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PubMed2005

Time-dependent effects of repeated cocaine administration on dopamine transmission in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) has been implicated in the development of behavioral sensitization, which is the progressive enhancement of locomotor activity that occurs with repeated administration of psychostimulants. Previous data suggest that mPFC dopamine (DA) transmission may be attenuated in cocaine-sensitized animals, but the onset and duration of this effect have not been investigated. After recovery from stereotaxic surgeries, animals were given four daily injections of saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) and were subsequently challenged with saline or cocaine after 1, 7 or 30 d of withdrawal, on which days in vivo microdialysis of the mPFC was conducted simultaneously with monitoring of locomotor activity. Compared to acutely administered controls, the results in cocaine-pretreated animals were as follows: 1d of withdrawal was associated with a significant attenuation in cocaine-induced locomotion and mPFC DA overflow; after 7d, behavioral sensitization was accompanied by a significant attenuation in cocaine-induced elevations in mPFC DA levels; 30 d of withdrawal led to the expression of sensitized behaviors paralleled by an augmentation in cocaine-induced mPFC DA. These data suggest that repeated cocaine produces temporally distinct behavioral effects associated with alterations in mPFC DA responsiveness to cocaine that may be involved in the development of behavioral sensitization.

Analysis of Variance↗
PubMed2003

Haloperidol increases the disruptive effect of alcohol on spatial working memory in rats: a dopaminergic modulation in the medial prefrontal cortex.

RATIONALE: The prefrontal cortex (PFC) has been considered the anatomic site for working memory. The medial portion of the PFC (mPFC) is also part of a "brain reward circuit" as constituted by the mesocorticolimbic dopaminergic system. OBJECTIVE: This study examined the effects of acute administration of alcohol (ETOH) in the mPFC or systemically on the performance of 5-s or 1-h delayed tasks in an eight-arm radial maze. Effects of haloperidol (HAL), a dopamine antagonist, combined with ETOH, were also examined in a 1-h delayed task. METHODS: Male Wistar rats trained in the radial maze and with bilateral cannulae implanted in the mPFC received intraperitoneal (IP) or intracortical (IC) drug administration. RESULTS: As compared to saline (SAL) IC, ETOH IC in doses of 100 microg and 180 microg (5 min before session) increased significantly the number of errors in the 1-h and 5-s post-delay performance, respectively. HAL in doses with little or no effect alone IC (10 or 32 microg, 10 min before session) or IP (3.2 mg/kg, 35 min before session) increased the disruptive effect of ETOH IC (100 microg) on 1-h delayed task. CONCLUSIONS: These results showed that ETOH administered directly in the mPFC disrupts short- and long-term spatial working memory. The increase of the disruptive effect of ETOH produced by a dopaminergic blockage, particularly in the mPFC, suggests that the dopaminergic neurotransmission in this cortical area might modulate ETOH effects on spatial working memory.

Animals↗
PubMed2002

Influence of reward expectation on visuospatial processing in macaque lateral prefrontal cortex.

The lateral prefrontal cortex (LPFC) has been implicated in visuospatial processing, especially when it is required to hold spatial information during a delay period. It has also been reported that the LPFC receives information about expected reward outcome. However, the interaction between visuospatial processing and reward processing is still unclear because the two types of processing could not be dissociated in conventional delayed response tasks. To examine this, we used a memory-guided saccade task with an asymmetric reward schedule and recorded 228 LPFC neurons. The position of the target cue indicated the spatial location for the following saccade and the color of the target cue indicated the reward outcome for a correct saccade. Activity of LPFC was classified into three main types: S-type activity carried only spatial signals, R-type activity carried only reward signals, and SR-type activity carried both. Therefore only SR-type cells were potentially involved in both visuospatial processing and reward processing. SR-type activity was enhanced (SR+) or depressed (SR-) by the reward expectation. The spatial discriminability as expressed by the transmitted information was improved by reward expectation in SR+ type. In contrast, when reward information was coded by an increase of activity in the reward-absent condition (SR- type), it did not improve the spatial representation. This activity appeared to be involved in gaze fixation. These results extend previous findings suggesting that the LPFC exerts dual influences based on predicted reward outcome: improvement of memory-guided saccades (when reward is expected) and suppression of inappropriate behavior (when reward is not expected).

Animals↗
PubMed2003

Electrophysiological effects of acute and chronic olanzapine and fluoxetine in the rat prefrontal cortex.

Since the prefrontal cortex (PFC) is thought to play an important role in depression and schizophrenia, we studied the effects of fluoxetine and olanzapine on PFC neurons in rats using extracellular, in vivo recordings. Acute or 5-day administration of olanzapine (1-10 mg/kg, iv or 20 mg/kg, sc) did not change the firing rate of PFC neurons. However, a 21-day treatment with olanzapine (20 mg/kg per day, sc) significantly increased the firing rate of PFC neurons and increased their responsiveness to the iontophoretic administration of the GABA(A) antagonist bicuculline. Acute administration of fluoxetine (10 mg/kg, iv) also did not change the firing rate of PFC neurons. However, a 21-day treatment with fluoxetine (10 mg/kg per day) significantly decreased the firing rate of PFC neurons and decreased their responsiveness to the iontophoretic administration of bicuculline. Co-administration of olanzapine (10 mg/kg per day, sc) during the last 5 days of a 21-day fluoxetine treatment (10 mg/kg per day) prevented the suppression of firing and decreased responsiveness to the iontophoretic administration of bicuculline of PFC neurons. In conclusion, chronic, but not acute, olanzapine treatment significantly enhanced the firing and excitability of PFC neurons. In addition, chronic, but not acute, fluoxetine treatment significantly suppressed the firing and excitability of PFC neurons. Further, short-term olanzapine treatment attenuated the suppression of firing and excitability of PFC neurons induced by chronic fluoxetine treatment. These effects of olanzapine, fluoxetine, and the olanzapine/fluoxetine combination in the PFC may play an important role in the beneficial therapeutic effect of these compounds in schizophrenia and depression and may have implications for the treatment of treatment-resistant depression.

Action Potentials↗
PubMed2002

Involvement of the rat medial prefrontal cortex in novelty detection.

The prefrontal cortex in humans has been implicated in processes that underlie novelty detection and attention. This study examined the contribution of the rat medial prefrontal cortex to novelty detection using the targeting, or orienting, response (OR) as a behavioral index. Lesions to the medial prefrontal cortex (specifically the prelimbic and infralimbic cortices) influenced neither the OR to a novel visual stimulus from a localized light source (V1), nor the change in this OR over the course of a series of exposures to V1. However, after exposure to V1, the OR to a 2nd visual stimulus from the same source, V2, was more pronounced in control rats than in lesioned rats. These results suggest that the medial prefrontal cortex in the rat contributes to the process of novelty detection.

Animals↗
PubMed1998

Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens.

The prefrontal cortex and nucleus accumbens are primary recipients of medial thalamic inputs, prominently including projections from the thalamic paraventricular nucleus. It is not known if paraventricular neurons collateralize to innervate both the prefrontal cortex and nucleus accumbens. We used dual retrograde tract tracing methods to examine this question. A small population of paraventricular neurons was found to innervate the prefrontal cortex and medial nucleus accumbens. These data suggest that the thalamic paraventricular nucleus may coordinately influence activity in the prefrontal cortex and ventral striatum.

Amidines↗
PubMed1998

Lesions of the caudal area of rabbit medial prefrontal cortex impair trace eyeblink conditioning.

The dorsolateral prefrontal cortex of the primate is an area known to be important for memory. Since the discovery of a homologous area in subprimate mammals, the caudal medial prefrontal cortex, rabbits have become useful in the investigation of working memory. The subprimate prefrontal cortex is intimately interconnected with the hippocampus, which is also recognized for its role in learning and memory. In addition, the hippocampus and prefrontal cortex have been shown to be similarly involved in a variety of tasks. Therefore, we hypothesized that the caudal medial prefrontal cortex of the rabbit would be necessary for acquisition of the hippocampally dependent trace eyeblink conditioning task. A total of 16 young rabbits (Oryctolagus cuniculus) received bilateral aspiration lesions of the prefrontal cortex. Six of the lesioned subjects were unable to acquire the trace eyeblink conditioning task, but were unimpaired when tested subsequently in the hippocampally independent delay conditioning task. The lesions of these 6 subjects either were limited to or extended into the caudal medial prefrontal cortex. In the remaining 10 subjects, which were not impaired in trace conditioning, the lesions were limited to the rostral pole. Our results support our original hypothesis and provide further evidence of the involvement of the subprimate caudal medial prefrontal cortex in learning.

Animals↗
PubMed2001

An examination of the effects of stimulus type, encoding task, and functional connectivity on the role of right prefrontal cortex in recognition memory.

Right anterior prefrontal cortex and other brain areas are active during memory retrieval but the role of prefrontal cortex and how it interacts with these other regions to mediate memory function remain unclear. To explore these issues we used positron emission tomography to examine the effects of stimulus material and encoding task on brain activity during visual recognition, assessing both task-related changes and functional connectivity. Words and pictures of objects were encoded using perceptual and semantic strategies, resulting in better memory for semantically encoded items. There was no significant effect of prior encoding strategy on brain activity during recognition. Right anterior prefrontal cortex was equally active during recognition of both types of stimuli irrespective of initial encoding strategy. Regions whose activity was positively correlated with activity in right anterior prefrontal cortex included widespread areas of prefrontal and inferior temporal cortices bilaterally. Activity in this entire network of regions was negatively correlated with recognition accuracy of semantically encoded items. These results suggest that initial encoding task has little impact on the set of brain regions that is active during subsequent recognition. Right anterior prefrontal cortex appears to be involved in retrieval mode, reflected in its equivalent activity across conditions differing in both stimulus type and encoding task, and also in retrieval effort, shown by the negative correlation between its functional connectivity and individual differences in recognition accuracy.

Adult↗
PubMed2006

Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala.

The prefrontal cortex and the amygdala have synergistic roles in regulating purposive behavior, effected through bidirectional pathways. Here we investigated the largely unknown extent and laminar relationship of prefrontal input-output zones linked with the amygdala using neural tracers injected in the amygdala in rhesus monkeys. Prefrontal areas varied vastly in their connections with the amygdala, with the densest connections found in posterior orbitofrontal and posterior medial cortices, and the sparsest in anterior lateral prefrontal areas, especially area 10. Prefrontal projection neurons directed to the amygdala originated in layer 5, but significant numbers were also found in layers 2 and 3 in posterior medial and orbitofrontal cortices. Amygdalar axonal terminations in prefrontal cortex were most frequently distributed in bilaminar bands in the superficial and deep layers, by columns spanning the entire cortical depth, and less frequently as small patches centered in the superficial or deep layers. Heavy terminations in layers 1-2 overlapped with calbindin-positive inhibitory neurons. A comparison of the relationship of input to output projections revealed that among the most heavily connected cortices, cingulate areas 25 and 24 issued comparatively more projections to the amygdala than they received, whereas caudal orbitofrontal areas were more receivers than senders. Further, there was a significant relationship between the proportion of 'feedforward' cortical projections from layers 2-3 to 'feedback' terminations innervating the superficial layers of prefrontal cortices. These findings indicate that the connections between prefrontal cortices and the amygdala follow similar patterns as corticocortical connections, and by analogy suggest pathways underlying the sequence of information processing for emotions.

Amygdala↗
PubMedDate not supplied

Memory for temporal order of new and familiar spatial location sequences: role of the medial prefrontal cortex.

Rats with medial prefrontal cortex or sham control lesions were tested on an eight-arm radial maze task to examine memory for the temporal order of a variable and a constant sequence of spatial locations as a function of temporal distance. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected or fixed for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal distance (0, 2, 4, or 6) or the number of arms that occurred between the two test arms in the study phase. For the variable sequences based on new information, control rats showed an increasing temporal distance function. Relative to control rats, medial prefrontal cortex-lesioned rats displayed a temporal order memory deficit across all distances. For the constant sequence based on familiar information, control rats performed well across all distances. Relative to controls, the medial prefrontal cortex-lesioned rats displayed a performance deficit. The results support the idea that the medial prefrontal cortex contributes to mnemonic operations associated with temporal order for new and familiar spatial location information.

Analysis of Variance↗
PubMed2006

Enhanced catecholamine synthesis in the prefrontal cortex after traumatic brain injury: implications for prefrontal dysfunction.

Traumatic brain injury (TBI)--induced dysfunction of the prefrontal cortex causes many high-level cognitive deficits, including working memory (WM) dysfunction. WM lies at the core of many high-level functions, yet the cellular and molecular mechanisms underlying its dysfunction are poorly understood. Lesion and pharmacological studies in rodents have implicated the medial prefrontal cortex (mPFC), which includes the prelimbic/infralimbic (PL/IL) cortices, in WM tasks. These studies have shown that optimal levels of catecholamine neurotransmission are critical for normalcy of WM function, suggesting that alterations in their synthesis may play a role in WM dysfunction. Using the cortical impact injury model of traumatic brain injury which reproducibly causes working memory deficits in rodents, we have measured the protein levels and activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine biosynthesis, and tissue dopamine (DA) and norepinephrine (NE) levels in microdissected PL/IL tissues. Our results show that TBI increases TH protein levels, its activity and tissue DA and NE content in the PL/IL. These findings suggest that altered catecholamine signaling within the PL/IL may contribute to impaired PFC function, and may have implications in the design and implementation of strategies to alleviate prefrontal dysfunction in brain injury patients.

Animals↗
PubMed2002

Postnatal development of parvalbumin- and GABA transporter-immunoreactive axon terminals in monkey prefrontal cortex.

In the primate prefrontal cortex, the axon terminals of the chandelier class of inhibitory local circuit neurons have a distinctive time course of postnatal development. In this study, we sought to determine whether the axon terminals of other classes of local circuit neurons are also refined during postnatal development. We examined postnatal changes in the density of punctate structures immunoreactive for the calcium binding protein parvalbumin, which identifies a subset of gamma-aminobutyric acid (GABA) -containing terminals, in the prefrontal cortex of 35 rhesus monkeys ranging in age from newborn to adult. In area 46, the density of parvalbumin- immunoreactive puncta in the superficial and middle layers was extremely low in the newborn animals, then increased more than 10-fold to adult levels, which were achieved by 3 to 4 years of age. In layer V, a band of labeled puncta present in the newborn animals also increased in density until 3 to 4 years of age. Developmental changes of parvalbumin-immunoreactive puncta in area 9 were similar to those in area 46. In contrast, the density of punctate structures labeled with an antibody against a GABA membrane transporter (GAT-1) did not change across development, suggesting that the number of GABAergic terminals is stable over time, but that the level of parvalbumin protein within the terminals varies. The time course of the observed changes in these parvalbumin-labeled terminals is markedly different from that of parvalbumin-immunoreactive chandelier cell terminal clusters. These findings suggest that morphologically specialized classes of inhibitory interneurons assume prominence within the prefrontal cortical network at different stages of postnatal development.

Aging↗
PubMed1994

Memory for spatial location as a function of temporal lag in rats: role of hippocampus and medial prefrontal cortex.

Rats with medial prefrontal cortex, hippocampus, or cortical control lesions were tested on an eight-arm radial maze task, in order to examine memory for the temporal order of spatial locations as a function of temporal lag. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal lag (0-6) or the number of arms that occurred between the two test arms in the study phase. The control rats performed at chance at a temporal lag of zero, but their performance was above chance for the remaining lags, improving after the temporal lag exceeded zero. The hippocampal-lesioned rats showed a marked deficit, performing at chance for all lags, with some savings for those items occurring at the end of the list. The medial prefrontal cortex-lesioned rats showed a less severe deficit. The results of these data support the notion that both the hippocampus and the medial prefrontal cortex play significant roles in memory for the temporal order of spatial locations.

Animals↗
PubMed1998

Topographic organization of connections between the hypothalamus and prefrontal cortex in the rhesus monkey.

Prefrontal cortices have been implicated in autonomic function, but their role in this activity is not well understood. Orbital and medial prefrontal cortices receive input from cortical and subcortical structures associated with emotions. Thus, the prefrontal cortex may be an essential link for autonomic responses driven by emotions. Classic studies have demonstrated the existence of projections between prefrontal cortex and the hypothalamus, a central autonomic structure, but the topographic organization of these connections in the monkey has not been clearly established. We investigated the organization of bidirectional connections between these areas in the rhesus monkey by using tracer injections in orbital, medial, and lateral prefrontal areas. All prefrontal areas investigated received projections from the hypothalamus, originating mainly in the posterior hypothalamus. Differences in the topography of hypothalamic projection neurons were related to both the location and type of the target cortical area. Injections in lateral eulaminate prefrontal areas primarily labeled neurons in the posterior hypothalamus that were equally distributed in the lateral and medial hypothalamus. In contrast, injections in orbitofrontal and medial limbic cortices labeled neurons in the anterior and tuberal regions of the hypothalamus and in the posterior region. Projection neurons targeting orbital limbic cortices were more prevalent in the lateral part of the hypothalamus, whereas those targeting medial limbic cortices were more prevalent in the medial hypothalamus. In comparison to the ascending projections, descending projections from prefrontal cortex to the hypothalamus were highly specific, originating mostly from orbital and medial prefrontal cortices. The ascending and descending connections overlapped in the hypothalamus in areas that have autonomic functions. These results suggest that specific orbitofrontal and medial prefrontal areas exert a direct influence on the hypothalamus and may be important for the autonomic responses evoked by complex emotional situations.

Animals↗
PubMed1992

Topography and collateralization of the dopaminergic projections to motor and lateral prefrontal cortex in owl monkeys.

The sources and histochemical characteristics of dopaminergic projections to motor and premotor areas of cortex were investigated in owl monkeys in which information from related studies was used to subdivide cortex into motor fields. Brainstem projections to frontal cortex were identified by injections of different fluorescent dyes in the primary motor cortex (M1) and the supplementary motor area (SMA), first identified by microstimulation. Injections were also placed in dorsal premotor cortex and lateral prefrontal cortex. The distribution of retrogradely labeled neurons was related to the location of tyrosine hydroxylase immunolabeled neurons on the same or alternate brain sections to identify the dopamine (DA) neurons. All DA cortically projecting neurons were located in the A8-A10 complex, largely in its dorsal components, including the parabrachial pigmented n. of the ventral tegmental area (VTA), pars gamma of the substantia nigra compacta, and the dorsal part of the retrorubral area (A8). Fewer cells were in the midline groups of VTA (n. linearis rostralis and caudalis) and in the n. paranigralis. DA neurons projecting to M1, SMA, and prefrontal cortex were largely intermixed, and some of these neurons were double or triple labeled by the fluorescent dyes, indicating collateralization to two or three fields; DA cells projecting to M1 were more numerous than to the other locations. The dorsal components of the A8-A10 complex from which arose the DA mesocortical projection were also characterized by the presence of calbindin-immunoreactive neurons and by a dense neurotensin and noradrenergic terminal innervation. Compared to rodents or felines, the DA neurons projecting to the lateral frontal lobe of primates appear to be shifted dorsally and laterally in the nigral complex. The topographic overlap, partial collateralization, and common histochemical characteristics of the DA mesocortical neurons projecting to different fields of the lateral frontal lobe suggest that some degree of functional unity exists within this projection.

Animals↗
PubMed2005

Spatial selectivity in human ventrolateral prefrontal cortex.

The functional organization of lateral prefrontal cortex is not well understood, and there is debate as to whether the dorsal and ventral aspects mediate distinct spatial and non-spatial functions, respectively. We show for the first time that recordings from human ventrolateral prefrontal cortex show spatial selectivity, supporting the idea that ventrolateral prefrontal cortex is involved in spatial processing. Our results also indicate that prefrontal cortex may be a source of control signals for neuroprosthetic applications.

Brain Mapping↗
PubMed1996

Evidence for the importance of dopamine for prefrontal cortex functions early in life.

There is considerable evidence that dorsolateral prefrontal cortex subserves critical cognitive abilities even during early infancy and that improvement in these abilities is evident over roughly the next 10 years. We also know that (a) in adult monkeys these cognitive abilities depend critically on the dopaminergic projection to prefrontal cortex and (b) the distribution of dopamine axons within dorsolateral prefrontal cortex changes, and the level of dopamine increases, during the period that infant monkeys are improving on tasks that require the cognitive abilities dependent on prefrontal cortex. To begin to look at whether these cognitive abilities depend critically on the prefrontal dopamine projection in humans even during infancy and early childhood we have been studying children who we hypothesized might have a selective reduction in the dopaminergic innervation of prefrontal cortex and a selective impairment in the cognitive functions subserved by dorsolateral prefrontal cortex. These are children treated early and continuously for the genetic disorder, phenylketonuria (PKU). In PKU the ability to convert the amino acid, phenylalanine (Phe), into another amino acid, tyrosine (Tyr), is impaired. This causes Phe to accumulate in the bloodstream to dangerously high levels and the plasma level of Tyr to fall. Widespread brain damage and severe mental retardation result. When PKU is moderately well controlled by a diet low in Phe (thus keeping the imbalance between Phe and Tyr in plasma within moderate limits) severe mental retardation is averted, but deficits remain in higher cognitive functions. In a four-year longitudinal study we have found these deficits to be in the working memory and inhibitory control functions dependent upon dorsolateral prefrontal cortex in PKU children with plasma Phe levels 3-5 times normal. The fact that even infants showed these impairments suggests that dopaminergic innervation to prefrontal cortex is critical for the proper expression of these abilities even during the first year of life. To test the hypothesis about the underlying biological mechanism we have created the first animal model of early and continuously treated PKU. As predicted, the experimental animals had reduced levels of dopamine and the dopamine metabolite, homovanillic acid (HVA), in prefrontal cortex and showed impaired performance on delayed alternation, a task dependent on prefrontal cortex function. Noradrenaline levels were unaffected; however some reduction in serotonin levels and in dopamine levels outside the prefrontal cortex was found. If prefrontal cortex functions are vulnerable in children with a moderate plasma Phe:Tyr imbalance because of the special properties of the dopamine neurons that project to prefrontal cortex, then other dopamine neurons that share those same properties should also be vulnerable in these children. The dopamine neurons in the retina share these properties (i.e. unusually high firing and dopamine turnover rates), and we have found that PKU children with plasma Phe levels 3-5 times normal are impaired in their contrast sensitivity, a behavioural measure sensitive to retinal dopamine levels.

Animals↗
PubMed1998

Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons.

An influence of the prefrontal cortex on noradrenergic locus coeruleus neurons would have profound implications for the function of the locus coeruleus system. Although the medial prefrontal cortex does not substantially innervate the core of the nucleus locus coeruleus, evidence indicates that the medial prefrontal cortex projects to regions containing locus coeruleus dendrites; indirect medial prefrontal cortex-locus coeruleus projections are also possible. Here, we examined influences of prefrontal cortex activity on locus coeruleus firing rates by activating or inactivating the medial prefrontal cortex while recording impulse activity of locus coeruleus neurons extracellularly in anaesthetized rats. Most of our electrical stimulation experiments were conducted in rats which underwent lesions of the ascending dorsal bundle of noradrenergic fibres from the locus coeruleus to eliminate locus coeruleus projections to the prefrontal cortex, because antidromic activation of locus coeruleus from the prefrontal cortex affects even non-driven locus coeruleus neurons through collaterals. Single pulse stimulation (1 mA, 0.3-0.5 ms) of the dorsomedial (frontal region 2) or prelimbic region of the medial prefrontal cortex synaptically activated 13/16 (81%) or 16/56 (29%) locus coeruleus neurons, respectively. Train stimulation (20 Hz for 0.5 s) synaptically activated greater percentages of locus coeruleus cells, 11/12 cells (92%) for the dorsomedial prefrontal cortex, and 41/50 cells (82%) for the prelimbic cortex. No inhibitory responses in the locus coeruleus were obtained with dorsomedial prefrontal stimulation, and weak inhibition was found in 16% of locus coeruleus cells with prelimbic stimulation. Electrical stimulation of more lateral frontal cortex (Fr1 area) had no effects on locus coeruleus activity. Chemical stimulation of the dorsomedial prefrontal cortex with L-glutamate (10 or 100 mM) or D,L-homocysteic acid (10 mM) phasically activated 15/26 (55%) locus coeruleus cells, and 15/68 cells (22%) with prelimbic stimulation; such activation was sometimes followed by long-lasting oscillatory activity. No locus coeruleus cells exhibited purely inhibitory responses with chemical stimulation of any prefrontal cortex site. Inactivation of the dorsomedial or prelimbic region of the prefrontal cortex with lidocaine microinjection (2%, 180 or 300 nl) reduced locus coeruleus firing rates in 6/10 (60%) or 7/19 (37%) locus coeruleus cells, respectively. In no case did lidocaine in any prefrontal cortex site activate a locus coeruleus neuron. These results indicate that the medial prefrontal cortex provides a potent excitatory influence on locus coeruleus neurons. The fact that inactivation of the medial prefrontal cortex suppressed locus coeruleus firing indicates that the medial prefrontal cortex also provides a resting tonic excitatory influence on locus coeruleus activity.

Anesthesia↗