Altered neuronal responsiveness to biogenic amines in rat cerebral cortex after serotonin denervation or depletion

To further investigate monoaminergic mechanisms in cerebral cortex, responsiveness of cortical neurons to microiontophoretic applications of serotonin (5-HT), dopamine (DA) or noradrenaline (NA) was examined in the frontoparietal region of control, 5,7-dihydroxytryptamine (5,7-DHT)- and p-chlorophenylalanine (PCPA)-treated rats anesthetized with urethane. As a rule, 100 nA applications of either one of these biogenic amines induced marked slowings or total interruptions of ‘spontaneous’ firing overlasting the 30s periods of ejection. Given the large amounts of monoamines ejected, it could be inferred that such microiontophoretic applications produced a maximal activation of receptors. In control rats, the responses to 5-HT, DA and NA were of approximately equal duration ( 5 min). Two to 4 weeks after denervation with 5,7-DHT, most neurons (75%) exhibited greatly prolonged responses to 5-HT( 14 min), and marked depressions of firing could be induced by small ejection currents (2 nA) having little or no effect in the controls. In addition, 85% of the units supersensitive to 5-HT showed considerably shortened responses to DA and NA( 1 min). After 2–14 days of depletion with PCPA, there was no change in the responsiveness to 5-HT in spite of a 91% lowering of cortical 5-HT content equivalent to that measured after denervation. Nevertheless, responsiveness to DA and NA was again diminished in a majority (80%) of the units tested. In control or PCPA-treated rats, acute administration of the 5-HT re-uptake blocker fluoxetine increased the duration of depressions induced by 100 nA applications of 5-HT but did not enhance responsiveness to low ejection currents. This suggested that, after 5-HT denervation, the suppression of re-uptake was mainly responsible for the prolongation of 5-HT responses (‘presynaptic’ component of supersentivity), whereas a modification of 5-HT receptors accounted for the greater efficacy of small doses of 5-HT (‘postsynaptic’ component). Responsiveness to the microiontophoretic application of phenylephrine (PHE), a noradrenergic α-agonist, was comparable with that to NA in PCPA- and 5,7-DHT-treated as well as in control rats. Therefore, the hyposensitivity to DA and NA appeared indicative of a desensitization of catecholamine receptors caused by the absence of 5-HT. Such a desensitization may be viewed as an adaptive change resulting from an increased release of endogenous DA and NA. This interpretation would in turn imply that, normally, 5-HT regulates catecholamine release in the neocortex.     

The influence of striatal stimulation and putative neurotransmitters on identified neurones in the rat substantia nigra

The response of two populations of neurones in the substantia nigra (nigro-striatal compacta neurones and reticulata neurones) to microelectrophoretically administered putative neurotransmitters and stimulation of the ipsilateral striatum has been investigated in anaesthetized rats. There were marked differences between compacta and reticulata neurones in respect to their action potential configurations, spontaneous firing rates and their responses to striatal stimulation. However, both compacta and reticulata neurones were excited and/or inhibited by striatal stimulation, although inhibition was usually the predominant response in both neuronal populations. Compacta neurones were strongly inhibited by noradrenaline (NA) and dopamine (DA) but were unaffected by acetylcholine (ACh) and 5-hydroxytryptamine (5-HT). Reticulata neurones were excited by ACh and showed mixed responses to 5-HT, DA and NA. Excitant amino acids overdepolarized compacta neurones preventing them from firing rapidly, but induced large increases in reticulata neurone firing rate; effects that were readily antagonized by D-alpha-aminoadipate. Compacta neurones were less sensitive than reticulata neurones to GABA and glycine. The action of these inhibitory amino acids were selectively and reversibly antagonized by bicuculline methochloride and strychnine, respectively. The striatal-evoked inhibition of both compacta and reticulata neurones was reversibly reduced by bicuculline methochloride and irreversibly reduced by tetanus toxin, but was unaffected by strychnine. These results demonstrate that nigrostriatal-compacta neurones and reticulata neurones are physiologically and pharmacologically distinct neuronal populations and both receive inhibitory GABAergic and excitatory striatal inputs.     

Transmitters and reticulospinal neurons

Glycine and GABA strongly depress the firing of reticulospinal neurons, glycine being more effective than GABA. The effects of strychnine and bicuculline methochloride on synaptic inhibition and on the actions of these amino acids are consistent with the earlier evidence that both glycine and GABA are inhibitory transmitters in the medullary reticular formation. However, although strychnine is consistently a relatively specific antagonist of glycine, bicuculline methochloride is far less specific in distinguishing between glycine and GABA on reticulospinal neurons. Studies of synaptic inhibition in the brain stem using bicuculline methochloride alone are therefore to be interpreted with caution. Both convulsants should be tested on the actions of glycine and GABA before conclusions about transmitter identity are made. Large propertions of reticulospinal neurons appear to be unaffected by ACh, 5-HT, NA, and DA. Of the amine-sensitive reticulospinal neurons, ACh and DA usually depress firing whereas 5-HT and NA usually cause excitation. These effects, however, are generally weak (especially excitation), and it is difficult to draw firm conclusions about the possible functional significance of these substances on reticulospinal neurons.     

Biogenic amine levels in the mid-term human fetus

Spectrophotofluorometric assays were used to measure concentrations of DA, NA, 5-HT and 5-HIAA present in extracts of brain tissue and CSF taken from midterm gestational fetuses of both sexes. The presence of biogenic amines was demonstrated in fetuses as early as 10.5 weeks gestation. In the hypothalamus, the concentrations (expressed in ng/100 mg tissue) ranged from 10.2 to 62.2 for NA, 11.6 to 258.8 for DA, 7.6 to 38.6 for 5-HT and 56.6 to 114.1 for 5-HIAA. Concentrations of DA and 5-HT were found to be significantly (P less than 0.05) higher in the hypothalamus than in the cortex, but those of NA and 5-HIAA were similar in both areas. No sex difference was observed. The concentrations of biogenic amines in the CSF (expressed in ng/ml) were 63.1-286.7 for NA, 43.2-108.1 for DA, 30.9-87.5 for 5-HT and 8.0-42.8 for 5-HIAA.     

Modulatory action of dopamine on acetylcholine-responsive striatal and accumbal neurons in awake, unrestrained rats

In ambulant rats, iontophoresis of low concentrations of dopamine (DA) enhances the response of neurons in striatum and nucleus accumbens to iontophoretic glutamate. In an extension of this line of investigation, we tested the effects of acetylcholine (ACh), a presumed modulator of neuronal function in these same brain regions, and assessed possible DA-ACh interactions. Data were obtained from spontaneously active neurons known to respond to ACh (5–30 nA) when the animals rested quietly with no overt movement. ACh iontophoresis either excited or inhibited striatal and accumbal activity but excitatory effects predominated in both areas. With multiple applications of ACh, especially at the lowest currents tested, either response often was interspersed with instances of no change in firing rate. Responsiveness to ACh also diminished during periods of spontaneous movement when basal firing showed phasic increases in activity. In fact, neurons with the highest rates of basal activity showed the smallest magnitude response to ACh. Prolonged applications (120–180 s) of DA attenuated basal firing as well as the iontophoretic effects of ACh both during the DA application itself and for up to 1 min after DA ejection offset. The result of these inhibitory effects was no net change in the relative magnitude of the ACh response. Thus, although ACh can modulate striatal and accumbal neuronal activity, DA does not regulate this effect in the same way that it regulates the neuronal responsiveness to glutamate.     

Neuromodulation of the prefrontal cortex during sleep: a microdialysis study in rats

To test the hypothesis that biogenic amines of the prefrontal cortex are involved in state-dependent cortical and behavioural activation, changes in extracellular levels of serotonin (5-HT), dopamine (DA), and noradrenaline (NA) were determined during the sleep-wake cycle in freely moving rats using microdialysis probes with parallel EEG recording. Serotonin gradually increased up to 450% during wakefulness (W) as compared to slow wave sleep (SWS), before decreasing toward stable levels during the next episode of SWS. Dopamine and its metabolite homovanillic acid (HVA) were reduced during W as compared to SWS. Although contradictory with the generally admitted enhancement of DA activity related to vigilance, this may be due to the particular role of DA neurons in the prefrontal cortex. However, DA and HVA showed dramatic changes announcing the transition between SWS and W. During paradoxical sleep (PS), DA and 5-HT showed complex changes, the direction of which depended on whether PS was followed by SWS or W. Biogenic amines of the prefrontal cortex are probably involved in cortical and behavioural activation.     

Ascending afferent regulation of rat midbrain dopamine neurons

Standard, extracellular single-unit recording techniques were used to examine the electrophysiological and pharmacological responsiveness of midbrain dopamine (DA) neurons to selected, ascending afferent inputs. Sciatic nerve stimulation-induced inhibition of nigrostriatal DA (NSDA) neurons was blocked by both PCPA (5-HT synthesis inhibitor) and 5,7-DHT (5-HT neurotoxin), suggesting mediation by a serotonergic (5-HT) system. Direct stimulation of the dorsal raphe (which utilizes 5-HT as a neurotransmitter and inhibits slowly firing NSDA neurons) inhibited all mesoaccumbens DA (MADA) neurons tested. Paradoxically, DPAT, a 5-HT_1a agonist which inhibits 5-HT cell firing, enhanced sciatic nerve stimulation-induced inhibition of NSDA neurons. MADA neurons were not inhibited by sciatic nerve stimulation and, therefore, could not be tested in this paradigm. In contrast to the dorsal raphe, electrical stimulation of the pedunculopontine tegmental nucleus preferentially excited slowly firing NSDA and MADA neurons. Thus, both excitatory and inhibitory ascending afferents influence the activity of midbrain DA neurons, and intact 5-HT systems are necessary for sciatic nerve stimulation to alter DA cell activity. However, the role that 5-HT plays in mediating peripheral sensory input remains unclear.     

Modulation of the firing activity of rat serotonin and noradrenaline neurons by (+/-)pindolol.

BACKGROUND: (+/-)Pindolol is a beta-adrenergic/5-HT1A receptor antagonist used in combination with certain antidepressant drugs to accelerate the onset of the antidepressive response. METHODS: The aim of the present study was to assess, using an in vivo electrophysiologic paradigm, the effect of (+/-)pindolol on the spontaneous firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. RESULTS: (+/-)Pindolol did not modify the firing activity of dorsal raphe 5-HT neurons at low doses (10 and 200 micrograms/kg, i.v.), but it prevented the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide (LSD, 10 micrograms/kg, i.v.) but not that of the 5-HT1A receptor 8-hydroxy-N,N-dipropyl-aminotetralin (8-OHDPAT, 5 micrograms/kg, i.v.). At a higher dose (500 micrograms/kg, i.v.), (+/-)pindolol decreased 5-HT neuronal firing and this effect was reversed by the selective 5-HT1A receptor antagonist WAY 100635 (100 micrograms/kg, i.v.), suggesting that it could act as a partial 5-HT1A autoreceptor agonist. In the locus coeruleus, the high dose of (+/-)pindolol decreased the firing activity of NA neurons and this effect was reversed by the 5-HT2A receptor antagonist MDL 100907 (200 micrograms/kg, i.v.). Finally, both a lesion of NA neurons and the administration of MDL 100907 prevented the suppressant effect of (+/-)pindolol on the firing of 5-HT neurons. CONCLUSIONS: It is suggested that, at low doses, (+/-)pindolol acts as a somatodendritic 5-HT1A autoreceptor antagonist whereas at a higher dose, it decreases the tonic excitatory input from NA neurons to 5-HT neurons.     

Lamina-selective changes in the density of synapses following perturbation of monoamines and acetylcholine in the rat medial prefrontal cortex

The rat medial prefrontal cortex is known to have diverse brain functions such as learning and memory, attention, and behavioral flexibility. Although these functions are affected by monoamines (dopamine (DA), noradrenaline (NA) and serotonin (5-HT)) and acetylcholine (ACh), the detailed mechanisms remain unclear. These neuromodulators also have effects on synapse formation and maintenance, and regulate plasticity in the central nervous system (CNS). To clarify the effects of these neuromodulators on changes in the density of synapses in the rat medial prefrontal cortex, we separately administered a D1- or D2-antagonist, NA neurotoxin, 5-HT synthetic inhibitor, or muscarinic ACh antagonist for 1 week, and counted the number of synapses on electron microscopic photographs taken from the prelimbic area of the medial prefrontal cortex. The density of synapses in lamina I was regulated by DA via D1-like receptors, and that in laminae II/III was decreased by depletion of NA or ACh. However, 5-HT did not have a regulatory effect on the synaptic density throughout the layers in this brain region. The data in this study and our previous studies indicate that there are appreciable regional differences in the magnitude of biogenic amine-mediated synaptic plasticity in the rat CNS. These neuromodulators may have a trophic-like effect on the selected neuronal circuit to maintain synaptic contacts in the rat CNS. The synaptic density in the medial prefrontal cortex regulated by monoamines and ACh could be important not only for synaptic plasticity in this region but also for pharmacotherapeutic drug treatment.     

Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram

Mirtazapine displayed marked affinity for cloned, human alpha2A-adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]-GTPgammaS) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2-AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at alpha2A-AR and 5-HT2C receptors.     

Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats.

The role of brain amines in mediating the effects of the wake-promoting agent modafinil, used in the treatment of sleepiness associated with narcolepsy is still uncertain. Therefore we studied the effects of modafinil on extracellular serotonin (5-HT), dopamine (DA) and noradrenaline (NA), in rat prefrontal cortex and in the medial hypothalamus area. Modafinil (128 mg/kg i.p.) significantly increased waking in the first 4 h of EEG sleep recording. This cortical and behavioral activation was associated with an initial increase in extracellular 5-HT, DA and NA during the first 60 min following modafinil administration. In the prefrontal cortex, 5-HT release remained high for 3 h after modafinil administration. In contrast, in the hypothalamus, only NA release was enhanced while DA and 5-HT levels remained low. In a first step, modafinil may generate waking partly via cortical monoamine release, particularly DA and 5-HT, and also hypothalamic NA. In a second step, maintenance of waking might depend on hypothalamic NA.     

Dorsal raphe stimulation differentially modulates dopaminergic neurons in the ventral tegmental area and substantia nigra

The serotoninergic (5-HT) input from the dorsal raphe nucleus (DRN) to midbrain dopamine (DA) neurons is one of the most prominent. In this study, using standard extracellular single cell recording techniques we investigated the effects of electrical stimulation of the DRN on the spontaneous activity of substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) DA neurons in anesthetized rats. Poststimulus time histograms (PSTH) revealed two different types of response in both SNpc and VTA. Some cells exhibited an inhibition-excitation response while in other DA neurons the initial response was an excitation followed by an inhibition. In SNpc, 56% of the DA cells recorded were initially inhibited and 31% of the DA cells were initially excited. In contrast, 63% of VTA DA cells were initially excited and 34% were initially inhibited. Depletion of endogenous 5-HT by the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), and the 5-HT synthesis inhibitor para-chlorophenylalanine (PCPA), almost completely eliminated the inhibition-excitation response in both SNpc and VTA DA cells, without changing the percentage of DA cells initially excited. Consequently, the proportion of DA neurons that were not affected by DR stimulation increased after 5-HT depletion (from 13% to 60% in SNpc and from 6% to 31% in VTA). In several DA cells, DRN stimulation caused important changes in firing rate and firing pattern. These data strongly suggest that the 5-HT input from the DRN is mainly inhibitory. It also suggests that 5-HT afferences modulate SNpc and VTA DA neurons in an opposite manner. Our results also suggest that non-5-HT inputs from DR can also modulate mesencephalic DA neurons. A differential modulation of VTA and SNpc DA neurons by 5-HT afferences from the DRN could have important implications for the development of drugs to treat schizophrenia or other neurologic and psychiatric diseases in which DA neurons are involved.     

Chemosensitivity of hypophysiotropic neurons to the microelectrophoresis of biogenic amines

The purpose of this study was to determine whether norepinephrine (NE), dopamine (DA), serotonin (5-HT), acetylcholine (ACh) and glutamate (Glut) when applied in the immediate vicinity and in minute quantities to single neurons within the preoptic-hypothalamic complex via microelectrophoresis, could modulate their electrical activity. The action of these putative neurotransmitters on medial-preoptic (MPO) and arcuate-ventromedial (ARC-VM) neurons was studied in the urethane anesthetized, ovariectomized female rat. Multi-barrelled glass microelectrodes were used for extracellular recording and for microelectrophoresis of the putative transmitters. Four specific neuron types were identified by median eminence electrical stimulation; namely, antidromically identified (AI) MPO neurons, uninvaded MPO neurons, AI ARC-VM neurons and uninvaded ARC-VM neurons. The major findings based on responsive neurons (i.e., those neurons which reacted to the chemical application by an increase or decrease in spontaneous activity) are summarized. The data demonstrate that NE had a pronounced excitatory effect on uninvaded and AI ARC-VM neurons and an inhibitory influence on AI MPO neurons. The influence of dopamine was not as clearly defined, although there was a slight trend towards excitation in uninvaded MPO neurons and inhibition in AI MPO neurons. Results based on the testing with 5-HT showed it to have an inhibitory action on uninvaded MPO neurons. Furthermore, ACh and Glut were shown to have an excitatory action on the majority of responsive neurons tested. The remaining neurons tested with either NE, DA or 5-HT displayed a similar number of excitatory and inhibitory responses. The findings obtained provide positive support for a catecholaminergic and cholinergic regulation or neurons projecting towards the median eminence which are presumably involved in pituitary function.     

Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons

Reboxetine is a non-tricyclic antidepressant with selective noradrenergic (NA) reuptake-blocking effects. The effects of acute and sustained administration of reboxetine, on the firing activity of locus coeruleus NA neurons and dorsal raphe 5-HT neurons, were assessed using in vivo extracellular unitary recording in rats anaesthetized with chloral hydrate. Reboxetine (0.1-1.25 mg/kg, i.v.) dose-dependently decreased the firing activity of NA neurons (ED50 = 480 +/- 14 microg/kg). A 2-day treatment with reboxetine at 1.25, 2.5, 5, or 10 mg/kg per day (using osmotic minipumps implanted subcutaneously) produced significant decreases of 52%, 68%, 81%, and 83%, respectively, of NA firing activity. When the reboxetine treatment (2.5 mg/kg per day) duration was prolonged to 7 days, a 66% decrease in NA firing activity was observed which further decreased to 80% after 21 days of treatment. In contrast, 5-HT neuron firing rate remained unaltered following short- and long-term reboxetine treatments. The suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of NA neurons was unchanged in long-term reboxetine-treated rats, but its effect on the firing activity of 5-HT neurons was blunted. The enhancement of NA firing activity by the 5-HT1A agonist 8-OH-DPAT was abolished in long-term reboxetine-treated rats, whereas, the inhibitory effect of the 5-HT2 agonist DOI was attenuated by about three-fold. In conclusion, sustained NA reuptake blockade by reboxetine lead to profound alterations in the function of NA neurons and of 5-HT receptors modulating their firing activity.     

Pharmacological characterization of medullary serotonin neurons

In the present study we investigated the characteristics of medullary raphe serotonergic neurons. Specifically, we sought to examine further the similarities between medullospinal 5-HT neurons and the more extensively studied neurons of the dorsal raphe. Intravenous administration of 5-methoxy-dimethyltryptamine (5-MeODMT) produced a dose-related inhibition of the firing of midline medullary 5-HT neurons. Microiontophoretically applied 5-MeODMT also inhibited medullary 5-HT neurons. The inhibitory potency of 5-MeODMT was nearly identical to that observed for dorsal raphe 5-HT neurons. Microiontophoretic or intravenous administration of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) did not alter the firing rate of medullary 5-HT neurons. Intravenous administration of the alpha 1-receptor antagonist prazosin resulted in an inhibition of the medullary 5-HT neuronal firing. The discharge of medullary 5-HT neurons increased during iontophoresis of norepinephrine. These data are discussed in relation to the identification and characterization of medullary 5-HT neurons. In addition, the data suggest that the firing rate of medullary 5-HT neurons is regulated in part by a tonic excitatory noradrenergic input.     

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

Extracellular single-cell recording and microiontophoretic techniques were used to characterize the effects of cocaine on the activity of mesoaccumbens A10 dopamine (DA) neurons in the rat ventral tegmental area (VTA), which have been implicated in the rewarding effects of this and other drugs of abuse. Because cocaine inhibits the reuptake of DA, norepinephrine (NE), and serotonin (5-HT), and exerts local anesthetic actions, the possible involvement of each of these various mechanisms in the effects of cocaine on A10 DA neurons was investigated. Intravenous administration of cocaine caused a significant, dose-dependent, partial inhibition (50-70%) of the firing of antidromically identified mesoaccumbens DA neurons. Similar partial inhibition of A10 neurons was observed following intravenous administration of nomifensine, GBR-12909, and norcocaine, all of which inhibit DA reuptake. Neither the selective 5-HT uptake inhibitor fluoxetine nor the selective NE uptake inhibitor desmethylimipramine (DMI) inhibited the firing of A10 DA neurons. The local anesthetic agent procaine, which lacks DA uptake blocking efficacy, caused a slight, transient increase in firing rate. These results suggest that the effects of cocaine on A10 DA neurons are due to inhibition of DA reuptake, a conclusion that has been supported by several other findings. Pretreatment with reserpine to deplete vesicular stores of DA significantly reduced the ability of intravenous cocaine to suppress A10 DA neuronal activity. Microiontophoretic administration of cocaine caused only a weak (15-20%) inhibition of the activity of A10 DA neurons, but significantly increased and prolonged the inhibition produced by iontophoretic DA. This effect was not observed with iontophoretically administered procaine iontophoresis of cocaine also significantly potentiated the inhibition of A10 DA activity caused by electrical stimulation of the nucleus accumbens (NAc). Both unilateral ibotenic acid lesions of the NAc and hemitransections of the brain rostral to the VTA significantly reduced the inhibitory effects of intravenous cocaine on A10 DA neurons, suggesting that both somatodendritic impulse-regulating DA autoreceptors and inhibitory NAc-VTA feedback processes are involved in the effects of intravenous cocaine on A10 DA neurons. Therefore, it is hypothesized that the relatively weak inhibitory effects of cocaine on A10 DA neurons may represent a poor compensatory response to enhanced DA neurotransmission within the NAc, and may help to explain the extremely potent rewarding effects of this important drug of abuse.     

The differential effects of 5-hydroxytryptamine, noradrenaline and raphe stimulation on nociceptive and non-nociceptive dorsal horn interneurones in the cat

The effects of 5-hydroxytryptamine (5-HT), noradrenaline (NA) and stimulation of the inferior central nucleus of the raphe (RN) were examined on nociceptive and non-nociceptive spinal neurones in anaesthetized cats. 5-HT reduced excitation evoked by noxious stimulation, but increased spontaneous firing anoked bydl-homocysteic acid (DLH) on both nociceptive and non-nociceptive cells. NA reduced spontaneous activity, DLH-evoked excitation and excitation evoked by a noxious stimulus on nociceptive neurones, but had little action on non-nociceptive units. RN inhibited spontaneous, stimulus-evoked and DLH-evoked firing of nociceptive cells and caused briefer inhibitions of non-nociceptive cells. Excitatory effects were also observed. Strychnine antagonized short-duration inhibitions from RN of non-nociceptive cells responding to hair movement, but failed to antagonize any of the other effects of RN. No antagonism of the inhibitory effect of RN was observed with phenoxybenzamine, phentolamine, sotalol, bicuculline or methysergide. However, methysergide antagonized some excitatory effects of 5-HT and RN, but also produced non-specific actions on some cells.It was concluded that, although glycine may mediate some of the brief duration inhibitions evoked by RN, the longer duration inhibitions were unlikely to have been mediated by either glycine or GABA. 5-HT may be a mediator of raphe-spinal actions but may have presynaptic inhibitory actions coupled with postsynaptic excitatory effects. NA could mediate some descending inhibition of nociceptive neurones.     

Modified coeruleo-cortical noradrenergic neurotransmission after serotonin depletion by PCPA: electrophysiological studies in the rat

To detect eventual modifications in the efficacy of the noradrenergic (NA) coeruleo-cortical system after serotonin (5-HT) depletion by parachlorophenylalanine (PCPA), three electrophysiological parameters were investigated in urethane-anesthetized rats which were treated for 2 days with daily injections of this inhibitor of 5-HT synthesis. 1) The spontaneous activity of locus coeruleus (LC) noradrenergic neurons showed a significant increase in PCPA-treated compared to control rats (4.3 vs. 2.6 Hz). 2) The sensitivity of NA autoreceptors was measured in the LC by the effect of intravenous administrations of clonidine or microiontophoretic applications of NA on spontaneous neuronal firing. In treated rats, clonidine and NA induced a lesser reduction of LC neuron firing than in the controls (27 vs. 75% decreases and 1,367 vs. 280 nC, respectively). 3) The responsiveness of cortical neurons to electrical stimulation of the LC was assessed by peristimulus time histograms in the dorsal fronto-parietal cortex. Following stimulation at 2 or 4 Hz, a majority of spontaneously firing cortical units was inhibited by electrical stimulation of the LC, but the percentage of such units was reduced and showed a decreased responsiveness after PCPA treatment. These findings suggest that following 5-HT depletion by PCPA, cortical NA neurotransmission is markedly reduced in its efficacy in spite of some increase in the spontaneous activity of coeruleo-cortical NA neurons.     

Impact of Prefrontal Cortex in Nicotine-Induced Excitation of Ventral Tegmental Area Dopamine Neurons in Anesthetized Rats

Systemic administration of nicotine increases dopaminergic (DA) neuron firing in the ventral tegmental area (VTA), which is thought to underlie nicotine reward. Here, we report that the medial prefrontal cortex (mPFC) plays a critical role in nicotine-induced excitation of VTA DA neurons. In chloral hydrate-anesthetized rats, extracellular single-unit recordings showed that VTA DA neurons exhibited two types of firing responses to systemic nicotine. After nicotine injection, the neurons with type-I response showed a biphasic early inhibition and later excitation, whereas the neurons with type-II response showed a monophasic excitation. The neurons with type-I, but not type-II, response exhibited pronounced slow oscillations (SOs) in firing. Pharmacological or structural mPFC inactivation abolished SOs and prevented systemic nicotine-induced excitation in the neurons with type-I, but not type-II, response, suggesting that these VTA DA neurons are functionally coupled to the mPFC and nicotine increases firing rate in these neurons in part through the mPFC. Systemic nicotine also increased the firing rate and SOs in mPFC pyramidal neurons. mPFC infusion of a non-α7 nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the excitatory effect of systemic nicotine on the VTA DA neurons with type-I response, but mPFC infusion of nicotine failed to excite these neurons. These results suggest that nAChR activation in the mPFC is necessary, but not sufficient, for systemic nicotine-induced excitation of VTA neurons. Finally, systemic injection of bicuculline prevented nicotine-induced firing alterations in the neurons with type-I response. We propose that the mPFC plays a critical role in systemic nicotine-induced excitation of VTA DA neurons.     

Monoaminergic modulation of the sensitivity of neurones in the cingulate cortex to iontophoretically applied substance P

The interactions of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) with substance P (SP) were studied on single neurones in the anterior cingulate cortex of the rat. Iontophoretic application of 5-HT potentiated the excitatory responses of some neurones to SP and reduced responses of others. However these effects were usually accompanied by parallel changes in baseline firing rate i.e. increase and decrease respectively. In studies where carbachol (CCh) was used as a control the excitatory responses to this substance were always altered in a similar fashion to those to SP. The effects of NA on SP-responses were more consistent. This amine caused a reduction of response to SP regardless of whether there was an increase, decrease, or no change in baseline firing rate. Responses to SP could be reduced on many cells in the absence of changes in response to CCh and even on some cells where CCh responses were concurrently enhanced. Lesions of the locus coeruleus which resulted in a depletion of NA in the ipsilateral cingulate cortex gave rise to a substantial increase in sensitivity of neurones to SP two weeks later. However, lesions of the median raphe(MR)-nucleus which strongly reduced cortical 5-HT had no detectable effect on SP-responses. The data indicate that both NA and 5-HT can alter cortical neurone-sensitivity to SP but that the former amine may be involved in a more specific and possibly a functional interaction.