Ventral mPFC Research Articles

Activation of dopamine D1 receptors in the medial prefrontal cortex produces bidirectional effects on cocaine-induced locomotor activity in rats: effects of repeated stress

We examined the effects of repeated stress and D1 receptor activation in the medial prefrontal cortex (mPFC) on acute-cocaine-induced locomotor activity in rats. Male rats were given 7 days of either handling (Controls) or a variety of stressors. After 8–17 days' withdrawal, rats received an intra-mPFC microinjection of the full D1 agonist, SKF 81297: 0, 0.03, 0.1 or 0.3 μg/side followed by an i.p. saline or cocaine injection (15 mg/kg, i.p.). The target sites were either the dorsal or ventral mPFC. We also divided rats into either high or low responders based on their locomotor response to an acute cocaine injection. In the dorsal PFC, low responder Control and Stress groups demonstrated an augmentation of cocaine-induced increases in activity after SKF 81297, compared with vehicle, microinjection. In contrast, high responder rats demonstrated a suppression of cocaine-induced increases in activity after intra-mPFC SFK 81297 infusion, with an apparent 10 times higher sensitivity in the Stress group. In the ventral PFC, low responder Controls showed no changes after SKF 81297 infusion, while the Stress group showed an increase in cocaine-induced activity in response to SKF 81297. In high responders given SFK 81297 into the ventral mPFC, cocaine-induced activity was suppressed in Controls, while stress pretreatment rendered animals resistant to SKF 81297 effects. These results indicate that D1 receptor activation effects in the mPFC are bidirectional depending on whether rats have a high or low locomotor response to cocaine. Further, daily stress alters the sensitivity of the mPFC to SKF 81297, which is dependent on whether the dorsal or ventral mPFC is targeted.

Long-term social isolation and medial prefrontal cortex: dopaminergic and cholinergic neurotransmission

Rearing rats in social isolation has been suggested as an animal model of schizophrenia, based mainly on the similarity between the attenuation of prepulse inhibition (PPI) in isolated rats and in schizophrenic patients. The medial prefrontal cortex (mPFC) plays a major role in the pathophysiology of schizophrenia. Thus, a postmortem micropunch analysis measuring dopamine (DA), DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) in the dorsal and ventral subregion of the mPFC, the caudate putamen (CPu) and nucleus accumbens (NAc) was carried out on socially isolated or group-housed male Sprague–Dawley (SD) rats. Additionally, in vivo microdialysis with d-amphetamine (1 mg/kg ip) stimulation was performed in isolated animals and their controls, examining the ventral mPFC for acetylcholine (ACh), DOPAC and HVA levels. Simultaneously, recording of motor activity was performed. In the neurochemical postmortem tissue analysis we found no difference in any of the brain regions tested between isolated and group-reared animals. Amphetamine increased ACh levels in the mPFC, induced a decrease in DOPAC and HVA levels, and increased motor activity. A close to significant Drug×Housing interaction reflected the fact that the amphetamine-induced decrease of DOPAC was confined to the group-housed animals. In conclusion, social isolation leads only to moderate changes in the dopaminergic system in the mPFC, whereas the cholinergic system remains unaffected.

In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT 1A receptors

The ventral part of the medial prefrontal cortex (mPFC) plays an important role in mood and cognition. This study examined the effect of the 5-HT in this region by measuring the electrophysiological response of ventral mPFC neurones to electrical stimulation of the dorsal and median raphe nuclei (DRN and MRN), which are the source of the 5-HT input. DRN or MRN stimulation evoked a consistent, short-latency, post-stimulus inhibition in the majority of ventral mPFC neurones tested (DRN: 44/73 neurones; MRN: 24/31 neurones). Some neurones responded to DRN or MRN stimulation with antidromic spikes indicating that they were mPFC-raphe projection neurones. Both DRN- and MRN-evoked inhibitions were attenuated by systemic administration of the 5-HT 1A antagonist WAY 100635 (0.1 mg/kg i.v.). DRN-evoked inhibition was also attenuated by iontophoretic application of WAY 100635 and by systemic administration of the 5-HT 1A antagonist, NAD-299 (4 mg/kg i.v.) but not the 5-HT 2 antagonist ketanserin (4 mg/kg, i.v.). These data suggest that DRN and MRN 5-HT neurones inhibit neurones in the ventral mPFC via activation of 5-HT 1A receptors. Some of these mPFC neurones may be part of a 5-HT 1A receptor-controlled postsynaptic feedback loop to the DRN and MRN.

The frontal cortex of the rat and visual attentional performance: dissociable functions of distinct medial prefrontal subregions.

A previous study using a rodent five-choice test of attention found poor choice accuracy and increased perseverative responding following medial prefrontal cortex (mPFC) lesions. As this rat cortical area includes at least two anatomically distinguishable subregions, the present study investigated their specific contributions to performance of this task. Rats were trained on the five-choice task prior to receiving excitotoxic lesions or sham surgery. In the first experiment, lesions of the dorsal mPFC (Zilles's Cg1) resulted in poor accuracy, but no changes in perseverative responding. Introducing variable delays for stimulus presentation abolished these accuracy deficits, suggesting that Cg1-lesioned rats were impaired at using temporal cues to guide performance. In the second experiment, lesions of the ventral mPFC increased perseverative responding, but had only short-lasting effects on accuracy. Rats with complete mPFC lesions had both choice accuracy impairments and increased perseverative responding. Additional evidence of the functional dissociation of dorsal and ventral mPFC came from the analysis of the spatial and temporal distribution of the correct and incorrect responses. Only rats with ventral mPFC lesions showed delay-dependent deficits and bias towards a location that had recently been associated with reward. Taken together, these results suggest dissociable 'executive' functions of mPFC subregions. Circuits centred on Cg1 are critical for the temporal organization of behaviour, while networks involving the ventral mPFC are important for maintaining behavioural flexibility.

Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology

Behavioral sensitization to the locomotor activating effects of amphetamine refers to the progressive, long lasting increase in locomotor activity that occurs with repeated injections. This phenomenon is thought to result from neuroadaptations occurring in the projection fields of mesocorticolimbic dopaminergic neurons. In the present study, we investigated the effects of amphetamine sensitization on Fos immunoreactivity (Fos-IR) in subterritories of the nucleus accumbens (core and shell) and medial prefrontal cortex (mPFC; dorsal and ventral) using stereology. Rats received five daily injections of amphetamine (1.5 mg/kg, i.p.) or saline. Behavioral sensitization was measured 48 h following the last injection, in response to a challenge injection of 1.5 mg/kg amphetamine. Sensitized rats showed a greater enhancement of locomotor activity upon drug challenge compared with their saline counterparts. Densities of Fos-positive nuclei were enhanced more in the dorsal than the ventral mPFC subterritory, whereas in the nucleus accumbens, densities of Fos-positive nuclei were increased more in the core than the shell of amphetamine-sensitized rats compared to controls. These results represent, to our knowledge, the first published report using stereological methods to quantify Fos-IR in the brain and suggest functional specialization of cortical and limbic regions in the expression of behavioral sensitization to amphetamine.

Behavioral effects of excitotoxic lesions of ventral medial prefrontal cortex in the rat are hemisphere-dependent

The ventral region of the medial prefrontal cortex (mPFC) is highly sensitive to stressful inputs and implicated in a variety of behaviors. Studies have also demonstrated numerous functional hemispheric asymmetries within this brain area of the rat. The present study examines the effects of ibotenic acid or sham lesions targeting the left, right or bilateral infralimbic cortex, on a variety of behaviors. Lesions (which destroyed infralimbic and ventral prelimbic cortex) were without effect on acquisition or reversal of a spatial learning task in the Morris water maze. Similarly unaffected were spontaneous and amphetamine-induced locomotor activity and sensitization, and prepulse inhibition of the acoustic startle response. In contrast, lesions significantly affected behavior in the elevated plus maze, as right-lesioned animals spent more time exploring the open arms of the maze than shams or left-lesioned rats, while not differing in closed arm entries. As well, in a simple taste aversion paradigm, right-lesioned rats drank significantly more of a sweetened milk/quinine solution than shams and left-lesioned rats, despite not differing in consumption of sweetened milk alone. The anxiolytic effects of right, but not left lesions of ventral mPFC, parallel the asymmetrical suppression of physiological stress responses previously reported for similar lesions. It is suggested that the right ventral mPFC plays a primary role in optimizing cautious and adaptive behavior in potentially threatening situations.

Expression of sensitization to amphetamine and dynamics of dopamine neurotransmission in different laminae of the rat medial prefrontal cortex

The present study investigated the effect of acute and repeated administrations of amphetamine (AMPH) on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the two main cytoarchitectonic subterritories of the medial prefrontal cortex (mPFC) (anterior cingulate and dorsocaudal prelimbic cortices vs ventral prelimbic and rostral infralimbic cortices). Both the acute locomotor effects of AMPH and the expression of behavioral sensitization following its repeated administration were also simultaneously assessed. The repeated, intermittent administration of AMPH over five consecutive days led to a significant sensitized locomotor response to a subsequent challenge that occurred following a 48-h withdrawal period. Basal dialysate DA levels were higher in the ventral mPFC compared with its dorsal counterpart in naive animals, that is prior to the acute administration of AMPH. However, the inverse relationship was observed in animals that had developed sensitization: basal dialysate DA levels were significantly lower in the ventral mPFC compared with the dorsal mPFC. In naı̈ve animals, AMPH produced a significant decrease in DA levels in both the ventral and dorsal subregions of the mPFC. However, the inverse relationship was observed in animals that had developed sensitization: dialysate DA levels in response to AMPH remained significantly decreased in the dorsal mPFC, whereas DA went back to baseline levels in the ventral mPFC. Given that a critical concentration of DA is required for normal function of the mPFC, our results suggest that AMPH-induced changes in DA levels in different subregions of the mPFC are critical for both the acute effects of the drug and the expression of behavioral sensitization to its repeated administration by producing either less or more selectivity or sharpening of stimuli to cortico-cortical dendrites and subcortical synaptic afferents to the pyramidal cells located in the dorso-ventral axis of the mPFC.

Normal conditioned inhibition and extinction of freezing and fear-potentiated startle following electrolytic lesions of medical prefrontal cortex in rats.

The authors investigated the role of medial prefrontal cortex (mPFC) in the inhibition of conditioned fear in rats using both Pavlovian extinction and conditioned inhibition paradigms. In Experiment 1, lesions of ventral mPFC did not interfere with conditioned inhibition of the fear-potentiated startle response. In Experiment 2, lesions made after acquisition of fear conditioning did not retard extinction of fear to a visual conditioned stimulus (CS) and did not impair "reinstatement" of fear after unsignaled presentations of the unconditioned stimulus. In Experiment 3, lesions made before fear conditioning did not retard extinction of fear-potentiated startle or freezing to an auditory CS. In both Experiments 2 and 3, extinction of fear to contextual cues was also unaffected by the lesions. These results indicate that ventral mPFC is not essential for the inhibition of fear under a variety of circumstances.