Clozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus rat

Clozapine is widely used in the treatment of schizophrenia; however its complete mechanism of action is not fully established. The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior. Our group has previously shown hyperresponsiveness to novel environment, neuronal atrophy in prefrontal cortex (PFC) and nucleus accumbens (NAcc) neurons as well as abnormal levels of nitric oxide (NO) in the PFC of the nVHL rat. In the present study, we aimed to investigate the role of repeated clozapine administration (2 mg/kg/day for 21 days) in a novel environment, neuronal rearrangement in PFC, NAcc and basolateral amygdala (BLA) as well as NO levels in this model. Clozapine administration reversed the hyperlocomotion observed in a novel environment in the nVHL rat with no effect on locomotion in sham animals. Quantitative morphological analysis demonstrated a retracted neuronal arborization and decreased spinogenesis in the NAcc, PFC and BLA in nVHL rat. Interestingly, clozapine administration also rescued neuronal atrophy in these brain regions. The nVHL also displayed increased NO levels in PFC, striatum and occipital cortex. Clozapine administration selectively reversed these abnormal levels of NO in striatum in nVHL rat while NO levels were increased in the PFC of sham animals. Our results further extend the usefulness of the nVHL as a model of schizophrenia-related behavior and suggest that clozapine reverses behavioral deficits in these animals by modulating neuronal reorganization and NO levels in the brain.     

Cocaine-induced increases in medial prefrontal cortical GABA transmission involves glutamatergic receptors

A recent study showed that cocaine-induced sensitization is associated with an increase in GABA (gamma-aminobutyric acid) transmission in the medial prefrontal cortex. Since previous studies have demonstrated that sensitization is associated with enhanced medial prefrontal cortex glutamatergic transmission, the present study examined the role of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate (AMPA/KA) receptors in cocaine-induced increases in medial prefrontal cortex GABA levels. Male Sprague-Dawley rats received four daily injections of saline (1 ml/kg, i.p.) or cocaine (15 mg/kg). One day later, animals were infused with NMDA or AMPA/KA antagonists 3-[(R)-2 carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) and 6,7-dinitroquinoxaline-2,3-dione (DNQX), respectively, into medial prefrontal cortex via microdialysis probe for 60 min before receiving systemic challenge injections of saline or cocaine. Cocaine-sensitized animals showed an increase in extracellular medial prefrontal cortex GABA levels that was blocked by prior medial prefrontal cortex infusion of DNQX, but not CPP. These data indicate that enhanced medial prefrontal cortex GABA transmission seen in cocaine-sensitized animals involves glutamatergic stimulation of AMPA receptors.     

Medial prefrontal cortical alpha<Subscript>1</Subscript> adrenoreceptor modulation of the nucleus accumbens dopamine response to stress in Long–Evans rats

Rationale The medial prefrontal cortex (PFC) receives stress-sensitive dopamine (DA) and noradrenergic (NE) projections from the ventral tegmental area and locus coeruleus, respectively, and evidence from various sources point to a complex functional interaction between these two systems. Stress will also stimulate DA transmission in the nucleus accumbens (NAcc), and our previous work has shown that this response is under the indirect inhibitory control of a DA-sensitive mechanism in PFC. Objective We examined the possibility that the NAcc DA stress response is also modulated by prefrontal cortical NE. Materials and methods We used voltammetry to study in freely behaving rats the effects of local applications of alpha₁ (benoxathian 0.1, 1, 10 nmol), alpha₂ (SKF86466), and beta_1/2 (alprenolol) receptor selective antagonists into the PFC on the NAcc DA response to tail-pinch stress. Results The NAcc DA stress response was dose-dependently inhibited by local PFC blockade of alpha₁ receptors. Additional tests revealed, however, that the DA stress response in NAcc is unaffected after local alpha₁ receptor activation with cirazoline. Furthermore, at equivalent doses, neither alpha₂ nor beta_1/2 receptor blockade significantly affected the NAcc DA stress response. Conclusions These data indicate that stress-induced activation of subcortical DA transmission is modulated by the NE input to PFC acting at alpha₁ receptors. They suggest that, under normal circumstances, this system exerts a facilitatory or enabling influence on the NAcc DA stress response.     

Brain Rewarding Stimulation Reduces Extracellular Glutamate Through Glial Modulation in Medial Prefrontal Cortex of Rats

Growing evidence implicates a critical involvement of prefrontal glial modulation of extracellular glutamate (GLU) in aversive behaviors. However, nothing is known about whether prefrontal glial cells modulate GLU levels in rewarding behaviors. To address this question, we measured GLU efflux in the medial prefrontal cortex (PFC) of rats associated with rewarding behaviors. We used intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB) as the rewarding behavior. GLU was indirectly measured using microdialysis combined with on-line fluorometric detection of NADH resulting from the reaction of GLU and NAD⁺ catalyzed by GLU dehydrogenase with a time resolution of 1 min. ICSS caused a minute-by-minute change of extracellular GLU in the medial PFC, with a slight decrease during the stimulation, followed by an increase afterward. This bidirectional change was tetrodotoxin insensitive and abolished by the gliotoxin fluorocitrate. To confirm and extend the previous studies of aversion-induced increase of extracellular GLU in the medial PFC, we also measured prefrontal GLU efflux associated with an aversive stimulation, immobilization stress. The temporal change in extracellular GLU caused by this stress was markedly different from that observed during ICSS. A rapid increase in GLU was detected during the aversive stimulation, followed by a large increase afterward. This bimodal change was tetrodotoxin insensitive, similar to that detected for ICSS. These findings indicate a bidirectional regulation of extracellular GLU by prefrontal glial cells associated with rat ICSS behavior, and reveal that glial modulation of GLU neurochemistry in the medial PFC contributes to rewarding as well as aversive behaviors in rats.     

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics

Rationale Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior.Objectives Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients.Methods We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded.Results Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning.Conclusions This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.     

Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning.

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.     

The role of afferents to the locus coeruleus in the handling stress-induced increase in the release of noradrenaline in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain

This study was aimed to identify the neuronal pathways that mediate the handling stress-induced increase in the release of noradrenaline in the medial prefrontal cortex of the rat brain. For that purpose a microdialysis probe was implanted in the vicinity of the locus coeruleus and a second probe was placed in the ipsilateral medial prefrontal cortex. Receptor specific antagonists acting on the alpha(2)-adrenoceptor (50 microM idazoxan), GABA(A) (50 microM bicuculline), GABA(B) (100 microM (3, 4-Dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid; CGP 52432), acetylcholine (10 microM atropine), corticotropin releasing factor (CRF) (100 microM butyl-ethyl-[2,5-dimethyl-7-(2,4, 6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine; CP-154, 526), NMDA glutamate (300 microM (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; CPP) and non-NMDA glutamate receptors (500 microM 6,7-dinitroquinoxaline-2, 3-dione; DNQX) were infused into the locus coeruleus by retrograde dialysis, whereas extracellular noradrenaline was recorded in the ipsilateral medial prefrontal cortex. During infusion of the various compounds rats were gently handled for 10 min. Infusion of idazoxan potentiates the handling-induced increase in the release of noradrenaline in the medial prefrontal cortex. The infusions of, atropine, bicuculline, CGP 52432 and DNQX were without effect on the handling response. Infusion of the NMDA receptor antagonist CPP or the non-peptide CRF receptor antagonist CP-154,526 suppressed the stimulation of noradrenaline during stress. It is concluded that alpha(2)-adrenoceptors, NMDA glutamate receptors and CRF receptors modify the handling stress response of locus coeruleus neurones. The data suggest no major role for glutamatergic, GABAergic, or cholinergic afferents to the locus coeruleus in mediating the stress response.     

Chronic haloperidol administration increases the density of D2 dopamine receptors in the medial prefrontal cortex of the rat

Rats received haloperidol (1.3–1.5 mg/kg/day) via their drinking water for 21 weeks. At the end of this period the density of D2 dopamine receptors and their affinity for [³H]-spiperone were measured in the striatum and medial prefrontal cortex. The chronic haloperidol treatment increased the density of D2 receptors in the striatum by 70% and in the medial prefrontal cortex by 50%. The chronic haloperidol did not significantly alter the apparent affinity of D2 receptors for [³H]-spiperone in either structure. These results indicate that the density of D2 receptors in the medial prefrontal cortex is influenced by chronic exposure to haloperidol in a manner that is very similar to the well-documented increase that occurs in the striatum.     

Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats

Rationale. Environmental stimuli previously paired with cocaine can induce craving in humans and reinstate extinguished cocaine-seeking behavior in laboratory animals. Previous evidence has implicated the amygdala and the prefrontal cortex (PFC) as possible substrates for conditioned-cued relapse. Objectives. In order to test directly the role of the PFC in a model of relapse, the present study examined the effects of reversible inactivation of three medial PFC areas, the anterior cingulate (ACing), the prelimbic cortex (PL), and the infralimbic cortex (IL), on the expression of conditioned-cued reinstatement of extinguished cocaine-seeking behavior. We also tested the involvement of the basolateral amygdala (BLA) and the parietal cortex immediately dorsal to the BLA, sensory cortex area 1 – barrel field (S1BF). Methods. During daily 3-h sessions, rats pressed a lever for IV cocaine infusions that were paired with a light-tone (LT) presentation. Following extinction of lever pressing in the absence of the LT, reinstatement of extinguished lever pressing was measured during response-contingent presentations of the LT in the absence of cocaine. For localized reversible inactivation, tetrodotoxin (TTX) (5 ng/0.5 μl/side) or vehicle was bilaterally infused just prior to reinstatement testing. Results. TTX inactivation of the BLA, ACing, or PL impaired the ability of LT presentations to reinstate extinguished lever pressing for cocaine-paired stimuli. In contrast, inactivation of the IL or the S1BF had no effect on conditioned-cued reinstatement. Furthermore, there was no effect of TTX in any of the tested brain regions on general locomotor activity. Conclusions. These results support a role for the dorsomedial PFC and the BLA in the circuitry that mediates drug-seeking behavior elicited by cocaine-associated stimuli. Placed within the context of recent studies using drug-primed and stress-induced reinstatement models, we suggest that the dorsomedial PFC may serve as a common link in the neural circuitry underlying reinstatement of drug-seeking behavior.     

Medial prefrontal serotonin in the rat is involved in goal-directed behaviour when affect guides decision making

Rationale Across species, serotonin (5-HT) depletion in the prefrontal cortex (PFC) has been shown to cause impaired performance on tests of cognitive flexibility and the processing of affective information (e.g. information with an ‘emotional’ content). While recent work has explored the specific role of the orbital PFC herein, the role of the medial PFC remains unclear. Objectives The aim of our current experiments was to study the role of medial PFC 5-HT in both the processing of affective information and reversal learning across stimulus modalities. Materials and methods To this end, we selectively destroyed 5-HT terminals in the medial PFC of male Wistar rats by means of local infusion of the toxin 5,7-dihydroxytryptamine. Both control and lesioned animals were tested in two reversal learning paradigms with either spatial or odour cues and an affective switch from non-preferred to preferred food rewards. Results Our results indicate that a pellet switch during reversal learning impaired performance in control animals but not in lesioned animals, independent of the stimulus modality. Conclusion These results indicate that lesioned animals are not guided in their behaviour by the affective value of the reward like intact animals and thus that medial prefrontal 5-HT is needed for affective processing in goal-directed behaviour.     

1H MRS-detectable metabolic brain changes and reduced impulsive behavior in adult rats exposed to methylphenidate during adolescence

Administration of methylphenidate (MPH, Ritalin) to children affected by attention deficit hyperactivity disorder (ADHD) is an elective therapy, which however raises concerns for public health, due to possible persistent neuro-behavioral alterations. We investigated potential long-term consequences at adulthood of MPH exposure during adolescence, by means of behavioral and brain MRS assessment in drug-free state. Wistar adolescent rats (30- to 44-day-old) were treated with MPH (0 or 2 mg/kg once/day for 14 days) and then left undisturbed until adulthood. Levels of impulsive behavior were assessed in the intolerance-to-delay task: Food-restricted rats were tested in operant chambers with two nose-poking holes, delivering one food pellet immediately, or five pellets after a delay whose length was increased over days. MPH-exposed animals showed a less marked shifting profile from the large/late to the small/soon reward, suggesting reduced basal levels of impulsivity, compared to controls. In vivo MRI-guided 1H MRS examinations at 4.7 T in anaesthetised animals revealed long-term biochemical changes in the dorsal striatum (STR), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of MPH-exposed rats. Notably, total creatine and taurine, metabolites respectively involved in bioenergetics and synaptic efficiency, were up-regulated in the STR and conversely down-regulated in the NAcc of MPH-exposed rats. A strong correlation was evident between non-phosphorylated creatine in the STR and behavioral impulsivity. Moreover, unaltered total creatine and increased phospho-creatine/creatine ratio were detected in the PFC, suggesting improved cortical energetic performance. Because of this enduring rearrangement in the forebrain function, MPH-exposed animals may be more efficient when faced with delay of reinforcement. In summary, MPH exposure during adolescence produced enduring MRS-detectable biochemical modifications in brain reward-related circuits, which may account for increased self-control capacity of adult rats.     

Neurotensin receptor antagonist SR 142948A alters Fos expression and extrapyramidal side effect profile of typical and atypical antipsychotic drugs.

Antipsychotic drugs (APDs) have previously been shown to alter Fos expression in a regionally specific manner. Increases in Fos expression in the nucleus accumbens (NAcc) are common to all clinically effective APDs. In contrast, APD-induced Fos expression increases in the caudate-putamen (CPu) and prefrontal cortex (PFC) are associated with the extrapyramidal side effect liability of typical APDs or the effectiveness against negative symptoms of atypical APDs, respectively. Considerable evidence suggests that the neuropeptide neurotensin (NT) mediates some of the effects of APDs. To determine whether NT neurotransmission is also involved in APD-induced Fos expression in brain regions relevant for therapeutic efficacy, the NT receptor antagonist SR 142948A (10 or 100 microg/kg i.p.) was coadministered with APDs (haloperidol (2.0 mg/kg s.c.), olanzapine (5 mg/kg i.p.), or clozapine (20 mg/kg s.c.)). Fos expression was evaluated in the PFC, NAcc shell, dorsomedial, and dorsolateral CPu and the lateral septum. SR 142948A attenuated haloperidol-induced Fos expression in the CPu but, in contrast, increased olanzapine-induced Fos expression in this brain region. The effects of the NT receptor antagonist were paralleled by its effects on catalepsy in olanzapine--but not haloperidol--treated animals.     

S-norfluoxetine microinfused into the basolateral amygdala increases allopregnanolone levels and reduces aggression in socially isolated mice

A decrease of brain allopregnanolone biosynthesis may play a role in emotion, impulsive behavior, and anxiety spectrum disorders by decreasing GABAergic neurotransmission. In male mice, four weeks of social isolation induces behavioral dysfunctions such as aggression, fear, and anxiety-like behavior associated with a decrease in allopregnanolone biosynthesis in selected corticolimbic structures comprising the basolateral amygdala (BLA), olfactory bulb, hippocampus, and medial prefrontal cortex. Importantly, no decrease in allopregnanolone biosynthesis has been found in the striatum and cerebellum. Given the importance of the amygdaloid complex in emotional behavior, we hypothesized that this brain area may play a pivotal role in decreasing social isolation-induced aggression. Thus, socially isolated mice were directly infused with S-norfluoxetine (S-NFLX) or pregnanolone (an analog of allopregnanolone) into the BLA and striatum. When S-NFLX (2.5, 3.75, and 5 nmol/0.2 μl) or pregnanolone (1.25, 2.5, 3.75, and 5.0 nmol/0.2 μl) is directly infused into the BLA, these agents dose-dependently reduced aggression (S-NFLX up to 93% and pregnanolone up to 96%) of a socially isolated mouse to a same-sex intruder. However, S-NFLX (3.75 and 5 nmol) infused directly into the striatum failed to alter aggression. Allopregnanolone content in the BLA after S-NFLX (3.75 nmol) infusion was increased by 3-fold and in the hippocampus, by 80%. Allopregnanolone levels did not change in the olfactory bulb or in the frontal cortex of the same mice. S-NFLX (3.75 nmol) infused into the striatum failed to increase the levels of allopregnanolone. These results suggest that S-NFLX, acting as a selective brain steroidogenic stimulant (SBSS), increases corticolimbic allopregnanolone levels and regulates aggression, which underscores the pivotal role of the BLA and hippocampus in the regulation of aggressiveness in socially isolated mice. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

The prefrontal cortex and (uniquely) human cooperation: a comparative perspective

Humans have an exceptional ability to cooperate relative to many other species. We review the neural mechanisms supporting human cooperation, focusing on the prefrontal cortex. One key feature of human social life is the prevalence of cooperative norms that guide social behavior and prescribe punishment for noncompliance. Taking a comparative approach, we consider shared and unique aspects of cooperative behaviors in humans relative to nonhuman primates, as well as divergences in brain structure that might support uniquely human aspects of cooperation. We highlight a medial prefrontal network common to nonhuman primates and humans supporting a foundational process in cooperative decision-making: valuing outcomes for oneself and others. This medial prefrontal network interacts with lateral prefrontal areas that are thought to represent cooperative norms and modulate value representations to guide behavior appropriate to the local social context. Finally, we propose that more recently evolved anterior regions of prefrontal cortex play a role in arbitrating between cooperative norms across social contexts, and suggest how future research might fruitfully examine the neural basis of norm arbitration.Subject terms: Social neuroscience, Decision     

Topographical distribution of possible glutamatergic pathways from the frontal cortex to the striatum and substantia nigra in rats

The topographical distribution of putative glutamatergic projections from the frontal cortex to the striatum and substantia nigra has been examined by measuring the high-affinity uptake of [¹⁴C]glutamate in synaptosomal preparations from rat anterior or posterior striatum and substantia nigra after a series of focal kainic acid lesions of the medial prefrontal cortex. The recorded changes in glutamate uptake suggest that the corticonigral glutamatergic projection arises from the rostral medial prefrontal areas, more caudal cortical areas projecting in turn to the anterior and posterior striatum.     

Electrical stimulation of rat medial prefrontal cortex enhances forebrain serotonin output: implications for electroconvulsive therapy and transcranial magnetic stimulation in depression.

Decreased activity of the prefrontal cortex (PFC), as well as reduced serotonergic neurotransmission, is considered as a characteristic feature of major depression. The mechanism by which electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) achieve their antidepressant effects may involve changes in PFC activity. It is, however, still unclear whether these changes are accompanied by increased synaptic availability of serotonin (5-HT). In the present study, 5-HT efflux in the rat ventral hippocampus and amygdala was analyzed using in vivo microdialysis during low-current electrical stimulation of PFC and other cortical regions. Electrical stimulation of the medial PFC produced current-dependent increases in limbic 5-HT output in both urethane-anesthetized and behaving rats. No effects on 5-HT levels were seen after comparable stimulation of either the lateral parts of the PFC, the medial precentral area, the primary motor cortex or the parietal cortex. This pronounced regional specificity of the effect of medial PFC stimulation on limbic 5-HT output suggests that activation of this particular area might play a crucial role in such antidepressant treatments as ECT and TMS.     

Human and Rodent Homologies in Action Control: Corticostriatal Determinants of Goal-Directed and Habitual Action

Recent behavioral studies in both humans and rodents have found evidence that performance in decision-making tasks depends on two different learning processes; one encoding the relationship between actions and their consequences and a second involving the formation of stimulus–response associations. These learning processes are thought to govern goal-directed and habitual actions, respectively, and have been found to depend on homologous corticostriatal networks in these species. Thus, recent research using comparable behavioral tasks in both humans and rats has implicated homologous regions of cortex (medial prefrontal cortex/medial orbital cortex in humans and prelimbic cortex in rats) and of dorsal striatum (anterior caudate in humans and dorsomedial striatum in rats) in goal-directed action and in the control of habitual actions (posterior lateral putamen in humans and dorsolateral striatum in rats). These learning processes have been argued to be antagonistic or competing because their control over performance appears to be all or none. Nevertheless, evidence has started to accumulate suggesting that they may at times compete and at others cooperate in the selection and subsequent evaluation of actions necessary for normal choice performance. It appears likely that cooperation or competition between these sources of action control depends not only on local interactions in dorsal striatum but also on the cortico-basal ganglia network within which the striatum is embedded and that mediates the integration of learning with basic motivational and emotional processes. The neural basis of the integration of learning and motivation in choice and decision-making is still controversial and we review some recent hypotheses relating to this issue.     

Abnormal Responses to Monetary Outcomes in Cortex, but not in the Basal Ganglia, in Schizophrenia

Psychosis has been associated with aberrant brain activity concurrent with both the anticipation and integration of monetary outcomes. The extent to which abnormal reward-related neural signals can be observed in chronic, medicated patients with schizophrenia (SZ), however, is not clear. In an fMRI study involving 17 chronic outpatients with SZ and 17 matched controls, we used a monetary incentive delay (MID) task, in which different-colored shapes predicted gains, losses, or neutral outcomes. Subjects needed to respond to a target within a time window in order to receive the indicated gain or avoid the indicated loss. Group differences in blood-oxygen-level-dependent responses to cues and outcomes were assessed through voxel-wise whole-brain analyses and regions-of-interest analyses in the neostriatum and prefrontal cortex (PFC). Significant group by outcome valence interactions were observed in the medial and lateral PFC, lateral temporal cortex, and amygdalae, such that controls, but not patients, showed greater activation for gains, relative to losses. In the striatum, neural activity was modulated by outcome magnitude in both groups. Additionally, we found that ratings of negative symptoms in patients correlated with sensitivity to obtained losses in medial PFC, obtained gains in lateral PFC, and anticipated gains in left ventral striatum. Sensitivity to obtained gains in lateral PFC also correlated with positive symptom scores in patients. Our findings of systematic relationships between clinical symptoms and neural responses to stimuli associated with rewards and punishments offer promise that reward-related neural responses may provide sensitive probes of the effectiveness of treatments for negative symptoms.     

Regional differences in the effect of haloperidol and atypical neuroleptics on interstitial levels of DOPAC in the rat forebrain: an in vivo microdialysis study

The effect of 'typical' and 'atypical' neuroleptics on interstitial levels of the dopamine metabolite 3,4- dihydroxyphenylacetic acid ([DOPAC]e) in the dorsolateral striatum (DLSt), the nucleus accumbens (NAc) and the medial prefrontal cortex (PFC) was investigated in awake rats by use of the microdialysis technique. All neuroleptics increased [DOPAC]e in the DLSt, NAc and in PFC. However, the 'atypical' neuroleptics clozapine, risperidone, sertindole and NNC 22-0031 showed an apparent cortical selectivity by preferentially elevating [DOPAC]e in the PFC compared with the DLSt and NAc, a feature which was not observed with the 'typical' neuroleptic haloperidol. Our data suggest that 'atypical' neuroleptics can be differentiated from the 'typical' neuroleptic, haloperidol, with respect to their ability to increase [DOPAC]e in PFC relative to DLSt and NAc.     

Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit

Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical–subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.