Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation

Mirtazapine has a low affinity for 5-HT(1A) receptors but shows 5-HT(1A)-agonistic-like effects in behavioral pharmacology test. However, there is to date no clear evidence that mirtazapine enhances 5-HT(1A) neurotransmission. The object of the present study was to assess the effects of mirtazapine on dialysate levels of dopamine and 5-HT in the medial frontal cortex of freely moving rats and to determine whether this drug could modulate 5-HT(1A) neurotransmission. In vivo microdialysis was used to study the effects of mirtazapine on extracellular dopamine and 5-HT levels, and the effect of the 5-HT(1A) antagonist WAY100,356 on extracellular dopamine level increased by mirtazapine in the rat prefrontal cortex. Mirtazapine (4-16 mg/kg, i.p.) produced a dose-dependent increase in extracellular dopamine levels in the medial prefrontal cortex (mPFC) of freely moving rats without modifying those of 5-HT. In the presence of the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-cyclohexane-carboxamide (WAY100,635; 0.3 mg/kg; i.p.), the influence of mirtazapine on cortical levels of dopamine was markedly attenuated. These results indicate that mirtazapine induces the enhancement of the output of cortical dopamine mediated via blockade of alpha(2)-adrenergic receptors and facilitation of post-synaptic 5-HT(1A) function.     

The effect of serotonin1A receptor agonism on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens

Serotonin (5-HT)_1A receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms (EPS) of antipsychotic drugs (APD) based, in part, on the effect of 5-HT_1A receptor stimulation on the release of dopamine (DA) in the nucleus accumbens (NAC) and striatum (STR), respectively. We investigated the effect of R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin (R(+)-8-OH-DPAT) and n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT_1A receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, R(+)-8-OH-DPAT (0.2 mg/kg) decreased basal DA release; R(+)-8-OH-DPAT (0.05 mg/kg) inhibited DA release produced by the 5-HT_2A/D₂ receptor antagonists clozapine (20 mg/kg), low dose risperidone (0.01 and 0.03 mg/kg) and amperozide (10 mg/kg), but not that produced by high dose risperidone (0.1 and 1.0 mg/kg) or haloperidol (0.01–1.0 mg/kg), potent D₂ receptor antagonists. This R(+)-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 (0.05 mg/kg). WAY100635 (0.1–0.5 mg/kg) alone increased DA release in the STR but not NAC. The selective 5-HT_2A receptor antagonist M100907 (1 mg/kg) did not alter the effect of R(+)-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT_1A receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT_2A receptors. The significance of these results for EPS and antipsychotic action is discussed.     

5-HT 2A receptor stimulation by DOI,a 5-HT 2A/2C receptor agonist,potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

(+/-)-([1-(2,5-Dimethoxy-4-iodophenyl)-aminopropane]-hydrochloride) (DOI) (2.5 mg/kg), a 5-HT(2A/2C) agonist, significantly potentiated D-amphetamine (AMPH) (1 mg/kg)-induced dopamine (DA) release in rat medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). This effect of DOI was completely prevented by M100907 (1 mg/kg), a selective 5-HT(2A) antagonist, which by itself had no effect on basal and AMPH-induced DA release in either region. Thus, 5-HT(2A) receptor agonism potentiates AMPH-induced DA release in the mPFC and NAC.     

The 5-HT1A receptor antagonist (S)-UH-301 decreases dopamine release in the rat nucleus accumbens and striatum

Summary In this study we employed in vivo microdialysis to examine the effects of the selective 5-HT_1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301] on extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens (NAC) and dorsal striatum of awake freely moving rats. Systemic administration of (S)-UH-301 (1.25, 2.5, 5.0mg/kg s.c.) dose-dependently decreased extracellular concentrations of DA, DOPAC and HVA in the NAC. (S)-UH-301 (2.5mg/kg s.c.) also decreased DA, but not DOPAC and HVA, concentrations in the striatum. Infusion of low concentrations (1, 10 M) of (S)-UH-301 into either the NAC or the striatum did not affect DA levels, while only the highest concentration (1,000 M) significantly decreased DA levels in both areas. Similarly, infusion of the selective 5-HT_1A receptor agonist (R)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-S-OH-DPAT] only in high concentrations (100, 1,000 M) decreased DA levels in both regions. These data suggest that (S)-UH-301 decreases DA release both in the NAC and the striatum probably indirectly via its purported DA-D₂/D₃ receptor agonistic properties. However, the observed inhibitory effect of (S)-UH-301 on DA release in the studied brain regions may also be explained, at least partly, by a serotonergic influence on the DA systems, acting at 5-HT_1A receptor sites located elsewhere in the brain.     

Glutamate-dopamine in vivo interaction in the prefrontal cortex modulates the release of dopamine and acetylcholine in the nucleus accumbens of the awake rat

Summary. In the context of the in vivo neurochemical literature this article reviews some recent microdialysis studies in our laboratory of glutamate-dopamine interaction in the prefrontal cortex (PFC) and its possible role in modulating dopamine and acetylcholine release in the nucleus accumbens. A functional glutamate-dopamine interaction in PFC has been reported by microdialysis studies showing that both stimulation and blockade of prefrontal glutamate receptors produce changes of basal and/or stimulated release of dopamine in this area of the brain. These studies suggest that dopamine function in PFC is modulated locally by prefrontal glutamatergic inputs and that glutamate and dopamine can act simultaneously to regulate GABA release in PFC. In particular, dopamine can enhance the increases of extracellular GABA produced by the stimulation of prefrontal glutamate receptors. We report also that the stimulation of prefrontal D2 and mGluI receptors and their interaction changes the release of dopamine and acetylcholine in the nucleus accumbens.     

Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: An lontophoretic study

In this study, we examined the interaction of 5-HT_1A and 5-HT_2A receptors in the rat medial prefrontal cortex (mPFc) using the techniques of extracellular single unit recording and microiontophoresis. The iontophoresis of the selective 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced a current-dependent suppression (2.5-20 nA) of the basal firing rate of spontaneously active mPFc cells. The iontophoretic (5-10 nA) and systemic administration (0.1-0.5 mg/kg, i.v. ) of the 5-HT_2A/5-HT_2C receptor antagonist ritanserin and the selective 5 HT_2A receptor antagonist MDL 28727 significantly potentiated and prolonged 8-OHDPATs suppressant action. In addition, the systemic administration of another selective 5-HT_2A antagonist MDL 100907, but not its less active enantiomer MDL 100009, also potentiated and prolonged 8-OHDPATs action. The potentiating effect of the 5-HT_2A receptor antagonists on the action of 8-OHDPAT is specific in that neither the iontophoresis of ritanserin nor MDL 28727 altered the suppressant action produced by the iontophoresis of the 5-HT₃ receptor agonist 2-methylserotonin onto mPFc cells. Moreover, the suppressant action of 8-OHDPAT was not altered by the systemic administration of the selective 5-HT₃ receptor antagonist granisetron (0.1-0.5 mg/kg, i.v.). On the other hand, the iontophoresis of a low current (0.5 nA) of the 5-HT_2A,2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potentiated the excitation induced by the iontophoresis of 1-glutamate on quiescent mPFc cells. The iontophoresis of 8-OHD-PAT at a current that had no effect on the firing rate of 1-glutamate activated when administered alone significantly attenuated the excitatory action produced by the iontophoresis of DOI. Overall these results confirm and extend the hypothesis that there is an interaction between 5-HT_1A and 5-HT_2A receptors in the mPFc at the neuronal level. © 1994 Wiley-Liss, Inc.     

Pharmacological characterization of dopamine, norepinephrine and serotonin release in the rat prefrontal cortex by neuronal nicotinic acetylcholine receptor agonists

Neuronal nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission by regulating neurotransmitter release, an action that involves multiple nAChRs. The effects of four nAChR agonists, nicotine (NIC), 1,1-dimethyl-4-phenylpiperzinium iodide (DMPP), cytisine (CYT) and epibatidine (EPI) were investigated on [3H]-norepinephrine (NE), [3H]-dopamine (DA) and [3H]-serotonin (5-HT) release from rat prefrontal cortical (PFC) slices. All four agonists evoked [3H]-DA release to a similar magnitude but with a differing rank order of potency of EPI>DMPP approximately NIC approximately CYT. Similarly, all four agonists also increased [3H]-NE release, but with a differing rank order of potency of EPI>CYT approximately DMPP>NIC. NIC-induced [3H]-NE and [3H]-DA release responses were both calcium-dependent and attenuated by the sodium channel antagonist, tetrodotoxin (TTX) and by the nAChR antagonists mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), but not by D-tubocurare (D-TC). The modulation of [3H]-5-HT release by nAChR agonists was distinct from that seen for catecholamines. DMPP produced robust increases with minimal release observed with other agonists. DMPP-induced [3H]-5-HT release was neither sensitive to known nAChR antagonists nor dependent on external calcium. The differences between nicotinic agonist induced catecholamine and serotonin release suggest involvement of distinct nAChRs.     

Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism

Atypical antipsychotic drugs (APDs) such as clozapine, but not the typical APD haloperidol, improve some aspects of cognition in schizophrenia. This advantage has been attributed, in part, to the ability of the atypical APDs to markedly increase acetylcholine (ACh) and dopamine (DA) release in rat medial prefrontal cortex (mPFC), while producing a minimal effect in the nucleus accumbens (NAC) or striatum. The atypical APD-induced preferential release of DA, but not ACh, in the mPFC is partially inhibited by the selective 5-HT(1A) antagonist WAY100635. However, little is known about these effects of atypical APDs in the ventral hippocampus (vHIP), another possible site of action of atypical APDs with regard to cognitive enhancement. The present study demonstrates that clozapine (10 mg/kg) comparably increases both ACh and DA release in the vHIP and mPFC. The increases in DA, but not ACh, release in both regions were partially attenuated by WAY100635 (0.2 mg/kg), which had no effect by itself on the release of either neurotransmitter in either region. Tetrodotoxin (TTX; 1 microM), a Na(+) channel blocker, in the perfusion medium, eliminated the clozapine (10 mg/kg)-induced ACh and DA release in the vHIP, indicating their neuronal origin. Haloperidol produced a slight increase in ACh release in the vHIP at 1 mg/kg, and DA release in the mPFC at 0.1 mg/kg. In conclusion, clozapine increases ACh and DA release in the vHIP and mPFC, whereas haloperidol has minimal effects on the release of these two neurotransmitters in either region. These differences may contribute, at least in part, to the superior ability of clozapine, compared to haloperidol, to improve cognition in schizophrenia. 5-HT(1A) agonism is important to the ability of clozapine and perhaps other atypical APDs to increase DA, but not ACh, release in the vHIP, as well as the mPFC. The role of hippocampus in the cognitive effects of atypical APDs warrants more intensive study.     

Modulation of neurotransmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in vitro

The atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone, and ziprasidone preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). These effects have been shown to depend upon potent 5-HT(2A) relative to weak D(2) antagonism, and 5-HT(1A) agonism as well. Atypical APDs also increase acetylcholine (ACh) release in the mPFC, but not the nucleus accumbens (NAC) or striatum (STR), whereas typical APDs such as haloperidol, S(-)-sulpiride and thioridazine do not produce either effect in the mPFC. This study examined the role of 5-HT(1A) agonism, 5-HT(2A) and D(2) antagonism, and the combination thereof, in the ability of clozapine to increase ACh release in rat mPFC. R(+)-8-OH-DPAT (0.2 mg/kg), a 5-HT(1A) agonist, WAY100635 (0.2-0.5 mg/kg), a 5-HT(1A) antagonist, and DOI (0.6-2.5 mg/kg), a 5-HT(2A/2C) agonist, increased ACh release in the mPFC, whereas M100907 (0.03-1 mg/kg), a 5-HT(2A) antagonist, did not. DOI (2.5 mg/kg) and M100907 (0.1 mg/kg) had no effect on ACh release in the NAC or STR. WAY100635 and M100907 inhibited the ability of R(+)-8-OH-DPAT and DOI, respectively, to increase ACh release in the mPFC. WAY100635, which inhibits clozapine-induced DA release in the mPFC, failed to inhibit clozapine (20 mg/kg)-induced ACh release in that region. Similarly, the combination of M100907 and haloperidol (0.1 mg/kg), which enhances DA release in the mPFC, failed to increase ACh release in that region. These results suggest that 5-HT(1A) agonism and 5-HT(2A) antagonism, as well as DA release, contribute minimally to the ability of clozapine, and perhaps other atypical APDs, to increase ACh release in the mPFC.     

DOI, a 5-HT2A/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.     

R(+)-8-OH-DPAT, a selective 5-HT1A receptor agonist, attenuated amphetamine-induced dopamine synthesis in rat striatum, but not nucleus accumbens or medial prefrontal cortex

R(+)-8-OH-DPAT (0.05, but not 0.025, 0.1, 1 mg/kg), a 5-HT_1A receptor agonist, decreased l-3,4-dihydroxyphenylalanine (DOPA) accumulation in rat striatum following NSD-1015, an l-aromatic amino acid decarboxylase inhibitor. Amphetamine (1 mg/kg) increased striatal DOPA accumulation, an effect attenuated by R(+)-8-OH-DPAT (0.05 mg/kg). However, both amphetamine (1 mg/kg) and R(+)-8-OH-DPAT (0.05 mg/kg) decreased cortical DOPA accumulation; there were no additional decreases from their combination. Neither amphetamine (1 mg/kg), R(+)-8-OH-DPAT (0.05 mg/kg), or the combination, significantly affected DOPA accumulation in the nucleus accumbens. The significance of and possible mechanisms for these findings are discussed.     

Quantification of 5-HT1A and 5-HT2A receptor Binding in Depressed Suicide Attempters and Non-Attempters

Objective: To determine serotonin system abnormalities related to major depression or previous suicidal behavior.

Methods: [¹¹C]WAY100635, [¹⁸F]altanserin and positron emission tomography were used to compare 5-HT_1A and 5-HT_2A binding in MDD patients divided into eight past suicide attempters (>4yrs prior to scanning) and eight lifetime non-attempters, and both groups were compared to eight healthy volunteers.

Results: The two receptor types differed in binding pattern across brain regions from each other, but there were no differences in binding between healthy volunteers and the two depressed groups or between depressed suicide attempters and non-attempters. No effects of depression severity or lifetime aggression were observed for either receptor.

Conclusion: Limitations of this study include small sample size and absence of high lethality suicide attempts in the depressed attempter group. No trait-like binding correlations with past suicide attempt or current depression were observed. Given the heterogeneity of nonfatal suicidal behavior, a larger sample study emphasizing higher lethality suicide attempts may find the serotonin biological phenotype seen in suicide decedents.     

D1 dopamine receptor activation reduces extracellular glutamate and GABA concentrations in the medial prefrontal cortex

The present study examined effect of administration of a selective D1 dopamine receptor agonist, SKF38393 on extracellular concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in mPFC, by using in vivo microdialysis. Perfusion with SKF38393 via a dialysis probe reduced concentrations of both Glu and GABA dose-relatedly, and these effects were prevented by co-perfusion with a D1 dopamine receptor antagonist, SCH23390 (40 microM). These results suggested that the dopaminergic hyperactivity may lead to the hypofunction of glutamatergic and GABAergic systems in mPFC via D1 dopamine receptor stimulation.     

Functional effects of chronic electroconvulsive shock on serotonergic 5-HT(1A) and 5-HT(1B) receptor activity in rat hippocampus and hypothalamus

The aims of this work were to determine the influence of chronic electroconvulsive shock (ECS) on presynaptic 5-HT(1A) receptor function, postsynaptic 5-HT(1A) receptor function in hippocampus and hypothalamus, and presynaptic 5-HT(1B) receptor function in hippocampus and hypothalamus. This represents part of an on-going study of the effects of ECS on serotonergic receptor activity in selected brain areas which may be relevant to the effects of electroconvulsive therapy (ECT) in humans. Chronic ECS reduced the ability of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) (0.2 mg/kg s.c.) to decrease 5-HT levels in hypothalamus as shown by in vivo microdialysis, indicative of a reduction in sensitivity of presynaptic 5-HT(1A) autoreceptors. The ability of the 5-HT(1B) receptor antagonist GR 127935 (5 mg/kg s.c.) to increase 5-HT levels in both hippocampus and hypothalamus was unaffected by chronic ECS. 8-OH-DPAT (0.2 mg/kg s.c.) increased cyclic AMP levels in hippocampus measured by in vivo microdialysis approximately 2-fold. The degree of stimulation of cyclic AMP formation was not altered by chronic ECS. However the cyclic AMP response to forskolin (50 micro M) administered via the microdialysis probe, which was approximately 4-fold of basal in sham-treated rats, was almost completely abolished in ECS-treated rats. Since this indicates that either adenylate cyclase catalytic unit activity or Gs protein activity is reduced in the hippocampus after chronic ECS, the lack of change in 8-OH-DPAT-induced cyclic AMP formation may be taken as possible evidence of an increase in sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus by chronic ECS. Chronic ECS increased basal plasma levels of corticosterone, ACTH and oxytocin. The ACTH response to s.c. injections of 0.2 mg/kg or 0.5 mg/kg 8-OH-DPAT was reduced by chronic ECS. Postsynaptic 5-HT(1A) receptor activity in the hypothalamus, in contrast to the hippocampus, thus appears to be desensitized after chronic ECS. We conclude that chronic ECS has regionally specific effects on both pre- and post-synaptic 5-HT(1A) receptors, but, in contrast to some antidepressant drugs, does not affect presynaptic 5-HT(1B) receptor activity.     

5-HT1A receptor function in depression: effect of chronic amitriptyline treatment

Summary Hypothermic responses to 5-HT_1A receptor activation by the selective ligand ipsapirone (IPS) were attenuated in depressed patients as compared to controls. Chronic treatment with amitriptyline (AMI) further impaired 5-HT_1Amediated hypothermia. The results indicate a subsensitive (presynaptic) 5-HT_1A receptor and/or a defective post-receptor signalling pathway in depression and are consistent with the hypothesis that 5-HT_1A receptors are down-regulted during AMI treatment.     

Dopamine and 5-HT turnover are increased by the mGlu2/3 receptor agonist LY379268 in rat medial prefrontal cortex, nucleus accumbens and striatum

We have shown, using in vivo microdialysis sampling, that systemic administration of the selective group II metabotropic (mGlu) receptor agonist LY379268, like the atypical antipsychotic clozapine, increased extracellular levels of dopamine, dopamine metabolites DOPAC and HVA, and the major 5-HT metabolite 5-HIAA, in rat medial prefrontal cortex (mPFC). Here, we have compared the effects of LY379268 with clozapine as well as risperidone on ex vivo tissue levels of dopamine, DOPAC, HVA, 5-HT and 5-HIAA in multiple brain regions. One to two hours following administration of LY379268, mPFC tissue levels of DOPAC, HVA and 5-HIAA were increased in a dose-dependent manner. Increases evoked by LY379268 (10 mg/kg s.c.) at the 2 h point were 189, 245 and 139% of basal levels, respectively. These effects were reversed within 4 h of administration. Clozapine (10 mg/kg s.c.) and risperidone (1 mg/kg s. c.) also increased levels of the dopamine metabolites to a similar extent but were without significant effect on tissue levels of 5-HIAA. LY379268 (10 mg/kg s.c.) also increased tissue levels of DOPAC, HVA and 5-HIAA by 169, 221 and 134% of basal levels in nucleus accumbens, respectively, and by 131, 179 and 132% of basal levels in striatum, respectively. These data show that activation of mGlu2/3 receptors can increase the turnover of dopamine and 5-HT in the areas of the brain implicated in the actions of atypical antipsychotics.     

Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims

Summary The density of 5-HT_1A binding using³H-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) as binding ligand, was studied in human frontal cortex of suicide victims and normal controls who died due to medical disease or accidentally. There was no difference in the maximum number of binding site (B_max) or K_d (an inverse measure of affinity) of 5-HT_1A receptor binding sites between normal controls and the entire group of suicide victims. However, nonviolent suicides had significantly higher B_max (22—25%) compared to both controls and violent suicides. A negative correlation between age and B_max of 5-HT_1A binding sites was found in male controls but not in female controls or suicide victims. This relationship was less apparent among the male controls over age 60.     

Mirtazapine in combination with perospirone synergistically enhances dopamine release in the rat prefrontal cortex via 5-HT1A receptor activation

Aims: The purpose of this study was to elucidate the mechanism underlying the clinical efficacy of mirtazapine–perospirone combination therapy for treatment‐resistant depression in a rat model. Methods: We studied the effect of combination therapy of the noradrenergic and specific serotonergic antidepressant mirtazapine and the serotonin‐dopamine antagonist perospirone on serotonin (5‐HT) and dopamine release in the rat medial prefrontal cortex (mPFC) by using microdialysis. Male Wistar rats (250–330 g bodyweight) underwent implantation of a guide cannula in the mPFC, and a microdialysis probe was then inserted into the guide cannula to ensure its final placement in the mPFC. Microdialysis and subsequent chromatographic analysis were performed to estimate the extracellular 5‐HT and dopamine concentrations. Results: When they were used individually, perospirone (0.25 mg/kg, intraperitoneally) and mirtazapine (4 mg/kg, intraperitoneally) induced increased dopamine release up to 134% and 190% relative to the pretreatment level, respectively. Their combination therapy synergistically and significantly (P < 0.0001) increased the dopamine concentration up to 397% of the pretreatment level compared with that induced by the individual drugs. This combination‐induced dopamine release was attenuated by 5‐HT_1A antagonist WAY 100635 (0.5 mg/kg, intraperitoneally), to a peak dopamine release of 151%. Extracellular 5‐HT release in the mPFC was not altered in any of the treatment groups. Conclusions: The large increase in the dopamine concentration in the rat mPFC after the combination therapy was unique and may be responsible for the profound antidepressive effect observed in patients with treatment‐resistant depression.     

D1 dopamine and NMDA receptors interactions in the medial prefrontal cortex: Modulation of spatial working memory in rats

Dopamine (DA) and N-methyl-d-aspartate (NMDA) receptors seem to be critically involved in working memory processing in the medial prefrontal cortex (mPFC). Effects of NMDA receptors blockade on dopamine D₁ receptors activation in the mPFC on spatial working memory was investigated. Adult male Wistar rats, well trained in an eight-arm radial maze and bilaterally cannulated in the mPFC, received intracortical administrations of saline (SAL) or SKF-38393 (DA D₁ receptor agonist) followed, 10 min later, by MK-801 (non-competitive NMDA receptor antagonist). They were tested in 1 h delayed tasks after 5 min of the second administration. SKF-38393 (0.56 and 1.8 μg) was disruptive to working memory, increasing significantly the number of errors in the 1 h post-delay performance when administered into the mPFC. MK-801, at doses with no significant effects alone (0.32 or 1.0 μg), reduced significantly the disruptive effect of 0.56 μg SKF-38393. These results showed that the disruptive effect of DA D₁ receptors activation in the mPFC on working memory was significantly reduced by an open-channel NMDA receptor blockade, suggesting that the processing of working memory in the mPFC involving DA D₁ receptors depend, at least in part, of NMDA receptors activity in this cortical area.