Stimulation Of Locus Coeruleus Research Articles

Modulation of Forebrain Electroencephalographic Activity in Halothane-Anesthetized Rat via Actions of Noradrenergic β-Receptors within the Medial Septal Region

The locus coeruleus (LC)-noradrenergic system modulates forebrain electroencephalographic (EEG) activity in halothane-anesthetized rat. For example, unilateral enhancement of LC neuronal activity increases cortical EEG (ECoG) and hippocampal EEG (HEEG) indices of arousal bilaterally (Berridge and Foote, 1991). Conversely, bilateral suppression of LC discharge activity increases EEG measures of sedation (Berridge, et al., 1993b). The EEG-activating effects of LC stimulation appear to involve noradrenergic beta-receptors (Berridge and Foote, 1991). Two candidate sites at which LC efferents could influence ECoG and HEEG are the medial septum/vertical limb of the diagonal band of Broca (MS) and the substantia innominata/nucleus basalis of Meynert (SI). To determine whether norepinephrine mediates such actions within either of these regions, the EEG effects of small infusions of a beta-agonist or antagonist into MS or SI were examined in halothane-anesthetized rat. Unilateral infusions (150 nl) of the beta-agonist isoproterenol (ISO) (3.75 microg, 17 nmol) into MS, but not SI (150-450 nl), elicited robust bilateral activation of ECoG and HEEG. Infusions of glutamate (0.5 microg, 3.0 nmol) into either MS or SI elicited bilateral ECoG and HEEG activation. Neither vehicle infusions into MS nor infusions of ISO into regions adjacent to MS altered forebrain EEG activity. Bilateral, but not unilateral, MS infusions of the beta-antagonist timolol (3.75 microg, 8.7 nmol) decreased EEG indices of arousal in the lightly anesthetized preparation. Power spectral analyses provided quantitative confirmation of these qualitative observations. These results indicate that under these experimental conditions, noradrenergic efferents, presumably arising from LC, modulate forebrain EEG state via actions at beta-receptors located within MS. The results presented in the accompanying report extend these observations to the unanesthetized preparation and incorporate additional measures of behavioral state.

Effect of neurotoxin DSP4 on EEG power spectra in the rat acute model of epilepsy

The effect of the adrenergic neurotoxin N-(chloroethyl)- N-ethyl-2-bromobenzylamine (DSP4) on electroencephalographic (EEG) activity was studied in the model of epilepsy induced by systemic application of penicillin (1000 000 IU/kg, i.p). DSP4 (50 mg/kg, i.p.) was administrated to male Wistar rats, while the control animals were rats from the same litters. EEG activity was recorded in acute and chronic experiments 3 or 4 weeks after DSP4 treatment, before and after penicillin administration. Occasional locus coeruleus (LC) stimulation served as an electrophysiological test of DSP4 toxic effect. EEG power spectra in DSP4 treated animals showed a tendency to be greater in lower frequency bands than in controls before penicillin administration; there was almost no effect of electrical LC stimulation, regardless on penicillin treatment. In the model of epilepsy, the mean total EEG power spectra were greater in the period of 135–330 min after penicillin administration, as well as during 345–540 min, in DSP4 treated animals as compared to the controls. It seems that neurotoxin DSP4 is an optimal tool for studying the removal of LC influence in the acute model of epilepsy. It is also suggested that norepinephrine (NE) may have a modulatory role in the systemic penicillin epilepsy.

Medullary responses to chemoreceptor activation are inhibited by locus coeruleus and nucleus raphe magnus.

The effect of electrical and L-glutamate stimulation of the nucleus locus coeruleus (LC) and nucleus raphe magnus (NRM) on multiunit activity evoked in the nucleus tractus solitarius (NTS) by activation of arterial chemoreceptors (15-25 micrograms kg-1 of sodium cyanoborohydride, i.v.) was studied in rats anaesthetized with urethane (1.1 g kg-1 i.p.). Multiunit discharge of NTS neurones in response to cyanide injection was composed by spikes higher than 200 microV and about 10 Hz frequency. Electrical and L-glutamate stimulation of the LC and the NRM significantly reduced the frequency of the cyanide-induced multiunit discharge. The results show that neurones of the NTS with input from arterial chemoreceptors can be inhibited by LC and and NRM cells, suggesting that these nuclei play a role in controlling chemosensory input at the NTS.

Locus coeruleus noradrenergic neurons as a micturition center.

The micturition reflex arch is composed of an afferent pathway from the urinary bladder to the pontine micturition center via the pelvic nerve and spinal cord. The efferent pathway projects from the center to the bladder through the sacral parasympathetic center of intermediolateral column cells. The pontine micturition center is thought to be noradrenergic (NA) neurons in the locus coeruleus (LC) due to the following observations: (1) LC stimulation induces bladder contraction in cats, and this response is blocked by intrathecal application of alpha 1-adrenergic antagonist (prazosin), but not the alpha 2- nor beta-adrenergic antagonist. Although this contraction is not observed after NA depletion with reserpine, with subsequent i.v. injection of L-dopa a NA precursor induces recurrence of the response. (2) The micturition reflex induced by bladder distention is similarly reversed with alpha 1-adrenergic antagonist and chemical destruction of NA cells by injecting 6-hydroxydopamine in the LC. However, subsequently applied alpha 1-adrenergic agonist induces the contraction due to bladder distention. (3) LC stimulation elicits spike generation of sacral intermediolateral cells. Microiontophoretically applied alpha 1-adrenergic antagonist inhibits the LC stimulation-induced spikes of the neuron, which is not antidromically activated by pelvic nerve stimulation. However, spikes in neurons activated antidromically were not affected by the drug. This indicates that the former and latter neurons are interneuron and parasympathetic projecting neurons, respectively. The existence of NA terminals from the LC and alpha 1-adrenergic receptors in the intermediolateral column cells supports the concept that NA cells in the LC are units constituting the micturition center.

Locus coeruleus stimulation by corticotropin-releasing hormone suppresses in vitro cellular immune responses

Previous studies have demonstrated that stressors alter cellular immune system function, and increase the activity of locus coeruleus neurons. Furthermore, stressors increase the release of corticotropin-releasing hormone (CRH) and locus coeruleus neurons are activated by CRH. Thus, the present study examined whether activation of the locus coeruleus by infusion of CRH modulates the function of blood and spleen lymphocytes assessed in vitro. CRH (100 ng) was administered into the region of the locus coeruleus in awake rats 1 hr before spleen and peripheral blood lymphocytes were collected for culture with nonspecific mitogens. Unilateral or bilateral microinfusion of CRH into the locus coeruleus produced a decrease in blood and spleen T-lymphocyte mitogenic responses to phytohemagglutinin, ConA, and an antibody to the T-lymphocyte antigen receptor. In contrast, infusion of saline into the locus coeruleus or CRH into the surrounding region of the dorsal pons did not alter spleen or blood lymphocyte responses. Plasma concentrations of adrenocorticotropic hormone, corticosterone, and IL-6 were increased by CRH infusion into the locus coeruleus. These results suggest that CRH-evoked activation of the locus coeruleus stimulates the hypophysial adrenal axis, possibly activates the sympathetic nervous system, and results in immunosuppression. Comparable changes in lymphocyte and hormone responses are produced by an aversive stimulus or a conditioned stressor, suggesting that activation of the locus coeruleus may be a component of stressor-induced immune alterations.

Influence of electrical stimulation of locus coeruleus on the rat blood-brain barrier permeability to sodium fluorescein.

The role of central adrenergic innervation of the brain capillaries is still a matter of discussion. The hypothesis that these nerves control the blood-brain barrier permeability was tested by electrically stimulating the locus coeruleus, the major central adrenergic nucleus, in the anaesthetized rat. Frequencies of 5, 15, and 30 Hz were used. A frequency dependent increase in blood-brain barrier permeability to sodium fluorescein was verified. Prior administration of the alpha-adrenoceptor antagonist phenoxybenzamine (10 mg/kg i.p., 24 h before electrical stimulation) totally blocked the effect of 15 Hz stimulation. The same dose of pindolol (a beta-adrenoceptor antagonist) given 1 h before electrical stimulation potentiated the effect of 5 Hz stimulation. Thus, blood-brain barrier permeability is increased, in a frequency dependent manner, by electrical stimulation of the locus coeruleus. The results obtained with phenoxybenzamine and pindolol suggest an opposite effect of alpha and beta-adrenoceptors on the control of sodium fluorescein transport through the blood-brain barrier.

Phasic stimulation of the locus coeruleus: effects on activity in the lateral geniculate nucleus.

Neurons in the locus coeruleus (LC) encode information related to behavioral state in a tonic pattern of firing and information related to the occurrence of a sensory stimulus in a phasic pattern of firing. The effects of phasic stimulation of the LC (6 pulses at 30 Hz), designed to approximate its physiological activation by sensory stimuli, were studied in the lateral geniculate nucleus (LGN) of anesthetized rats. Phasic stimulation of the LC significantly increased neuronal firing in the LGN with a mean latency 320 ms from onset of stimulation. Receiver operating characteristic analyses on a trial-by-trial basis showed that phasic LC stimulation can result in a highly discriminable signal in the LGN. This increased neuronal firing rate in the LGN was specific for the site of stimulation and was reduced by the norepinephrine synthesis inhibitor alpha-methyl-p-tyrosine and by intravenous WB-4101 (alpha 1-receptor antagonist). Neurons in the LGN have a single-spike firing mode when sensory information is faithfully relayed from retina to cortex and a burst-firing mode when the transfer of this information is degraded. Phasic LC stimulation reduced burst firing (2-5 ms interspike intervals, ISIs) at low frequencies (< or = 4 Hz) in the LGN, and for some neurons there was an absolute decrease in burst-like ISIs after LC stimulation, despite an increase in mean firing rate.

Intracerebral vascular changes induced by cold pressor test: A model of sympathetic activation

Cerebral vascular changes seem to play a fundamental role in the pathogenesis of various functional disturbances, (i.e. those suggested for migraine pathogenesis). However the exact role of single regulatory aspects (metabolic-neuronal-mechanic) are not completely understood and easily investigated in man. In particular, the role of autonomic nervous system is widely debated and recently the stimulation of tegmental noradrenergic nuclei (locus coeruleus in particular) has proved capable of inducing, in the animal, both the reduction and the increase of extracerebral blood flow. In order to evaluate the vascular effect of locus coeruleus stimulation in man, we investigated intracerebral vascular changes induced by the cold pressor test (CPT) (a well standardized method for activating both nociceptive and sympathetic pathways) by means of transcranial Doppler sonography. The examinations were performed in 14 healthy controls. CPT induced a constant and evident reduction in mean arterial velocity of the middle cerebral artery. The response was triggered during the first minute following hand immersion in ice water and reached its maximum level by the 3rd minute. Pretreatment with the alfa2-agonist clonidine caused a marked reduction of the cerebrovascular response. These data suggest that: a) intracerebral vascular response induced by CPT may be attributed to a central noradrenergic mechanism (possibly modulated at the locus coeruleus level) and b) transcranial Doppler monitoring of CPT effect is a potential tool for investigating peculiar patterns of functional disturbances of cerebral circulation.

Anticonvulsant activity of the noradrenergic locus coeruleus system: Role of beta mediation

Many experimental observations have demonstrated the modulatory role exerted by several neural structures and neurotransmitters on spontaneous and paroxysmal bioelectric activity of the hippocampus. Recently, the control exerted by locus coeruleus (LC) and its noradrenergic (NA) efferent pathway on different experimental models of epilepsy (e.g. cortical cobalt chronic epilepsy, amygdaloid and hippocampal kindling) was emphasised. On this basis, a series of experiments was performed to elucidate the functional role of LC-NA system on the hippocampal penicillin (PCN) focus and the type of adrenergic receptor involved. The experiments were carried out on 25 rats in which an epileptiform hippocampal focus was obtained through intrahippocampal PCN administration (100–200 I.U.). In these conditions, LC, ipsilateral to PCN hippocampal focus, was stimulated before and after intraperitoneal (i.p.) administration of a β-adrenergic receptor antagonist propranolol (2 mg/kg). Results showed a significant reduction of hippocampal spiking frequency during LC stimulation; after i.p. propranolol injection, LC stimulation, at the same parameters, failed to induce any sort of modification of PCN hippocampal spiking frequency. Furthermore, intrahippocampal application of a β-selective agonist 2-fluoro-noradrenaline (2-FNA) mimics the inhibitory effects of LC stimulation. All data suggest that the LC-NA system is able to induce a net reduction of hippocampal epileptiform focus and the inhibitory NA control involves the activation of adrenergic beta receptors.

Cotransmitter-mediated locus coeruleus action on motoneurons

This article reviews evidence for a direct noradrenergic projection from the dorsolateral pontine tegmentum (DLPT) to spinal motoneurons. The existence of this direct pathway was first inferred by the observation that antidromically evoked responses occur in single cells in the locus coeruleus (LC), a region within the DLPT, following electrical stimulation of the ventral horn of the lumbar spinal cord of the cat. We subsequently confirmed that there is a direct noradrenergic pathway from the LC and adjacent regions of the DLPT to the lumbar ventral horn using anatomical studies that combined retrograde tracing with immunohistochemical identification of neurotransmitters. These anatomical studies further revealed that many of the noradrenergic neurons in the LC and adjacent regions of the DLPT of the cat that send projections to the spinal cord ventral horn also contain colocalized glutamate (Glu) or enkephalin (ENK). Recent studies from our laboratory suggest that Glu and ENK may function as cotransmitters with norepinephrine (NE) in the descending pathway from the DLPT. Electrical stimulation of the LC evokes a depolarizing response in spinal motoneurons that is only partially blocked by α 1 adrenergic antagonists. In addition, NE mimicks only the slowly developing and not the fast component of LC-evoked depolarization. Furthermore, the depolarization evoked by LC stimulation is accompanied by a decrease in membrane resistance, whereas that evoked by NE is accompanied by an increased resistance. That Glu may be a second neurotransmitter involved in LC excitation of motoneurons is supported by our observation that the excitatory response evoked in spinal cord ventral roots by electrical stimulation of the LC is attenuated by a non-N- methyl- d-aspartate glutamatergic antagonist. ENK may participate as a cotransmitter with NE to mediate LC effects on lumbar monosynaptic reflex (MSR) amplitude. Electrical stimulation of the LC has a biphasic effect on MSR amplitude, facilitation followed by inhibition. Adrenergic antagonists block only the facilitatory effect of LC stimulation on MSR amplitude, whereas the ENK antagonist naloxone reverses the inhibition. The chemical heterogeneity of the cat DLPT system and the differential responses of motoneurons to the individual cotransmitters help to explain the diversity of postsynaptic potentials that occur following LC stimuli.

The human locus coeruleus and anxiogenesis

Electrical stimulation of locus coeruleus (LC), via permanently implanted electrodes with confirmed localization and effectiveness, did not elicit any subjective or behavioral manifestations of anxiety. This is evidence against the hypothesis that LC is a mediator of anxiogenesis in man.

Dual effect of the locus coeruleus on neuronal activity in the visual cortex

The effects exerted by electrical stimulation of the locus coeruleus (LC) on neuronal activity in the visual cortex have been studied in acute experiments on rabbits. The pattern of cortical afterprocesses affecting poststimulus histograms of neuronal activity has been found not always to correspond to the direction of change in the neuronal excitation level in the period of LC stimulation. An analysis of crossed interval histograms for a pair of neurons located in the same microvolume of the cortex has revealed the existence of two independent postsynaptic effects of LC stimulation: a “fast” (synaptic) effect and a “slow” (modulatory) effect. The findings are discussed with allowance for morphological features of the synaptic connections and interneuronal transmission in the noradrenergic system of the brain.

The function of noradrenergic neurons in mediating antinociception induced by electrical stimulation of the locus coeruleus in two different sources of Sprague-Dawley rats

Although noradrenergic neurons in the nucleus locus coeruleus are known to project to the spinal cord, these neurons appear to innervate different regions of the spinal cord in Sprague-Dawley rats obtained from two different vendors. Recent anatomical studies demonstrated that the noradrenergic neurons in the locus coeruleus in Sasco Sprague-Dawley rats primarily innervate the ventral horn, whereas Harlan Sprague-Dawley rats have coeruleospinal projections that terminate in the dorsal horn of the spinal cord. This report describes the results of behavioral experiments that were designed to determine the functional significance of these anatomical differences. Electrical stimulation of neurons in the locus coeruleus produced antinociception in both Harlan and Sasco rats. The antinociception in Harlan rats was readily reversed by intrathecal injection of yohimbine, a selectiveα 2-adrenoceptor antagonist, or by phentolamine, a non-selectiveα 2-adrenoceptor antagonist. In contrast, these antagonists did not alter the antinociception produced by locus coeruleus stimulation in eisco rats. Finally, theα 2-antagonist, idazoxan, did not alter the antinociceptive effect of locus coeruleus stimulation in either group of rats. These observations indicate that coeruleospinal noradrenergic neurons in Harlan and Sasco Sprague-Dawley rats have different physiological functions. Thus, electrical stimulation of noradrenergic neurons in the locus coeruleus that innervate the spinal cord dorsal horn (Harlan rats) produces antinociception. but stimulation of coeruleospinal noradrenergic neurons that project to the ventral horn (Sasco rats) does not produce antinociception. It is likely that genetic differences between ohese outbred stocks of rats account for the fundamental differences in the projections of coeruleospinal neurons and their function in controlling nociception.

Yohimbine reduces inhibition of lamina X neurones by stimulation of the locus coeruleus

The effects of yohimbine, on inhibition of C-fibre evoked responses of spinal lamina X neurones by electrical stimulation of the locus coeruleus (LC) were studied in rats. LC stimulation inhibited by 67.33 +/- 25.14%, the C-fibre evoked responses in 24 out of 30 WDR neurones and the C-component of the flexion reflex by 77.62 +/- 18.77%. The A-fibre evoked responses with wide dynamic range (WDR) and low threshold (LT) neurones were not significantly affected by LC stimulation. After administration of yohimbine, LC-induced inhibition of lamina X neurones was attenuated by 77.43 +/- 23.22% without significant changes in C-fibre evoked responses. The results suggest that alpha 2-adrenoceptors may be involved in mediation of LC-induced inhibition on lamina X neurones.

The functional role of monoanimergic and aminoacidergic mechanisms of the locus coeruleus in anxiety states of different aversive origins

Dopamine and glutamine acid microinjection in the locus coeruleus of rats does not influence the alarm state in the test of "Threatening situation" avoidance, but weakens the state of alarm in the test of "illuminated site" avoidance. The local injection of GABA and noradrenaline mesatone effect imitators in this brain formation weakens the alarm state in the test of "threatening situation" avoidance but is not effective in the test of "illuminated site" avoidance. On the contrary, the chemical stimulation of locus coeruleus by serotonin influences the anxiolytic effect in two different experimentally modelled states of alarm. The participation of locus coeruleus and acidergic mechanisms in anxiety of diverse aversive genesis is discussed.

Chemical stimulation of the nucleus locus coeruleus: cardiovascular responses and baroreflex modification

Microinjection of glutamate (Glu, 2.5 nmol) or homocysteic acid (HA, 0.1–0.5 nmol) into the nucleus locus coeruleus (LC) decreased both blood pressure and heart rate. These microinjections also produced a facilitatory or occlusive effect on depressor and bradycardiac responses evoked by electrical stimulation of the aortic depressor nerve (ADN). Destruction of the nucleus tractus solitarius (NTS), which totally eliminated ADN-evoked responses, had no effect on the cardiovascular responses evoked by LC stimulation. These results suggest that the neuronal populations that contribute to the LC-induced cardiovascular responses overlap at least partly with the baroreflex substrate other than the NTS.

Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat.

Electrical stimulation techniques were employed in the chloral hydrate anaesthetized male rat to evaluate if the pontine noradrenergic nucleus locus coeruleus can influence the activity of midbrain dopamine neurons in the ventral tegmental area and zona compacta, substantia nigra. Single-pulse locus coeruleus stimulation evoked an excitation, followed by an inhibition, of the electrical activity of single midbrain dopamine neurons. Neither of these responses were observed in animals pretreated with reserpine, implicating noradrenaline as a mediator. The alpha 1-adrenoceptor antagonist prazosin decreased the excitation, while other adrenoceptor antagonists were without general effect. Burst-type stimulation produced only a more long-lasting inhibition. The influence from the locus coeruleus on midbrain dopamine neurons could be important in behavioural situations involving novelty and reward, and might also be of importance for the actions of psychotropic drugs.

Differential regional hemodynamic changes produced by L-glutamate stimulation of the locus coeruleus

The locus coeruleus (LC) exerts an inhibitory influence on the cardiovascular system. Microinjection of the excitatory amino acid, L-glutamate, into the LC elicits a decrease in arterial pressure as a result of a decrease in total peripheral resistance (TPR). The aim of the present study was to examine the role of the LC in the regulation of the regional hemodynamics. Employing anesthetized rats, the blood flow to the renal, mesenteric and hind-limb vascular beds was measured with an electromagnetic flowmeter. The changes in regional blood flow tnd vascular resistance evoked by chemical stimulation of the LC were examined separately in each region. During the depressor response elicited by LC stimulation, the hind-limb and renal vascular resistance was signfficantly decreased, while the mesenteric resistance was unchanged. The vasodilatation appeared to be more prominent in the hind-limb muscle than in the systemic circulation. Renal nerve denervation attenuated the decrease in renal vascular resistance elicited by LC stimulation. However, a small part of this response still remained in the denervated kidney. The present results suggest therefore that: (1) LC neurons exert differential hemodynamic effects on the hind-limb muscle, renal and mesenteric vascular beds; (2) the largest contribution to the decrease in TPR is related to vasodilatation in the hind-limb muscles; and (3) the renal vasodilatation elicited by LC stimulation is not mediated solely by the renal innervation.

Tonic activation of locus coeruleus neurons by systemic or intracoerulear microinjection of an irreversible acetylcholinesterase inhibitor: Increased discharge rate and induction of c-fos

Recent studies in this laboratory have demonstrated that intramuscular injection of the irreversible acetylcholinesterase (AChE) inhibitor, soman (pinacolylmethylphosphonofluoridate), produces a rapid (1–2 h) and profound depletion (70% of control) of norepinephrine (NE) in the olfactory bulb and forebrain. NE is decreased only in convulsing animals. As NE-containing locus coeruleus (LC) neurons provide the only NE input to the olfactory bulb and the major NE innervation of the forebrain, the reduction of NE suggests that soman may cause tonic activation of LC neurons leading to rapid depletion of NE. Activation of LC may result from: (i) facilitation of cholinergic transmission in LC; (ii) soman-induced activation of excitatory inputs to LC; or (iii) generalized activation of LC neurons due to seizures. The present experiments were designed to assess these alternatives. We examined whether LC neuronal activity, c-fos expression, and AChE staining are altered after peripheral (systemic) or direct intracoerulear injection of soman in anesthetized rats. Both modes of soman administration rapidly and potently increase the spontaneous discharge rate of LC neurons. This activation was associated with a desynchronization of the electroencephalogram, but not with seizures. The discharge of LC neurons remained elevated at all postsoman intervals examined (up to 2 h) and was rapidly and completely reversed by systemic injection of the muscarinic receptor antagonist scopolamine hydrochloride, but not by the nicotinic receptor antagonist mecamylamine. Both systemic and intracoerulear soman administration completely inhibited AChE staining in LC and rapidly induced the expression of c-fos in LC neurons. These results demonstrate that soman potently and tonically activates LC neurons. This effect appears to be mediated by direct inhibition of AChE in LC leading to a rapid accumulation of ACh. Unhydrolyzed ACh tonically activates LC neurons via muscarinic receptors. Soman-induced activation of LC neurons does not require seizures. We conclude that depletion of forebrain and olfactory bulb NE after systemic administration of soman results from tonic hypercholinergic stimulation of LC.

Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain

The present electrophysiological experiments were undertaken to investigate the effect of desipramine and d-amphetamine on noradrenergic neurotransmission in the rat central nervous system. The effectiveness of electrical stimulation of the locus coeruleus and of microiontophoretic application of norepinephrine (NE) in suppressing the firing activity of CA 3 pyramidal neurons was studied in the dorsal hippocampus. Desipramine (0.5 and 5 mg/kg i.v.) and d-amphetamine (0.25 and 5 mg/kg i.v.) decreased the effectiveness of locus coerulcus stimulation and prolonged the effect of microiontophoretically applied NE on the same pyramidal neurons. Subsequent i.v. administration of idazoxan, an α 2-adrenoceptor antagonist, reversed the effects of desipramine and d-amphetamine on the effectiveness of locus coerulcus stimulation and decreased that of microiontophoretically applied NE. In addition, idazoxan prevented the effect of subsequent administration of desipramine (5 mg/kg i.v.) on the effectiveness of locus coerulcus stimulation. High doses of d-amphetamine (5 and 10 mg/kg i.v.) decreased the firing activity of hippocampus pyramidal neurons by 70 and 98%, respectively, whereas low doses of desipramine (0.5 mg/kg i.v.) or of d-amphetamine (0.25 mg/kg i.v.) were without effect. After Icsioning of NE projections with 6-hydroxydopamine. the effect of the 5 mg/kg dose of d-amphetamine on the firing activity of hippocampus pyramidal neurons was markedly reduced, whereas the cumulative 10 mg/kg dose of d-amphetamine completely suppressed, as in control rats, the firing activity of these neurons. This effect of d-amphctaminc in 6-hydroxydopamine-pretreated rats was reversed by the administration of the 5-HT 1A receptor antagonist BMY 7378. These data provide evidence that acute administration of desipramine and d-amphetamine decreases the effectiveness of locus coeruleus stimulation by increasing the activation of terminal α 2-adrenoceptor autoreceptors. In addition, acute administration of high doses of d-amphetamine decreases the firing rate of hippocampus pyramidal neurons by increasing NE and serotonin release.