beta-Phenylethylamine enhances single cortical neurone responses to noradrenaline in the rat

The firing rates of single neurones in the rat cerebral cortex were recorded using multibarrel glass microelectrodes, and the response to drugs applied by microiontophoresis was investigated. A greater number of cells responded to noradrenaline (NA) (30-66 nA) than to beta-phenylethylamine (PE) (30-100 nA). When responses were obtained to both, 90% of the neurones gave the same response to NA and PE. Applications of PE with small currents (0-12 nA) caused an increase in the response to NA without affecting the baseline firing rate or the response to acetylcholine, glutamate, GABA or 5-hydroxytryptamine. An increase was seen in both excitatory and inhibitory responses to NA. The enhancement lasted up to 39 minutes after the end of the PE application. Applications of NA with small currents (0-3 nA) failed to alter responses to NA. Possible mechanisms of the effect of PE on response to NA are discussed. These results provide further evidence for the hypothesis that trace amines can modulate catecholamine neurotransmission.     

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.     

Effects of adrenalectomy on the excitability of neurosecretory parvocellular neurones in the hypothalamic paraventricular nucleus

Glucocorticoids are well known to inhibit the release of hypophysiotrophic hormones from neurones originating in the paraventricular nucleus (PVN), but the cellular mechanisms of the inhibition are not well understood. Here, we examined the effects of adrenalectomy (ADX) on the spontaneous firing activity in the neurosecretory parvocellular PVN neurones of rat brain slices. The neurones were identified by injecting a retrograde dye into the pituitary stalk and classified according to their electrophysiological properties. The intranuclear distribution, electrophysiological properties, and hypophysiotrophic hormone phenotype of the labelled type II PVN neurones were similar to neurosecretory parvocellular PVN neurones. In the neurones of sham-operated rats under the cell-attached recording mode, we observed three spontaneous activity patterns: tonic regular (24%), tonic irregular (36%), and silent (40%). Noradrenaline (100 microM) induced an excitatory or an inhibitory effect on the spontaneous activity. Noradrenergic excitation was blocked by prazosin (2 microM, alpha(1)-adrenoceptor antagonist), and mimicked by phenylephrine (100 microM, alpha(1)-adrenoceptor agonist), whereas noradrenergic inhibition was blocked by yohimbine (2 microM, alpha(2)-adrenoceptor antagonist) and mimicked by clonidine (50 microM, alpha(2)-adrenoceptor agonist). In the neurones of ADX rats, we found burst firing in 35% of neurones tested and an increase in the frequency of spontaneous firing. The burst firing was not observed in the neurones of the sham-operated rats. ADX caused a 1.7-fold increase in the proportion of neurones showing the noradrenergic excitation. Supplementation of the ADX rats with corticosterone (10 mg pellet) reversed the ADX-induced burst firing, and the potentiation of noradrenergic excitation. In summary, our results show that removal of corticosterone by ADX can elevate the neuronal excitability by increasing the spontaneous firing rate and by potentiating the alpha(1)-adrenoceptor-mediated noradrenergic excitation, and it can facilitate hormone release by inducing burst firing. Our results provide new insight to the cellular mechanisms of the feedback inhibition by glucocorticoids in the neurosecretory parvocellular neurones of the PVN.     

Specific enhancement of neuronal responses to catecholamine by p-tyramine

Extracellular recording and iontophoresis techniques were used to study the interactions of the trace amine, p-tyramine (p-TA) with putative neurotransmitters on single neurones in the cerebral cortex and caudate nucleus of the rat. p-TA, when applied with weak iontophoretic currents which did not result in any change in neuronal firing rate, caused a pronounced potentiation of depressant responses to iontophoretically applied dopamine (DA). Depressant responses of cortical neurones to noradrenaline were also markedly potentiated by weak background applications of p-TA. This potentiating action of p-TA was related to the amount of the trace amine applied and was apparently specific for catecholamines, since depressant responses to 5-hydroxytryptamine and γ-aminobutyric acid were unaffected. Excitatory responses to iontophoretically applied glutamate were also unaltered by weak applications of p-TA. Excitatory responses of most neurones to acetylcholine (ACh) were also unaffected by p-TA in the cortex and caudate nucleus. However, responses to ACh of a small number of cells in both brain areas were reduced in size during weak applications of p-TA. It is suggested that p-TA may act as a modulator of neurotransmission, particularly that mediated by DA in the central nervous system.     

Characterization of hypothalamic noradrenaline receptors in the supraoptic nucleus and periventricular region of the paraventricular nucleus of mice in vitro

In an attempt to determine the basis for apparently conflicting reports of the effects of noradrenaline (NA) on the neurohypophyseal system and its effects on the parvocellular periventricular region of the paraventricular nucleus (PVN), recordings were made from the neurons in the supraoptic nucleus (SON) and the periventricular region in the mouse hypothalamic slice preparation. Of 47 SON neurons, 43 (91%) were excited and two (4%) were inhibited by NA. Seven SON neurons increased the firing rate with increase of NA concentration (10(-7)-10(-4) M). Both the alpha 1-agonists phenylephrine and methoxamine also increased the activity of all SON neurons tested whereas application of the alpha 2-agonist clonidine and the beta-agonist isoproterenol had weak and inconsistent effects. While the alpha 2-antagonist yohimbine had no consistent influence, the alpha 1-antagonist prazosin blocked or reversed the effects of NA. Another group of 37 neurons in the periventricular region of the PVN was also tested; 13 (35%) were excited and 22 (59%) inhibited by application of NA (10(-5) M). When tested with phenylephrine or methoxamine, 6 of the 7 neurons were excited and one inhibited but all the 4 neurons tested were excited by isoproterenol. Clonidine strongly depressed the activity of all 12 neurons tested. The NA-induced excitatory effects were suppressed or reversed by pre-application of prazosin and the beta-antagonist propranolol while the inhibitory ones were suppressed or reversed by yohimbine. Synaptic blockade did not affect the excitatory responses of SON cells to NA nor the inhibitory responses of periventricular neurons to NA or clonidine. We conclude that SON neurons receive adrenergic excitatory effects mainly through alpha 1-receptors. The periventricular neurons receive the excitatory effects through alpha 1- or beta-receptors and receive the inhibitory effects through alpha 2-receptors.     

Iontophoresis of amphetamine in the neostriatum and nucleus accumbens of awake, unrestrained rats

When administered systemically to ambulant animals, amphetamine (AMPH) has both excitatory and inhibitory effects on single-unit activity in the neostriatum and nucleus accumbens. To determine the extent to which these results reflect a direct action of the drug, AMPH was applied iontophoretically to neostriatal and accumbal neurons under naturally occurring behavioral conditions. AMPH dose-dependently (5–40 nA) inhibited the vast majority of spontaneously active units. The inhibition, which was evident at low ejection currents (5–10 nA), had relatively short onset (4–12 s) and offset (6–24 s) latencies, and was positively correlated with basal firing rate. Even stronger dose-dependent inhibitory responses were recorded when neurons having no or a very low rate of spontaneous activity were tonically activated by continuous, low-current applications of glutamate (Glu). Systemic injection of either SCH-23390 (0.1 mg/kg) or haloperidol (0.2 mg/kg), relatively selective D₁ and D₂ receptor antagonists, respectively, blocked the AMPH-induced inhibition. Prolonged AMPH iontophoresis (2–3 min; 5–30 nA) inhibited both spontaneous impulse activity and Glu-induced excitations, resulting in a complete blockade of the Glu response at relatively high AMPH ejection currents (≥20 nA). Taken together, these results suggest that although dopamine is largely responsible for the inhibitory effects of iontophoretic AMPH, dopamine alone cannot account for the complex response of neostriatal and accumbal neurons to systemic AMPH administration.     

A pharmacological study of the modulation of neuronal and behavioural nociceptive responses in the rat trigeminal region

Electrical stimulation of the brain, particularly in the periventricular grey areas, caused long-lasting increases in behavioural escape thresholds to heating and mechanical stimuli applied to the facial region of the rat. The brain stimulation selectively suppressed responses to noxious stimuli. Responses to non-noxious stimuli, evoked by low threshold brush, were unaffected. The same animals that were studied in the behavioural tests were then anaesthetized with urethane and the inhibitory effect of the same brain stimulation was studied in single neurones recorded in the caudal trigeminal nucleus. A clear correlation (r_s = 0.63) emerged between degree of behavioural antinociception and the amount of inhibition seen in nociceptive neurones. In addition the mean duration of the inhibition (6 min) was similar to the mean duration of the antinociceptive effect (7.3 min). Other classes of non-nociceptive neurones were unaffected by the stimulation. The neurones were also studied using iontophoretically applied monoamine candidates for the inhibitory neurotransmitter, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). The profile of the effects of NA most closely fitted that of the inhibitory neurotransmitter. This profile was expressed in terms of depression and excitation of different classes of neurones, and by the duration of effects. The depressant effects could be antagonized by iontophoretic idazoxan. In addition clonidine induced long-lasting depression of firing. 5-HT was more likely than NA to excite nociceptive neurones and to depress non-nociceptive neurones. Only NA consistently elevated thermal response thresholds in a similar manner to that produced by brain stimulation. These results provide some support for the hypothesis that selective descending inhibition of nociceptive responses in neurones of the rat caudal trigeminal nucleus is mediated by NA, possibly by an action at α₂-adrenoceptors.     

The influence of vasopressin on tonic activity of cardiovascular neurones in the ventrolateral medulla of the hypertensive rat

In normotensive Wistar rats, vasopressin may act as an excitatory neurotransmitter at synapses of paraventricular neurones on rostral ventrolateral medullary vasomotor neurones. We studied the influence of this neurotransmitter in spontaneously hypertensive rats to determine if it contributed to the increases in sympathetic nerve traffic in these rats.A five-barrel micropipette assembly was used for extracellular recording of neuronal activity and for microiontophoresis of drugs into the vicinity of identified medullary vasomotor neurones.Excitatory effects of iontophoretically applied vasopressin were blocked by simultaneous iontophoretic application of V(1a) antagonist. Similar application of the vasopressin receptor antagonist did not block an excitatory effect of iontophoretically applied glutamate. Excitatory effects produced by activating paraventricular neurones were also blocked by the V(1a) antagonist. However, the vasopressin antagonist did not alter the ongoing activity of medullary vasomotor neurones. Therefore, in these anaesthetised hypertensive rats, we concluded that vasopressin neurones do not exert a significant tonic drive to rostral ventrolateral medullary-spinal vasomotor neurones.     

Interactions between amino acid neurotransmitters and flurazepam in the neocortex of unanesthetized rats

The effects induced by the benzodiazepine flurazepam (FLU) upon neuronal responses to glutamic acid (GLUT), gamma-aminobutyric acid (GABA), and glycine (GLY) were studied in the cortex of unanesthetized rats using single-unit extracellular recordings in conjunction with iontophoretic techniques. The application of FLU (5-20 nA) did not affect excitatory responses to GLUT, but the spontaneous firing rate was depressed by equivalent doses of this benzodiazepine. A selective increase of GABA, but not of GLY-induced responses was seen when either low currents (5-10 nA) of FLU or GLUT driving currents were used to study the neuronal responses of the inhibitory amino acids upon steady neuronal firing. Our data demonstrate that in unanesthetized animals FLU does not affect GLUT-induced effects while it selectively increases GABA-mediated inhibition.     

Electrophysiological effects of locally applied noradrenergic agents at cerebellar Purkinje neurons: receptor specificity

We have investigated the receptor subtype(s) mediating the noradrenergic inhibition of cerebellar Purkinje cell spontaneous firing rate using local application of specific agonists and antagonists, in situ, via pressure microejection. Extracellular action potentials were recorded from Purkinje neurons in anesthetized Fischer 344 rats. Timolol, a beta-receptor antagonist, did not affect norepinephrine (NE)-induced inhibition in 9 of 12 cells studied. Phentolamine, an alpha-receptor antagonist, blocked the effect of NE in 8 of 11 cells. To further determine the subtype of alpha-receptor involved, the effects of the alpha 1-antagonist prazosin and alpha 2-antagonists idazoxan and yohimbine were examined. While prazosin had no effect on NE-mediated inhibition, both idazoxan and yohimbine blocked NE effects. Idazoxan was also successful in blocking phencyclidine (PCP), an indirect noradrenergic agonist. The inhibitory action of NE upon Purkinje cell firing rate was mimicked by the selective alpha 2-agonist clonidine; this action of clonidine was blocked by idazoxan but not by timolol or prazosin. In addition, the alpha 1-adrenergic agonist phenylephrine and the beta-adrenergic agonist isoproterenol inhibited Purkinje cell firing rate. Phenylephrine effects were blocked by prazosin but not by timolol or idazoxan. Isoproterenol-induced inhibition was blocked by timolol but not phentolamine. Taken together, these studies suggest that both alpha- and beta-receptors alter Purkinje cell firing rate; the depressant action of locally applied NE, however, seems to be mediated primarily via an alpha 2-adrenergic receptor.     

Some electrophysiological and pharmacological properties of the cortical, noradrenergic projection of the locus coeruleus in the rat

The effect of repetitive stimulation of the locus coeruleus (LC) on the discharge rate of spontaneously active neurons of the visual, rostral and cingulate cortex was investigated in untreated and catecholamine-depleted rats under chloral hydrate anesthesia. In untreated animals, the inhibitory transsynaptic effects predominated over the excitatory ones. In catecholamine-depleted rats, the percentage of inhibited cells was significantly reducted in all areas. The vast majority of spontaneously active neurons in all cortical regions was depressed by microiontophoretically applied noradrenaline (NA). A few cells were resistant to NA; no excitatory effects were noticed on any cell. The transsynaptically mediated depression of the discharge rate of cells in all three cortical areas was reversibly antagonized by the iontophoretically administered beta-receptor blocking drug practolol. On the contrary the a-receptor blocking drugs piperoxane and WB4101 were ineffective in this respect. Thus, we tentatively conclude from these data that the NA-elicited depression of cells in the cortex is mediated by a receptor of the beta-type. Repetitive stimulation of the reticular formation elicited a desynchronizing effect on the EEG of chloral hydrate anaesthetized rats. LC stimulation, in contrast, hardly produced any modification of the EEG as judged by visual examination of the recordings.     

Effects of adenosine and related compounds on an inhibitory process in rat cerebral cortex

Inhibition of neurons in the rat cerebral cortex was evoked by local cortical stimulation. Adenosine, AMP, and ATP applied by microiontophoresis produced no change of this inhibition. Theophylline and aminophylline, administered intravenously or iontophoretically, blocked the depression of neuronal firing by adenosine, but did not themselves affect the duration of inhibition. Dipyridamole and hexobendine, at iontophoretic doses which potentiated responses to adenosine, produced some reduction of inhibitory duration. We conclude that endogenous purines do not normally contribute to local cortical inhibition, but that their accumulation can inhibit this phenomenon, possibly presynaptically.     

Electrophysiological characterization of adrenoceptors in the rat dorsal hippocampus. I. Receptors mediating the effect of microiontophoretically applied norepinephrine

The rat hippocampus receives a dense noradrenergic innervation originating exclusively from the locus coeruleus. The present electrophysiological study was undertaken to characterize the adrenoceptor mediating the suppressant effect of microiontophoretically applied norepinephrine (NE) on CA1 and CA3 dorsal hippocampus pyramidal neurons of the rat. The rank order of potency of microiontophoretically applied agonists, in suppressing the firing rate of hippocampus pyramidal neurons was: oxymetazoline greater than NE greater than phenylephrine greater than isoproterenol greater than clonidine. In the hippocampus, oxymetazoline was more potent than NE, whereas it was ineffective in the lateral geniculate nucleus where the effect of NE is mediated by an alpha 1-adrenoceptor. Low currents of clonidine antagonized the effect of NE suggesting that clonidine may exert a partial agonistic effect. The rank order of potency of i.v. administered adrenergic antagonists in blocking the suppressant effect of microiontophoretically applied NE was: idazoxan much greater than prazosin much greater than propranolol. Idazoxan also blocked the effect of oxymetazoline, phenylephrine, and isoproterenol but did not modify the effect of microiontophoretically applied gamma-aminobutyric acid (GABA). In addition, idazoxan, applied by microiontophoresis, readily blocked the suppressant effect of NE without affecting that of GABA. These results suggest that the suppressant effect of microiontophoretically applied NE on rat dorsal hippocampus pyramidal neurons is primarily mediated by alpha 2-adrenoceptors.     

Tryptamine modifies cortical neurone responses evoked by stimulation of nucleus raphe medianus

Electrical stimulation of 5-hydroxytryptamine (5-HT) containing cell bodies in the nucleus raphe medianus (NRM) evoked complex responses on most cortical neurones. The predominant response pattern was biphasic, a short latency inhibition being followed by a long latency excitation. Occasional cells showed a third phase, a very long latency weak inhibition. When tryptamine was applied iontophoretically with ejecting currents which did not alter cell firing rate the excitatory effects of NRM stimulation were profoundly reduced. The initial inhibition of cell firing was not altered by tryptamine but some evidence suggested that the long latency inhibition could be potentiated. The results may suggest that tryptamine can modify the neuronal effects of synaptically released 5-hydroxytryptamine.     

Postnatal development of alpha-adrenoceptor-mediated autoinhibition in the locus coeruleus

Rats, from birth to postnatal day 34, were anesthetized with urethane and a neuropharmacological study was carried out of the autoreceptors located on the somadendritic membranes of locus coeruleus (LC) neurons. Iontophoretic application of noradrenaline (NA) caused inhibition of LC cell firing at all developmental stages, and such inhibition was totally blocked by the alpha 2-antagonist piperoxane. The sensitivity of LC neurons to iontophoretically applied NA appeared to become reduced with age. In LC neurons from birth to postnatal day (PD) 8, the prolonged period of suppressed firing after antidromic activation by stimulation of the dorsal noradrenergic bundle was not shortened by piperoxane. After PD 9, the proportion of LC neurons in which piperoxane could antagonize the postactivation inhibition increased with age. These results indicated that although LC neurons, even at birth, had alpha 2-adrenoceptors on the somadendritic membranes which were responsible for the NA-induced inhibition, inhibition of LC cell firing caused by NA released from the terminals of axon collaterals and/or possibly from dendrodendritic synapses did not occur until PD 9.     

An alpha 2 receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurones

Extracellular recordings were made of 59 neurones with long, ascending projections (spinocervical tract (SCT) and dorsal column postsynaptic (DCPS) neurones) in the lumbar dorsal horn of anaesthetized and paralyzed cats. All showed prominent excitatory responses to innocuous stimuli, applied to their cutaneous receptive fields on the ipsilateral hindlimb. The majority of the population investigated (83%) was multireceptive, being activated by noxious as well as innocuous cutaneous stimuli. Drug effects were examined on a regular cycle of responses to these cutaneous stimuli and also to DL-homocysteic acid (DLH). In 49 multireceptive SCT and DCPS neurones, ionophoretically-applied L-noradrenaline (NA) produced a potent selective inhibition of the nociceptive responses (to heat or pinch) in 40 out of 44 SCT and 3 out of 5 DCPS neurones, with no statistically significant change in the responses to innocuous brush or DLH, or in spontaneous activity. NA had no effect on the majority of cells (8 out of 11) that responded only to innocuous stimuli. In 19 SCT neurones that showed NA-selectivity, the alpha 2-selective agonists clonidine (in 12 out of 15) and metaraminol (in 2 out of 3) mimicked this selective effect, whereas, the alpha 1 agonist, phenylephrine and the beta agonist, isoprenaline did not. Furthermore, the alpha 2 antagonists, yohimbine and idazoxan (RX781094), either reversed or reduced the potency of the NA-elicited inhibition of nociceptive responses in all 7 SCT neurones tested. These results are discussed in relation to other evidence for spinal antinociceptive effects of noradrenergic systems acting at a spinal level and the possible involvement of an alpha 2 receptor in such effects.     

Effects of noradrenaline on the responsiveness of cultured cerebellar neurons to excitatory amino acids

The effects of noradrenaline (NA) on the responsiveness of cultured cerebellar neurons to excitatory amino acids were intracellularly investigated. NA applied to external medium to a final concentration of 10 microM or lower slightly decreased the firing frequency of spontaneous spikes, induced a small hyperpolarization or slightly increased the input resistance of Purkinje cells. In addition, bath-applied NA was found to enhance the depolarizations induced by iontophoretically applied glutamate and aspartate but to a smaller extent for the latter. These direct and modulating effects of NA were also observed when NA was applied by iontophoresis. The sites sensitive to iontophoresed NA were found to be not uniformly distributed but localized in restricted regions on individual Purkinje cells. The enhancement by NA of the glutamate or aspartate response was blocked by beta-adrenergic antagonists, propranolol or pindolol, and extracellularly applied cAMP mimicked the NA action. These results suggest the possibility that NA physiologically modulates excitatory amino acid-mediating synaptic transmission in the cerebellum probably by acting on beta-rather than alpha-adrenergic receptors.     

Differential effects of D1 and D2 dopamine receptor agonists on substantia nigra pars reticulata neurons

Dopamine was shown in previous studies to exert a dual effect on non-dopaminergic neurons of the substantia nigra pars reticulata: it increases the firing rates of about 50% of cells, and consistently lessens the ability of iontophoretically applied or endogenously released GABA to inhibit their firing. These studies were undertaken to determine (1) whether the two effects could occur independently and, (2) whether different dopamine receptor subtypes might mediate the two responses. Extracellular, single unit activities of pars reticulata neurons were monitored in male rats anesthetized with chloral hydrate. Repeated 30-s iontophoretic pulses of GABA were delivered at an ejection current sufficient to inhibit cell firing by at least 50%, but not totally. After establishing a consistent response to GABA, co-iontophoresis of a test compound was initiated to determine its effects on basal firing rates and responsiveness to GABA. When acetylcholine and glutamate were evaluated in the test paradigm using ejection currents which excited cells by 54.0 +/- 4.9%, neither compound consistently altered the inhibition elicited by GABA. This confirmed that increases in cell firing could occur without concurrent GABA-attenuating effects, and supported the contention that the dual effects of dopamine could be dissociated and perhaps independently mediated. To examine whether the effects of dopamine involve actions at different dopamine receptor subtypes within the nigra, the D1 agonist SKF 38393 and the D2 agonist LY 171555 were substituted in the procedure. Applications of R,S(+/-)-SKF 38393 caused current-dependent increases in firing with a maximal increase at 8 nA of 55 +/- 18% above baseline (n = 14). The excitatory effect appeared to be D1-mediated since R(+)-SKF 38393, but not the inactive S(+)-enantiomer, could elicit the response. Conversely, graded applications of LY 171555 caused only occasional and more modest increases in basal activities, but consistently and markedly attenuated responses to GABA, decreasing GABA's inhibitory potency by 60.9 +/- 4.3% at 10 nA (n = 17). These results provide support for discrete roles of D1 and D2 receptors in substantia nigra pars reticulata, and suggest mechanistically distinct ways by which dendritically released dopamine could act to modify basal ganglia output from this region.     

Noradrenergic potentiation of excitatory transmitter action in cerebrocortical slices: evidence for mediation by an alpha 1 receptor-linked second messenger pathway.

Considerable evidence from intact, anesthetized preparations suggests that norepinephrine (NE) can modulate the efficacy of synaptic transmission within local circuits of the mammalian neocortex; i.e. both iontophoretic application of NE and activation of the coeruleocortical pathway are capable of facilitating cortical neuronal responses to non-noradrenergic synaptic inputs and putative transmitter agents. In the present study, the effects of NE on somatosensory cortical neuronal responses to putative excitatory transmitters were characterized using in vitro tissue slice preparations. Somatosensory unit responses to iontophoretic pulses of acetylcholine (ACh) or glutamate (Glu) (10-60 nA; 5-25 s duration) were examined before, during and after a period of continuous NE (1-35 nA; 4-25 min duration) microiontophoresis. Quantitative analysis of per-event histograms indicated that both Glu- and ACh-evoked excitatory discharges were routinely (Glu 94%, n = 54; ACh 67%, n = 9) potentiated above control levels during NE administration. In 8 cells, NE revealed robust excitatory discharges to otherwise subthreshold iontophoretic doses of Glu. The alpha-specific agonist, phenylephrine, mimicked (n = 3), NE-induced potentiation of Glu-evoked discharges whereas the alpha antagonist phentolamine blocked (n = 5) enhancement of these responses. Moreover, activation of protein kinase C by iontophoretic application of phorbol 12,13-diacetate (5-15 nA, n = 4) mimicked the potentiating actions of NE on Glu-evoked excitatory responses. Results from other experiments further indicated that these facilitating actions of NE on Glu-evoked responses do not involve beta receptor activation or intracellular increases in cyclic AMP. In summary, these results demonstrate that NE can facilitate cortical neuronal responses to threshold and subthreshold level applications of putative excitatory transmitter agents. Moreover, it appears that, unlike noradrenergic facilitating influences on GABA-induced inhibition, these actions are mediated by an alpha adrenoceptor mechanism which may be linked to intracellular activation of protein kinase C. Overall, these findings reinforce the idea that noradrenergic modulatory actions on excitatory and inhibitory neuronal responses may involve the activation of separate receptor-linked second messenger systems.     

Activation of lateral geniculate neurons by locus coeruleus or dorsal noradrenergic bundle stimulation: Selective blockade by the alpha1-adrenoceptor antagonist prazosin

Presentation of a stimulus train to the locus coeruleus (LC) or dorsal noradrenergic bundle (DB) resulted in a facilitation of thev spontaneous firing of single units in the dorsal lateral geniculate nucleus (LGNd) of the rat. These stimulation effects were blocked by the alpha₁-adrenoceptor antagonists WB-4101 and prazosin. Both drugs also blocked the activation of LGNd neurons by iontophoretic norepinephrine (NE). The cholinergic agonists acetylcholine (ACh) and carbachol (CCh) activated LGNd neurons in a similar fashion to NE, however, these responses were selectively blocked by the muscarinic antagonist scopolamine. The response to ACh was also sensitive to WB-4101 suggesting that the drug possesses some cholinergic blocking activity. In contrast to WB-4101, prazosin displayed a high degree of selectivity for noradrenergic but not cholinergic response. On the basis of the observation that prazosin selectively antagonizes both the stimulation effects and iontophoretic NE (but not CCh), we conclude that activation of LGNd neurons by LC or DB stimulation is mediated predominantly via the release of NE from coeruleo-geniculate fibers, rather than the inadvertent activation of a cholinergic pathway. Moreover, inasmuch as the systemic administration of prazosin effectively blocks central noradrenergic neurotransmission at dosescomparable to those uses clinically, the possibility that prazosin exerts its antihypertensive action in part via a central mechanism requires further investigation.