Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum

The in vivo effects of olanzapine on the extracellular monoamine levels in rat prefrontal cortex (Pfc), nucleus accumbens (Acb) and striatum (Cpu) were investigated by means of microdialysis. Sequential doses of olanzapine at 0.5, 3 and 10 mg/kg (SC) dose-dependently increased the extracellular dopamine (DA) and norepinephrine (NE) levels in all three brain areas. The increases appeared 30 min after olanzapine administration, reached peaks around 60–90 min and lasted for at least 2 h. The highest DA increases in the Acb and Cpu were induced by olanzapine at 3 mg/kg but at 10 mg/kg in the Pfc. The peak DA increase in the Pfc (421% ± 46 of the baseline) was significantly larger than those in the Acb (287% ± 24) and Cpu (278% ± 28). Similarly, the highest NE increase in the Pfc (414%±40) induced by 10 mg/kg olanzapine was larger than those in the Acb (233% ± 39) and Cpu (223% ± 24). The DA and NE increases in the Pfc induced by olanzapine at 3 and 10 mg/kg (SC) were slightly larger than those induced by clozapine at the same doses. In contrast, haloperidol (0.5 and 2 mg/kg, SC) did not change Pfc DA and NE levels. Extracellular levels of a DA metabolite, DOPAC, and tissue concentrations of a released DA metabolite, 3-methoxytyramine, were also increased by olanzapine, consistent with enhanced DA release. However, olanzapine at the three sequential doses did not alter the extracellular levels of either 5-HT or its metabolite, 5-HIAA, in any of the three brain areas. In conclusion, the present studies demonstrate that in the case of sequential dosing olanzapine more effectively enhances DA and NE release in the Pfc than in the subcortical areas, which may have an impact on its atypical antipsychotic actions. Received: 7 May 1997/Final version: 15 September 1997     

The atypical antipsychotic quetiapine increases both noradrenaline and dopamine release in the rat prefrontal cortex

Quetiapine is a novel atypical antipsychotic drug with multi-receptorial affinity. Using in vivo microdialysis, we investigated if quetiapine modulates extracellular noradrenaline and dopamine in brain areas generally believed to be involved in the pathophysiology of schizophrenia and in the action of antipsychotic drugs. Quetiapine (5, 10 and 20 mg/kg, i.p.) increased levels of noradrenaline in both the prefrontal cortex and the caudate nucleus, while it increased dopamine levels mainly in the prefrontal cortex. It is argued that the marked increase of dopaminergic transmission in the prefrontal cortex induced by quetiapine might be relevant to its therapeutical action.     

Mianserin markedly and selectively increases extracellular dopamine in the prefrontal cortex as compared to the nucleus accumbens of the rat

The atypical antidepressant mianserin, administered at doses of 1, 5 and 10 mg/kg SC, dose-dependently increased up to about 6 times extracellular dopamine in the medial prefrontal cortex of the rat, as estimated by vertical concentric microdialysis probes. Mianserin failed to modify extracellular dopamine in the nucleus accumbens. Mianserin also dose-dependently increased extracellular noradrenaline in the prefrontal cortex. Yohimbine, an ₂ antagonist, increased extracellular dopamine in the prefrontal cortex but the maximal increase was lower than that elicited by mianserin. Yohimbine also increased extracellular noradrenaline in the prefrontal cortex, but to a lesser extent than dopamine. Clonidine, an ₂ agonist, decreased extracellular dopamine and noradrenaline in the prefrontal cortex but failed to affect extracellular dopamine in the nucleus accumbens. Ritanserin, a 5HT₂ antagonist, at doses of 1.0 mg/kg, failed to increase extracellular dopamine in the prefrontal cortex, but significantly potentiated the increase in extracellular noradrenaline due to yohimbine. Ritanserin failed to potentiate the increase in extracellular noradrenaline elicited by yohimbine in the prefrontal cortex. The results are interpreted to indicate that mianserin increases extracellular DA as a result of the concurrent blockade of ₂ and 5HT₂ receptors. Failure to affect extracellular dopamine in the nucleus accumbens is explained as due to the lack of a significant effect of ₂ and 5HT₂ tone on DA release in the nucleus accumbens as compared to the prefrontal cortex. The results are consistent with the postulated relationship between antidepressant drug action and the ability to increase extracellular dopamine in the prefrontal cortex.     

Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.     

Blockade of NMDA receptors in the prefrontal cortex increases dopamine and acetylcholine release in the nucleus accumbens and motor activity

Objectives  The present study investigates the effects of injections of a specific N-methyl-d-aspartic acid (NMDA) antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) into the prefrontal cortex (PFC) on the extracellular concentrations of dopamine and acetylcholine in the nucleus accumbens (NAc) and on motor activity in the freely moving rat. Materials and methods  Sprague–Dawley male rats were implanted with guide cannulas into the medial PFC and NAc to perform bilateral microinjections and microdialysis experiments. Spontaneous motor activity was monitored in the open field. Results  Injections of CPP (1 μg/0.5 μL) into the PFC produced a significant increase of the baseline extracellular concentrations of dopamine (up to 130%), dihydroxyphenylacetic acid (DOPAC; up to 120%), homovanillic acid (HVA; up to 130%), and acetylcholine (up to 190%) in the NAc as well as motor hyperactivity. In the NAc, perfusion of the NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate antagonists CPP (50 μM)+6,7-dinitroquinoxaline-2,3-dione (DNQX; 50 μM) through the microdialysis probe blocked acetylcholine release, but not DOPAC and HVA increases produced by CPP injections into the PFC. Also, increases in motor activity produced by prefrontal injections of CPP were significantly reduced by bilateral injections into the NAc of a mixed D1/D2 antagonist, flupenthixol (5 and 25 μg/0.5 μL). Injections into the NAc of the muscarinic antagonist scopolamine (1 and 10 μg/0.5 μL) further increased, and of the nicotinic antagonist mecamylamine (1 and 10 μg/0.5 μL) did not change, the increases in motor activity produced by prefrontal CPP injections. Conclusions  These results suggest that the dysfunction of NMDA receptors in the PFC could be a key factor in the neurochemical and motor effects associated with corticolimbic hyperactivity.     

Systemic administration of amperozide,a new atypical antipsychotic drug,preferentially increases dopamine release in the rat medial prefrontal cortex

The putative atypical antipsychotic drug amperozide (APZ) shows high affinity for serotonin 5-HT₂ receptors but only low affinity for dopamine (DA) D₂ receptors. By employing microdialysis, we examined the effects of APZ on extracellular concentrations of DA in the nucleus accumbens (NAC), the dorsolateral striatum (STR) and the medial prefrontal cortex (MPC) of awake rats. A 5.0 mg/kg (SC) dose of APZ failed to affect DA concentrations in the NAC, while it increased DA outflow in the STR (by 46%) and the MPC (by 207%). A higher dose of APZ (10 mg/kg, SC) enhanced dialysate DA from the NAC and the STR by 30%, and from the MPC by 326%. Similarly, clozapine (2.5 and 10 mg/kg, SC) produced a greater release of DA in the MPC (+ 127 and + 279%) than in the NAC (+ 52 and + 98%). The selective 5-HT₂ receptor antagonist ritanserin (1.5 and 3.0 mg/kg, SC) also produced a slightly higher increase of DA output in the MPC (+ 25 and + 47%) compared with the NAC (+ 19 and + 21%). In contrast, the selective D₂ receptor antagonist raclopride (0.5 and 2.0 mg/kg, SC) increased DA release in the NAC (+ 65 and + 119%) to a greater extent than in the MPC (+ 45 and + 67%). These data suggest that the 5-HT₂ receptor antagonistic properties of APZ and clozapine may contribute to their preferential effects on DA transmission in the MPC. Infusion of low doses (1,10 µM, 40 min) of APZ through the probe in the DA terminal areas did not affect significantly DA outflow, while infusion of high doses (100, 1000 µM, 40 min) resulted in a more pronounced elevation of DA levels in the NAC (up to 961%) and the STR (up to 950%) than in the MPC (up to 316%). These findings indicate that the selective action of systemically administered APZ on DA in the MPC is most likely mediated at a level other than the terminal region. Taken together, the present results provide support for the notion that 5-HT₂ receptor antagonism may be of considerable significance for the action of atypical antipsychotic drugs on mesolimbocortical dopaminergic neurotransmission.     

Neurotensin effects on evoked release of dopamine in slices from striatum,nucleus accumbens and prefrontal cortex in rat

Summary The effects of neurotensin (NT) on the K⁺-evoked release of endogenous and tritiated dopamine in striatum and on ³H-dopamine in slices from nucleus accumbens and prefrontal cortex were investigated. In striatum, NT (1–1000 nM) elicited a dose-dependent increase in endogenous and ³H-dopamine release. The dose-response curves were comparable with the two methods. Concerning the comparison of NT modulation of ³H-dopamine release in the three cerebral structures, the peptide induced a more marked effect in striatum with a maximal effect of 150% increase. In accumbens, NT (1–1000 nM) potentiated the K⁺-evoked 3H-dopamine release, but in contrast with striatum, the plateau corresponded to a 50% increase. In prefrontal cortex, NT (1–1000 nM) induced small but significant effects, with a maximal increase of 50% at 100 nM. Acetyl-NT (8–13) displayed an action similar to the natural peptide while NT (1–8) did not exhibit any effect, suggesting that the action of NT involved a receptor. The presence of tetrodotoxin did not alter the facilitating effects of NT in the three structures, indicating that interneurons were not involved in the action of NT. The comparison of the effects of NT showed that in terms of efficacy, NT induced an increase in dopamine release more marked in striatum than in nucleus accumbens and prefrontal cortex. These results are consistent with differences in NT receptors localization in these three dopaminergic structures. Send offprint request to: A. Boireau     

Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats

The aim of the present study was to investigate the relationship between physical abstinence and changes in dopamine release in the nucleus accumbens and in the medial prefrontal cortex induced by mecamylamine and naloxone in rats chronically exposed to nicotine. The rats were implanted with osmotic minipumps (Alzet) delivering nicotine tartrate at a rate of 9 mg/kg/day (3.16 mg of free base) and 8 days later with a dialysis probe in the nucleus accumbens or in the medial prefrontal cortex. Steady-state dopamine output from the nucleus accumbens of the rats implanted with nicotine minipumps was higher than that of sham implanted rats; no differences were observed in the prefrontal cortex. In nicotine but not in sham implanted rats mecamylamine (1 mg/kg s.c.) precipitated a physical abstinence syndrome and brought dopamine output back to control values in the nucleus accumbens. In contrast mecamylamine (1 mg/kg s.c.) increased dopamine output in the medial prefrontal cortex of nicotine but not sham-implanted rats. Naloxone (2 mg/kg) precipitated a physical abstinence syndrome qualitatively similar to that produced by mecamylamine but failed to modify extracellular dopamine in the nucleus accumbens or in the prefrontal cortex of nicotine-implanted and sham-implanted rats. The results indicate that the mesolimbic and mesocortical dopamine system undergo opposite changes during mecamylamine-precipitated abstinence in rats chronically exposed to nicotine and that physical abstinence signs can be dissociated from changes in dopamine transmission.     

Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation

Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has been associated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypical antipsychotics such as olanzapine. In rodents, early life exposure to stressful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg s.c.), olanzapine (5 mg/kg s.c.), and haloperidol (0.5 mg/kg s.c.) on dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of the mPFC in group- and isolation-reared rats. Rats reared in isolation showed significant and robust deficits in prepulse inhibition of the acoustic startle. In group-reared animals, both clozapine and olanzapine produced a significant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics compared with group-reared animals. In contrast, the administration of haloperidol failed to modify dialysate DA levels in mPFC in either group- or isolation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D2 or D3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate, GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA responsiveness to the atypical antipsychotic drugs clozapine and olanzapine may explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, namely hyperactivity and attention deficit.     

Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum.

The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, clozapine (2.5-20 mg/kg), olanzapine (10 mg/kg), risperidone (1 mg/kg), and ziprasidone (3 mg/kg) significantly increased ACh release in rat medial prefrontal cortex (mPFC), whereas the typical APDs, haloperidol (0.1-1 mg/kg), S(-)-sulpiride (10-25 mg/g), and thioridazine (5-20 mg/kg) did not. None of seven APDs increased ACh release in the nucleus accumbens or striatum at the doses effective in the mPFC. Thus, atypical and typical APDs may differ in the ability to increase cortical ACh release, a possible factor contributing to cognitive improvement in schizophrenia. After perfusion with neostigmine, an AChesterase inhibitor, clozapine, but not haloperidol, increased ACh release in all three aforementioned brain regions with an enhanced effect in the mPFC, indicating the importance of studying ACh release in the absence of AChesterase inhibition. Clozapine, and perhaps other atypical APDs, alone or in combination with an AChesterase inhibitor, may improve cognition in schizophrenia, and perhaps other cognitive disorders, e.g., early Alzheimer's disease, by enhancing cortical cholinergic transmission.     

Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats

The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural subtrates are responsible for the reinforcing actions of these two drugs.     

Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism.

The effect of various doses of tianeptine on the extracellular concentrations of dopamine was studied in the striatum and nucleus accumbens of the rat. At 5 (but not 2.5) mg/kg intraperitoneally, tianeptine increased the extracellular dopamine only in the nucleus accumbens. At 10 mg/kg, the effect was also seen in the striatum but it was less marked and shorter-lasting. At 10 mg/kg (i.p.), tianeptine significantly raised the extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in both regions. The effect of 10 mg/kg tianeptine on dopamine and its metabolites was not significantly changed in animals which had received this dose twice daily for 15 days. Intracerebroventricular administration of 150 micrograms/20 microliters 5,7-dihydroxytryptamine, which markedly depleted serotonin in the brain, did not modify the effect of 10 mg/kg tianeptine on the extracellular concentrations of dopamine and HVA in the nucleus accumbens but reduced the effect on DOPAC. Various doses of tianeptine (1, 3 and 10 mg/kg i.p.) did not change the synthesis of serotonin and dopamine in the striatum and nucleus accumbens. The results show that tianeptine increased the extracellular concentrations of dopamine more in the nucleus accumbens than in striatum. The effect on the output of DA in the nucleus accumbens could be involved in the antidepressant activity of tianeptine.     

In alcohol-treated rats, naloxone decreases extracellular dopamine and increases acetylcholine in the nucleus accumbens: evidence of opioid withdrawal

Withdrawal from ethanol is aversive. The question is why. As with the withdrawal from morphine, nicotine, diazepam and sugar, the ethanol withdrawal state may involve an increase in nucleus accumbens (NAc) acetylcholine (ACh) causing an alteration of the dopamine (DA)-ACh balance in favor of ACh. Therefore the effects of acute and chronic alcohol (1 gm/kg/day i.p.) treatment on extracellular concentrations of NAc ACh and DA were determined before and after naloxone-precipitated withdrawal. Ethanol initially increased DA to 119% of baseline as measured by microdialysis. This was still the case on the 21st day of ethanol injection when DA increased to 126%. There was no effect of ethanol on ACh. However, naloxone (3 mg/kg s.c.) injected the next day decreased extracellular DA to 83% of baseline and caused a significant rise in ACh to 119%. This state of high ACh combined with low DA may contribute to the aversive aspects of alcohol withdrawal.     

Systemic morphine simultaneously decreases extracellular acetylcholine and increases dopamine in the nucleus accumbens of freely moving rats.

Microdialysis was used to measure extracellular levels of acetylcholine (ACh) and dopamine (DA) simultaneously in the nucleus accumbens (NAC) of freely moving rats. Systemic injection of morphine (20 mg/kg) significantly decreased ACh (30%, p less than .01) while it increased DA (55%, p less than .01). The effects of morphine were eliminated by naloxone. The results confirm that morphine increases DA and in addition, demonstrate an inhibitory influence of this opiate on extracellular levels of ACh in the NAC.     

Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain

Aripiprazole,7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-carbostycil (OPC-14597), a novel atypical antipsychotic drug, is a dopamine D2 receptor partial agonist with functional 5-HT2A receptor antagonist, and 5-HT1A receptor partial agonist properties as well. Other atypical antipsychotic drugs, e.g. clozapine, but not typical antipsychotic drugs, e.g. haloperidol, produce significant increases in dopamine and acetylcholine release in the medial prefrontal cortex in rats, effects believed to be related to the ability to improve cognitive function. The increase in the medial prefrontal cortex dopamine release by the atypical antipsychotic drugs has been shown to be partially inhibited by N-[2[4-)2-methoxyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT1A receptor antagonist. Aripiprazole, 0.1 and 0.3 mg/kg, significantly increased dopamine release in the hippocampus. Moreover, aripiprazole, 0.3 mg/kg, slightly but significantly increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. These increases were significantly inhibited by WAY100635. By contrast, aripiprazole, 3.0 mg/kg and 10 mg/kg, significantly decreased dopamine release in the nucleus accumbens but not the medical prefrontal cortex. However, aripiprazole 10 mg/kg significantly decreased dopamine release in the both regions. Aripiprazole had no effect on acetylcholine release in the medial prefrontal cortex, hippocampus, or nucleus accumbens at any dose, except for 3.0 mg/kg, which decreased acetylcholine release in the nucleus accumbens only. Aripiprazole, 0.3 mg/kg, transiently potentiated haloperidol (0.1 mg/kg)-induced dopamine release in the medial prefrontal cortex but inhibited that in the nucleus accumbens. The present study demonstrated that aripiprazole, at low doses of 0.1 and 0.3 mg/kg, increases dopamine release in the medial prefrontal cortex and hippocampus. It also suggests that the function of both the medial prefrontal cortex and hippocampus may contribute to the ability of aripiprazole to improve negative symptom and cognition.     

Pretreatment with corticosterone attenuates the nucleus accumbens dopamine response but not the stimulant response to cocaine in rats

It has been suggested that stress, via corticosterone secretion, can modulate some of the behavioural responses to cocaine. In particular, we have demonstrated that daily exposure to electric footshock stress or daily pretreatment with corticosterone shifts the ascending limb of the dose-response curve for the acquisition of cocaine self-administration upwards and to the left. It has been suggested that this corticosterone-induced increase in sensitivity to low doses of cocaine is associated with an enhancement of dopaminergic neurotransmission. The present study was designed to test this hypothesis. Adult male rats were pretreated with corticosterone (2.0 mg/kg intraperitoneally) 15 min prior to an injection of cocaine (5.0, 10.0 or 20.0 mg/kg intraperitoneally), and motor activity and extracellular dopamine concentrations in the nucleus accumbens were monitored. Cocaine administration resulted in dose-related increases in motor activity that were unaffected by pretreatment with corticosterone. However, rather than augmenting cocaine-induced increases in dopamine in the nucleus accumbens, corticosterone pretreatment actually caused attenuation at the two highest doses of cocaine tested. These data suggest dissociation between locomotor activation and nucleus accumbens dopamine responses to cocaine, and indicate that other brain regions and/or mechanisms may be involved in the changes in sensitivity to cocaine induced by corticosterone.     

The atypical antipsychotic sertindole enhances efflux of dopamine and its metabolites in the rat cortex and striatum

Previous studies have shown that sertindole (1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl ]-2 imidazolidinone), an atypical antipsychotic drug that is a potent 5-HT2A and dopamine D2 receptor antagonist, preferentially affects mesocorticolimbic rather than mesostriatal dopamine neurons. Using in vivo microdialysis in conscious rats, we investigated the effects of sertindole on dopamine release and metabolism in the striatum and the medial prefrontal cortex. Systemic administration of sertindole dose dependently enhanced dopamine release in the medial prefrontal cortex and the striatum to the same extent.     

Presynaptic regulation of extracellular dopamine levels in the medial prefrontal cortex and striatum during tyrosine depletion

Rationale

Available neurochemical probes that lower brain dopamine (DA) levels in man are limited by their tolerability and efficacy. For instance, the acute lowering of brain tyrosine is well tolerated, but only modestly lowers brain DA levels. Modification of tyrosine depletion to robustly lower DA levels would provide a superior research probe.

Objectives

The objective of this study was to determine whether the subthreshold stimulation of presynaptic DA receptors would potentiate tyrosine depletion-induced effects on extracellular DA levels in the medial prefrontal cortex (MPFC) and striatum of the rat.

Methods

We administered quinpirole, a predominantly DA type 2 (D2R) receptor agonist, into the MPFC and striatum by reverse dialysis. A tyrosine- and phenylalanine-free neutral amino acid mixture [NAA(?)] IP was used to lower brain tyrosine levels. DA levels in the microdialysate were measured by HPLC with electrochemical detection.

Results

Quinpirole dose-dependently lowered DA levels in MPFC as well as in the striatum. NAA(?) alone transiently lowered DA levels (80 % baseline) in the striatum, but had no effect in MPFC. The co-administration of NAA(?) and a subthreshold concentration of quinpirole (6.25 nM) lowered DA levels (50 % baseline) in both the MPFC and striatum. This effect was blocked by the mixed D2R/D3R antagonist haloperidol at IP doses that on their own did not affect DA levels (10.0 nmol/kg in the MPFC and 0.10 nmol/kg in the striatum).

Conclusions

Pharmacological stimulation of inhibitory D2R receptors during tyrosine depletion markedly lowers the extracellular DA levels in the MPFC and striatum. The data suggest that combining tyrosine depletion with a low dose of a DA agonist should robustly lower brain regional DA levels in man.     

Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential?

Drugs differing in their primary mechanism of action but having in common the ability to act as antidepressants such as fluoxetine (10 mg/kg SC), clomipramine (10 mg/kg IP), imipramine (10 mg/kg IP), desipramine (10 mg/kg IP) and (±)8-OHDPAT (0.03 mg/kg SC) increase extracellular concentrations of dopamine in the rat prefrontal cortex but not in the medial nucleus accumbens. Buspirone (1 mg/kg SC) increased dopamine both in the prefrontal cortex and in the nucleus accumbens. Extracellular 5HT was increased by fluoxetine, clomipramine and imipramine but not by desipramine while 8-OHDPAT and buspirone decreased it. These results raise the possibility that the property of stimulating dopamine transmission in the prefrontal cortex has a role in the antidepressant properties of these drugs.