Dopamine In Medial Prefrontal Cortex Research Articles

Prefrontal cortical dopamine deficit may cause impaired glucose metabolism in schizophrenia

The brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between negative symptoms of schizophrenia and high fasting blood glucose. We then show that glucose metabolism and negative symptoms are improved when intermittent theta burst stimulation (iTBS) on prefrontal cortex (PFC) is performed in patients with predominantly negative symptoms of schizophrenia. These findings led us to hypothesize that the prefrontal cortical dopamine deficit, which is known to be associated with negative symptoms, may be responsible for abnormal glucose metabolism in schizophrenia. To explore this, we optogenetically and chemogenetically inhibited the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine projection in mice and found both procedures caused glucose intolerance. Moreover, microinjection of dopamine two receptor (D2R) neuron antagonists into mPFC in mice significantly impaired glucose tolerance. Finally, a transgenic mouse model of psychosis named Disc1tr exhibited depressive-like symptoms, impaired glucose homeostasis, and compared to wild type littermates reduced D2R expression in prefrontal cortex.

Long-term memory, synaptic plasticity and dopamine in rodent medial prefrontal cortex: Role in executive functions.

Mnemonic functions, supporting rodent behavior in complex tasks, include both long-term and (short-term) working memory components. While working memory is thought to rely on persistent activity states in an active neural network, long-term memory and synaptic plasticity contribute to the formation of the underlying synaptic structure, determining the range of possible states. Whereas, the implication of working memory in executive functions, mediated by the prefrontal cortex (PFC) in primates and rodents, has been extensively studied, the contribution of long-term memory component to these tasks received little attention. This review summarizes available experimental data and theoretical work concerning cellular mechanisms of synaptic plasticity in the medial region of rodent PFC and the link between plasticity, memory and behavior in PFC-dependent tasks. A special attention is devoted to unique properties of dopaminergic modulation of prefrontal synaptic plasticity and its contribution to executive functions.

Repeated administration of rapastinel produces exceptionally prolonged rescue of memory deficits in phencyclidine-treated mice

Rapastinel, a positive N-methyl-D-aspartate receptor (NMDAR) modulator with rapid-acting antidepressant properties, rescues memory deficits in rodents. We have previously reported that a single intravenous dose of rapastinel, significantly, but only transiently, prevented and rescued deficits in the novel object recognition (NOR) test, a measure of episodic memory, produced by acute or subchronic administration of the NMDAR antagonists, phencyclidine (PCP) and ketamine. Here, we tested the ability of single and multiple subcutaneous doses per day of rapastinel to restore NOR and operant reversal learning (ORL) deficits in subchronic PCP-treated mice. Rapastinel, 1 or 3 mg/kg, administered subcutaneously, 30 min before NOR or ORL testing, respectively, transiently rescued both deficits in subchronic PCP mice. This effect of rapastinel on NOR and ORL was mammalian target of rapamycin (mTOR)-dependent. Most importantly, 1 mg/kg rapastinel given twice daily for 3 or 5 days, but not 1 day, restored NOR for at least 9 and 10 weeks, respectively, which is an indication of neuroplastic effects on learning and memory. Both rapastinel (3 mg/kg) and ketamine (30 mg/kg), moderately increased the efflux of dopamine, norepinephrine, and serotonin in medial prefrontal cortex; however, only ketamine increased cortical glutamate efflux. This observation was likely the basis for the contrasting effects of the two drugs on cognition.

Concomitant D1 and D2 dopamine receptor agonist infusion in prelimbic cortex is required to foster extinction of amphetamine-induced conditioned place preference

Dopamine (DA) in medial prefrontal cortex is crucial in extinction of aversive or appetitive experiences. Although attention has been mostly focused on the infralimbic area of prefrontal cortex, a role of the prelimbic (PL) area has been envisaged pointing to DA transmission in the extinction of drug conditioned behavior. Evidence shows that DA exerts its action also via both D1 and D2 receptor subtypes.Here we investigated the effects of D1 and D2 receptor agonist microinfusion in the PL cortex of C57BL/6J mice on expression and extinction of amphetamine-induced conditioned place preference (CPP), in order to ascertain the effects of selective vs concomitant receptor subtypes stimulation.SKF38393 and Quinpirole were used at doses not impairing expression of amphetamine-induced CPP on the day of infusion. Acute infusion of each agonist alone did not affect extinction in subsequent days in comparison with Vehicle-treated mice, while concomitant infusion of both agonists produced a clear-cut advance of extinction of preference for the compartment previously paired with amphetamine.These results show that concomitant stimulation of D1 and D2 receptors in PL is required to foster extinction suggesting a synergic action between receptors or a heteromeric receptor involvement.

Effects of muscarinic M1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.

Cocaine addiction is a chronic illness characterized by maladaptive drug-induced neuroplastic changes that confer lasting vulnerability to relapse. Over several weeks we observed the effects of the M1 receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. food choice procedure. The drug showed unusual long-lasting effects, as rats gradually stopped self-administering cocaine, reallocating behavior towards the food reinforcer. The effect lasted as long as tested and at least 4 weeks. To begin to elucidate how VU0364572 modulates cocaine self-administration, we then examined its long-term effects using dual-probe in vivo dopamine and glutamate microdialysis in nucleus accumbens and medial prefrontal cortex, and ex vivo striatal dopamine reuptake. Microdialysis revealed marked decreases in cocaine-induced dopamine and glutamate outflow 4 weeks after VU0364572 treatment, without significant changes in dopamine uptake function. These lasting and marked effects of M1 receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M1 receptors are known to modulate medium spiny neuron responses to corticostriatal glutamatergic signaling acutely, and we hypothesize that VU0364572 may oppose the addiction-related effects of cocaine by causing lasting changes in this system.

Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity

RationaleAberrant glutamatergic, dopaminergic, and GABAergic neurotransmission has been implicated in schizophrenia. Cariprazine reverses the behavioral effects observed in the rat phencyclidine (PCP)-induced model of schizophrenia; however, little is known about its in vivo neurochemistry.ObjectivesThe study aims to compare the effects of cariprazine and aripiprazole on PCP-induced changes in the extracellular levels of glutamate, dopamine, serotonin, noradrenaline, and GABA in the rat medial prefrontal cortex (mPFC), and on locomotor activation.MethodsMicrodialysis was performed in awake rats with probes placed into the mPFC. Rats (n = 7/group) received vehicle (saline), cariprazine (0.05, 0.2, or 0.8 mg/kg), or aripiprazole (3 or 20 mg/kg) via gavage. After 60 min, 5 mg/kg PCP was administered intraperitoneally (i.p.). Samples were taken before drug administration, during pretreatment, and after PCP injection. Locomotor activity recording and microdialysis sampling occurred simultaneously.ResultsPCP treatment increased extracellular levels of all the neurotransmitters tested except GABA, for which there were no significant changes. Cariprazine and aripiprazole dose-dependently inhibited the PCP-induced increases of tested neurotransmitters. Overall effects were significant for higher cariprazine doses and both aripiprazole doses for glutamate and noradrenaline, for higher cariprazine doses and 20 mg/kg aripiprazole for dopamine, and for 0.8 mg/kg cariprazine and 20 mg/kg aripiprazole for serotonin and locomotor activity.ConclusionBoth cariprazine and aripiprazole dose-dependently attenuated PCP-induced hyperlocomotion and acute increases in glutamate, dopamine, noradrenaline, and serotonin levels in the mPFC; cariprazine was approximately 5-fold more potent than aripiprazole.

Pharmacological modulation of AMPA receptor phosphorylation by dopamine and muscarinic receptor agents in the rat medial prefrontal cortex

Two key transmitters in the medial prefrontal cortex (mPFC), dopamine and acetylcholine, are believed to interact with each other to modulate local glutamatergic transmission, although molecular mechanisms underlying their crosstalk are poorly understood. Here we investigated effects of pharmacological manipulations of dopamine and muscarinic receptors on phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult rat mPFC in vivo. We found that an agonist selective for Gαs-coupled dopamine D1 receptors, SKF81297, increased AMPA receptor GluA1 subunit phosphorylation at a protein kinase A-sensitive site (S845), while SKF81297 had no effect on GluA1 phosphorylation at S831. An agonist for Gαi/o-coupled dopamine D2 receptors, quinpirole, also increased S845 but not S831 phosphorylation. When coinjected, the two agonists induced an additive increase in S845 phosphorylation. The D1 receptor antagonist SCH23390 blocked the SKF81297/quinpirole-stimulated S845 phosphorylation. The D2 antagonist eticlopride also partially blocked S845 responses to SKF81297/quinpirole. VU0152100, a positive allosteric modulator selective for Gαi/o-coupled muscarinic M4 receptors, reduced the S845 phosphorylation induced by SKF81297 and quinpirole injected alone or together. In contrast, coinjection of subthreshold doses of tropicamide, an M4 antagonist, and SKF81297 facilitated S845 phosphorylation. Additionally, coadministered SFK81297 and quinpirole increased the abundance of mPFC GluA1 at extrasynaptic sites. These data reveal that both D1 and D2 receptors upregulate GluA1 phosphorylation in mPFC neurons probably via a direct and indirect mechanism, respectively. The indirect mechanism involves M4 receptors which generally counteract the effect of dopamine on GluA1 phosphorylation.

L-Tyrosine availability affects basal and stimulated catecholamine indices in prefrontal cortex and striatum of the rat

We previously found that L-tyrosine (L-TYR) but not D-TYR administered by reverse dialysis elevated catecholamine synthesis in vivo in medial prefrontal cortex (MPFC) and striatum of the rat (Brodnik et al., 2012). We now report L-TYR effects on extracellular levels of catecholamines and their metabolites. In MPFC, reverse dialysis of L-TYR elevated in vivo levels of dihydroxyphenylacetic acid (DOPAC) (L-TYR 250–1000 μM), homovanillic acid (HVA) (L-TYR 1000 μM) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (L-TYR 500–1000 μM). In striatum L-TYR 250 μM elevated DOPAC. We also examined L-TYR effects on extracellular dopamine (DA) and norepinephrine (NE) levels during two 30 min pulses (P2 and P1) of K+ (37.5 mM) separated by t = 2.0 h. L-TYR significantly elevated the ratio P2/P1 for DA (L-TYR 125 μM) and NE (L-TYR 125–250 μM) in MPFC but lowered P2/P1 for DA (L-TYR 250 μM) in striatum. Finally, we measured DA levels in brain slices using ex-vivo voltammetry. Perfusion with L-TYR (12.5–50 μM) dose-dependently elevated stimulated DA levels in striatum. In all the above studies, D-TYR had no effect. We conclude that acute increases within the physiological range of L-TYR levels can increase catecholamine metabolism and efflux in MPFC and striatum. Chronically, such repeated increases in L-TYR availability could induce adaptive changes in catecholamine transmission while amplifying the metabolic cost of catecholamine synthesis and degradation. This has implications for neuropsychiatric conditions in which neurotoxicity and/or disordered L-TYR transport have been implicated.

Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon

Motivated behaviors and many psychopathologies typically involve changes in dopamine release from the projections of the ventral tegmental area (VTA) and/or the substantia nigra pars compacta (SNc). The morphogen Sonic Hedgehog (Shh) specifies fates of midbrain dopamine neurons, but VTA-specific effects of Shh signaling are also being uncovered. In this study, we assessed the role of the Shh receptor Cdon in the development of VTA and SNc dopamine neurons. We find that Cdon is expressed in the proliferating progenitor zone of the embryonic ventral midbrain and that the number of proliferating cells in this region is increased in mouse Cdon−/− embryos. Consistent with a role of Shh in the regulation of neuronal proliferation in this region, we find that the number of tyrosine hydroxylase (TH)-positive neurons is increased in the VTA of Cdon−/− mice at birth and that this effect endures into adulthood. In contrast, the number of TH-positive neurons in the SNc is not altered in Cdon−/− mice at either age. Moreover, adult Cdon−/− mice have a greater number of medial prefrontal cortex (mPFC) dopamine presynaptic sites, and increased baseline concentrations of dopamine and dopamine metabolites selectively in this region. Finally, consistent with increased dopamine function in the mPFC, we find that adult Cdon−/− mice fail to exhibit behavioral plasticity upon repeated amphetamine treatment. Based on these data, we suggest that Cdon plays an important role encoding the diversity of dopamine neurons in the midbrain, influencing both the development of the mesocortical dopamine pathway and behavioral outputs that involve this neural circuitry.

Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies

Dopamine (DA) neurotransmission, particularly the ventral tegmental area-nucleus accumbens (VTA-NAcc) projection, underlies reward and aversion processing, and deficient DA function could underlie motivational impairments in psychiatric disorders. 6-hydroxydopamine (6-OHDA) injection is an established method for chronic DA depletion, principally applied in rat to study NAcc DA regulation of reward motivation. Given the increasing focus on studying environmental and genetic regulation of DA function in mouse models, it is important to establish the effects of 6-OHDA DA depletion in mice, in terms of reward and aversion processing. This mouse study investigated effects of 6-OHDA-induced NAcc DA depletion using the operant behavioural test battery of progressive ratio schedule (PRS), learned non-reward (LNR), learned helplessness (LH), treadmill, and in addition Pavlovian fear conditioning. 6-OHDA NAcc DA depletion, confirmed by ex vivo HPLC-ED, reduced operant responding: for gustatory reward under effortful conditions in the PRS test; to a stimulus recently associated with gustatory non-reward in the LNR test; to escape footshock recently experienced as uncontrollable in the LH test; and to avoid footshock by physical effort in the treadmill test. Evidence for specificity of effects to NAcc DA was provided by lack of effect of medial prefrontal cortex DA depletion in the LNR and LH tests. These findings add significantly to the evidence that NAcc DA is a major regulator of behavioural responding, particularly at the motivational level, to both reward and aversion. They demonstrate the suitability of mouse models for translational study of causation and reversal of pathophysiological DA function underlying motivation psychopathologies.

Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex.

Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after exvivo tissue extraction or invivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors. Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release.

Dcc haploinsufficiency results in blunted sensitivity to cocaine enhancement of reward seeking

Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild-type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine-induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence.

Amphetamine in adolescence disrupts the development of medial prefrontal cortex dopamine connectivity in a DCC-dependent manner.

Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.

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.

Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline

Hypobaric hypoxia (HH), an environmental stress resulting from ascent to high altitude, affects perception, memory, judgment, and attention, resulting in degradation of many aspects of normal functioning. Alpha 2A adrenergic agonist, guanfacine proved to be beneficial in the amelioration of neurological outcomes of many neuropsychiatric disorders involving adrenergic imbalance and neurodegeneration. Adrenergic dysregulation and neuronal damage have been implicated in hypoxia-induced cognitive deficits, however, efficacy of guanfacine as a countermeasure for HH-induced cognitive decline remains to be evaluated. We, therefore, have studied the effect of this drug on the HH-induced cognitive deficits, adrenergic dysfunction and neuronal damage. Rats were exposed to HH at a simulated altitude of 25,000 feet for 7days and received an IM injection of either saline or guanfacine at a dose of 1mg/kg. Adrenergic transmission was evaluated by biomarkers i.e. norepinephrine (NE), dopamine (DA) and tyrosine hydroxylase (TH) in medial prefrontal cortex (PFC) by biochemical and immunohistochemical assays. Spine and dendritic morphology of pyramidal neurons in layer II of medial PFC was studied using Golgi–Cox staining and Neurolucida neuronal tracing. The cognitive performance was assessed by Delayed Alternation Task using a T-Maze. There was a significant reduction in HH-induced increases in NE, DA and TH levels with guanfacine treatment. Guanfacine rescued HH-induced dendritic atrophy and mushroom type spine loss. The spatial working memory deficits induced by HH were significantly ameliorated with guanfacine treatment. Furthermore, the cognitive performance showed a positive correlation with dendritic arbors and spine numbers. These results showed that the HH-induced cognitive decline is associated with adrenergic dysregulation and neuronal damage in layer II of medial PFC, and that guanfacine treatment during HH ameliorated these functional and morphological deficits. The study suggests a potential role of the alpha-2A adrenergic agonist, guanfacine, in amelioration of PFC dysfunction caused by high altitude exposure.

Role of medial prefrontal cortex dopamine in age differences in response to amphetamine in rats: Locomotor activity after intra‐mPFC injections of dopaminergic ligands

Changes in medial prefrontal cortex (mPFC) dopamine receptor expression and in mPFC projections to the nucleus accumbens in adolescence suggest that there may be age differences in the regulation of drug-related behavior by the mPFC. The age-specific role of prelimbic D1 dopamine receptors on amphetamine-induced locomotor activity was investigated. In experiment 1, rats aged postnatal day 30 (P30), P45, and P75, corresponding to early and late adolescence and adulthood, were given an injection of D1 and D2 antagonists into the prelimbic mPFC before a systemic injection of 1.5 mg/kg of amphetamine and locomotor activity was recorded. In experiment 2, effects of intra-prelimbic injections of a D1 agonist and antagonist on locomotor activity produced by a lower dose (0.5 mg/kg) of amphetamine were investigated. D2 receptor antagonist did not alter amphetamine-induced activity, whereas the D1 receptor antagonist reduced activity produced by 1.5 mg/kg of amphetamine more in P30 than in P45 and P75 rats. In addition, D1 agonist enhanced the locomotor activating effects of 0.5 mg/kg of amphetamine in adolescent rats and decreased activity in adult rats. These results suggest that insufficient activation of mPFC D1 receptors may underlie the reduced activity at the low dose of amphetamine in early adolescent compared to adult rats.

Ginkgo bilobaleaf extract (EGb 761®) and its specific acylated flavonol constituents increase dopamine and acetylcholine levels in the rat medial prefrontal cortex: possible implications for the cognitive enhancing properties of EGb 761®

Experimental and clinical data suggest that the Ginkgo biloba standardized extract EGb 761® exerts beneficial effects in conditions which are associated with impaired cognitive function. However, the neurochemical correlates of these memory enhancing effects are not yet fully clarified. The aim of this study was to examine the effect of repeated oral administration of EGb 761® and some of its characteristic constituents on extracellular levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT), acetylcholine (ACh) and the metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the medial prefrontal cortex (mPFC) of awake rats by use of in vivo microdialysis technique. Subacute (14 days, once daily), but not acute, oral treatment with EGb 761® (100 and 300 mg/kg) or the flavonoid fraction, which represents about 24% of the whole extract caused a significant and dose-dependent increase in extracellular DA levels in the mPFC. Repeated administration of EGb 761® also caused a modest but significant increase in the NA levels, whereas the concentrations of 5-HT and those of the metabolites DOPAC, HVA and 5-HIAA were not affected. The same treatment regimen was used in a subsequent study with the aim of investigating the effects of two Ginkgo-specific acylated flavonols, 3-O-(2''-O-(6'''-O-(p-hydroxy-trans-cinnamoyl)-β-D-glucosyl)-α-L-rhamnosyl)quercetin (Q-ag) and 3-O-(2''-O-(6'''-O-(p-hydroxy-trans-cinnamoyl)-β-D-glucosyl)-α-L-rhamnosyl)kaempferol (K-ag). Both compounds together represent about 4.5% of the whole extract. Repeated oral treatment with Q-ag (10 mg/kg) for 14 days caused a significant increase in extracellular DA levels of 159% and extracellular acetylcholine (ACh) levels of 151% compared to controls. Similarly, administration of K-ag (10 mg/kg) induced a significant rise of DA levels to 142% and ACh levels to 165% of controls, whereas treatment with isorhamnetin, an O-methylated aglycon component of EGb 761® flavonol glycosides had no effect. None of the tested flavonoids had a significant effect on extracellular DOPAC and HVA levels. The present findings provide evidence that the subacute treatment with EGb 761® and its flavonol constituents increases DA and ACh release in the rat mPFC, and suggest that the two Ginkgo-specific acylated flavonol glycosides Q-ag and K-ag are active constituents contributing to these effects. As seen for isorhamnetin, the effect on neurotransmitter levels seems not to be a general effect of flavonols but rather to be a specific action of acylated flavonol glycosides which are present in EGb 761®. The direct involvement of these two flavonol derivatives in the increase of dopaminergic and cholinergic neurotransmission in the prefrontal cortex may be one of the underlying mechanisms behind the reported effects of EGb 761® on the improvement of cognitive function.

Repeated exposure to cocaine alters medial prefrontal cortex dopamine D2‐like receptor modulation of glutamate and dopamine neurotransmission within the mesocorticolimbic system

Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Previous studies have demonstrated that sensitization to cocaine is associated with a decrease in dopamine D₂ receptor function in the medial prefrontal cortex. The present report tested the hypothesis that reduced medial prefrontal cortex D₂ receptor function as a result of repeated cocaine exposure results in augmented excitatory transmission to the nucleus accumbens and ventral tegmental area, possibly as a partial result of enhanced inhibition of local dopamine release. Dual probe microdialysis experiments were conducted in male Sprague-Dawley rats 1, 7 or 30 days following the last of four daily injections of saline (1.0 mL/kg) or cocaine (15 mg/kg). Infusion of quinpirole (0.01, 1.0 and 100 μM), a D₂-like receptor agonist, into the medial prefrontal cortex produced a dose-dependent decrease in cortical, nucleus accumbens and ventral tegmental area extracellular glutamate levels in control but not sensitized animals. Quinpirole also reduced basal dopamine levels in the medial prefrontal cortex in sensitized animals following 1 day of withdrawal from cocaine. Following 30 days of withdrawal, quinpirole also reduced dopamine levels in sensitized animals relative to saline controls, but not relative to baseline levels. These findings indicate that the expression of sensitization to cocaine is associated with altered modulation of mesocorticolimbic glutamatergic transmission at the level of the medial prefrontal cortex.

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’.

The alpha-7 receptor agonist EVP-6124 increases dopamine and glutamate efflux in rat medial prefrontal cortex and nucleus accumbens

The alpha-7 receptor agonist EVP-6124 increases dopamine and glutamate efflux in rat medial prefrontal cortex and nucleus accumbens