Locus coeruleus: From global projection system to adaptive regulation of behavior.

The brainstem nucleus locus coeruleus (LC) is a major source of norepinephrine (NE) projections throughout the CNS. This important property was masked in very early studies by the inability to visualize endogenous monoamines. The development of monoamine histofluorescence methods by Swedish scientists led to a plethora of studies, including a paper published in Brain Research by Loizou in 1969. That paper was highly cited (making it a focal point for the 50th anniversary issue of this journal), and helped to spark a large and continuing set of investigations to further refine our understating of the LC-NE system and its contribution to brain function and behavior. This paper very briefly reviews the ensuing advances in anatomical, physiological and behavioral aspects of the LC-NE system. Although its projections are ubiquitously present throughout the CNS, recent studies find surprising specificity within the organizational and operational domains of LC neurons. These and other findings lead us to expect that future work will unmask additional features of the LC-NE system and its roles in normative and pathological brain and behavioral processes. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

Selective suppression of excitatory synapses on GABAergic interneurons by norepinephrine in juvenile rat prefrontal cortical microcircuitry.

The noradrenergic system of the brain is thought to facilitate neuronal processes that promote behavioral activation, alertness, and attention. It is known that norepinephrine (NE) can be significantly elevated in the prefrontal cortex under normal conditions such as arousal and attention, and following the administration of psychostimulants and various other drugs prescribed for psychiatric disorders. However, how NE modulates neuronal activity and synapses in the local prefrontal circuitry remains elusive. In this study, we characterized the actions of NE on individual monosynaptic connections among layer V pyramidal neurons (P) and fast-spiking (FS) GABAergic interneurons in the juvenile (postnatal days 20-23) rat prefrontal local circuitry. We found that NE selectively depresses excitatory synaptic transmission in P-FS connections but has no detectable effect on the excitatory synapses in P-P connections and the inhibitory synapses in FS-P connections. NE apparently exerts distinctly different modulatory actions on identified synapses that target GABAergic interneurons but has no effect on those in the pyramidal neurons in this specific developmental period. These results indicate that, depending on the postsynaptic targets, the effects of NE in prefrontal cortex are synapse-specific, at least in the juvenile animals.

Effects of repeated 3,4-methylenedioxymethamphetamine administration on neurotransmitter efflux and sensory-evoked discharge in the ventral posterior medial thalamus.

3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of Long-Evans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whisker-evoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may "distort," rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.

MDMA (3,4-methylenedioxymethamphetamine)-mediated distortion of somatosensory signal transmission and neurotransmitter efflux in the ventral posterior medial thalamus.

MDMA (3,4-methylenedioxymethamphetamine, Ecstasy) is reported to enhance tactile sensory perception, an effect that is believed to contribute to its popularity as a recreational drug. To date, no literature exists that addresses the neurophysiological mechanisms underlying the effects of MDMA on somatosensation. However, MDMA interactions with the serotonin transporter protein (SERT) are well known. The rat trigeminal somatosensory system has been studied extensively and receives serotonergic afferents from the dorsal raphe nucleus. Given that these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that short-term low-dose MDMA administration (3 mg/kg i.p.) led to a significant increase in 5-hydroxytryptamine (5-HT) efflux in the ventral posterior medial (VPM) thalamus, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We further evaluated the potential for MDMA to modulate whisker-evoked discharge (WED) of individual neurons in this region. After surgically implanting stainless steel 8-wire multichannel electrode bundles, we recorded spike train activity from single cells of halothane-anesthetized rats while mechanically activating the whisker pathway. We found that short-term low-dose MDMA (3 mg/kg i.p.) increased the spontaneous firing rate but reduced the magnitude and duration of WED in individual VPM thalamic neurons. It is noteworthy that the time course of drug action on neuronal firing patterns was generally consistent with increased 5-HT efflux as shown from our microdialysis studies. Based on these results, we propose the working hypothesis that MDMA may "distort" rather than enhance tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.

Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes.

AIM: This study assessed the efficacy and safety of two different dosing regimens of fixed-dose combination (FDC) rosiglitazone (RSG) plus glimepiride (GLIM) compared with RSG or GLIM monotherapy in drug-naive subjects with type 2 diabetes mellitus (T2DM). METHODS: Drug-naive subjects (n = 901) were enrolled into this 28-week, double-blind, parallel-group study if their glycosylated haemoglobin A(1c) (HbA(1c)) was >7.5% but

Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI.

AIMS: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. METHODS: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. RESULTS: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). CONCLUSIONS: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.

Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study.

OBJECTIVE: This study was designed to compare the efficacy, safety and tolerability of rosiglitazone (RSG) added to submaximal doses of metformin (MET) with dose escalation to the maximal effective dose of MET monotherapy in type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: In this multi-center, double-blind, randomized, parallel-group study, 766 subjects with a baseline MET dose of 1000 mg/day were randomized to receive either RSG 4 mg/day (4 mg/1000 mg) or MET 500 mg/day (1500 mg/day total dose) for 8 weeks. Only the RSG dose was increased in the combination group - to 8 mg/day (8 mg/1000 mg) - and only the MET dose was increased in the MET monotherapy group - to 2000 mg/day for the remaining 16 weeks. RESULTS: After 24 weeks, RSG added to MET (8 mg/1000 mg/day) was at least as effective as 2000 mg/day of MET in improving HbA(1c), with mean reductions of -0.93% (95% CI: -1.06%, -0.80%) and -0.71% (95% CI: -0.83%, -0.60%), respectively, from baseline in subjects that completed the study according to the investigator (mean treatment effect/difference of -0.20% [95% CI: -0.36%, -0.04%]). In addition, a higher percentage of subjects in the RSG + MET group achieved American Diabetes Association target levels of HbA(1c) < 7% (58.1% versus 48.4%) and American Association of Clinical Endocrinologists target levels of HbA(1c)

A matter of focus: monoaminergic modulation of stimulus coding in mammalian sensory networks.

Although the presence of neuromodulators in mammalian sensory systems has been noted for some time, a groundswell of evidence has now begun to document the scope of these regulatory mechanisms in several sensory systems, highlighting the importance of neuromodulation in shaping feature extraction at all levels of neural processing. The emergence of more sophisticated models of sensory encoding and of the interaction between sensory and regulatory regions of the brain will challenge sensory neurobiologists to further incorporate a concept of sensory network function that is contingent on neuromodulatory and behavioral state.

Evidence that dopamine-beta-hydroxylase immunoreactive neurons in the lateral reticular nucleus project to the spinal cord in the rat.

The existence of noradrenergic projections from the lateral reticular nucleus (LRt) to the dorsal quadrant of cervical, thoracic, or lumbar spinal cord was investigated using a combined method of WGA-apo-HRP-gold retrograde tracing and dopamine-beta-hydroxylase (DBH) immunocytochemistry. Preliminary retrograde tracing studies indicated that LRt neurons projecting to cervical, thoracic, or lumbar spinal cord were characteristically located near the perimeter of the LRt. Double-labeling experiments demonstrated that a portion of these peripherally-located, spinal-projecting neurons were DBH-immunoreactive. Double-labeled neurons were also located at the parvocellular division of the contralateral LRt in the thoracic injection cases. Double-labeled neurons were not observed at the subtrigeminal division in cervical, thoracic, or lumbar injection case. The results suggest the possibility that the noradrenergic LRt-spinal pathway might be involved in a variety of pain processing and cardiovascular regulatory functions in the rat.

Topographic organization and neurochemical identity of dorsal raphe neurons that project to the trigeminal somatosensory pathway in the rat.

The primary goals of this study were to: 1) examine the distribution of neurons within the dorsal raphe (DR) nucleus that project to cortical and subcortical sites along the trigeminal somatosensory pathway in rat; 2) determine the extent to which different regions within this ascending sensory system receive collateral projections from the same DR neuron; and 3) identify the putative transmitters contained within these DR projection neurons. Long-Evans hooded rats received pressure injections of various combinations of retrograde fluorescent tracers; into the whisker-related regions of the primary somatosensory cortex (barrel field cortex [BC]), ventral posterior medial thalamus (VPM), and principal nucleus of the trigeminal complex (PrV). The distribution of retrogradely labeled neurons within the DR was examined by fluorescence microscopy. The major finding was that cortically projecting neurons were located within the midline regions of the rostral portion of the DR, whereas cells projecting to subcortical trigeminal somatosensory structures were distributed bilaterally in the lateral wing regions of the DR as well as in the midline portions of the nucleus. Single neurons that send axon collaterals to multiple cortical and subcortical trigeminal somatosensory targets were observed in the dorsomedian and ventromedian regions of the DR. DR neurons that projected to cortical and subcortical sites contained serotonin but not tyrosine hydroxylase, the marker enzyme for catecholamine transmitters. Taken together, these findings provide further evidence of neurochemical specificity and functional anatomical organization within the DR efferent projection system.

Effects of intravenous cocaine administration on cerebellar Purkinje cell activity.

The goal of the present study was to investigate the effects of intravenous cocaine administration on cerebellar Purkinje cell firing. Extracellular neuron activity was recorded and cells were locally excited with spaced microiontophoretic pulses of glutamate. Glutamate-evoked and spontaneous discharges were compared before and immediately following cocaine administration. Cocaine injections (1. 0 and 0.25 mg/kg, i.v.) induced a reversible suppression of both spontaneous activity and glutamate-evoked excitation. Procaine was ineffective in producing similar actions. Cocaine only inhibited glutamate-induced excitation in animals pre-treated with reserpine (5 mg/kg, i.p.). Propranolol injections (10 mg/kg, i.p.) were ineffective in blocking cocaine-induced inhibitions. Yohimbine (5 mg/kg, i.p.) pre-treatment abolished cocaine-induced suppressions of either spontaneous or glutamate-evoked excitation. Therefore, cocaine administration decreases Purkinje cell spontaneous and glutamate-evoked discharges by a mechanism involving alpha(2)-adrenoceptor activation. It is suggested that by changing the normal function of the cerebellum cocaine can produce drug-related alterations in overt behavior and cognition.

Norepinephrine exhibits two distinct profiles of action on sensory cortical neuron responses to excitatory synaptic stimuli.

Located within the central gray of the caudal pons, the locus coeruleus (LC) is the sole source of norepinephrine (NE) projections to the forebrain. NE is released both tonically and phasically from axonal varicosities in LC efferent target circuits. NE has been shown to produce a diverse set of actions, including suppression of spontaneous and stimulus evoked discharge, augmentation of synaptically evoked excitation, and inhibition and gating of otherwise subthreshold synaptic inputs. Utilizing an extracellular in vitro tissue slice preparation and microiontophoretic techniques, the dose-dependent actions of NE on glutamate-evoked discharges of layer II/III and layer V sensory cortical neurons were investigated. Noradrenergic effects were further examined in terms of cell and adrenoceptor specificity. The results indicate two exclusive modulatory actions of NE: 1) ejection current-dependent suppression of glutamate evoked discharge, and 2) ejection current-dependent facilitation of glutamate-evoked discharge followed by suppression of the maximal facilitated response. These effects were observed in both normal and low Ca(2+) / high Mg(2+) bathing media, suggesting a postsynaptic site for NE's actions. The facilitation of glutamate evoked discharge was selectively mimicked by the alpha-1 agonist, phenylephrine, whereas the dose-dependent suppression was mimicked by the beta-agonist isoproterenol. These results suggest that the suppressant and facilitating actions of NE are mediated by beta and alpha-1 receptors, respectively. In general, these results are consistent with previous demonstrations of NE modulatory actions on central neurons, but indicate that in the cerebral cortex these effects are both cell- and receptor-specific.

Differential modulatory effects of norepinephrine on synaptically driven responses of layer V barrel field cortical neurons.

The effects of norepinephrine (NE) and the alpha-1 agonist phenylephrine (PE) on synaptically evoked responses of electrophysiologically identified pyramidal neurons in layer V of rat somatosensory cortex were studied in brain slices using intracellular recording techniques. When added to the bathing medium NE (10 microM) tended to increase the synaptic responsiveness of regular spiking neurons and decrease the responsiveness of intrinsic burst neurons. NE had mixed effects on layer V cells which were characterized as intermediate types between regular spiking and intrinsic burst neurons. PE exerted a similar spectrum of actions on layer V cortical neurons. For both adrenergic agents the greatest facilitating effect was observed on responses to low intensity synaptic stimulation. These results suggest that NE exerts different modulatory actions on different electrophysiologically-defined classes of layer V sensory cortical neurons.

Origin, distribution, and morphology of galaninergic fibers in the rodent trigeminal system.

The neuropeptide galanin (Gal) is found throughout the central nervous system. Of particular interest is the fact that Gal is present within the majority of noradrenergic locus coeruleus (LC) neurons. However, very few, if any, Gal-immunoreactive fibers have been identified in many of the major efferent targets of LC, including sensory neocortex and dorsal thalamus. The goal of the present study was to examine the Gal fiber innervation of the rodent trigeminal somatosensory system and its connection to the LC. Our results show that at least two different morphological profiles of Gal-immunoreactive fibers are present within relay nuclei along the ascending trigeminal pathway. Numerous small caliber Gal-immunoreactive fibers with bouton-like swellings were noted within the barrel cortex, the ventroposterior medial (VPM) nucleus, the posterior medial (POm) nucleus, the zona incerta (ZI), the reticular nucleus (nRT) of the thalamus, and the principal (PrV) and spinal (SpV) nuclei of the trigeminal complex. Immunoreactive fibers were prevalent in, but not restricted to, layer I of the barrel cortex. Within the somatosensory thalamus, the density of Gal-immunoreactive fibers was higher in POm than in VPM. Laminae I and II of SpV and the nRT and ZI also contained dense, large-diameter Gal-immunoreactive fibers. These large-diameter Gal-immunoreactive fibers did not co-contain dopamine beta-hydroxylase (DBH). In contrast, virtually every small-caliber Gal-immunoreactive fiber colocalized with DBH. To determine whether Gal-immunoreactive fibers originated from LC, we combined immunohistochemical procedures with fluorescent tracing techniques. After retrograde tracer injections into several trigeminal relay nuclei, we observed that approximately 50% of the labeled LC neuronal population was immunoreactive for Gal. Our results suggest an extensive Gal-immunoreactive fiber innervation of the rodent trigeminal system, much of which may originate from LC neurons in the brainstem.

Projection patterns from the raphe nuclear complex to the ependymal wall of the ventricular system in the rat.

The goal of the present study was to characterize the anatomical and neurochemical relationships that the raphe nuclear complex maintains with respect to lateralized and centralized components of the ventricular system. From this investigation, we 1) determined the ipsilateral vs. contralateral distribution of raphe efferents to the ependymal wall of the lateral ventricle, 2) assessed the degree of collateralization of individual ependymal projection neurons to other sites along the ventricular path, 3) compared the topography of raphe neurons that project to the ventricular lining as well as the lumen of the fourth and lateral ventricles, and 4) evaluated the neurochemical identity of raphe neurons that innervate the ventricular system. After tracer injections into the lateral ventricle, labeled cells were distributed evenly on both sides of the midline in the dorsomedial subregion of the intermediate dorsal raphe nucleus. Further rostrally, labeled cells were clustered bilaterally above the medial longitudinal fasciculi and extended into the median raphe nucleus. Injections that involved the ependymal wall of the lateral ventricle resulted in prominent ipsilateral labeling within the dorsal raphe nucleus, just ventral to the cerebral aqueduct. Most of the labeled cells in this latter group had collateral projections to other sites along the ventricular path. Most of the ventricle projection cells contained serotonin but not nicotinamide adenine dinucleotide phosphate diaphorase. These findings indicate that the raphe nuclear complex is topographically organized with respect to the ventricular system. Selected subsets of serotoninergic dorsal raphe neurons may influence discrete segments of the ventricular system independently as well as coordinate functions throughout the system through axon collaterals to other sites along the ventricular neuraxis.

Systemically administered cocaine alters stimulus-evoked responses of thalamic somatosensory neurons to perithreshold vibrissae stimulation.

Previous studies have shown that systemically administered cocaine can transiently alter responses of primary somatosensory cortical neurons to threshold level stimulation of peripheral receptive fields. The goal of the present investigation was 2-fold: (1) characterize the effects of systemic cocaine on stimulus-evoked responses of the ventral posterior medial (VPM) thalamic neurons which relay somatosensory information to the cortex and (2) determine the time course and magnitude of changes in monoamine levels within the somatosensory thalamus following systemic administration of cocaine. Extracellularly recorded responses of single VPM thalamic neurons to whisker stimulation were monitored before and after cocaine administration in halothane anaesthetized rats. Each cell was first characterized by assessing its response profile to a range of perithreshold level deflections of the optimal whisker on the contralateral face. Drug effects on stimulus-response curves, response magnitude and latency were determined from quantitative analysis of spike train data. The results indicate that cocaine elicits a predictable augmentation or attenuation of the sensory response magnitude, with the direction of the change inversely related to the initial magnitude of the stimulus-evoked discharge. In addition, cocaine consistently reduced the response time of somatosensory thalamic neurons to peripheral receptive field stimulation. At the same dose and over the same time period, cocaine also produced marked elevation of norepinephrine and serotonin levels within the ventrobasal thalamus, as determined by in vivo microdialysis. These results suggest that cocaine-induced increases in norepinephrine and serotonin are responsible for drug-related modulation of the transfer of sensory signals through primary thalamocortical relay circuits.

Phasic activation of the locus coeruleus enhances responses of primary sensory cortical neurons to peripheral receptive field stimulation.

In the present study we examined the effects of phasic activation of the nucleus locus coeruleus (LC) on transmission of somatosensory information to the rat cerebral cortex. The rationale for this investigation was based on earlier findings that local microiontophoretic application of the putative LC transmitter, norepinephrine (NE), had facilitating actions on cortical neuronal responses to excitatory and inhibitory synaptic stimuli and more recent microdialysis experiments that have demonstrated increases in cortical levels of NE following phasic or tonic activation of LC. Glass micropipets were used to record the extracellular activity of single neurons in the somatosensory cortex of halothane-anesthetized rats. Somatosensory afferent pathways were activated by threshold level mechanical stimulation of the glabrous skin on the contralateral forepaw. Poststimulus time histograms were used to quantitate cortical neuronal responses before and at various time intervals after preconditioning burst activation of the ipsilateral LC. Excitatory and postexcitatory inhibitory responses to forepaw stimulation were enhanced when preceded by phasic activation of LC at conditioning intervals of 200-500 ms. These effects were anatomically specific in that they were only observed upon stimulation of brainstem sites close to (>150 micron) or within LC and were pharmacologically specific in that they were not consistently observed in animals where the LC-NE system had been disrupted by 6-OHDA pretreatment. Overall, these data suggest that following phasic activation of the LC efferent system, the efficacy of signal transmission through sensory networks in mammalian brain is enhanced.

Lateralization and functional organization of the locus coeruleus projection to the trigeminal somatosensory pathway in rat.

The primary goals of this study were to (1) examine the distribution of locus coeruleus (LC) neurons, which project to cortical and subcortical sites along the trigeminal somatosensory pathway in rats, and (2) determine the extent to which different regions within this ascending sensory system receive collateral projections from the same LC neuron. Long-Evans hooded rats received unilateral pressure injections of different combinations of retrograde fluorescent tracers into whisker-related regions of primary (SI) and secondary (SII) somatosensory cortices, the ventrobasal (VB) and posterior group (POm) nuclei of the thalamus, and the principalis nucleus of the trigeminal complex (PrV). Coronal sections (40-100 microm) through the LC were examined by fluorescence microscopy, and the distribution of retrogradely labeled cells was recorded. The major finding was that whisker-related regions of the cortex receive efferent projections from neurons concentrated in the caudal portion of the ipsilateral LC, whereas subcortical trigeminal somatosensory structures receive bilateral input from both LC nuclei. Despite the bilateral nature of the LC projection to subcortical sites, the majority of LC efferents to VB and POm thalamus originate in the ipsilateral LC nucleus, whereas projections to PrV originate primarily from the contralateral LC. An additional finding was that a relatively large proportion of LC cells, which project to a single somatosensory structure, also send axon collaterals to other relay sites along the same ascending somatosensory pathway. Taken together, these results suggest that the LC-noradrenergic system maintains a more selective relationship with functionally related efferent targets than has been previously appreciated.

Monoaminergic substrates underlying cocaine-induced enhancement of somatosensory-evoked discharges in rat barrel field cortical neurons.

Previously, we have described a selective potentiating effect of systemically administered cocaine (0.25-1.0 mg/kg i.v.) on long-latency excitatory responses (E2) of rat "barrel field" cortical neurons to mystacial vibrissae stimulation. The rat trigeminal system receives both norepinephrine (NE) and serotonin (5-HT)-containing afferents, but only minimal input from dopaminergic sources. The goal of the present study was to determine which of these monoamine systems was responsible for the previously observed facilitating action of cocaine on E2 responses of barrel field cortical neurons. Two approaches were used: 1) evaluation of cocaine effects on cortical neuron responses to whisker stimulation in NE- or 5-HT-depleted animals and 2) assessment of the effects of selective monoamine uptake blockers on cortical neuron responses to whisker deflection. Extracellular recordings were obtained from spontaneously active neurons in the barrel field cortex of halothane-anesthetized rats. Spontaneous activity and cellular responses to mechanical displacement of a single whisker were monitored before and after systemic (i.v.) administration of either cocaine or one of the following selective uptake blockers, fluoxetine (5-HT), desipramine (NE) and GBR12909 (dopamine). Cocaine-induced increases in the E2 response were observed in N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4, noradrenergic neurotoxin)-treated animals, but were reduced or abolished in p-chlorophenylalanine-treated (5-HT depletion) rats. Fluoxetine and desipramine, but not GBR12909, produced cocaine-like potentiation of the E2 response to whisker stimulation. These results point to a 5-HT-dependent mechanism as the substrate underlying cocaine's facilitating effects on long-latency somatosensory cortical neuron responses to receptive field stimulation.