Ventral mPFC Research Articles

Role of dorsal medial prefrontal cortex dopamine D1-family receptors in relapse to high-fat food seeking induced by the anxiogenic drug yohimbine.

In humans, relapse to maladaptive eating habits during dieting is often provoked by stress. In rats, the anxiogenic drug yohimbine, which causes stress-like responses in both humans and nonhumans, reinstates food seeking in a relapse model. In this study, we examined the role of medial prefrontal cortex (mPFC) dopamine D1-family receptors, previously implicated in stress-induced reinstatement of drug seeking, in yohimbine-induced reinstatement of food seeking. We trained food-restricted rats to lever press for 35% high-fat pellets every other day (9-15 sessions, 3 h each); pellet delivery was accompanied by a discrete tone-light cue. We then extinguished operant responding for 10-16 days by removing the pellets. Subsequently, we examined the effect of yohimbine (2 mg/kg, i.p.) on reinstatement of food seeking and Fos (a neuronal activity marker) induction in mPFC. We then examined the effect of systemic injections of the D1-family receptor antagonist SCH23390 (10 μg/kg, s.c.) on yohimbine-induced reinstatement and Fos induction, and that of mPFC SCH23390 (0.5 and 1.0 μg/side) injections on this reinstatement. Yohimbine-induced reinstatement was associated with strong Fos induction in the dorsal mPFC and with weaker Fos induction in the ventral mPFC. Systemic SCH23390 injections blocked both yohimbine-induced reinstatement and mPFC Fos induction. Dorsal, but not ventral, mPFC injections of SCH23390 decreased yohimbine-induced reinstatement of food seeking. In addition, dorsal mPFC SCH23390 injections decreased pellet-priming-induced reinstatement, but had no effect on ongoing high-fat pellet self-administration or discrete-cue-induced reinstatement. Results indicate a critical role of dorsal mPFC dopamine D1-family receptors in stress-induced relapse to palatable food seeking, as well as relapse induced by acute re-exposure to food taste, texture, and smell.

Do you like me? Neural correlates of social evaluation and developmental trajectories

Social acceptance is of key importance for healthy functioning. We used functional magnetic resonance imaging (fMRI) to examine age-related changes in the neural correlates of social acceptance and rejection processing. Participants from four age groups participated in the study: pre-pubertal children (8–10 years), early adolescents (12–14 years), older adolescents (16–17 years) and young adults (19–25 years). During the experiment, participants were presented with unfamiliar faces of peers and were asked to predict whether they expected to be liked or disliked by the other person, followed by feedback indicating acceptance or rejection. Results showed that activation in the ventral mPFC and striatum to social feedback was context-dependent; there was increased activation when participants had positive expectations about social evaluation, and increased activation following social acceptance feedback. Age-related comparisons revealed a linear increase in activity with age in these brain regions for positive expectations of social evaluation. Similarly, a linear increase with age was found for activation in the striatum, ventral mPFC, OFC, and lateral PFC for rejection feedback. No age-related differences in neural activation were shown for social acceptance feedback. Together, these results provide important insights in the developmental trajectories of brain regions implicated in social and affective behavior.

Default mode network abnormalities in bipolar disorder and schizophrenia

The default-mode network (DMN) consists of a set of brain areas preferentially activated during internally focused tasks. We used functional magnetic resonance imaging (fMRI) to study the DMN in bipolar mania and acute schizophrenia. Participants comprised 17 patients with bipolar disorder (BD), 14 patients with schizophrenia (SZ) and 15 normal controls (NC), who underwent 10-min resting fMRI scans. The DMN was extracted using independent component analysis and template-matching; spatial extent and timecourse were examined. Both patient groups showed reduced DMN connectivity in the medial prefrontal cortex (mPFC) (BD: x = − 2, y = 54, z = − 12; SZ: x =−2, y = 22, z = 18). BD subjects showed abnormal recruitment of parietal cortex (correlated with mania severity) while SZ subjects showed greater recruitment of the frontopolar cortex/basal ganglia. Both groups had significantly higher frequency fluctuations than controls. We found ventral mPFC abnormalities in BD and dorsal mPFC abnormalities in SZ. The higher frequency of BOLD signal oscillations observed in patients suggests abnormal functional organization of circuits in both disorders. Further studies are needed to determine how these abnormalities are related to specific symptoms of each condition.

Lesions to the ventral, but not the dorsal, medial prefrontal cortex enhance latent inhibition

The acquisition of a conditioned response to a stimulus when it is paired with a reinforcer is retarded if the stimulus has previously been repeatedly pre-exposed in the absence of the reinforcer. This effect, called latent inhibition, has previously been found to be insensitive to lesions of the medial prefrontal cortex (mPFC) in rats. Using an on-baseline conditioned emotional response procedure, which is especially sensitive to small variations in the absolute magnitude of latent inhibition, we found increased latent inhibition following excitotoxic lesions of the mPFC (Experiment 1) or the ventral mPFC alone (Experiment 2) as compared with sham-operated control rats. Lesions restricted to the dorsal mPFC, however, were without effect (Experiment 2). These results are consistent with those of experiments employing another type of interference procedure, extinction. Together, these findings suggest that when different contingencies between a stimulus and a reinforcer are established in separate learning phases, lesions to the ventral mPFC result in increased interference between first-learned and second-learned contingencies. As a consequence, retrieval of the second-learned contingency is impaired, and performance is dominated by the first-learned contingency. These findings are discussed in light of the use of latent inhibition to model cognitive deficits in schizophrenia.

Anxiolytic-like effects induced by blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the medial prefrontal cortex of rats

The endocannabinoid anandamide, in addition to activating cannabinoid type 1 receptors (CB1), may act as an agonist at transient receptor potential vanilloid type 1 (TRPV1) channels. In the periaqueductal gray, CB1 activation inhibits, whereas TRPV1 increases, anxiety-like behavior. In the medial prefrontal cortex (mPFC), another brain region related to defensive responses, CB1 activation induces anxiolytic-like effects. However, a possible involvement of TRPV1 is still unclear. In the present study, we tested the hypothesis that TRPV1 channel contributes to the modulation of anxiety-like behavior in the mPFC. Male Wistar rats (n = 5-7 per group) received microinjections of the TRPV1 antagonist capsazepine (1-60 nmol) in the ventral portion of the mPFC and were exposed to the elevated plus maze (EPM) or to the Vogel conflict test. Capsazepine increased exploration of open arms in the EPM as well as the number of punished licks in the Vogel conflict test, suggesting anxiolytic-like effects. No changes in the number of entries into the enclosed arms were observed in the EPM, indicating that there were no changes in motor activity. Moreover, capsazepine did not interfere with water consumption or nociceptive threshold, discarding potential confounding factors for the Vogel conflict test. These data suggest that TRPV1 in the ventral mPFC tonically inhibits anxiety-like behavior. TRPV1 could facilitate defensive responses opposing, therefore, the anxiolytic-like effects reported after local activation of CB1 receptors.

Effects of a diet rich in omega‐3 essential fatty acids on behavior in an attentional task and monoamine transmitter levels in the medial prefrontal cortex of adolescent rats

Omega‐3 essential fatty acids (Ω3‐EFAs) have been suggested as a treatment for depression and ADD. Male adolescent rats were put on a diet balanced 1:1 with Ω3:Ω 6 essential fatty acids (EFAs) or a diet high in Ω6 EFAs acids (25:1 Ω6:Ω 3) from postnatal days 21 to 45. Male adolescent rats were tested in the intradimension/extradimensional attentional set‐shifting (ID/ED) task on days 40‐45 of age. The ID/ED has previously been used only in adult animals. Following completion of the ID/ED, animals were implanted with a 2mm microdialysis probe into the ventral mPFC (vmPFC). After determination of basal levels of norepinephrine (NE), DA and 5‐HT, animals were again run in the ID/ED task. Implantation of a microdialysis probe into the vmPFC did not affect performance in the ID/ED task. Basal levels of NE were higher in the 25:1 dietary group while basal levels of DA and 5‐HT did not differ between groups. Extracellular 5‐HT decreased during the task in the 1:1 dietary group but not in the 25:1 group. These data suggest that a diet rich in omega‐3 EFAs in adolescent rats produces changes in neurotransmitter levels but does not alter attention in an ID/ED task. Supported by EAST and MH074811‐01.

Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking

Associative learning processes have an important role in the initiation and persistence of heroin-seeking. Here we show in a rat self-administration model that reexposure to cues previously associated with heroin results in downregulation of AMPA receptor subunit GluR2 and concomitant upregulation of clathrin-coat assembly protein AP2ml in synaptic membranes of the medial prefrontal cortex (mPFC). Reduced AMPA receptor expression in synaptic membranes was associated with a decreased AMPA/NMDA current ratio and increased rectification index in mPFC pyramidal neurons. Systemic or ventral (but not dorsal) mPFC injections of a peptide inhibiting GluR2 endocytosis attenuated both the rectification index and cue-induced relapse to heroin-seeking, without affecting sucrose-seeking. We conclude that GluR2 receptor endocytosis and the resulting synaptic depression in ventral mPFC are crucial for cue-induced relapse to heroin-seeking. As reexposure to conditioned stimuli is a major cause for heroin relapse, inhibition of GluR2 endocytosis may provide a new target for the treatment of heroin addiction.

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 10 days (6 h/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 1 day. 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 1 day, 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.

Selective Activation of Medial Prefrontal-to-Accumbens Projection Neurons by Amygdala Stimulation and Pavlovian Conditioned Stimuli

Medial prefrontal cortex (mPFC) neurons respond to Pavlovian conditioned stimuli, and these responses depend on input from the basolateral amygdala (BLA). In this study, we examined the mPFC efferent circuits mediating conditioned responding by testing whether specific subsets of mPFC projection neurons receive BLA input and respond to conditioned stimuli. In urethane-anesthetized rats, we identified mPFC neurons that projected to the nucleus accumbens (NAcc) or to the contralateral mPFC (cmPFC) using antidromic activation. Stimulation of the BLA and Pavlovian conditioned odors selectively activated a subpopulation of ventral mPFC neurons that projected to NAcc, but elicited virtually no activation in mPFC neurons that projected to cmPFC. BLA stimulation typically evoked inhibitory responses among nonactivated neurons projecting to either site. These results suggest that the ventral mPFC-to-NAcc pathway may support behavioral responses to conditioned cues. Furthermore, because projections from the BLA (which also encode affective information) and the mPFC converge within the NAcc, the BLA may recruit the mPFC to drive specific sets of NAcc neurons, and thereby exert control over prefrontal cortical-striato-thalamocortical information flow.

The selective 5-HT1A receptor antagonist WAY-100635 inhibits neuronal activity of the ventromedial prefrontal cortex in a rodent model of Parkinson’s disease

The ventral part of the medial prefrontal cortex (mPFC) plays an important role in initiation and control of voluntary movement, mood and cognition. However, after the degeneration of the nigrostriatal pathway, the neuronal activity of the ventral mPFC and the role of serotonin(1A) (5-hydroxytryptamine, 5-HT(1A)) receptors in the firing of the neurons are still unknown. The present study is to investigate the change of neuronal activity in the ventral mPFC and the effect of systemic administration of the selective 5-HT(1A) receptor antagonist WAY-100635 on the activity of the neurons in normal and 6-hydroxydopamine (6-OHDA)-lesioned rats. Single unit responses were recorded extracellularly with glass microelectrodes from ventral mPFC neurons in normal rats and 6-OHDA unilaterally lesioned rats in vivo. 6-OHDA lesion of the substantia nigra pars compacta (SNc) significantly increased the firing rate with no change in the firing pattern of neurons of the ventral mPFC in rats. Systemic administration of WAY-100635 (0.1 mg/kg, i.v.) did not change the mean firing rate and firing pattern of ventral mPFC neurons in normal rats. In contrast, WAY-100635 significantly decreased the mean firing rate of the neurons in rats with 6-OHDA lesion of the SNc. These data suggest that the degeneration of the nigrostriatal pathway results in an increase of neuronal activity of ventral mPFC and dysfunction of 5-HT(1A) receptor.

Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat

The medial prefrontal cortex (mPFC) has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and working memory. Using retrograde tracing techniques, we examined, compared, and contrasted afferent projections to the four divisions of the mPFC in the rat: the medial (frontal) agranular (AGm), anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices. Each division of the mPFC receives a unique set of afferent projections. There is a shift dorsoventrally along the mPFC from predominantly sensorimotor input to the dorsal mPFC (AGm and dorsal AC) to primarily 'limbic' input to the ventral mPFC (PL and IL). The AGm and dorsal AC receive afferent projections from widespread areas of the cortex (and associated thalamic nuclei) representing all sensory modalities. This information is presumably integrated at, and utilized by, the dorsal mPFC in goal directed actions. In contrast with the dorsal mPFC, the ventral mPFC receives significantly less cortical input overall and afferents from limbic as opposed to sensorimotor regions of cortex. The main sources of afferent projections to PL/IL are from the orbitomedial prefrontal, agranular insular, perirhinal and entorhinal cortices, the hippocampus, the claustrum, the medial basal forebrain, the basal nuclei of amygdala, the midline thalamus and monoaminergic nuclei of the brainstem. With a few exceptions, there are few projections from the hypothalamus to the dorsal or ventral mPFC. Accordingly, subcortical limbic information mainly reaches the mPFC via the midline thalamus and basal nuclei of amygdala. As discussed herein, based on patterns of afferent (as well as efferent) projections, PL is positioned to serve a direct role in cognitive functions homologous to dorsolateral PFC of primates, whereas IL appears to represent a visceromotor center homologous to the orbitomedial PFC of primates.

Bidirectional Modulation of Goal-Directed Actions by Prefrontal Cortical Dopamine

Instrumental actions are a vital cognitive asset that endows an organism with sensitivity to the consequences of its behavior. Response-outcome feedback allows responding to be shaped in order to maximize beneficial, and minimize detrimental, outcomes. Lesions of the medial prefrontal cortex (mPFC) result in behavior that is insensitive to changes in outcome value in animals and compulsive behavior in several human psychopathologies. Such insensitivity to changes in outcome value is a defining characteristic of instrumental habits: responses that are controlled by antecedent stimuli rather than goal expectancy. Little is known regarding the neurochemical substrates mediating this sensitivity. The present experiments used sensitivity to posttraining outcome devaluation to index the action-habit status of instrumental responding. Infusions of dopamine into the ventral mPFC (vmPFC), but not dorsal mPFC, restored outcome sensitivity bidirectionally-decreasing responding following outcome devaluation and increasing responding when the outcome was not devalued. This bidirectionality makes the possibility that these infusions nonspecifically dysregulated vmPFC dopamine transmission unlikely. VmPFC dopamine promoted instrumental responding appropriate to outcome value. Reinforcer consumption data indicated that this was not a consequence of altered sensitivity to the reinforcer itself. We suggest that vmPFC dopamine reengages attentional processes underlying goal-directed behavior.

Neuron number decreases in the rat ventral, but not dorsal, medial prefrontal cortex between adolescence and adulthood

Neuroimaging studies have established that there are losses in the volume of gray matter in certain cortical regions between adolescence and adulthood, with changes in the prefrontal cortex being particularly dramatic. Previous work from our laboratory has demonstrated that cell death can occur as late as the fourth postnatal week in the rat cerebral cortex. The present study examined the possibility that neuronal loss may occur between adolescence and adulthood in the rat prefrontal cortex. Rats of both sexes were examined during adolescence (at day 35) and young adulthood (at day 90). The volume, neuronal number, and glial number of the medial prefrontal cortex (mPFC) were quantified using unbiased stereological techniques. Neurons were lost from the ventral, but not dorsal, mPFC between adolescence and adulthood, suggesting a late wave of apoptosis that was region-specific. This was accompanied by a decrease in the volume of the female ventral mPFC. In contrast to neuron number, the number of glial cells was stable in the ventral mPFC and increased between adolescence and adulthood in the dorsal mPFC. Sex-specific developmental changes in neuron number, glial number, and volume resulted in sex differences in adults that were not seen during adolescence. The loss of neurons at this time may make the peri-adolescent prefrontal cortex particularly susceptible to the influence of environmental factors.

Evidence for a different role of the ventral and dorsal medial prefrontal cortex for social reactive aggression: An interactive fMRI study

Interactive paradigms inducing reactive aggression are absent in the brain mapping literature. We used a competitive reaction time task to investigate brain regions involved in social interaction and reactive aggression in sixteen healthy male subjects with fMRI. Subjects were provoked by increasingly aversive stimuli and were given the opportunity to respond aggressively against their opponent by administering a stimulus as retaliation. fMRI revealed an increase of medial prefrontal cortex (mPFC) activity during retaliation. The dorsal mPFC was active when subjects had to select the intensity of the retaliation stimulus, and its activity correlated with the selected stimulus strength. In contrast, ventral mPFC was active during observing the opponent suffering but also during retaliation independent of the stimulus strength. Ventral mPFC activation, stronger in low callous subjects, correlated positively with skin conductance response during observation of the suffering opponent. In conclusion, dorsal mPFC activation seems to represent cognitive operations related to more intense social interaction processes whereas the ventral mPFC might be involved in affective processes associated with compassion to the suffering opponent.

Dissociable Medial Prefrontal Contributions to Judgments of Similar and Dissimilar Others

Human social interaction requires the recognition that other people are governed by the same types of mental states-beliefs, desires, intentions-that guide one's own behavior. We used functional neuroimaging to examine how perceivers make mental state inferences when such self-other overlap can be assumed (when the other is similar to oneself) and when it cannot (when the other is dissimilar from oneself). We observed a double dissociation such that mentalizing about a similar other engaged a region of ventral mPFC linked to self-referential thought, whereas mentalizing about a dissimilar other engaged a more dorsal subregion of mPFC. The overlap between judgments of self and similar others suggests the plausibility of "simulation" accounts of social cognition, which posit that perceivers can use knowledge about themselves to infer the mental states of others.

Excitatory actions of the ventral midline thalamus (rhomboid/reuniens) on the medial prefrontal cortex in the rat

The medial prefrontal cortex (mPFC) has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and working memory. The present report examined the effects of stimulation of the midline thalamus, concentrating on ventral nuclei of the midline thalamus, on evoked activity at the mPFC. The nucleus reuniens (RE) of the ventral midline thalamus is a major source of projections to the hippocampus and to the mPFC, and has been shown to exert pronounced excitatory effects on the hippocampus. No previous study has systematically examined the actions of the ventral midline thalamus on the mPFC. We showed that stimulation of the dorsal and ventral midline thalamus, but not of an intermediate region lying between them (null zone), produced short latency, large amplitude evoked potentials throughout the dorsoventral extent of the medial PFC. The largest effects were elicited with ventral midline stimulation (rhomboid/reuniens nuclei) at the ventral mPFC--the prelimbic (PL) and infralimbic (IL) cortices. Specifically, stimulation of RE produced evoked potentials (early negative component, N2) at the PL cortex at a mean latency of 22.6 msec and mean amplitude of 0.85 mV, indicative of monosynaptic effects. In addition, we showed that paired pulse stimulation of RH/RE produced strong facilitatory actions (paired pulse facilitation) at IL (83%) and PL (75%). These findings indicate that RE exerts strong direct excitatory effects on the mPFC, and coupled with the demonstration that RE produces similar actions on the hippocampus, indicates that RE is in a position to influence and possibly coordinate the activity of these two forebrain structures subserving memory.

The Link between Social Cognition and Self-referential Thought in the Medial Prefrontal Cortex

The medial prefrontal cortex (mPFC) has been implicated in seemingly disparate cognitive functions, such as understanding the minds of other people and processing information about the self. This functional overlap would be expected if humans use their own experiences to infer the mental states of others, a basic postulate of simulation theory. Neural activity was measured while participants attended to either the mental or physical aspects of a series of other people. To permit a test of simulation theory's prediction that inferences based on self-reflection should only be made for similar others, targets were subsequently rated for their degree of similarity to self. Parametric analyses revealed a region of the ventral mPFC--previously implicated in self-referencing tasks--in which activity correlated with perceived self/other similarity, but only for mentalizing trials. These results suggest that self-reflection may be used to infer the mental states of others when they are sufficiently similar to self.

Injections of baclofen into the ventral medial prefrontal cortex block the initiation, but not the expression, of cocaine sensitization in rats

Increased excitatory output from the medial prefrontal cortex (mPFC) is thought to play a key role in the development of sensitization to cocaine. Gamma-aminobutyric acid (GABA) inhibits this excitatory output. The present studies were designed to determine the effects of intra-mPFC injections of the GABA(B) agonist baclofen on cocaine-induced motor activity and on the development of sensitization to cocaine. Rats received bilateral cannula implants above the ventral mPFC. Initial studies examined the dose-response effects of injection of baclofen (0.05-0.5 nmol/side) into the mPFC on the acute motor-stimulant response to cocaine (15 mg/kg, i.p.). Additional studies determined whether coadministration of intra-mPFC baclofen (0.5 nmol/side) and systemic cocaine (15 mg/kg, i.p.) could alter the initiation and/or expression of cocaine-induced behavioral sensitization. Intra-mPFC baclofen dose-dependently blocked cocaine-induced motor activity. In sensitization studies, intra-mPFC baclofen was able to prevent the initiation, but not the expression of cocaine-induced sensitization. The data suggest that the ability of GABA to modulate excitatory output from the mPFC may be attenuated in animals sensitized to cocaine.

Prefrontal D1 and ventral hippocampal N-methyl- d-aspartate regulation of startle gating in rats

Background: Sensorimotor gating, as measured by prepulse inhibition of the startle reflex, is deficient in schizophrenia patients, and in rats after specific manipulations of limbic cortico–striato–pallido–thalamic circuitry. For example, prepulse inhibition in rats is disrupted after D1 blockade in the medial prefrontal cortex, and after N-methyl- d-aspartate infusion into the ventral hippocampus. In the present study, we examined whether these two substrates form part of an integrated circuit regulating sensorimotor gating, which might contribute to the loss of prepulse inhibition in patient populations. Methods: Prepulse inhibition was assessed in male Sprague–Dawley rats after systemic or intra-medial prefrontal cortex administration of the D1 antagonist, SCH 23390. Separate rats received intra-medial prefrontal cortex infusion of the retrograde transported label Fluoro-Gold. In rats with sham or electrolytic lesions of the medial prefrontal cortex, prepulse inhibition was tested after infusion of N-methyl- d-aspartate or vehicle into ventral hippocampus regions that were determined to send projections to the medial prefrontal cortex. Results: Prepulse inhibition was disrupted after systemic SCH 23390 treatment and after infusion of SCH 23390 into medial prefrontal cortex sites within the prelimbic and cingulate cortices. Fluoro-Gold infusion into these medial prefrontal cortex sites labeled cells in the ventral hippocampus complex, including regions CA1 and entorhinal cortex. N-methyl- d-aspartate infusions into these ventral hippocampus regions disrupted prepulse inhibition in rats after sham but not electrolytic lesions of the medial prefrontal cortex. Conclusions: Prepulse inhibition appears to be regulated by interacting substrates within the ventral hippocampus and MPFC. Specifically, NMDA activation of the ventral hippocampus appears to disrupt prepulse inhibition in a manner that is dependent on the integrity of infralimbic or cingulate cortical regions that also support a D1-mediated regulation of prepulse inhibition. Conceivably, dysfunction within these hippocampal-frontal circuits may contribute to sensorimotor gating deficits in schizophrenia.

Repeated injections of sulpiride into the medial prefrontal cortex induces sensitization to cocaine in rats

Recent studies have suggested that the medial prefrontal cortex (mPFC) plays an important role in the development of sensitization to cocaine. In particular, a recent report proposed that sensitization is associated with a decreased dopamine D(2) receptor function in the mPFC. The present study was designed to further examine the involvement of mPFC dopamine D(2) receptors in cocaine sensitization. The experiments described below sought to determine the effects of acute or repeated intra-mPFC injections of the dopamine D(2) antagonist sulpiride on subsequent motor-stimulant and nucleus accumbens dopamine responses to cocaine. Rats received bilateral cannulae implants above the ventral mPFC for microinjections and above the nucleus accumbens for in vivo microdialysis. Initial studies examined the effects of intra-mPFC sulpiride pretreatment on the acute motor-stimulant and nucleus accumbens dopamine responses to cocaine. Follow-up studies determined the effects of repeated intra-mPFC sulpiride injections on subsequent behavioral and nucleus accumbens dopamine responses to a cocaine challenge. Intra-mPFC sulpiride enhanced the cocaine-induced increases in motor activity and dopamine overflow in the nucleus accumbens. Repeated intra-mPFC sulpiride induced behavioral and neurochemical cross-sensitization to cocaine. The data support previous findings that sensitization is associated with a decrease in dopamine D(2) receptor function in the mPFC.