Stressor controllability modulates stress-induced dopamine and serotonin efflux and morphine-induced serotonin efflux in the medial prefrontal cortex.

It has previously been shown that inescapable (IS) but not escapable (ES) stress potentiates the rewarding properties of morphine as measured by conditioned place preference and psychomotor activation, and that this potentiation may be mediated by dorsal raphe nucleus (DRN) serotonin (5-HT) neurons. The medial prefrontal cortex (mPFC) has been implicated in both reward and stress, and is a projection region of the DRN. The mPFC also contains dopaminergic afferents from the ventral tegmental area, which has been the focus of many studies exploring both the rewarding properties of drugs and the aversive properties of stress. The role of the mPFC in stress/drug reactivity interactions is largely unknown. The present study used in vivo microdialysis to examine 5-HT and dopamine (DA) efflux in the mPFC of rats during IS, ES or no stress (NS). IS and ES rats received the stressor in yoked pairs. The stressor consisted of tailshocks that could be terminated for both rats by the ES rats. Large increases in 5-HT and DA levels were observed during IS but not ES or NS. DA and 5-HT efflux were also measured 24 h later in the same rats in response to morphine (3 mg/kg) or saline. Sustained increases in 5-HT levels were observed after morphine in rats that had previously received IS but not in rats that had received ES or NS. No changes in DA efflux were observed after morphine. Thus, 5-HT and DA in the mPFC may be involved in stressor controllability effects, and the sensitization of 5-HT neurons by IS extends to the mPFC and to morphine as a challenge.     

Emerging role for the medial prefrontal cortex in alcohol-seeking behaviors

The medial prefrontal cortex (mPFC) plays an important role in high-order executive processes and sends highly organized projections to sub-cortical regions controlling mood, motivation and impulsivity. Recent preclinical and clinical studies have demonstrated alcohol-induced effects on the activity and composition of the PFC which are implicated in associative learning processes and may disrupt executive control over impulsivity, leading to an inability to self-limit alcohol intake. Animal studies have begun to dissect the role of the mPFC circuitry in alcohol-seeking behavior and withdrawal, and have identified a key role for projections to sub-cortical sites including the extended amygdala and the nucleus accumbens (NAc). Importantly, these studies have highlighted that alcohol can have contrasting effects on the mPFC compared to other addictive substances and also produce differential effects on the structure and activity of the mPFC following short-term versus long-term consumption. Because of these differences, how the mPFC influences the initial aspects of alcohol-seeking behavior and how we can better understand the long-term effects of alcohol use on the activity and connectivity of the mPFC need to be considered. Given the lack of preclinical data from long-term drinking models, an increased focus should be directed towards identifying how long-term alcohol use changes the mPFC, in order to provide new insights into the mechanisms underlying the transition to dependence.     

Comparison of effects of hypotension and handling stress on the release of noradrenaline and dopamine in the locus coeruleus and medial prefrontal cortex of the rat

The effects of two different types of stress (hypotension and handling) on the release of dopamine, noradrenaline and DOPAC in the locus coeruleus (LC) and medial prefrontal cortex (mPFC) was studied by means of the dual-probe microdialysis technique. One probe was implanted in the vicinity of the LC and a second probe was implanted in the mPFC. Both probes were used to record simultaneously noradrenaline, dopamine and DOPAC. Samples from the LC were collected in the presence of nomifensine, which was added to the perfusion fluid in a concentration of 50 μM. Hypotension (20 min) induced by intravenous administration of nitroprusside stimulated the release of noradrenaline in the LC and mPFC to about 190% and 150% of control values, respectively. Hypotension also strongly stimulated the release of dopamine in the mPFC (to 320% of control) and DOPAC in the LC (to 270% of control). The effect of hypotension on extracellular dopamine, noradrenaline and DOPAC was decreased by halothane anaesthesia, and was blocked by chloral hydrate anaesthesia. Handling stress (10 min) stimulated the release of noradrenaline in the LC and mPFC to 180% and 160% of control values, respectively. Handling stimulated the release of dopamine in the mPFC to about 160% of control. The effect of hypotension or handling stress was further evaluated in animals in which the LC was lesioned by an infusion of 6-OH-dopamine. Lesioning of the noradrenergic LC neurons did not the prevent the hypotension-related stimulation of dopamine release, but shortened the time course of the effect dramatically. Lesioning of the noradrenergic neurons had no effect on the stimulatory effect of handling on the release of dopamine in the mPFC. This study shows that mesocortical dopamine neurons, in contrast to noradrenaline neurons, respond much stronger to hemodynamic stress than to an emotional stress. During certain conditions like hypotension stress, but not during handling stress, the LC activity is able to modulate the release of dopamine from mesocortical neurons. Received: 23 November 1998 / Accepted: 23 April 1999 / Published online: 21 June 1999     

Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex.

Recent hypotheses suggest that changes in neuronal structure and connectivity may underlie the etiology of depression. The medial prefrontal cortex (mPFC) is affected by depression and shows neuronal remodeling during adulthood. This plasticity may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is intensely expressed in the adult mPFC. As the expression of PSA-NCAM is increased by serotonin in other cerebral regions, antidepressants acting on serotonin reuptake may influence PSA-NCAM expression and thus counteract the effects of depression by modulating neuronal structural plasticity. Using immunohistochemistry, we have studied the relationship between serotoninergic fibers and PSA-NCAM expressing neurons in the adult rat mPFC and the expression of serotonin receptors in these cells. The effects of fluoxetine treatment for 14 days on mPFC PSA-NCAM expression have also been analyzed. Although serotoninergic fibers usually do not contact PSA-NCAM immunoreactive neurons, most of these cells express 5-HT3 receptors. In general, chronic fluoxetine treatment induces significant increases in the number of PSA-NCAM immunoreactive neurons and in neuropil immunostaining and coadministration of the 5-HT3 antagonist ondansetron blocks the effects of fluoxetine on PSA-NCAM expression. These results indicate that fluoxetine, acting through 5-HT3 receptors, can modulate PSA-NCAM expression in the mPFC. This modulation may mediate the structural plasticity of this cortical region and opens new perspectives on the study of the molecular bases of depression.     

Ibotenic acid lesions of medial prefrontal cortex augment swim-stress-induced locomotion.

Locomotor activity of rats with sham or ibotenic acid lesions of the medial prefrontal cortex (MPFC) was assessed after animals were exposed to a 15-min swim or control stress. Swim-stress-induced locomotor activity was augmented in the MPFC-lesioned rats. These and other data suggest that lesions of the MPFC are followed by an exaggeration of the normal behavioral response to stress. Dysregulation of dopamine transmission in the basal ganglia may be involved.     

Neuropharmacological assessment of cocaine self-administration into the medial prefrontal cortex

Neuronal systems involved in the initiation of reinforcement following the response-contingent delivery of cocaine into the medial prefrontal cortex were investigated. Dose-effect analyses demonstrated that different concentrations of cocaine result in distinguishable patterns of self-administration which could be empirically determined by measuring the relative frequency distribution of the interinfusion intervals. The substitution of equimolar d-amphetamine or lidocaine resulted in rates and patterns of responding similar to vehicle or a low dose of cocaine, suggesting that reinforcement occurs from actions on specific receptors rather than through a local anesthetic neuronal blockade or through properties of a general psychomotor stimulant. The co-infusion of equimolar concentrations of sulpiride attenuated intake and produced patterns of responding similar to those seen after decreasing the cocaine dose consistent with an excitatory role for D2 dopaminergic receptors in these processes. Sulpiride and cocaine may act at separate sites since the decreased intake was not reversed by increasing the concentration of cocaine. D1 dopaminergic, muscarinic-cholinergic and beta-noradrenergic receptor antagonists either did not modulate drug-intake or had minimal effects. Cocaine reinforcement may result in part from an activation of D2 receptors initiating neuronal activity in pathways or circuits mediating reinforcement processes.     

Electrophysiological effects of phencyclidine in the medial prefrontal cortex of the rat

The effects of local applications of phencyclidine (PCP) and dopamine (DA) on neurons of the medial prefrontal cortex were investigated using single unit recording techniques. The activity of the majority of cells in the deeper layers of the medial prefrontal cortex was depressed by both phencyclidine and DA, whereas increases, as well as decreases, in the firing rates were observed in cells located in the superficial cortical layers. The stereospecificity of the responses of deeper cells to phencyclidine was demonstrated using the enantiomers of 1-(-1-phenylcyclohexyl)-3-methylpiperidine (PCMP). Phencyclidine was found to be 1.5 times more potent than (+) PCMP and 3 times more potent than (-) PCMP. Finally, the DA receptor antagonist fluphenazine, blocked the phencyclidine-elicited depressions of unit activity in the deep prefrontal cortex. Taken together, the data indicate that the DA-like effects of phencyclidine on neurons of the medial prefrontal cortex are mediated by DA receptors and provide pharmacological support for the idea that psychomotor stimulant drugs have specific actions on targets of the ventral tegmental area (A10) dopamine system.     

Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting.

Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired set-shifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.     

Opioid peptides and self-stimulation of the medial prefrontal cortex in the rat

The possible involvement of opioid peptides as part of the neurochemical substrates of self-stimulation (SS) in the medial prefrontal cortex (MPC) of the rat was investigated in two different groups of rats bilaterally implanted with monopolar electrodes in the MPC. In the first group, morphine (5, 10 and 20 g) and an enkephalin analogue (BW 180) (5, 10, 20 and 40 g) and an enkephalin analogue (BW 180) (5, 10, 20 and 40 g) were injected through cannulae implanted into the lateral ventricles (IV). In the second group, naloxone (0.04, 0.4, and 1.6 g) and morphine (5, 10 and 20 g) were injected through cannulae implanted into the MPC, 1.5 mm above the tip of the stimulating electrodes. In the first group, spontaneous motor activity (SMA) was measured as a control for non-specific effects (sedation or motor dysfunction). In the second group SS, contralateral to the microinjected side, served as control. SS and SMA were measured 1 and 2 h postinjection. One hour after IV injection of morphine SS was not affected, although SMA was decreased. Two hours postinjection, on the contrary, SS was increased while SMA remained decreased. Similar effects were found with IV microinjections of BW 180. Naloxone, intraperitoneally injected, reversed all these effects. Naloxone or morphine injected intracerebrally (MPC) produced no changes in SS either in the injected or in the contralateral side, which served as control. The present results suggest that the effects found with IV injections of opioids on SS of the MPC are indirect (through activation of other brain areas) and not mediated by a direct action on the neurochemical substrates underlying this behaviour in the MPC.Supported by the European Training Program in Brain and Behaviour Research Present address: University of Oxford, Department of Pharmacology, South Parks Road, Oxford OX1 3QT, Great Britain     

Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment.

Profound neuroplastic changes have been demonstrated in various limbic structures after chronic stress exposure and antidepressant treatment in animal models of mood disorders. Here, we examined in rats the effect of chronic social stress and concomitant antidepressant treatment on cell proliferation in the medial prefrontal cortex (mPFC). We also examined possible hemispheric differences. Animals were subjected to 5 weeks of daily social defeat by an aggressive conspecific and received concomitant, daily, oral fluoxetine (10 mg/kg) during the last 4 weeks. Bromodeoxyuridine (BrdU) labeling and quantitative stereological techniques were used to evaluate the treatment effects on proliferation and survival of newborn cells in limbic structures such as the mPFC and the hippocampal dentate gyrus, in comparison with nonlimbic structures such as the primary motor cortex and the subventricular zone. Phenotypic analysis showed that neurogenesis dominated the dentate gyrus, whereas in the mPFC most newborn cells were glia, with smaller numbers of endothelial cells. Chronic stress significantly suppressed cytogenesis in the mPFC and neurogenesis in the dentate gyrus, but had minor effect in nonlimbic structures. Fluoxetine treatment counteracted the inhibitory effect of stress. Hemispheric comparison revealed that the rate of cytogenesis was significantly higher in the left mPFC of control animals, whereas stress inverted this asymmetry, yielding a significantly higher incidence of newborn cells in the right mPFC. Fluoxetine treatment abolished hemispheric asymmetry in both control and stressed animals. These pronounced changes in gliogenesis after chronic stress exposure may relate to the abnormalities of glial cell numbers reported in the frontolimbic areas of depressed patients.     

Dopamine neurons projecting to the medial prefrontal cortex possess release-modulating autoreceptors

The ability of dopamine (DA) agonists and antagonists to modulate the K+-evoked overflow of radioactivity from superfused slices of prefrontal cortex of the rat, preincubated with [3H]DA in the presence of 1 microM desipramine, was examined. Apomorphine and the putative autoreceptor-selective DA agonist EMD 23 448 inhibited the K+-evoked overflow of radioactivity, while the DA antagonist sulpiride enhanced the evoked overflow in a dose-dependent and stereoselective manner. The latter effect was partially reversed by EMD 23 448. More than 95% of the radioactivity retained by the slices chromatographed with DA, while deaminated metabolites represented the majority of both the basal efflux (84% metabolites, 4-5% DA) and evoked overflow (84% metabolites, 14% DA) of radioactivity. These findings indicate that mesoprefrontal DA neurons possess release-modulating nerve terminal autoreceptors. Previous studies have shown that these neurons lack synthesis-modulating autoreceptors. Thus, autoreceptors on prefrontal DA terminals appear to be coupled to regulation of the release but not the synthesis of DA.     

Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex

Acute administration of 1.0-2.0 mg/kg delta 9-tetrahydrocannabinol (delta 9-THC) increased presynaptic dopamine (DA) efflux in the medial prefrontal cortex of rats, as measured by intracerebral microdialysis in awake, behaving rats. These data are congruent with suggestions that (1) marijuana's euphorigenic effects and abuse potential may be related to augmentation of presynaptic DA mechanisms, and (2) the medial prefrontal cortex may be an important site of action for drugs of abuse in general and for delta 9-THC in particular.     

Role of ventral medial prefrontal cortex in incubation of cocaine craving

Cue-induced drug-seeking in rodents progressively increases after withdrawal from cocaine, suggesting that cue-induced cocaine craving incubates over time. Here, we explored the role of the medial prefrontal cortex (mPFC, a brain area previously implicated in cue-induced cocaine seeking) in this incubation. We trained rats to self-administer cocaine for 10days (6h/day, infusions were paired with a tone-light cue), and then assessed after 1 or 30 withdrawal days the effect of exposure to cocaine cues on lever presses in extinction tests. We found that cue-induced cocaine-seeking in the extinction tests was higher after 30 withdrawal days than after 1day. The time-dependent increases in extinction responding were associated with large (ventral mPFC) or modest (dorsal mPFC) increases in ERK phosphorylation (a measure of ERK activity and an index of neuronal activation). After 30 withdrawal days, ventral but not dorsal injections of muscimol+baclofen (GABAa+GABAb receptor agonists that inhibit neuronal activity) decreased extinction responding. After 1 withdrawal day, ventral but not dorsal mPFC injections of bicuculline+saclofen (GABAa+GABAb receptor antagonists that increase neuronal activity) strongly increased extinction responding. Finally, muscimol+baclofen had minimal effect on extinction responding after 1day, and in cocaine-experienced rats, ventral mPFC injections of muscimol+baclofen or bicuculline+saclofen had no effect on lever presses for an oral sucrose solution. The present results indicate that ventral mPFC neuronal activity plays an important role in the incubation of cocaine craving.     

Asenapine restores cognitive flexibility in rats with medial prefrontal cortex lesions

RATIONALE: Cognitive inflexibility in schizophrenia is treatment-resistant and predictive of poor outcome. This study examined the effect of asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, on cognitive dysfunction in the rat. OBJECTIVES: The objective of this paper was to establish whether asenapine has a beneficial effect on the performance of rats with ibotenic acid-induced lesion of the medial prefrontal cortex (mPFC) in an intradimensional/extradimensional (ID/ED) test of cognitive flexibility. METHODS: The effect of subcutaneously administered asenapine (0.75, 7.5, 75 mug/kg) on ID/ED performance of controls or mPFC-lesioned rats was examined using a within-subjects, repeated-measures design. In a second experiment, lesioned and control rats were tested with or without asenapine in a modified version of the task, with multiple set-shifts, before brains were processed for Fos-immunoreactivity in the mPFC. RESULTS: The mPFC lesion-induced deficit in the ID/ED task was stable with repeated testing over more than two months. Asenapine (75 mug/kg s.c., p < 0.05) completely restored the performance of lesioned rats. Experiment 2 replicated both lesion and asenapine effects and demonstrated that it is possible to measure set-shifting multiple times within a test session. Asenapine (75 mug/kg s.c.) was associated with differential activation of the neurons in the anterior mPFC of lesioned animals, but was without effect in controls. CONCLUSION: Asenapine can ameliorate mPFC lesion-induced impairment in attentional set-shifting, and is associated with a greater activation of the spared neurons in the anterior mPFC. These data suggest that asenapine may benefit impaired cognitive flexibility in disorders such as schizophrenia.     

The medial prefrontal cortex mediates 3-methoxytyramine-induced behavioural changes in rat

L-3,4-Dihydroxyphenylalanine (L-DOPA) remains a common treatment for Parkinson's disease; however, side effects (i.e., dyskinesia and hallucinations) also remain problematic. We recently reported that the dopamine metabolite 3-methoxytyramine causes stereotypy in rats via dopamine receptors, raising the possibility that 3-methoxytyramine is involved in the adverse side effects of chronic L-DOPA treatment. Thus, the present study examined the sites of 3-methoxytyramine action in the rat brain. After intracerebroventricular administration of 3-methoxytyramine, significantly more neurones expressed c-Fos in mesocortico-limbic dopamine areas including frontal cortex, medial prefrontal cortex, parietal cortex, piriform cortex, the nucleus accumbens shell, and ventral tegmental area. 3-Methoxytyramine injection into the medial prefrontal cortex specifically resulted in behavioural changes characteristic of those elicited by the more general intracerebroventricular injection of 3-methoxytyramine. This suggests that the medial prefrontal cortex mediates the 3-methoxytyramine-induced behavioural changes and that a reduction of its action there may alleviate the adverse effects of chronic L-DOPA treatment.     

Anticipatory cues differentially provoke in vivo peptidergic and monoaminergic release at the medial prefrontal cortex.

Like primary reinforcers, the anticipation of reward ought to affect neurochemical release in brain regions, such as the medial prefrontal cortex (mPFC), which are associated with appraisal processes. To assess the neurochemical changes associated with anticipation, rats were exposed to the pairing of auditory (60-dB white noise), visual, and olfactory cues with the daily presentation of a palatable snack (Cue Relevant group). Rats of a second group were similarly trained, but for a 2-week period, the snack was no longer provided following cue presentation (Extinction group). In the third condition, the presentation of the snack and cues was uncorrelated (Cue Irrelevant group). Analyses of dialysates collected in vivo from the mPFC revealed that release of corticotropin-releasing hormone (CRH), gastrin-releasing peptide (GRP), and the 5-HT catabolite, 5-hydroxyindole acetic acid (5-HIAA), had increased bilaterally in response to the anticipatory cues, whereas DA release increased only within the right mPFC. In the case of CRH and GRP, these increases were also apparent in the extinction condition, despite the fact that behavioral arousal to the anticipatory cues (increased exploration, rearing, grooming, and vigilance) was only evident in the Cue Relevant condition. In contrast, the elevated DA and 5-HIAA were apparent exclusively in the Cue Relevant condition. Thus, CRH and GRP systems may serve to allocate salience and/or incentive reward value to biologically significant stimuli or reflect the emotional response to the anticipatory stimulus. The activity of DA and 5-HT neurons, in contrast, is more closely aligned with the cognitive appraisal of predictor stimuli.