Regulation of dopamine synthesis in the medial prefrontal cortex is mediated by release modulating autoreceptors: studies in vivo

Previous studies have suggested that rat mesoprefrontal dopamine (DA) neurons are devoid of synthesis and impulse-modulating autoreceptors. We have examined further the presynaptic regulatory parameters of these neurons in vivo and have developed a model based on the following observations. Prefrontal DA turnover, measured as the rate of DA disappearance after inhibition of tyrosine-3-monooxygenase by alpha-methyltyrosine, is relatively rapid (T1/2 = 15 min) and is suppressed by apomorphine (50 micrograms/kg) pretreatment, suggesting that prefrontal DA release is sensitive to regulation by DA agonists. Prefrontal DOPA accumulation (measured after inhibition of decarboxylase with m-hydroxybenzylamine) is also diminished after administration of DA agonists, such as apomorphine, BHT-920, 3-[4-(4-phenyl)-1,2,3,6-tetrahydropyridyl-1] butyl indole (EMD 23 448) and 3-(3-hydroxyphenyl)-N-n-propylpiperidine[(+)-3-PPP]. However, the apomorphine-induced inhibition of prefrontal, but not striatal, DOPA synthesis is blocked by either cessation of impulse-dependent DA release (after gamma-butyrolactone) or by depletion of intraneuronal DA (after reserpine), suggesting that DA agonists affect prefrontal DA synthesis only in the presence of DA release. Inhibition of impulse flow after administration of gamma-butyrolactone does not increase the rate of prefrontal tyrosine hydroxylation in vivo, suggesting that synaptic DA does not influence medial prefrontal DA synthesis under basal conditions. After treatment with m-hydroxybenzylamine (30 min), prefrontal DA levels are substantially reduced (-70%) and inhibition of prefrontal synthesis by DA agonists is associated with an increase in intraneuronal DA relative to m-hydroxybenzylamine-treated controls, suggesting that agonist-induced synthesis inhibition is a consequence of activation of release-modulating autoreceptors with a subsequent decrease in DA release and increase in end product inhibition of tyrosine hydroxylation. These and other data in the accompanying paper suggest that the nerve terminals of mesoprefrontal DA neurons are unique in their constitution of functional autoreceptors in that they contain only a release-modulating mechanism.     

Differential effects of phorbol ester on prefrontal cortex and striatal dopamine terminals: dependence on rate and duration of stimulation

Compared to the nigrostriatal dopamine (DA) neurons, the mesocortical DA neurons projecting to the prefrontal cortex (PFC) are able to sustain higher levels of release when driven at high stimulation frequencies. The effect of a well known activator of protein kinase C (PKC), 4-beta-phorbol-12, 13-dibutyrate (PDBu), were compared on PFC and striatal DA terminals. DA release was monitored from slices of the rabbit PFC and striatum obtained from the same animal. The PKC activator, PDBu (30-1000 nM) enhanced the stimulation-evoked release (SER) of DA from PFC and striatum. The magnitude of the facilitation of DA release produced by PDBu was much greater from the PFC than from the striatum. In the striatum, PDBu produced a bell-shaped dose-response curve, i.e., 0.03 and 1 microM PDBu enhanced SER of DA by 25%, whereas 0.1 and 0.3 microM PDBu enhanced DA release by 60 and 100%, respectively (1 Hz, 120 pulses). In the PFC, 0.03 microM enhanced the SER of DA by 70% and 1 microM by 250% (1 Hz, 120 pulses). In addition, in the PFC, PDBu enhance the basal release of DA (+65% at 1 microM); this effect was not seen in the striatum. The inactive isomer, 4-alpha-phorbol-12, 13-dibutyrate (0.03-1 microM) failed to increase the SER and the basal release of DA from PFC or striatum. The SER of DA was dependent on the rate and duration of stimulation. However, under all conditions of stimulation studied DA release from PFC was always greater than from the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)     

M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse.

Muscarinic autoreceptors modulate cholinergic neurotransmission in animals ranging from insects to humans. No previous studies have characterized autoreceptor modulation of acetylcholine (ACh) release in prefrontal cortex of intact mouse. Data obtained from experiments in 45 mice considered ACh as a phenotype and tested the hypothesis that pharmacologically defined M2 receptors modulate ACh release in prefrontal cortex of C57BL/6J mouse. In vivo microdialysis quantified ACh release during delivery of Ringer's (control) or Ringer's containing muscarinic receptor antagonists. The lowest concentration of each antagonist [scopolamine, pirenzepine, or 11-2[(-[(diethylamino)methyl]-1-piperidinyl)-acetyl]-5,11-dihydro-6H-pyrido(2,3-b)(1,4)-benzodiazepine-one (AF-DX116)] that significantly increased ACh release was determined and defined as the minimum ACh-releasing concentration. Dialysis delivery of scopolamine caused a concentration-dependent increase in ACh release, consistent with the existence of muscarinic autoreceptors. The order of potency for causing increased ACh release was scopolamine = AF-DX116 > pirenzepine. Administration of pertussis toxin into prefrontal cortex blocked the AF-DX116-induced increase in ACh release. These findings support the conclusion that M2 receptors modulate ACh release in C57BL/6J mouse prefrontal cortex. Nearly every human gene has a mouse homolog and the appeal of mouse models is reinforced by the identification of mouse genes causing phenotypic deviants. The present data encourage comparative phenotyping of cortical ACh release in additional mouse strains.     

Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum

Research has shown that there are important neurochemical differences between the mesocortical and mesostriatal dopamine systems. The work reported in this paper has sought to compare the regulation of dopamine release in the medial prefrontal cortex and the anterior caudate-putamen. In vivo microdialysis was used to recover dialysate fluid for subsequent assay for dopamine concentrations. The responses to D2 antagonist (haloperidol) administration, which has been shown to increase impulse-dependent dopamine release, were compared. Results demonstrated a diminished effect of systemic haloperidol administration on dopamine efflux in the prefrontal cortex. The responses to systemic administration of a nonimpulse-dependent, transporter-mediated, dopamine releaser (d-amphetamine) were also contrasted. Results again demonstrated a diminished pharmacological effect in the cortex. The potential interaction of stimulation of these two types of dopamine release was examined by coadministration of these compounds. Haloperidol pretreatment dramatically potentiated the dopamine-releasing effect of amphetamine administration. This effect was observed in both the cortex and the striatum. Subsequent work demonstrated that this effect of haloperidol was mediated by D2-like receptors in the prefrontal cortex. These results are discussed in relation to other neurochemical and neuroanatomical studies demonstrating sparse densities of dopamine transporter sites and dopamine D2 receptors in the cortex compared with the striatum. They demonstrate a functional correlate to the recently reported, largely extrasynaptic localization of dopamine transporter sites in the prefrontal cortex. Furthermore, they demonstrate the existence of cortical D2-like autoreceptors that may normally be "silent" under basal conditions.     

Dopamine autoreceptors modulate the in vivo release of dopamine in the frontal, cingulate and entorhinal cortices

The regulation by autoreceptors of dopamine release in the rat neocortex was inferred from measurements of 3-methoxytyramine after the peripheral injection of a selective (CGS 15855A) or nonselective (apomorphine) dopamine autoreceptor agonist. Basal levels of dopamine release were greatly decreased in the frontal cortex and caudate putamen after the injection of CGS 15855A or apomorphine. The pargyline-induced accumulations of 3-methoxytyramine in the frontal cortex, cingulate cortex and caudate putamen were attenuated by 52 to 82% after the injection of either agonist. 3-Methoxytyramine accumulations in the entorhinal cortex were attenuated by 68% by apomorphine. Thus, as in the caudate putamen, dopamine autoreceptors modulate the in vivo release of dopamine in the frontal cortex and the turnover of the releasable dopamine pool in the frontal, cingulate and entorhinal cortices.     

Nicotinic receptor modulation of dopamine transporter function in rat striatum and medial prefrontal cortex

Nicotine activates nicotinic acetylcholine receptors (nAChRs) on dopamine (DA) terminals to evoke DA release, which subsequently is taken back up into the terminal via the DA transporter (DAT). nAChRs may modulate DAT function thereby contributing to the regulation of synaptic DA concentrations. The present study determined the dose-response for nicotine (0.1-0.8 mg/kg, s.c.) to modulate DA clearance in striatum and medial prefrontal cortex (mPFC) using in vivo voltammetry in urethane anesthetized rats and determined if this effect was mediated by nAChRs. Exogenous DA (200 microM) was pressure-ejected at 5-min intervals until reproducible baseline signals were obtained. Subsequently, nicotine or saline was administered, and DA pressure ejection continued at 5-min intervals for 60 min. In both striatum and mPFC, signal amplitude decreased by approximately 20% across the 60-min session in saline-injected rats. A monophasic dose-response curve was found in striatum, with a maximal 50% decrease in signal amplitude after 0.8 mg/kg. In contrast, a U-shaped dose-response curve was found in mPFC, with a maximal 50% decrease in signal amplitude after 0.4 mg/kg. Onset of nicotine response occurred 10 to 15 min after injection in both brain regions; however, the amount of time before maximal response was 45 and 30 min in striatum and mPFC, respectively. Mecamylamine (1.5 mg/kg) completely inhibited the nicotine-induced (0.8 and 0.4 mg/kg) decrease in signal amplitude in striatum and mPFC, respectively, indicating mediation by nAChRs. Thus, nicotine enhances DA clearance in striatum and mPFC in a mecamylamine-sensitive manner, indicating that nAChRs modulate DAT function in these brain regions.     

Upregulation of presynaptic proteins and protein kinases associated with enhanced glutamate release from axonal terminals (synaptosomes) of the medial prefrontal cortex in rats with neuropathic pain

Although nerve injury-induced long-term postsynaptic changes have been investigated, less is known regarding the molecular mechanisms within presynaptic axonal terminals. We investigated the molecular changes in presynaptic nerve terminals underlying chronic pain-induced plastic changes in the medial prefrontal cortex (mPFC). After neuropathic pain was induced by spared nerve injury (SNI) in rats, we assessed the release of the excitatory neurotransmitter glutamate by using in vitro synaptosomal preparations from the mPFC. We also measured the levels of synaptic proteins and protein kinases in synaptosomes using Western blotting. The results showed that unilateral long-term SNI augmented depolarization-evoked glutamate release from synaptosomes of the bilateral mPFC. This result was confirmed by a rapid destaining rate of FM1-43 dye in SNI-operated rats. Unilateral long-term nerve injury also significantly increased synaptic proteins (including synaptophysin, synaptotagmin, synaptobrevin, syntaxin, and 25-kDa synaptosome-associated protein) in synaptosomal fractions from the bilateral mPFC, and ultrastructure images demonstrated increased synaptic vesicular profiles in synaptosomes from SNI animals. Chronic pain upregulated the phosphorylation of endogenous protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Ca²⁺/calmodulin-dependent kinase II (CaMKII), and synapsin I, the primary presynaptic target of ERK1/2 and CaMKII. Both presynaptic proteins and protein kinases were upregulated after SNI in a time-dependent manner. These results indicate that the long-term neuropathic pain-induced enhancement of glutamate release in the mPFC is linked to increased synaptic vesicle proteins and the activation of the ERK1/2- and CaMKII-synapsin signaling cascade in presynaptic axonal terminals.     

Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex

Central dopaminergic neurons have been suggested to be involved in the pathophysiology of several psychiatric disorders, including depression, and appear to be modulated by noradrenergic activity both at the nerve terminal level and at the somatodendritic level. In recent years reboxetine, a selective noradrenaline reuptake inhibitor that differs from tricyclic antidepressants by its low affinity for muscarinic, cholinergic and alpha(1)-adrenergic receptors, has been introduced clinically. In the present study the effect of reboxetine on the function of the mesolimbocortical dopamine system was investigated by means of single cell recording and microdialysis in rats following administration of reboxetine in doses that appear to yield clinically relevant plasma concentrations. Reboxetine (0.625--20 mg/kg intravenously) induced an increase in burst firing, but not in average firing frequency of dopamine (DA) cells in the ventral tegmental area (VTA). Moreover, reboxetine (0.15--13.5 mg/kg intraperitoneally) caused a significantly enhanced DA output in the medial prefrontal cortex, whereas no effect was observed in the nucleus accumbens. Local administration of reboxetine (333 microM, 60 min), by means of reversed microdialysis into these brain regions, caused a significant increase in DA output in both brain regions. However, local administration of reboxetine into the VTA (333 microM, 60 min) did not affect DA availability in these terminal areas. Our results imply that clinical treatment with reboxetine may result in facilitation of both prefrontal DA output and the excitability of VTA DA neurons, effects that may contribute to its antidepressant action, especially on drive and motivation.     

Kappa receptor regulation of dopamine release from striatum and cortex of rats and guinea pigs

The effects of opioid agonists with selectivity for kappa, mu and delta types of opioid receptors on the K+-stimulated release of [3H]dopamine (DA) from striatum and cortex of rat and guinea pig loaded previously with the monoamine have been studied. The kappa agonist U50488H did not affect base-line release of [3H]DA measured in 5 mM K+, but produced a dose-dependent inhibition of the release of [3H]DA stimulated by 20 mM K+ from slices of striatum in rat and guinea pig, with an IC50 of about 0.5 nM in each case. In contrast, the mu-selective agonist, Tyr-D-Ala-Gly-(Me)Phe-Gly-ol, and the delta-selective agonist, [D-Pen2-D-Pen5]enkephalin, did not inhibit stimulated release from the slice preparations at concentrations up to 1 microM. The inhibitory effects of U50488H were antagonized by naloxone, and the potent and selective kappa antagonist, nor-binaltorphimine (nor-BNI). Similar results were obtained when release of [3H]DA from rat and guinea pig cortex slices was examined. In guinea pig cortex, the maximum inhibition of DA release induced by U50488H was 80% of control-stimulated fractional release. In rat cortex and in striatum of both species the maximum release was about 40% of control fractional release. Thus, in the guinea pig, the mesocortical dopaminergic pathway appears more sensitive to the inhibitory effects of U50488H than the nigrostriatal system. The effects of the opioids on the K+ (12.5 mM)-stimulated release of [3H]DA from guinea pig striatal synaptosomes also were determined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Presynaptic inhibitory dopamine receptors on noradrenergic nerve terminals: analysis of biphasic actions of dopamine and apomorphine on the release of endogenous norepinephrine in rat hypothalamic slices

Electrical field stimulation (5 Hz)- or high K+ (20 mM)-evoked release of endogenous norepinephrine from superfused rat hypothalamic slices in the presence of cocaine (20 microM) was measured by high-performance liquid chromatography with an electrochemical detector. Apomorphine (10-1000 nM) dose-dependently facilitated the electrically evoked release. Apomorphine (1 microM)-induced facilitation was abolished by pretreatment with yohimbine (100 nM), was converted to inhibition by yohimbine (1 microM), but was not antagonized by propranolol (300 nM). Epinephrine (100 nM) decreased the electrically evoked release and the decrease was antagonized by yohimbine (100 nM) and by apomorphine (100 nM), but not by S-sulpiride (100 nM). In the presence of yohimbine (1 microM), apomorphine (10-1000 nM) dose-dependently inhibited the electrically evoked release. Furthermore, in the presence of tetrodotoxin (300 nM), apomorphine (100 nM) also decreased the high K+-evoked release and this decrease was antagonized by S-sulpiride (100 nM). Dopamine produced biphasic actions on the electrically evoked release, a dose-dependent decrease at 30 and 100 nM and an increase at 300 and 1000 nM. Dopamine (300 nM)-induced increase was antagonized by propranolol (300 nM) but not by yohimbine (100 nM). The dopamine (100 nM)-induced decrease was antagonized by S-sulpiride (1 nM), but not by the R-isomer. S-sulpiride (10 to 100 nM) alone dose-dependently increased the electrically evoked release, whereas the R-isomer had no effect. Haloperidol (100 nM) also increased the electrically evoked release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relative selectivity of 6,7-dihydroxy-2-dimethylaminotetralin, N-n-propyl-3-(3-hydroxyphenyl)piperidine, N-n-propylnorapomorphine and pergolide as agonists at striatal dopamine autoreceptors and postsynaptic dopamine receptors

6,7-Dihydroxy-2-dimethylaminotetralin (TL-99), N-n-propyl-3-(3-hydroxyphenylpiperidine [(+/-)-3-PPP], N-n-propylnorapomorphine and pergolide were evaluated for activity on a number of biochemical parameters that are presumed to indicate an agonist effect at dopamine (DA) autoreceptors (antagonism of the gamma-hydroxybutyrate-induced increase in dopa formation), at postsynaptic DA receptors (elevation of acetylcholine levels) or at both types of DA receptors (diminution of DA synthesis and homovanillic acid levels) in rat striatum. All four agents decreased striatal dopa accumulation (in the presence and in the absence of gamma-hydroxybutyrate). N-propylnorapomorphine, pergolide and TL-99 also reduced homovanillic acid levels and increased acetylcholine concentrations in striatum whereas (+/-)-3-PPP was inactive. The compounds were all more potent in diminishing dopa accumulation caused by gamma-hydroxybutyrate treatment than in increasing acetylcholine levels [(+/-)-3-PPP showing the highest dissociation] indicating a preferential agonist activity at DA autoreceptors. The relative selectivity of the compounds for DA autoreceptors and postsynaptic DA receptors was evaluated further by studying the antagonism by these drugs of the activation of striatal dopa formation (index of both DA autoreceptor and postsynaptic DA receptor stimulation) and tyrosine hydroxylase (index of postsynaptic DA receptor stimulation only) induced by haloperidol or reserpine. The DA agonists were all more potent in antagonizing the neuroleptic-induced increase in DA synthesis than in counteracting the drug-induced activation of tyrosine hydroxylase, with (+/-)-3PPP exhibiting the highest dissociation. The present results indicate that the DA agonists studied possess some selectivity for striatal DA autoreceptors, (+/-)-3-PPP being the most selective in this respect.     

Different direct pathways of locus coeruleus to medial prefrontal cortex and centrolateral thalamic nucleus: Electrical stimulation effects on the evoked responses to nociceptive peripheral stimulation

Projections from the locus coeruleus (LC) to the centrolateral thalamus (C1) and the medial prefrontal cortex (PfCx) were studied using orthodromic and antidromic stimulation techniques. The LC is a major noradrenergic source in the central nervous system, and its descending projections provide an important source of pain suppression at spinal level. Previously, the author has described a cortico-thalamic loop involved in pain modulation. The present paper reports on a study of the participation of LC as part of an ascending pain-control system acting on the cortico-thalamic loop. Rats were anaesthetized with halothane, and single unit recordings were made in LC using glass micropipettes. Stainless steel electrodes were placed in cortex and thalamus for electrical stimulation. Stimulation in PfCx or C1 produces antidromic responses in neurons in LC. The latencies, conduction velocity and location of neurons in LC projecting to PfCx or Cl structures are described. Separate projections to both structures have significantly different conducting velocities, arriving earlier at Cl (mean conduction velocities 0.27 and standard deviation ±0.06m/s) and then at PfCx (mean conduction velocities 0.20± 0.04 m/s). The presence of orthodromic responses suggests reciprocal connections. The paper also describes the suppression of spontaneous and nociceptive-evoked activity in the PfCx and Cl following electrical stimulation in LC. It is proposed that the LC innervation could be associated with an ascending noradrenergic system acting upon a C1-PfCx pain-modulation mechanism.     

Widespread functional connectivity and fMRI fluctuations in human visual cortex in the absence of visual stimulation

To what extent does the visual system's activity fluctuate when no sensory stimulation is present? Here, we studied this issue by examining spontaneous fluctuations in BOLD signal in the human visual system, while subjects were placed in complete darkness. Our results reveal widespread slow fluctuations during such rest periods. In contrast to stimulus-driven activity, during darkness, functionally distinct object areas were fluctuating in unison. These fMRI fluctuations became rapidly spatially de-correlated (39% drop in correlation level, P < 0.008) during visual stimulation. Functional connectivity analysis revealed that the slow spontaneous fluctuations during rest had consistent and specific neuro-anatomical distribution which argued against purely hemodynamic noise sources. Control experiments ruled out eye closure, low luminance and mental imagery as the underlying sources of the spontaneous fluctuations. These results demonstrate that, when no stimulus is present, sensory systems manifest a robust level of slow organized fluctuation patterns.     

Simulating transcranial magnetic stimulation during PET with a large-scale neural network model of the prefrontal cortex and the visual system.

Transcranial magnetic stimulation (TMS) exerts both excitatory and inhibitory effects on the stimulated neural tissue, although little is known about the neurobiological mechanisms by which it influences neuronal function. TMS has been used in conjunction with PET to examine interregional connectivity of human cerebral cortex. To help understand how TMS affects neuronal function, and how these effects are manifested during functional brain imaging, we simulated the effects of TMS on a large-scale neurobiologically realistic computational model consisting of multiple, interconnected regions that performs a visual delayed-match-to-sample task. The simulated electrical activities in each region of the model are similar to those found in single-cell monkey data, and the simulated integrated summed synaptic activities match regional cerebral blood flow (rCBF) data obtained in human PET studies. In the present simulations, the excitatory and inhibitory effects of TMS on both locally stimulated and distal sites were studied using simulated behavioral measures and simulated PET rCBF results. The application of TMS to either excitatory or inhibitory units of the model, or both, resulted in an increased number of errors in the task performed by the model. In experimental studies, both increases and decreases in rCBF following TMS have been observed. In the model, increasing TMS intensity caused an increase in rCBF when TMS exerted a predominantly excitatory effect, whereas decreased rCBF following TMS occurred if TMS exerted a predominantly inhibitory effect. We also found that regions both directly and indirectly connected to the stimulating site were affected by TMS.     

Cardiovascular and metabolic responses during functional electric stimulation cycling at different cadences

Fornusek C, Davis GM. Cardiovascular and metabolic responses during functional electric stimulation cycling at different cadences.

Objective

To determine the influence of pedaling cadence on cardiorespiratory responses and muscle oxygenation during functional electric stimulation (FES) leg cycling.

Design

Repeated measures.

Setting

Laboratory.

Participants

Nine subjects with T4 through T10 spinal cord injury (SCI) (American Spinal Injury Association grade A).

Interventions

FES cycling was performed at pedaling cadences of 15, 30, and 50 revolutions per minute (rpm).

Main Outcome Measures

At each cadence, heart rate, oxygen uptake, and cardiac output were recorded during 35 minutes of cycling. Near infrared spectroscopy was used to quantify quadriceps muscle oxygenation.

Results

All pedaling cadences induced similar elevations in cardiorespiratory metabolism, compared with resting values. Higher average power output was produced at 30rpm (8.2±0.7W, P<.05) and 50rpm (7.9±0.5W, P<.05) compared with 15rpm (6.3±0.6W). Gross mechanical efficiency was significantly higher (P<.05) at 30 and 50rpm than at 15rpm. Quadriceps muscle oxygenation did not differ with pedaling cadences.

Conclusions

Cardiorespiratory responses and muscle metabolism adjustments during FES leg cycling were independent of pedal cadence. FES cycling at a cadence of 50rpm may not confer any advantages over 30 or 15rpm for cardiovascular fitness promotion in persons with SCI.     

R(+)-8-OH-DPAT, a serotonin(1A) receptor agonist, potentiated S(-)-sulpiride-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens but not striatum

The serotonin (5-HT)(2A/2C) receptor antagonist ritanserin has been reported to potentiate the dopamine (DA) D(2/3) receptor antagonist raclopride-induced DA release in medial prefrontal cortex (mPFC) and nucleus accumbens (NAC) but not striatum (STR). Because of reciprocal interactions between 5-HT(2A) and 5-HT(1A) receptors, we tested the hypothesis that 5-HT(1A) receptor agonism also potentiates D(2/3) receptor antagonist-induced DA release using a combination of the 5-HT(1A) receptor agonist R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin [R(+)-8-OH-DPAT] and the D(2/3) receptor antagonist S(-)-sulpiride (SUL). R(+)-8-OH-DPAT (0.05 mg/kg s.c.) potentiated low but not high dose SUL (1, 3 but not 10 or 25 mg/kg s.c.)-induced DA release in NAC, but had no effect in STR at all doses tested (1, 3, 10, and 25 mg/kg s.c.). However, R(+)-8-OH-DPAT (0.05 mg/kg s.c.) alone had no effect on basal, potentiated SUL (10 and 25 mg/kg s.c.)-induced DA release in mPFC; the effect of low dose SUL (1 and 3 mg/kg s.c.) was not tested because it alone had no effect on DA release. This potentiation was abolished by pretreatment with the 5-HT(1A) receptor antagonist WAY100635 (0.05 mg/kg s.c.), which alone had no effect on DA release. These results suggest that 5-HT(1A) receptor agonism facilitates DA release in mPFC and NAC but not STR in combination with D(2) receptor antagonism.     

The effect of circuit type,volume delivered and "rapid release" on flow rates during manual hyperinflation

Traditionally, manual hyperinflation has been performed using "rapid release" to promote a fast peak expiratory flow rate (PEFR) but rapid release has not been described. In addition, it has been demonstrated that different resuscitation circuits provide varying degrees of resistance to expiratory flow and it is known that a variety of circuits are used in Australia for manual hyperinflation. The aim of this study was to document current practice, the effect of rapid release, controlling inspiration, different volumes and circuit type on flow rates, and the inspiratory to expiratory flow rate (I:E) ratio during manual hyperinflation. Using a test lung model, 15 physiotherapists performed 11 trials using the Air Viva 2, a Mapleson-C and a Mapleson-F circuit, both with and without rapid release, and delivering two volumes. The order of the trials was randomised. Rapid release produced a faster PEFR irrespective of circuit type or volume delivered. The effect of rapid release, and the absolute PEFR, was less for the Air Viva 2 compared with the Mapleson circuits. Expiratory flow rate was faster for the larger volume. The theoretically optimal I:E ratio to move secretions was achieved delivering the lower target volume with the Mapleson circuits and using rapid release.