Dopamine Release In mPFC Research Articles

Activation of type 4 dopaminergic receptors in the prelimbic area of medial prefrontal cortex is necessary for the expression of innate fear behavior

The prelimbic area (PL) of the medial Prefrontal cortex (mPFC) is involved in the acquisition and expression of conditioned and innate fear. Both types of fear share several neuronal pathways. It has been documented that dopamine (DA) plays an important role in the regulation of aversive memories in the mPFC. The exposure to an aversive stimulus, such as the smell of a predator odor or the exposure to footshock stress is accompanied by an increase in mPFC DA release. Evidence suggests that the type 4 dopaminergic receptor (D4R) is the molecular target through which DA modulates fear expression. In fact, the mPFC is the brain region with the highest expression of D4R; however, the role of D4R in the expression of innate fear has not been fully elucidated. Therefore, the principal objective of this work was to evaluate the participation of mPFC D4R in the expression of innate fear. Rats were exposed to the elevated plus-maze (EPM) and to the cat odor paradigm after the intra PL injection of L-745,870, selective D4R antagonist, to measure the expression of fear-related behaviors. Intra PL injection of L-745,870 increased the time spent in the EPM open arms and decreased freezing behavior in the cat odor paradigm. Our results also showed that D4R is expressed in GABAergic and pyramidal neurons in the PL region of PFC. Thus, D4R antagonism in the PL decreases the expression of innate fear-behavior indicating that the activation of D4R in the PL is necessary for the expression of innate fear-behavior.

Phasic dopamine release in the medial prefrontal cortex enhances stimulus discrimination

Phasic dopamine (DA) release is believed to guide associative learning. Most studies have focused on projections from the ventral tegmental area (VTA) to the striatum, and the action of DA in other VTA target regions remains unclear. Using optogenetic activation of VTA projections, we examined DA function in the medial prefrontal cortex (mPFC). We found that mice perceived optogenetically induced DA release in mPFC as neither rewarding nor aversive, and did not change their previously learned behavior in response to DA transients. However, repetitive temporal pairing of an auditory conditioned stimulus (CS) with mPFC DA release resulted in faster learning of a subsequent task involving discrimination of the same CS against unpaired stimuli. Similar results were obtained using both appetitive and aversive unconditioned stimuli, supporting the notion that DA transients in mPFC do not represent valence. Using extracellular recordings, we found that CS-DA pairings increased firing of mPFC neurons in response to CSs, and administration of D1 or D2 DA-receptor antagonists in mPFC during learning impaired stimulus discrimination. We conclude that DA transients tune mPFC neurons for the recognition of behaviorally relevant events during learning.

Regulation of Intermittent Hypoxia on Brain Dopamine in Amphetaminized Rats.

We investigated intermittent hypoxia (IH) on dopamine (DA) release in rat brain treated with or without amphetamine (AMPH). Rats were divided into four groups including normoxia, IH, AMPH, and AMPH + IH treatments. The cerebrospinal fluid (CSF) was collected and the DA levels were detected by high performance liquid chromatography (HPLC). The plasma prolactin (PRL) concentration was measured by radioimmunoassay (RIA). We found that IH reduced basal DA concentration in media prefrontal cortex (mPFC), but increased that in striatum, where DA level was also increased in rats treated with AMPH or AMPH + IH. Angiotensin II (Ang II) increased the DA release in mPFC and striatum and this effect was enhanced in AMPH + IH group. The stimulatory effect of IH on plasma PRL was attenuated in presence of AMPH. Tyrosine hydroxylase (TH) expression was decreased by IH, but increased by AMPH + IH in mPFC. IH or AMPH treatment decreased the expression of vesicular monoamine transporter-2 (VMAT-2) in rat brain. These data suggested that IH altered the DA release and changed the protein expression levels in different parts of rat brain treated with AMPH. IH may play a role in regulating DA metabolism in AMPH addiction.

Ethanol reduces evoked dopamine release and slows clearance in the rat medial prefrontal cortex.

Ethanol (EtOH) intoxication affects cognitive performance, contributing to attentional deficits and poor decision making, which may occur via actions in the medial prefrontal cortex (mPFC). mPFC function is modulated by the catecholamines dopamine and norepinephrine. In this study, we examine the acute effects of EtOH on electrically evoked dopamine release and clearance in the mPFC of anesthetized rats naïve to alcohol or chronically exposed to alcohol during adolescence. Dopamine release and clearance was evoked by electrical stimulation of the ventral tegmental area (VTA) and measured in the mPFC of anesthetized rats with fast-scan cyclic voltammetry. In Experiments 1 and 2, effects of a high dose of EtOH (4g/kg, intraperitoneally) on dopamine neurotransmission in the mPFC of EtOH-naïve rats and rats given EtOH exposure during adolescence were investigated. Effects of cumulative dosing of EtOH (0.5 to 4g/kg) on the dopamine release and clearance were investigated in Experiment 3. Experiment 4 studied effects of EtOH locally applied to the VTA on the dopamine neurotransmission in the mPFC of EtOH-naïve rats. A high dose of EtOH decreased evoked dopamine release within 10minutes of administration in EtOH-naïve rats. When tested via cumulative dosing from 0.5 to 4g/kg, both 2 and 4g/kg EtOH inhibited evoked dopamine release in the mPFC of EtOH-naïve rats, while 4g/kg EtOH also slowed dopamine clearance. A similar effect on electrically evoked dopamine release in the mPFC was observed after infusion of EtOH into the VTA. Interestingly, intermittent EtOH exposure during adolescence had no effect on observed changes in mPFC dopamine release and clearance induced by acute EtOH administration. Taken together, these data describe EtOH-induced reductions in the dynamics of VTA-evoked mPFC dopamine release and clearance, with the VTA contributing to the attenuation of evoked mPFC dopamine release induced by EtOH.

D1 receptors regulate dendritic morphology in normal and stressed prelimbic cortex.

Both stress and dysfunction of prefrontal cortex are linked to psychological disorders, and structure and function of medial prefrontal cortex (mPFC) are altered by stress. Chronic restraint stress causes dendritic retraction in the prelimbic region (PL) of mPFC in rats. Dopamine release in mPFC increases during stress, and chronic administration of dopaminergic agonists results in dendritic remodeling. Thus, stress-induced alterations in dopaminergic transmission in PL may contribute to dendritic remodeling. We examined the effects of dopamine D1 receptor (D1R) blockade in PL during daily restraint stress on dendritic morphology in PL. Rats either underwent daily restraint stress (3h/day, 10 days) or remained unstressed. In each group, rats received daily infusions of either the D1R antagonist SCH23390 or vehicle into PL prior to restraint; unstressed and stressed rats that had not undergone surgery were also examined. On the final day of restraint, rats were euthanized and brains were processed for Golgi histology. Pyramidal neurons in PL were reconstructed and dendritic morphology was quantified. Vehicle-infused stressed rats demonstrated dendritic retraction compared to unstressed rats, and D1R blockade in PL prevented this effect. Moreover, in unstressed rats, D1R blockade produced dendritic retraction. These effects were not due to attenuation of the HPA axis response to acute stress: plasma corticosterone levels in a separate group of rats that underwent acute restraint stress with or without D1R blockade were not significantly different. These findings indicate that dopaminergic transmission in mPFC during stress contributes directly to the stress-induced retraction of apical dendrites, while dopamine transmission in the absence of stress is important in maintaining normal dendritic morphology.

Decreased prefrontal cortex dopamine activity following adolescent social defeat in male rats: role of dopamine D2 receptors.

Adverse social experience in adolescence causes reduced medial prefrontal cortex (mPFC) dopamine (DA) and associated behavioral deficits in early adulthood. This study aims to determine whether mPFC DA hypofunction following social stress is specific to adolescent experience and if this results from stress-induced DA D2 receptor activation. Male rats exposed to repeated social defeat during adolescence or adulthood had mPFC DA activity sampled 17 days later. Separate experiments used freely moving microdialysis to measure mPFC DA release in response to adolescent defeat exposure. At P40, 49 and 56 mPFC DA turnover was assessed to identify when DA activity decreased in relation to the adolescent defeat experience. Finally, nondefeated adolescent rats received repeated intra-mPFC infusions of the D2 receptor agonist quinpirole, while another adolescent group received intra-mPFC infusions of the D2 antagonist amisulpride before defeat exposure. Long-term decreases or increases in mPFC DA turnover were observed following adolescent or adult defeat, respectively. Adolescent defeat exposure elicits sustained increases in mPFC DA release, and DA turnover remains elevated beyond the stress experience before declining to levels below normal at P56. Activation of mPFC D2 receptors in nondefeated adolescents decreases DA activity in a similar manner to that caused by adolescent defeat, while defeat-induced reductions in mPFC DA activity are prevented by D2 receptor blockade. Both the developing and mature PFC DA systems are vulnerable to social stress, but only adolescent defeat causes DA hypofunction. This appears to result in part from stress-induced activation of mPFC D2 autoreceptors.

Tyrosine-free amino acid mixtures reduce physiologically-evoked release of dopamine in a selective and activity-dependent manner

Depletion of the catecholamine precursor tyrosine using tyrosine-free amino acid mixtures is an important tool in neuropsychological studies, and often considered dopamine selective on the basis of neuropharmacological studies. However, little is known of the effects of tyrosine depletion when catecholamine neurons are activated physiologically. Here we investigated the effect of tyrosine-free amino acid mixtures on catecholamine release evoked in vivo using a stimulation paradigm aimed to approximate the phasic firing pattern of these neurons that accompanies cognitive and behavioural change. Dopamine and noradrenaline release was monitored by microdialysis in rat medial prefrontal cortex (mPFC) and striatum (chloral hydrate anaesthesia, perfusion medium containing 1 µM cocaine). Electrical stimulation of the medial forebrain bundle (MFB) caused a short-lasting, frequency-dependent increase in dopamine and noradrenaline. A full tyrosine-free amino acid mixture reduced the release of dopamine in mPFC and striatum, across a range of stimulation frequencies, and the effect was greater as stimulation frequency increased. Similar results were obtained using a smaller tyrosine-free amino acid mixture. In the same experiments showing decreased dopamine, neither tyrosine-free mixture of amino acids significantly altered stimulation-evoked release of noradrenaline. These results show that tyrosine depletion using tyrosine-free amino acid mixtures causes a selective, activity-dependent decrease in dopamine release when dopamine neurons are driven physiologically.

Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder

Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.

Intracerebroventricular administration of ouabain alters synaptic plasticity and dopamine release in rat medial prefrontal cortex

Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5μl of 1mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5mg/kg lithium, twice a day, 7days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which did not be affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.

Novel δ1-receptor agonist KNT-127 increases the release of dopamine and l-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex

The effects of systemic δ1-agonist on neurotransmission remains obscure, since no selective δ1-agonist exists that can penetrate the blood–brain barrier. Recently, we succeeded in synthesizing a putative δ1-receptor agonist, KNT-127, which has been demonstrated the effectiveness of systemic administration against anxiety and depressive-like behavior. To clarify the functional selectivity of KNT-127 and neurotransmission regulating system of δ1-receptor, the present study investigated the interaction between KNT-127 and δ-receptor antagonists on the release of dopamine, l-glutamate and GABA in nucleus accumbens (NAc), striatum and median pre-frontal cortex (mPFC) using multi-probe microdialysis. Intraperitoneal administration of KNT-127 increased the release of dopamine and l-glutamate in three regions, but decreased and increased GABA releases in respective NAc and mPFC without affecting that in striatum. The effects of KNT-127 in the three regions were abrogated by δ1-antagonist but not by δ2-antagonist. MK801 inhibited KNT-127-induced dopamine release in striatum and NAc, but enhanced that in mPFC, inhibited KNT-127-induced mPFC GABA release without affecting KNT-127-induced GABA reduction in NAc. Muscimol enhanced KNT-127-induced dopamine release in mPFC. Sulpiride inhibited KNT-127-induced reduction of GABA release in NAc. The results indicated that KNT-127 is a selective δ1-agonist, and suggested that δ1-receptor directly activates the release of dopamine and l-glutamate in the striatum, NAc and mPFC, but not that of GABA in the three regions. δ1-receptor indirectly inhibited GABA release in NAc via activated dopaminergic transmission, while δ1-receptor indirectly enhanced GABA release in mPFC via activated glutamatergic transmission.

Dopamine D2 and serotonin 5-HT1A receptors mediate the actions of aripiprazole in mesocortical and mesoaccumbens transmission

The antipsychotic agent aripiprazole acts as a partial agonist of dopamine D2 and serotonin 5-HT1A receptors. However, the detailed actions of aripiprazole in mesolimbic and mesocortical transmission remain to be clarified. To address this, we examined the effects of systemic and local administrations of aripiprazole on extracellular levels of dopamine and GABA in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and anterior (aVTA) and posterior (pVTA) ventral tegmental areas. Intraperitoneal injection of aripiprazole (0.5 mg/kg) increased dopamine release in mPFC without affecting those in aVTA, pVTA, or NAc, whereas 10 mg/kg decreased the release in all four regions. Local sulpiride administration in aVTA increased concentration-dependently dopamine release in both aVTA and NAc without affecting that in mPFC, whereas local aripiprazole administration in aVTA concentration-dependently decreased dopamine release in aVTA and mPFC without affecting that in NAc. Blockade of 5-HT1A receptor in aVTA produced aripiprazole-induced dopamine release in aVTA and prevented the aripiprazole-induced reduction of dopamine release in mPFC. Local administration of aripiprazole in mPFC increased dopamine and decreased GABA releases, whereas local administration of sulpiride had no effect on dopamine or GABA. In mPFC, blockade of 5-HT1A receptor prevented the aripiprazole-induced dopamine elevation and GABA reduction; however, under the activation of GABA A receptor, local perfusion with aripiprazole in mPFC decreased GABA release without affecting dopamine release. The results suggested that the combination of 5-HT1A and D2 partial agonistic actions of aripiprazole against mesocortical and mesoaccumbens transmission, explains, at least in part, the atypical antipsychotic properties of aripiprazole. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Connecting the dots of the cerebro‐cerebellar role in cognitive function: Neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex

Cerebellar involvement in autism, schizophrenia, and other cognitive disorders is typically associated with prefrontal cortical pathology. However, the underlying neuronal mechanisms are largely unknown. It has previously been shown in mice that stimulation of the dentate nucleus (DN) of the cerebellum evokes dopamine (DA) release in the medial prefrontal cortex (mPFC). Here, we investigated the neuronal circuitry by which the cerebellum modulates mPFC DA release. Fixed potential amperometry was used to determine the contribution of two candidate pathways by which the cerebellum may modulate mPFC DA release. In urethane anesthetized mice, DA release evoked by DN stimulation (50 Hz) was recorded in mPFC following local anesthetic lidocaine (0.02 μg) or ionotropic glutamate receptor antagonist kynurenate (0.5 μg) infusions into the mediodorsal or ventrolateral thalamic nucleus (ThN md; ThN vl), or the ventral tegmental area (VTA). Following intra-VTA lidocaine or kynurenate infusions, DA release was decreased by ∼50%. Following intra-ThN md and ThN vl infusions of either drug, DA release was decreased by ∼35% and 15%, respectively. Reductions in DA release following lidocaine or kynurenate infusions were not significantly different indicating that neuronal cells in the VTA and ThN were activated primarily if not entirely by glutamatergic inputs. The present study suggests that neuropathological changes in the cerebellum commonly observed in autism, schizophrenia, and other cognitive disorders could result in a loss of functionality of cerebellar-mPFC circuitry that is manifested as aberrant dopaminergic activity in the mPFC. Additionally, these results specifically implicate glutamate as a modulator of mPFC dopaminergic activity.

In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain

Aripiprazole is an atypical antipsychotic drug with high in vitro affinity for 5-HT(1A), 5-HT(2A) and dopamine (DA) D2 receptors. However, its in vivo actions in the brain are still poorly characterized. The aim was to study the in vivo actions of aripiprazole in the rat and mouse brain. Brain microdialysis and single-unit extracellular recordings were performed. The systemic administration of aripiprazole reduced 5-HT output in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus of the rat. Aripiprazole also reduced extracellular 5-HT in the mPFC of wild-type (WT) but not of 5-HT(1A) (-/-) knockout (KO) mice. Aripiprazole reversed the elevation in extracellular 5-HT output produced by the local application of the 5-HT(2A/2C) receptor agonist DOI in mPFC. Aripiprazole also increased the DA output in mPFC of WT but not of 5-HT(1A) KO mice, as observed for atypical antipsychotic drugs, in contrast to haloperidol. Contrary to haloperidol, which increases the firing rate of DA neurons in the ventral tegmental area (VTA), aripiprazole induced a very moderate reduction in dopaminergic activity. Haloperidol fully reversed the inhibition in dopaminergic firing rate induced by apomorphine, whereas aripiprazole evoked a partial reversal that was significantly different from that evoked by haloperidol and from the spontaneous reversal of dopaminergic activity in rats treated with apomorphine. These results indicate that aripiprazole modulates the in vivo 5-HT and DA release in mPFC through the activation of 5-HT(1A) receptors. Moreover, aripiprazole behaves as a partial agonist at DA D2 autoreceptors in vivo, an action which clearly distinguishes it from haloperidol.

κ opioids selectively control dopaminergic neurons projecting to the prefrontal cortex

Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. Kappa opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of kappa opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.

Effects of ketamine and n-methyl- d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268

Previous studies have shown that the metabotropic glutamate receptor (mGluR)2/3 agonist LY354740 attenuated glutamate release in medial prefrontal cortex (mPFC) induced by the non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist phencyclidine. In the present study we examined the effects of the more potent mGluR2/3 selective agonist LY379268 on ketamine-evoked glutamate and dopamine (DA) release in mPFC of male rats. Subjects were implanted with a unilateral microdialysis probe in the mPFC and were tested 12–24 h after implantation. Ketamine (18 mg/kg, s.c.) evoked a significant release of glutamate and DA, although the glutamate response was slower in onset compared with DA. Pretreatment with either systemic (3 mg/kg s.c.) or local (1 μM, in the probe) LY379268 blocked ketamine-evoked glutamate, but not DA, release. When applied directly to the mPFC via the dialysis probe, ketamine (1 mM in the probe) had no effect on glutamate release but did significantly enhance the release of DA. Application of NMDA (500 μM in the probe), on the other hand, decreased DA while increasing glutamate release. The effect of NMDA on evoking glutamate release was blocked by systemic but not local administration of LY379268. These findings indicate that systemic ketamine increases both glutamate and DA release in mPFC and that the effect on glutamate can be blocked by stimulating mPFC group II mGluR receptors. Local ketamine, on the other hand, does not increase glutamate but does increase DA release. This suggests that ketamine acts outside of the mPFC to enhance glutamate, but within the mPFC to enhance DA release. The origin of the ketamine effect on mPFC glutamate is currently not known.

SR46349-B, a 5-HT2A/2C Receptor Antagonist, Potentiates Haloperidol-induced Dopamine Release in Rat Medial Prefrontal Cortex and Nucleus Accumbens

The combination of M100907, a putative antipsychotic drug (APD) and serotonin (5-HT)2A antagonist, and the typical APD haloperidol, can enhance dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect which has been postulated to be of value to improve cognition and negative symptoms. The present study demonstrated that another putative APD and 5-HT2A/2C antagonist, SR46349-B (10 mg/kg, but not 1–3 mg/kg) alone, but not M100907 (0.1 and 3 mg/kg) alone, increased mPFC DA release, whereas neither drug alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. SR46349-B (3 mg/kg) potentiated haloperidol-induced DA release in both regions, whereas M100907 (0.1 mg/kg) potentiated haloperidol (0.1 mg/kg)-induced mPFC DA release and inhibited it in the NAC. WAY100635 (0.2 mg/kg), a 5-HT1A antagonist, abolished the effects of haloperidol plus M100907 as well as SR46349-B on DA release in the mPFC, but did not do so in the NAC. Thus, 5-HT2A and 5-HT2A/2C antagonism together with haloperidol-induced D2 antagonism may potentiate mPFC DA release via 5-HT1A agonism, whereas the combined effects of these agents on NAC DA release is not dependent upon 5-HT1A receptor stimulation. Interestingly, similar to the effect of SR46349-B, high dose M100907 (3 mg/kg), which might have antagonist activity at 5-HT2C receptors, potentiated 1 mg/kg haloperidol-induced DA release in the mPFC and NAC. These results suggest that 5-HT2A/2C antagonism may be more advantageous than selective 5-HT2A antagonism as an adjunct to D2 antagonists to improve cognition and negative symptoms in schizophrenia.

5-HT 2A receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner

Combined serotonin (5-HT) 2A and dopamine (DA) D 2 blockade has been shown to contribute to the ability of atypical antipsychotic drugs (APDs) to increase DA release in rat medial prefrontal cortex (mPFC). We provide additional support for this hypothesis by examining the effect of the selective 5-HT 2A antagonist M100907 plus haloperidol, a potent D 2 antagonist APD, on DA release in the mPFC and nucleus accumbens (NAC). Haloperidol (0.01–1.0 mg/kg) produced an inverted U-shaped increase in DA release in the mPFC, with a significant increase only at 0.1 mg/kg. Haloperidol (0.1 and 1.0 mg/kg) significantly increased DA release in the NAC. M100907 (0.1 mg/kg) by itself had no effect on DA release in either region. This dose of M100907 potentiated the ability of low (0.01–0.1 mg/kg), but not high dose (0.3–1.0 mg/kg) haloperidol to increase mPFC DA release, whereas it abolished the effect of both 0.1 and 1.0 mg/kg haloperidol on NAC DA release. These results suggest that the relatively higher ratio of 5-HT 2A to D 2 antagonism may contribute to the potentiation of haloperidol-induced mPFC DA release, whereas 5-HT 2A antagonism can diminish haloperidol-induced NAC DA release, even when combined with extensive D 2 antagonism, which may not be synergistic with 5-HT 2A antagonism in the mPFC.

DOI, a 5-HT 2A/2C receptor agonist, attenuates clozapine-induced cortical dopamine release

(±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 1.25, 2.5 and 5 mg/kg), a serotonin (5-HT) 2A/2C agonist, produced an inverted U-shaped increase in DA release in rat medial prefrontal cortex (mPFC) with a significant effect only at 2.5 mg/kg. This effect was completely abolished by M100907 (0.1 mg/kg), a 5-HT 2A antagonist, and WAY100635 (0.2 mg/kg), a 5-HT 1A antagonist, neither of which when given alone affected dopamine release. DOI (2.5 mg/kg), but not the 5-HT 2C agonist Ro 60-0175 (3 mg/kg), attenuated clozapine (20 mg/kg)-induced mPFC dopamine release. These results suggest that 5-HT 2A receptor stimulation increases basal cortical dopamine release via 5-HT 1A receptor stimulation, and inhibits clozapine-induced cortical dopamine release by diminishing 5-HT 2A receptor blockade.

5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release.

Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)(2A) than dopamine D(2) antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT(1A) agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT(1A) receptor activation, as a result of the blockade of 5-HT(2A) and D(2) receptors. M100907 (0.1 mg/kg), a 5-HT(2A) antagonist, significantly increased the ability of both S:(-)-sulpiride (10 mg/kg), a D(2) antagonist devoid of 5-HT(1A) affinity, and R:(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT(1A) agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT(1A) antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R:(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT(1A) partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT(2A) and D(2) receptor blockade, regardless of intrinsic 5-HT(1A) affinity, may promote the ability of 5-HT(1A) receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT(2A) antagonists and typical APDs, which are D(2) antagonists, may facilitate 5-HT(1A) agonist activity.