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PubMed2004

Infusions of midazolam into the medial prefrontal cortex produce anxiolytic effects in the elevated plus-maze and shock-probe burying tests.

Previous research has shown that lesions of the medial prefrontal cortex (MPFC) inhibit fear-related behavior in rats (Brain Res. 969 (2003) 183-194). However, at present little is known about the role of specific neurotransmitter receptor systems within the MPFC in the mediation of fear and anxiety. For example, extensive research has demonstrated the effectiveness of benzodiazepines in decreasing fear-related behavior. However, no research has yet been published regarding the effects of micro-infusions of benzodiazepines, or any other GABA-A receptor agonist, into the MPFC. In addition, previous work has suggested that there may be functional differences between the dorsal and ventral subregions of the MPFC in regard to fear and anxiety. Therefore, the present study examined the effects of dorsal and ventral MPFC infusions of the benzodiazepine midazolam in two well-validated animal models of anxiety, the elevated plus maze and the shock probe burying test. The results showed that bilateral (5 microg/side) infusions of midazolam into the MPFC produced anxiolytic effects in both behavioural tests, without affecting general activity or pain sensitivity. Furthermore, these anxiolytic effects were found in both the dorsal and ventral regions of the MPFC. The present findings indicate that the benzodiazepine receptors of the MPFC are capable of modulating fear-related behaviors.

Analysis of Variance↗

PubMed2004

Chronic nicotine and smoke treatment modulate dopaminergic activities in ventral tegmental area and nucleus accumbens and the gamma-aminobutyric acid type B receptor expression of the rat prefrontal cortex.

Dopaminergic afferents from the mesencephalic areas, such as ventral tegmental area (VTA), synapse with the gamma-aminobutyric acid (GABA)-ergic interneurons in the prefrontal cortex (PFC). Pharmacological and electrophysiological data show that the reinforcement, the dependence-producing properties, as well as the psychopharmacologic effects of nicotine depend to a great extent on activation of nicotinic receptors within the mesolimbocortical dopaminergic projection. To explore further the relationship between the mesencephalic dopaminergic neurons and PFC GABAergic neurons, we investigated the effects of nicotine and passive exposure to cigarette smoke on the regulation of tyrosine hydroxylase (TH) in VTA and substantia nigra (SNC) and dopamine (DA) D1 receptor levels in nucleus accumbens (NAc) and caudate-putamen (CPu). Also, the simultaneous changes in GABAB receptors mRNAs in the PFC were studied. The results showed that chronic nicotine and smoking treatment differentially changed the levels of TH protein in VTA and SNC and DA D1 receptor levels in Nac and CPu. GABAB1 and GABAB2 receptor mRNA levels also showed different change patterns. Ten and thirty minutes of smoke exposure increased GABAB1 receptor mRNA to a greater extent than that of GABAB2, whereas GABAB2 was greatly enhanced after 1 hr of smoke exposure. The TH levels in VTA were closely related to DA D1 receptor levels in NAc and with GABAB receptor mRNA changes in PFC. These results suggest that the mesolimbic pathway and GABAB receptor mRNA in PFC are modulated by nicotine and cigarette smoke, implying an important role in nicotine's psychopharmacological effects.

Animals↗

PubMed1996

Dorsal lesions of the prefrontal cortex: effects on alcohol consumption and subcortical monoaminergic systems.

Male Wistar rats were subjected to either bilateral aspiration lesions of the dorsal regions of the prefrontal cortex (PFC) or sham lesions and placed on a 6-week, modified sucrose-fading procedure. At the time of sacrifice, the size of the lesion, both in anterior-posterior and medial-lateral dimensions, was measured. Following sacrifice, levels of dopamine (DA), serotonin (5-HT), norepinephrine (NE), and their metabolites were measured in the midbrain (raphe) and nucleus accumbens (NA). Lesioned animals had reductions in 5-HT in the NA, and DA and NE in the raphe. The lesioned group drank more of a solution of 5% alcohol than controls early in the sucrose fading, and less during the later stages. In the lesioned group, the size of the left- and right-hemisphere lesions predicted 5-HIAA levels in the NA, and 5-HT and 5-HIAA levels in the raphe. A laterality effect was noted, such that the size of left-hemisphere lesions were positively associated with raphe 5-HT and 5-HIAA levels, and negatively associated with 5-HT levels in the NA, while right-hemisphere lesions showed the opposite relationships. In addition, the width of the left-hemisphere lesion predicted some measures of alcohol intake. These results suggest that, in the rat, the dorsal PFC is involved in the regulation of monoamines in subcortical regions known to be important in the regulation of reinforced behaviors, and that this regulation differs between hemispheres and shows a laterality effect. In addition, the dorsal PFC appears to have a subtle involvement in the regulation of alcohol intake.

Amines↗

PubMed2006

Different functionality of the medial and orbital prefrontal cortex during a sexually motivated task in rats.

This study was designed to analyze whether the electroencephalographic (EEG) activity of the medial (mPFC) and orbital prefrontal cortex (oPFC) was modified during the performance of male rats in a T maze under two different conditions, sexually motivated (with previous intromission and females in the goal boxes of the lateral arms) or sexually non-motivated (without previous intromission and with empty goal boxes). Relative power (RP) of three EEG band frequencies, and inter-hemispheric correlation (r) were calculated and a comparison was made between rats under motivated and non-motivated conditions. In the mPFC of sexually motivated males, an increase of the RP in the 6-7 Hz band as well as a decrease in the 8-11 Hz band was observed in relation to an awake-quiet state and during the walk in the maze stem. Similarly, an increase in the r of the 6-7 Hz band was observed during the walk in the maze stem and when remaining near to a receptive female, when compared to non-motivated males. In the oPFC, only the RP of the 6-7 Hz band was increased during the walk in the maze stem of the motivated males. These data suggest that, among sexually motivated males, the mPFC is involved both in anticipatory and motor execution during the performance of the T maze task, whereas the oPFC is only involved in the motor execution of the T maze. These results are in line with other studies suggesting that the mPFC and oPFC are functionally distinct, regions which may work together during certain behaviors and physiological conditions.

Analysis of Variance↗

PubMed1994

Effects of cocaine microinjections into the nucleus accumbens and medial prefrontal cortex on schedule-induced behaviour: comparison with systemic cocaine administration.

The effects of cocaine HCl infusions into either the nucleus accumbens (NACC) or medial prefrontal cortex (PFC) were compared on the performance of schedule-induced polydipsia (SIP) and related behaviours. Food-deprived rats were exposed to a fixed-time 60-s schedule of food delivery in daily 30-min sessions until stable levels of behaviour were obtained (14 days). Rats were then bilaterally infused with cocaine into either the NACC or PFC via chronically indwelling guide cannulae. Each subject received a sequence of five cocaine infusions (0, 12.5, 25, 50, 100 micrograms) according to a Latin Square design. For comparison, following these intracranial infusions each rat received a sequence of five IP injections of cocaine (0, 2.5, 5, 10, 20 mg/kg) also in a counterbalanced order. NACC and PFC infusions of cocaine and IP cocaine dose-dependently reduced SIP. Cocaine infusions into the NACC, but not the PFC, increased locomotor activity but the characteristic temporal profile of locomotor activity during SIP was retained. IP cocaine also increased locomotor activity in a dose-dependent manner, but the temporal profile of activity was flattened following 20 mg/kg cocaine. NACC and PFC infusions of cocaine had little effect on the total number of panel presses to gain access to the food pellets, but did slightly decrease the high rates of responding immediately prior to the pellet delivery. IP cocaine increased the total number of panel presses at the higher doses, mainly by increasing the low rates of responding. The effects of cocaine infusions into the PFC were behaviourally the most selective, as they reduced SIP without having substantial effects either on locomotor activity or panel pressing.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Prefrontal cortex dysfunction in Borna disease virus (BDV)--infected rats.

Viruses have been proposed to play a role in the pathogenesis of schizophrenia; however, the mechanisms by which infection could cause the affective, cognitive, and movement disorders of schizophrenia are not understood. The neurotropic RNA virus, Borna disease (BD) virus, linked to schizophrenia by serologic studies, causes movement and behavior disorders in a wide variety of mammalian and bird hosts. BD rats have hyperactivity and stereotyped behaviors similar to those that follow neurotoxic or electrolytic lesions in frontal cortex or its catecholamine afferents in rats. BD rats have high levels of viral nucleic acid in the prefrontal cortex (PFC), abnormal mesocortical dopamine activity (elevated levels of DOPAC in PFC), yet no alteration in specific binding of D1 or D2 receptor radioligands in PFC. Since frontal lobe dysfunction is frequently reported in schizophrenia, the BD rat model may provide insights into pathogenesis and management of this debilitating psychiatric disease.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Ventromedial prefrontal cortex activation is critical for preference judgments.

Preference judgment, the process of selecting a response from several alternatives based on which alternative the subject likes best, is an important aspect of daily life. The current study examined whether neural substrates that are thought to be critical for generating somatic markers are involved in preference judgments. Fifteen healthy, right-handed subjects performed a preference judgment task during functional magnetic resonance imaging. The medial frontal gyrus was significantly more activated during the preference judgment trials, relative to visual discrimination trials. Other areas that were also differentially activated included the posterior parietal cortex, the anterior cingulate and the left anterior insula. These findings are consistent with the role of the ventromedial prefrontal cortex in the representation of complex appetitive states.

Adult↗

PubMed2006

White matter changes compromise prefrontal cortex function in healthy elderly individuals.

Changes in memory function in elderly individuals are often attributed to dysfunction of the prefrontal cortex (PFC). One mechanism for this dysfunction may be disruption of white matter tracts that connect the PFC with its anatomical targets. Here, we tested the hypothesis that white matter degeneration is associated with reduced prefrontal activation. We used white matter hyperintensities (WMH), a magnetic resonance imaging (MRI) finding associated with cerebrovascular disease in elderly individuals, as a marker for white matter degeneration. Specifically, we used structural MRI to quantify the extent of WMH in a group of cognitively normal elderly individuals and tested whether these measures were predictive of the magnitude of prefrontal activity (fMRI) observed during performance of an episodic retrieval task and a verbal working memory task. We also examined the effects of WMH located in the dorsolateral frontal regions with the hypothesis that dorsal PFC WMH would be strongly associated with not only PFC function, but also with areas that are anatomically and functionally linked to the PFC in a task-dependent manner. Results showed that increases in both global and regional dorsal PFC WMH volume were associated with decreases in PFC activity. In addition, dorsal PFC WMH volume was associated with decreased activity in medial temporal and anterior cingulate regions during episodic retrieval and decreased activity in the posterior parietal and anterior cingulate cortex during working memory performance. These results suggest that disruption of white matter tracts, especially within the PFC, may be a mechanism for age-related changes in memory functioning.

Aged↗

PubMed1996

Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia.

Serotonin-5-HT1A receptors were measured with [3H]8-hydroxy-2-(di-n-propyl)aminotetralin ([3H]8-OH-DPAT) in postmortem prefrontal cortex of 12 pairs of subjects with schizophrenia and age-matched control subjects. The saturation binding isotherms of [3H]8-OH-DPAT revealed high- and low-affinity binding sites. The density (Bmax) of the high-affinity sites was significantly elevated by an average of 79% in subjects with schizophrenia. The dissociation constant (Kd) of the high-affinity sites in subjects with schizophrenia was not significantly different from the control subjects. These results provide further evidence for a role of the serotonergic system in the pathophysiology of schizophrenia.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2001

Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.

The infralimbic area (IL) and prelimbic area (PL) have been postulated as an autonomic motor region in the medial prefrontal cortex. The present study was conducted to reveal the projection sites of IL and PL of the monkey, Macaca fuscata, using biotinylated dextran amine as an anterograde tracer. IL and PL projected densely to the ventromedial caudate nucleus, the core and shell of the nucleus accumbens (Acb), parvicellular lateral basal and magnocellular accessory basal nuclei of the amygdala, lateral preoptic area, ventromedial hypothalamic nucleus, tubero-mammillary nucleus (TM), medial part of the magnocellular and dorsal part of the parvicellular (MDpc) dorsomedial thalamic nuclei, reunience and medial part of the medial pulvinar nucleus, and dorso-lateral part of the periaqueductal gray (PAGdl) in the mesencephalon. Moderately to weakly projected areas were the intermediate and lateral parts of the agranular insular cortex, orbital part of area 12, agranular and dysgranular part of the temporal pole cortex (TPa-g), auditory temporal cortex, lateral and medial (MS) septal nuclei, bed nucleus of the stria terminalis, diagonal band of Broca, substantia innominata, and medial preoptic area, dorsomedial, lateral, and posterior hypothalamic nuclei, magnocellular lateral basal and lateral amygdaloid nuclei, paratenial, paraventricular (PV), inter-antero-medial (IAM), reticular, central medial (CeM), parafascicular (PF) and limitans nuclei of the thalamus, lateral habenular nucleus, pedunculo-pontine nucleus, dorsal part of the lateral lemniscal nucleus, ventral tegmental area (VTA), dorsal raphe, superior central nucleus, medial and lateral parabrachial nuclei (PBl) and nucleus locus coeruleus (LC). A few scattered terminals were observed in the perifornical nucleus of the hypothalamus and substantia nigra pars compacta. PL and area 24 were characterized by projections to the entorhinal (Ent) and piriform (Pir) cortex as well as to the magnocellular part of the ventral anterior thalamic nucleus (VAmc). The morphology of the terminal arborization in each nuclei was different in appearance, perhaps reflecting the synaptic interaction between the nerve terminals and postsynaptic dendrites. PL projected uniquely to Ent, Pir and VAmc and IL projected uniquely to TPa-g, MS, IAM, CeM, MDpc, PF, PBl and LC. IL projected more strongly than PL to the shell of Acb, amygdaloid nuclei, PV, TM, VTA and PAGdl. The present results support the hypothesis that IL is a major cortical autonomic motor area and PL integrates limbic and autonomic inputs in the primate.

Animals↗

PubMed1994

The inhibitory input from the substantia nigra to the mediodorsal nucleus neurons projecting to the prefrontal cortex in the cat.

The effects of stimulation of the substantia nigra pars reticulata (SNr) on the neurons of the mediodorsal nucleus (MD) projecting to the prefrontal cortex (PF) were studied in cats. The MD neurons projecting to the ventral part of the PF tended to be located in the ventral part of the MD, while those projecting to the dorsal part of the PF in the dorsal part. Spontaneous discharges of 30/57 tested MD neurons were suppressed by SNr stimulation at a latency ranging from 2 to 15 ms. The latency of the suppression corresponded well to that of antidromic responses of SNr neurons elicited by MD stimulation (from 1.4 to 14.0 ms). Intracellular recordings in a few MD neurons showed IPSP by SNr stimulation. The SNr is considered to exert an inhibitory effect on the MD neurons projecting to the PF.

Animals↗

PubMed2005

Cognitive impairment in aged rhesus monkeys associated with monoamine receptors in the prefrontal cortex.

The "frontal aging hypothesis" has been proposed by many researchers suggesting that the earliest and most severe age-related changes in the cortex occur in the frontal lobes. Two of these changes include decreases in cognitive functions mediated by the prefrontal cortex (PFC) and significant decreases in norepinephrine (NE) and dopamine (DA). To investigate whether the changes in these neurotransmitter systems are directly related to the cognitive decline seen in aging we utilized the rhesus monkey as a model of normal human aging. Our goal was to determine if age-related changes in cognition is associated with changes in norepinephrine and dopamine receptor binding density in the PFC. Eight young monkeys between five and ten years of age (six males and two female) and eight aged monkeys between 25 and 32 years of age (five males and three females) were behaviorally characterized. Subsequently on-the-slide in vitro binding assays were used to quantify the alpha-1 adrenergic, alpha-2 adrenergic and DA1 receptors as well as the NE and DA uptake receptors. Aged animals as a group demonstrated significant cognitive impairments and aging produced a significant decrease in alpha-1 adrenergic and alpha-2 adrenergic receptor binding in the PFC but no significant change in binding for the DA1 receptor or the NE or DA uptake receptors. Further analysis revealed a significant relationship between monoamine receptor binding and cognitive performance on three tasks: delayed non-matching to sample, delayed recognition span test and the conceptual set-shifting task.

Adrenergic alpha-Agonists↗

PubMed2006

The influence of rTMS over the right dorsolateral prefrontal cortex on intentional set switching.

High frequency (HF) repetitive transcranial magnetic stimulation (rTMS) has an excitatory effect on neurons of a specific brain area. The dorsolateral prefrontal cortex (DLPFC) has been associated with executive functions, such as task set switching. One important experimental paradigm for investigating such higher order cognitive control is the task-switching (TS) paradigm. A TS paradigm requires switching between two conditional response tasks with mutually incompatible response-selection rules. In the present study, the influence of HF rTMS over the right DLPFC in healthy female volunteers on a modified TS paradigm was investigated. As expected, reaction time on cued switching trials decreased significant after rTMS, as compared to non-cued switch trials. No changes emerged after the placebo sham condition. Mood remained unchanged after rTMS. These findings demonstrate the role of the right DLPFC in cued intentional set switch initiation.

Adolescent↗

PubMed1986

Topography of projections from the medial prefrontal cortex to the amygdala in the rat.

The projections from the rat medial prefrontal cortex to the amygdaloid complex were investigated using retrograde transport of fluorescent dyes and anterograde transport of horseradish peroxidase-WGA. The ventral anterior cingulate, prelimbic, infralimbic and medial orbital areas and the taenia tecta were found to project to the amygdaloid complex. The projections from the prelimbic area arose bilaterally. The medial orbital, prelimbic and anterior cingulate areas send convergent projections to the basolateral nucleus. The prelimbic area has additional projections to the posterolateral cortical nucleus and amygdalo-hippocampal area. The infralimbic area does not project to the basolateral nucleus and cortico-amygdaloid projections from this area are focussed on the anterior cortical nucleus and the anterior amygdaloid area. Both prelimbic and infralimbic areas project to an area situated between the central, medial and basomedial nuclei. Based on similar projections, this area appears to be a caudal continuation of the anterior amygdaloid area. The results indicate that the medial prefrontal component of the "basolateral limbic circuit" is restricted to the anterior cingulate and prelimbic areas. No evidence was obtained to support the existence of a medial prefronto-amygdaloid component of the "visceral forebrain".

Amidines↗

PubMed1997

Near-infrared optical detection of sequential brain activation in the prefrontal cortex during mental tasks.

To examine the spatiotemporal differences of brain activation during mental tasks, changes in the oxygenation and hemodynamics in two regions of the prefrontal cortex were measured simultaneously by near-infrared spectroscopy (NIRS). Subjects were eight healthy adults who attempted to solve three different mathematical problems. The behavior of concentration changes in oxy-, deoxy-, and total hemoglobin in one brain region varied with the time course (more than 10 min). This suggested that regional brain activity varied during the performance of the mental task. In each single subject, the pattern of these changes varied with each problem, and this variation differed from subject to subject. When NIRS traces in two regions were compared, it was seen that activated regions moved alternatively: when in one region total hemoglobin that had first increased returned to the resting level, in the other it started to increase. These region-dependent temporal variations of brain activity might reflect mental processes. It is thus concluded that NIRS has the potential for imaging the sequence of brain activation.

Adult↗

PubMed1995

Postnatal maturation of GABA-immunoreactive neurons of rat medial prefrontal cortex.

A light microscopic immunocytochemical approach has been used to examine the distribution and maturation of gamma-aminobutyric acid- (GABA) containing cells in rat medial prefrontal cortex (mPFC) at progressive postnatal stages. Between P1 and P5, labeled cells in the cortical plate show less differentiated morphological characteristics when compared to cells in the deeper laminae. By P10, however, most labeled cells in superficial laminae show more differentiated characteristics with some having a distinctive multipolar appearance. Between P1 and P5, there is a significant increase (50%) in the density of GABA-containing cells in the superficial laminae, while concurrently there is an overall decreases in the subjacent deeper laminae. As the cortex continues to expand, there is a corresponding decrease in the density of GABA-immunoreactive cells in the outer two-thirds of the cortical mantle until approximately P15, stabilizing at 20-25 cells/100,000 microns2 for all laminae. Between P1 and P15, there is also a significant increase (133%) in the average size of labeled cells, followed by a gradual decrease of 30% between P15 and P41. During P1-7, there is a marked increase in the density of labeled axosomatic terminals in both the superficial (200%) and deep laminae (116%). In the superficial layers, however, the density of labeled terminals again increases by 86% between P12 and P18. In general, the present findings are consistent with the idea that there is a progressive maturation of the intrinsic GABAergic system in rat mPFC in a classic "inside-out" pattern, and this involves extensive postnatal changes occurring during the first 3 postnatal weeks.

Animals↗

PubMed2006

Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity, acetylcholine release and dopamine metabolism in the nucleus accumbens.

The aim of the present study was to investigate the effects of stimulation of D2 receptors in the prefrontal cortex (PFC) on spontaneous motor activity and the hyperactivity induced by the psychomimetic phencyclidine (PCP). In addition, the effects of prefrontal D2 stimulation under PCP treatment on dialysate concentrations of acetylcholine, choline, dopamine, DOPAC and HVA in the nucleus accumbens were also investigated. Sprague-Dawley male rats were implanted with guide cannulae to perform bilateral injections into the medial PFC of the D2 agonist quinpirole (1.5 and 5 microg/side). Horizontal and vertical spontaneous motor activity and the motor activity induced by systemic injections of the PCP (5 mg/kg i.p.) were monitored in the open field. PFC injections of quinpirole (1.5 and 5 microg/side) significantly decreased horizontal and vertical spontaneous motor activity in a dose-related manner. These effects were blocked by the D2 antagonist raclopride (5 microg/side). Microinjections of quinpirole (1.5 and 5 microg/side) into the PFC also significantly attenuated the hyperactivity produced by PCP (5 mg/kg i.p.). PCP also increased dialysate concentrations of acetylcholine, and dopamine metabolites in the nucleus accumbens. These increases were also reduced by injections of quinpirole (5 microg/side) into the PFC. These results suggest that the stimulation of prefrontal D2 receptors plays an inhibitory role in regulating spontaneous and PCP-induced motor activity and also in the neurochemical changes produced by PCP in the nucleus accumbens.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Activation of prefrontal cortex in children during a nonspatial working memory task with functional MRI.

Functional magnetic resonance imaging (fMRI) was used to examine the pattern of activity of prefrontal cortex in prepubertal children during performance of a nonspatial working memory task. The children observed sequences of letters and responded whenever a letter repeated with exactly one nonidentical letter intervening. In a comparison task, subjects monitored similar sequences of letters for any occurrence of a single, prespecified target letter. Location of activation closely approximated that observed in a recent fMRI study with adults using exactly the same task. Activation of the inferior and middle frontal gyri was reliably observed within individual subjects during performance of the working memory task relative to the comparison task. Activation increased and decreased with a time course that was highly consistent with the task manipulations and correlated with behavioral performance. To our knowledge, this study is one of the first to demonstrate the applicability of fMRI to a normative developmental population. Issues of age dependence of the hemodynamic responses of fMRI are discussed.

Adult↗