Lesions of dopamine neurons in the medial prefrontal cortex: effects on self-administration of amphetamine and dopamine synthesis in the brain of the rat

It has been suggested that dopamine (DA)-containing neurons within the medial prefrontal cortex subserve a role in the positive reinforcing effects of psychomotor stimulants. Injections of 6-hydroxydopamine (6-OHDA) into this region, which destroyed a major portion of the DA innervation, but maintained the integrity of noradrenergic and serotonergic neurons, failed to alter either the acquisition or maintenance of the intravenous self-administration of d-amphetamine in rats. Compared to vehicle-injected controls (sham lesions), the animals treated with 6-OHDA acquired the drug-abuse behaviour and maintained comparable, stable rates of self-injection. The lesions increased concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens septi but not in the striatum. The increased synthesis of DA in the nucleus accumbens septi [demonstrated by increased accumulation of dihydroxyphenylalanine (DOPA)] was abolished by the intravenous administration of d-amphetamine, in patterns mimicking those of animals trained in self-administration.     

Dopamine in the medial prefrontal cortex controls genotype-dependent effects of amphetamine on mesoaccumbens dopamine release and locomotion.

Mice of background DBA/2J are hyporesponsive to the behavioral effects of D-amphetamine in comparison with the widely exploited murine background C57BL/6J. In view of the important role of dopamine (DA) release in the nucleus accumbens (NAc) regarding the behavioral effects of psychostimulants, we tested the hypothesis of an inverse relationship between mesocortical and mesoaccumbens DA functioning in the two backgrounds. Systemic D-amphetamine induces a sustained increase in DA release in the medial prefrontal cortex (mpFC) accompanied by a poor increase in the NAc in mice of the low-responsive DBA/2J background, as shown by intracerebral microdialysis in freely moving animals. The opposite occurs in C57BL/6J mice, which show low prefrontal cortical DA outflow accompanied by high accumbal extracellular DA. Moreover, the DBA/2J background showed lower locomotor activity than C57BL/6J mice following D-amphetamine challenge. Selective DA depletion in the mpFC of DBA/2J mice produced a clear-cut increase in D-amphetamine-induced DA outflow in the NAc as well as locomotor activity that reached levels similar to those observed in C57BL/6J mice. Finally, local infusion of D-amphetamine by reverse microdialysis produced a similar increase in extracellular DA in both the mpFC and the NAc of DBA/2J mice. This finding points to similar transporter-related mechanisms in the two brain areas and supports the hypothesis that low accumbal DA release induced by systemic D-amphetamine in the DBA/2J background is determined by the inhibitory action of prefrontal cortical DA. The present results indicate that genotype-dependent susceptibility to addictive properties of D-amphetamine involves unbalanced DA transmission in the mesocorticolimbic system.     

Sensitized activation of Fos and brain-derived neurotrophic factor in the medial prefrontal cortex and ventral tegmental area accompanies behavioral sensitization to amphetamine

Behavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. Male Sprague-Dawley rats underwent unilateral intra-VTA infusion of the retrograde tracer Fluorogold (FG), followed by 5 daily injections of either amphetamine (2.5 mg/kg, i.p.) or saline vehicle. Four weeks later, rats were challenged with amphetamine (1.0 mg/kg, i.p.) or saline (1.0 mL/kg, i.p.). Repeated amphetamine treatment produced locomotor sensitization upon drug challenge. Two hours later, rats were euthanized, and mPFC sections were double-immunolabeled for either Fos-FG or Fos-BDNF. Tissue from the VTA was also double-immunolabeled for Fos-BDNF. Amphetamine challenge increased Fos and BDNF expression in the mPFC regardless of prior drug experience, and further augmented mPFC BDNF expression in sensitized rats. Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.     

Effect of amphetamine on extracellular acetylcholine and monoamine levels in subterritories of the rat medial prefrontal cortex

The present study sought to investigate the contributions of the dorsal prelimbic/anterior cingulate and ventral prelimbic/infralimbic cortices to the reverse microdialysis of amphetamine (1, 10, 100, 500, and 1000 microM) on dialysate acetylcholine, choline, norepinephrine, and serotonin levels. The results demonstrate that basal levels of acetylcholine, choline, and serotonin were homogeneous within subregions of the medial prefrontal cortex. In contrast, dialysate norepinephrine levels were significantly higher in the anterior cingulate cortex compared with the infralimbic cortex. Reverse microdialysis of amphetamine in both subareas of the medial prefrontal cortex produced a dose-dependent increase in norepinephrine and serotonin levels; the magnitude of this effect was similar in both subterritories of the medial prefrontal cortex. Microinfusion of amphetamine increased dialysate acetylcholine levels in a dose-dependent manner only in the infralimbic cortex. Finally, amphetamine decreased choline levels in both subregions of the medial prefrontal cortex. The magnitude of this effect was larger in the anterior cingulate cortex compared with its infralimbic counterpart. Since depletions of frontal cortical acetylcholine result in severe cognitive deficits, the present data raise the possibility that the type of neural integrative processes that acetylcholine mediates depends, at least in part, on the subterritories that characterize the medial prefrontal cortex.     

Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting.

Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired set-shifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.     

Long-term social isolation and medial prefrontal cortex: dopaminergic and cholinergic neurotransmission

Rearing rats in social isolation has been suggested as an animal model of schizophrenia, based mainly on the similarity between the attenuation of prepulse inhibition (PPI) in isolated rats and in schizophrenic patients. The medial prefrontal cortex (mPFC) plays a major role in the pathophysiology of schizophrenia. Thus, a postmortem micropunch analysis measuring dopamine (DA), DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) in the dorsal and ventral subregion of the mPFC, the caudate putamen (CPu) and nucleus accumbens (NAc) was carried out on socially isolated or group-housed male Sprague-Dawley (SD) rats. Additionally, in vivo microdialysis with D-amphetamine (1 mg/kg ip) stimulation was performed in isolated animals and their controls, examining the ventral mPFC for acetylcholine (ACh), DOPAC and HVA levels. Simultaneously, recording of motor activity was performed. In the neurochemical postmortem tissue analysis we found no difference in any of the brain regions tested between isolated and group-reared animals. Amphetamine increased ACh levels in the mPFC, induced a decrease in DOPAC and HVA levels, and increased motor activity. A close to significant Drug x Housing interaction reflected the fact that the amphetamine-induced decrease of DOPAC was confined to the group-housed animals. In conclusion, social isolation leads only to moderate changes in the dopaminergic system in the mPFC, whereas the cholinergic system remains unaffected.     

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

Rationale Recent studies have suggested that the medial prefrontal cortex (mPFC) plays an important role in the development of sensitization to cocaine. In particular, a recent report proposed that sensitization is associated with a decreased dopamine D₂ receptor function in the mPFC. The present study was designed to further examine the involvement of mPFC dopamine D₂ receptors in cocaine sensitization.Objectives The experiments described below sought to determine the effects of acute or repeated intra-mPFC injections of the dopamine D₂ antagonist sulpiride on subsequent motor-stimulant and nucleus accumbens dopamine responses to cocaine.Methods Rats received bilateral cannulae implants above the ventral mPFC for microinjections and above the nucleus accumbens for in vivo microdialysis. Initial studies examined the effects of intra-mPFC sulpiride pretreatment on the acute motor-stimulant and nucleus accumbens dopamine responses to cocaine. Follow-up studies determined the effects of repeated intra-mPFC sulpiride injections on subsequent behavioral and nucleus accumbens dopamine responses to a cocaine challenge.Results Intra-mPFC sulpiride enhanced the cocaine-induced increases in motor activity and dopamine overflow in the nucleus accumbens. Repeated intra-mPFC sulpiride induced behavioral and neurochemical cross-sensitization to cocaine.Conclusions The data support previous findings that sensitization is associated with a decrease in dopamine D₂ receptor function in the mPFC.     

Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: involvement of dopamine in the medial prefrontal cortex

Fragile X syndrome is an X-linked form of mental retardation including, among others, symptoms such as stereotypic behaviour, hyperactivity, hyperarousal, and cognitive deficits. We hypothesized that hyperactivity and/or compromised attentional, cognitive functions may lead to impaired performance in cognitive tasks in Fmr1 knockout mice, the most widely used animal model of fragile X syndrome, and suggested that psychostimulant treatment may improve performance by acting on one or both components. Since hyperactivity and cognitive functions have been suggested to depend on striatal and prefrontal cortex dopaminergic dysfunction, we assessed whether amphetamine produced beneficial, positive effects by acting on dopaminergic corticostriatal systems. Our results show that Fmr1 knockout mice are not able to discriminate between a familiar object and a novel one in the object recognition test, thus showing a clear-cut cognitive impairment that, to date, has been difficult to demonstrate in other cognitive tasks. Amphetamine improved performance of Fmr1 knockout mice, leading to enhanced ability to discriminate novel versus familiar objects, without significantly affecting locomotor activity. In agreement with behavioural data, amphetamine produced a greater increase in dopamine release in the prefrontal cortex of Fmr1 knockout compared with the wild-type mice, while a weak striatal dopaminergic response was observed in Fmr1 knockout mice. Our data support the view that the psychostimulant ameliorates performance in Fmr1 knockout mice by improving merely cognitive functions through its action on prefrontal cortical dopamine, irrespective of its action on motor hyperactivity. These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome.     

Acquisition of intracranial self-stimulation in medial prefrontal cortex of rats facilitated by amphetamine

Two groups of rats were trained to lever press for intracranial self-stimulation (ICSS) in the medial prefrontal cortex (mPFC) using a uniform amount of stimulation for all animals. One group acquired the lever pressing task very gradually during saline pretreatment but dramatically improved its rate of acquisition during the third week of training when pretreated with d-amphetamine (0.5 mg/kg). Administration of amphetamine to the other group of rats before each of the first five training sessions greatly facilitated acquisition of the ICSS task, and a significant improvement in performance over the saline control group appeared on the third day of training. After ICSS performance had stabilized, testing the animals revealed a significant amphetamine-induced increase in rate over the dose range of 0.25 to 1.0 mg/kg. These effects of amphetamine suggest that ICSS in mPFC is sensitive to changes in catecholamine neurotransmission during both the acquisition and maintenance of this behavior.     

Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex

Acute administration of 1.0-2.0 mg/kg delta 9-tetrahydrocannabinol (delta 9-THC) increased presynaptic dopamine (DA) efflux in the medial prefrontal cortex of rats, as measured by intracerebral microdialysis in awake, behaving rats. These data are congruent with suggestions that (1) marijuana's euphorigenic effects and abuse potential may be related to augmentation of presynaptic DA mechanisms, and (2) the medial prefrontal cortex may be an important site of action for drugs of abuse in general and for delta 9-THC in particular.     

Idazoxan preferentially increases dopamine output in the rat medial prefrontal cortex at the nerve terminal level.

The effects of the alpha2-adrenoceptor antagonist idazoxan on extracellular concentrations of dopamine in major dopaminergic terminal regions in the brain were investigated by means of microdialysis in freely moving rats. Systemic administration of idazoxan markedly increased dopamine output in the medial prefrontal cortex, whereas it failed to affect dopamine efflux in the striatum or in the nucleus accumbens. Local perfusion of idazoxan via reversed dialysis markedly enhanced dopamine efflux in cortical but not subcortical areas, in which dopamine output was but little affected. Infusion of idazoxan into the ventral tegmental area did not alter the dopamine efflux in the medial prefrontal cortex. Moreover, the increase in cortical dopamine efflux induced by systemic administration of idazoxan was unaffected by tetrodotoxin perfusion of the ventral tegmental area. These data show that the alpha2-adrenoceptor antagonist idazoxan preferentially increases basal dopamine output in the medial prefrontal cortex through a local mechanism, an effect which appears largely independent of dopaminergic neuronal activity. An enhanced output of cortical dopamine may contribute to the purported augmentation by alpha2-adrenoceptor antagonists of the therapeutic effects of both antidepressant and antipsychotic drugs.     

Opioid peptides and self-stimulation of the medial prefrontal cortex in the rat

The possible involvement of opioid peptides as part of the neurochemical substrates of self-stimulation (SS) in the medial prefrontal cortex (MPC) of the rat was investigated in two different groups of rats bilaterally implanted with monopolar electrodes in the MPC. In the first group, morphine (5, 10 and 20 g) and an enkephalin analogue (BW 180) (5, 10, 20 and 40 g) and an enkephalin analogue (BW 180) (5, 10, 20 and 40 g) were injected through cannulae implanted into the lateral ventricles (IV). In the second group, naloxone (0.04, 0.4, and 1.6 g) and morphine (5, 10 and 20 g) were injected through cannulae implanted into the MPC, 1.5 mm above the tip of the stimulating electrodes. In the first group, spontaneous motor activity (SMA) was measured as a control for non-specific effects (sedation or motor dysfunction). In the second group SS, contralateral to the microinjected side, served as control. SS and SMA were measured 1 and 2 h postinjection. One hour after IV injection of morphine SS was not affected, although SMA was decreased. Two hours postinjection, on the contrary, SS was increased while SMA remained decreased. Similar effects were found with IV microinjections of BW 180. Naloxone, intraperitoneally injected, reversed all these effects. Naloxone or morphine injected intracerebrally (MPC) produced no changes in SS either in the injected or in the contralateral side, which served as control. The present results suggest that the effects found with IV injections of opioids on SS of the MPC are indirect (through activation of other brain areas) and not mediated by a direct action on the neurochemical substrates underlying this behaviour in the MPC.Supported by the European Training Program in Brain and Behaviour Research Present address: University of Oxford, Department of Pharmacology, South Parks Road, Oxford OX1 3QT, Great Britain     

Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens

A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin_2C receptor (5-HT_2CR) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT_2CR located in the medial prefrontal cortex (mPFC) has also been shown to inhibit cocaine-induced behaviors perhaps through inhibition of DA function in the NAc.Using in vivo microdialysis in halothane-anesthetized rats, we tested this hypothesis by assessing the influence of mPFC 5-HT_2CRs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT_2CR agonist Ro 60-0175 at 5 μg/0.2 μl, but not 1 μg/0.2 μl, potentiated the increase in accumbal DA outflow induced by the intraperitoneal administration of 10 mg/kg of cocaine. Conversely, cocaine-induced accumbal DA outflow was significantly reduced by the intra-mPFC injection of the selective 5-HT_2CR antagonist SB 242084 (0.5 μg/0.2 μl) or SB 243213 (0.5 and 1 μg/0.2 μl).These results show that mPFC 5-HT_2CRs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT_2CRs on accumbal DA output is dependent on the functional balance among different 5-HT_2CR populations located within the mesocorticoaccumbens system, and that 5-HT_2CRs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.     

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.     

Homovanillic acid in rat caudate and prefrontal cortex following phencyclidine and amphetamine

Phencyclidine (PCP) and d-amphetamine (AMP) had different effects upon homovanillic acid (HVA) levels in rat prefrontal cortex as compared to caudate. Lower doses of PCP increased HVA in prefrontal cortex only while lower doses of AMP decreased HVA in caudate alone. Higher doses of both drugs produced a decreased HVA in caudate and an increase in prefrontal cortex. At some doses PCP may selectively activate mesocortical dopaminergic neurons.     

Electrophysiological effects of phencyclidine in the medial prefrontal cortex of the rat

The effects of local applications of phencyclidine (PCP) and dopamine (DA) on neurons of the medial prefrontal cortex were investigated using single unit recording techniques. The activity of the majority of cells in the deeper layers of the medial prefrontal cortex was depressed by both phencyclidine and DA, whereas increases, as well as decreases, in the firing rates were observed in cells located in the superficial cortical layers. The stereospecificity of the responses of deeper cells to phencyclidine was demonstrated using the enantiomers of 1-(-1-phenylcyclohexyl)-3-methylpiperidine (PCMP). Phencyclidine was found to be 1.5 times more potent than (+) PCMP and 3 times more potent than (-) PCMP. Finally, the DA receptor antagonist fluphenazine, blocked the phencyclidine-elicited depressions of unit activity in the deep prefrontal cortex. Taken together, the data indicate that the DA-like effects of phencyclidine on neurons of the medial prefrontal cortex are mediated by DA receptors and provide pharmacological support for the idea that psychomotor stimulant drugs have specific actions on targets of the ventral tegmental area (A10) dopamine system.     

Role of the simultaneous enhancement of NMDA and dopamine D1 receptor-mediated neurotransmission in the effects of clozapine on phencyclidine-induced acute increases in glutamate levels in the rat medial prefrontal cortex

Clozapine (CLZ) can improve both the positive and negative symptoms of treatment-resistant schizophrenia (TRS), which does not respond to typical antipsychotics. This suggests that elucidation of the pharmacological mechanism for CLZ could lead to further clarification of the pathophysiology of TRS. This study examined the effects of CLZ on phencyclidine (PCP)-induced hyperlocomotion and on the acute increases in glutamate levels that occur in the medial prefrontal cortex (mPFC) in order to test the hypothesis that CLZ effect is associated with the simultaneous enhancement of N-methyl-d-aspartate (NMDA) and dopamine D₁ receptor-mediated neurotransmission. CLZ effect on PCP-induced hyperlocomotion and increases in glutamate levels were examined by using behavioral rating scores and in vivo microdialysis, respectively. CLZ and haloperidol (HAL) dose-relatedly attenuated PCP-induced hyperlocomotion, and concentration-relatedly blocked PCP-induced acute increases in glutamate levels in the mPFC, with the decrease in saline-induced locomotor activity induced by CLZ being much weaker than that induced by HAL. CLZ also blocked, in a dose-related manner, acute increases in glutamate levels in the mPFC that were induced by local perfusion with a competitive NMDA receptor antagonist, CPP, in this region. Although an enhanced blocking effect of the sub-threshold concentration of NMDA perfusion on PCP-induced acute increases in glutamate levels in the mPFC was noted after co-perfusion with a dopamine D₁ receptor agonist, SKF-38393, perfusion with SKF-38393 did not reverse the CLZ blocking of PCP-induced increases in glutamate levels. Therefore, CLZ may block PCP-induced acute increases in glutamate levels in the mPFC by an enhancement of the NMDA receptor-mediated neurotransmission that is not accelerated by an enhanced dopaminergic transmission via dopamine D₁ receptors. This blocking effect may partially explain the CLZ-induced attenuation of PCP-induced hyperlocomotion.     

Time-dependent effects of repeated cocaine administration on dopamine transmission in the medial prefrontal cortex

The medial prefrontal cortex (mPFC) has been implicated in the development of behavioral sensitization, which is the progressive enhancement of locomotor activity that occurs with repeated administration of psychostimulants. Previous data suggest that mPFC dopamine (DA) transmission may be attenuated in cocaine-sensitized animals, but the onset and duration of this effect have not been investigated. After recovery from stereotaxic surgeries, animals were given four daily injections of saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) and were subsequently challenged with saline or cocaine after 1, 7 or 30 d of withdrawal, on which days in vivo microdialysis of the mPFC was conducted simultaneously with monitoring of locomotor activity. Compared to acutely administered controls, the results in cocaine-pretreated animals were as follows: 1d of withdrawal was associated with a significant attenuation in cocaine-induced locomotion and mPFC DA overflow; after 7d, behavioral sensitization was accompanied by a significant attenuation in cocaine-induced elevations in mPFC DA levels; 30 d of withdrawal led to the expression of sensitized behaviors paralleled by an augmentation in cocaine-induced mPFC DA. These data suggest that repeated cocaine produces temporally distinct behavioral effects associated with alterations in mPFC DA responsiveness to cocaine that may be involved in the development of behavioral sensitization.     

Increase of extracellular dopamine in the medial prefrontal cortex during spontaneous and naloxone-precipitated opiate abstinence

Abstinence from chronic morphine has been shown to reduce extracellular dopamine in the nucleus accumbens as measured by brain microdialysis (Acquas et al. 1991). In the present study, we investigated if similar changes take place in the prefrontal cortex. Withdrawal from a schedule of increasing doses of morphine administered intraperitoneally twice a day for 9 days up to a daily dose of 60 mg/kg resulted in doubling of basal extracellular concentrations of dopamine in the prefrontal cortex and in a mild withdrawal syndrome (ptosis, piloerection, hunched-back posture). Administration of a low dose of naloxone (0.5 mg/kg SC) to rats withdrawn from chronic morphine resulted in a full withdrawal syndrome with wet dog shakes and diarrhoea and an increase of extracellular dopamine that peaked at 40 min and returned to the pre-naloxone values by 80 min. The results show that dopamine neurotransmission in the medial prefrontal cortex responds to opiate withdrawal in a manner opposite to dopamine transmission in the nucleus accumbens and indicate that the dopamine system is affected by abstinence in a topographically specific manner, consistent with a different functional role of mesocortical as compared to mesolimbic dopamine systems.     

Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex

The novel antidepressant mirtazapine has been shown to increase extracellular noradrenaline and dopamine in the medial prefrontal cortex. Our previous studies indicate that extracellular dopamine in the cerebral cortex originates largely from noradrenergic terminals, such release being controlled by alpha(2)-adrenoceptors. Because mirtazapine inhibits alpha(2)-adrenoceptors, the possibility that it might corelease dopamine and noradrenaline was investigated. By means of microdialysis, the effect of mirtazapine on extracellular dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline in the medial prefrontal cortex, densely innervated by dopaminergic and noradrenergic neurons, and in the occipital cortex, receiving equal noradrenergic but scarce dopaminergic projections, was compared. Basal extracellular concentration of noradrenaline was similar in both cortices, while dopamine in the occipital cortex was only about 50% lower than in the medial prefrontal cortex, reflecting noradrenergic rather than dopaminergic projections. The intraperitoneal (i.p.) administration of mirtazapine (5 and 10 mg/kg) increased extracellular dopamine, DOPAC and noradrenaline to approximately the same extent in both cortices, an effect totally suppressed by the alpha(2)-adrenoceptors agonist clonidine (0.15 mg/kg, i.p.). To exclude the possibility that mirtazapine-induced increase in dopamine might result from reduced dopamine removal from extracellular space, noradrenaline and dopamine uptake mechanisms were blocked by perfusing 100 microM desipramine into either cortex. The combined i.p. administration of mirtazapine (5 mg/kg) and the local perfusion of desipramine produced an additional increase in extracellular dopamine, DOPAC and noradrenaline in the medial prefrontal cortex and occipital cortex compared with the increase produced by either drug given alone. The results suggest that mirtazapine by inhibiting alpha(2)-adrenoceptors produces a corelease of noradrenaline and dopamine from noradrenergic terminals in the cerebral cortex.