPFC with respect to the development and expression of sensitization, as well as with respect to the psychostimulant being studied (amphetamine versus cocaine) appear to exist. The present study examined the role of the dorsal mPFC in the development and expression of 3,4-methylenedioxymethamphetamine (MDMA)-induced sensitization. Bilateral ibotenic acid or sham lesions of the dorsal mPFC were performed 7 days prior to or 4 days after a context-dependent sensitization-inducing regimen of MDMA (15 mg/kg i.p.) or saline. Rats were then challenged with MDMA (5 mg/kg i.p.) after 12 days of withdrawal. Ibotenic acid lesions did not affect the activating effects of MDMA, but prevented the development and expression of MDMA sensitization. Thus, the distance traveled during the development phase of sensitization increased in sham-lesioned rats but not in ibotenic-lesioned animals. Similarly, sham-lesioned rats showed a sensitized response when challenged with MDMA after the withdrawal period, an effect not observed in ibotenic-lesioned animals. These data reinforce the view that the dorsal mPFC is involved in psychostimulant sensitization and more specifically they indicate that the dorsal mPFC plays a key role in the development and expression of MDMA-induced behavioral sensitization.     

CRF receptor antagonist attenuates stress-induced noradrenaline release in the medial prefrontal cortex of rats

Noradrenaline release in rat medial prefrontal cortex (PFC) was measured using a brain microdialysis technique. Immobilization stress increased noradrenaline release to a maximum level of 248.7 ± 12.8% of the basal release, which was significantly attenuated by preinjection of α-helical CRF_9–41 (50 μg/rat) into the lateral cerebroventricle. Intracerebroventricular injection of CRF also increased noradrenaline release in the medial PFC. These results suggest that immobilization-stress facilitates noradrenaline release in the medial PFC through activation of the CRF system in the brain.     

Transcranial magnetic stimulation of medial prefrontal cortex modulates face expressions processing in a priming task

The medial prefrontal cortex (mPFC) and the right somatosensory cortex (rSC) are known to be involved in emotion processing and face expression recognition, although the possibility of segregated circuits for specific emotions in these regions remains unclear. To investigate this issue, we used transcranial magnetic stimulation (TMS) together with a priming paradigm to modulate the activation state of the mPFC and the rSC during emotional expressions discrimination. This novel paradigm allows analyzing how TMS interacts with the ongoing activity of different neuronal populations following prime processing. Participants were asked to discriminate between angry and happy faces that were preceded by a congruent prime (a word expressing the same emotion), an incongruent prime (a word expressing the opposite emotion) or a neutral prime. In TMS trials, a single pulse was delivered over the mPFC, rSC or Vertex (control site) between prime and target presentation. TMS applied over the mPFC significantly affected the priming effect, by selectively increasing response latencies in congruent trials. This indicates that the mPFC contains different neural representations for angry and happy expressions. TMS over rSC did not significantly affect the priming effect, suggesting that rSC is not involved in processing verbal emotional stimuli.     

Atypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobia

Generalized social phobia (GSP) involves the fear of being negatively evaluated. Previous work suggests that self-referentiality, mediated by the medial prefrontal cortex (MFPC), plays an important role in the disorder. However, it is not clear whether this anomalous MPFC response to self-related information in patients with GSP concerns an increased representation of their own or others' opinions. In this article, we examine whether GSP is associated with increased response to own (1st person) or other individuals' (2nd person) opinions relative to healthy individuals. Unmedicated individuals with GSP (n = 15) and age-, IQ-, and gender-matched comparison individuals (n = 15) read 1st (e.g., I'm ugly), and 2nd (e.g., You're ugly) person viewpoint comments during functional magnetic resonance imaging. We observed significant group-by-viewpoint interactions within the ventral MPFC. Whereas the healthy comparison individuals showed significantly increased (or less decreased) BOLD responses to 1st relative to 2nd person viewpoints, the patients showed significantly increased responses to 2nd relative to 1st person viewpoints. The reduced BOLD responses to 1st person viewpoint comments shown by the patients correlated significantly with severity of social anxiety symptom severity. These results underscore the importance of dysfunctional self-referential processing and MPFC in GSP. We believe that these data reflect a reorganization of self-referential reasoning in the disorder with a self-concept perhaps atypically related to the view of others.     

D1 dopamine receptor activation reduces extracellular glutamate and GABA concentrations in the medial prefrontal cortex

The present study examined effect of administration of a selective D1 dopamine receptor agonist, SKF38393 on extracellular concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in mPFC, by using in vivo microdialysis. Perfusion with SKF38393 via a dialysis probe reduced concentrations of both Glu and GABA dose-relatedly, and these effects were prevented by co-perfusion with a D1 dopamine receptor antagonist, SCH23390 (40 microM). These results suggested that the dopaminergic hyperactivity may lead to the hypofunction of glutamatergic and GABAergic systems in mPFC via D1 dopamine receptor stimulation.     

Acquired personality traits of autism following damage to the medial prefrontal cortex

Abstract

Recent neuroimaging studies on “theory of mind” have demonstrated that the medial prefrontal cortex (PFC) is involved when subjects are engaged in various kinds of mentalising tasks. Although a large number of neuroimaging studies have been published, a relatively small amount of neuropsychological evidence supports involvement of the medial PFC in theory of mind reasoning. We recruited two neurological cases with damage to the medial PFC and initially performed the standard neuropsychological assessments for intelligence, memory, and executive functions. To examine theory of mind performance in these two cases, four kinds of standard and advanced tests for theory of mind were used, including first- and second-order false belief tests, the strange stories test, and the faux pas recognition test. Both patients were also requested to complete the questionnaire for the autism-spectrum quotient. Neither case showed impairment on standard theory of mind tests and only mild impairments were seen on advanced theory of mind tests. This pattern of results is basically consistent with previous studies. The most interesting finding was that both cases showed personality changes after surgical operations, leading to characteristics of autism showing a lack of social interaction in everyday life. We discuss herein the possible roles of the medial PFC and emphasize the importance of using multiple approaches to understand the mechanisms of theory of mind and medial prefrontal functions.     

Apomorphine and haloperidol effects on striatal H-dopamine release in anesthetized, awake restrained and freely moving rats

The ability of apomorphine (APO) and haloperidol (HAL) to affect the spontaneous release of newly synthesized ³H-DA in the striatum was studied in halothane anesthetized, gallamine paralyzed, awake restrained and freely moving rats. The striatum was continuously superfused through a push-pull cannula with a physiological medium enriched in ³H-tyrosine. Basal levels of ³H-DA release were different in the four experimental models: highest in halothane anesthetized rats, intermediate in awake restrained and gallamine treated rats and lowest in freely moving rats. In all experimental models IV or SC injection of APO (1 mg/kg) inhibited the release of ³H-DA (30–50%) from 15 to 90 min following its administration. In awake restrained and freely moving rats, stereotyped behaviour was observed for one hour following the APO injection. In halothane anesthetized rats the inhibitory effect of APO on ³H-DA release was prevented by pretreatment with HAL (2 mg/kg IV). Injection of HAL (2 mg/kg IV or SC) failed to enhance the release of ³H-DA in anesthetized and awake restrained rats, whilst a long-lasting increase in ³H-DA release was observed in gallamine treated and freely moving animals (55% and 120% respectively). However, catalepsy was observed in both restrained and freely moving rats. It is concluded that the modifications of ³H-DA release produced by HAL but not those produced by APO are dependent on the experimental model used, a fact possibly related to the different sites of action of these two drugs.     

Similar effects ofd-amphetamine and cocaine on extracellular dopamine levels in medial prefrontal cortex of rats

The effects of behaviorally equivalent doses of D-amphetamine and cocaine on extracellular dopamine (DA) levels in the left and right medial prefrontal cortex (PFC) were investigated using microdialysis in anesthetized rats. The two drugs increased extracellular DA levels to a similar extent and, in each case, there was a tendency for the effects to be greater in the left than in the right side of the brain. For both drugs, there was a strong negative correlation between basal levels and the magnitude of the drug response; this relationship, while important to consider when comparing one drug to another, could not account for the left-right differences in drug effects. Contrary to some previous reports, the present data indicate that D-amphetamine and cocaine do not differ substantially with regard to their effects on dopamine neurotransmission in the PFC.     

Footshock stress facilitates self-stimulation of the medial prefrontal cortex but not the lateral hypothalamus in the rat

The effects of stress on self-stimulation were investigated by exposing rats to either controllable, uncontrollable or no footshock. Both controllable and uncontrollable footshock increased medial prefrontal cortex self-stimulation rates immediately as well as 24 h following treatment. Controllable footshock produced a greater enhancement than uncontrollable footshock. In contrast, self-stimulation of the lateral hypothalamus was unaffected by either footshock treatment. These results are interpreted with reference to the neurochemical response of the mesocortical dopaminergic system to acute stress.     

In vivo effects of phosphodiesterase inhibition on basal cyclic guanosine monophosphate levels in the prefrontal cortex, hippocampus and cerebellum of freely moving rats

We have characterized the various phosphodiesterases (PDE) that degrade cyclic GMP in the prefrontal cortex, hippocampus, and cerebellum using the microdialysis technique to measure in vivo extracellular cyclic GMP in awake rats. The following PDE blockers were used (100 and 1,000 microM): 8-methoxymethyl-IBMX (8-MM-IBMX), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), milrinone, rolipram, and zaprinast. For solubility reasons, sildenafil was tested only at 100 microM. All drugs were administered locally in the brain regions through the dialysis probe. At 100 microM, 8-MM-IBMX enhanced the cyclic nucleotide extracellular levels in the prefrontal cortex and hippocampus but not in the cerebellum; EHNA and milrinone were active only in the hippocampus; rolipram was devoid of any effect; zaprinast and sildenafil were effective in all three brain areas. At 1 mM, 8-MM-IBMX, milrinone, and zaprinast increased extracellular cyclic GMP in all the brain regions examined, EHNA became active also in the prefrontal cortex and rolipram showed a significant effect only in the cerebellum. This is the first in vivo functional study showing that, in cortex, PDE1, -2, and -5/9 degrade cGMP, with PDE9 probably playing a major role; in hippocampus, PDE5/9 and PDE1 are mainly involved and seem almost equally active, but PDE2 and -3 also contribute; in cerebellum, PDE5/9 are the main cGMP hydrolyzing enzymes, but also PDE1 and -4 significantly operate.