Effect of serotonin axon injury on the somatostatinergic system in rat frontoparietal cortex

In order to investigate the possibility that, in the rat, some cerebral cortex somatostatin (SS) receptors may be localized presynaptically on the terminals of serotonergic neurons, serotonin [5-hydroxytryptamine, (5-HT)] neurons in the central nervous system were damaged with a local intracerebral injection of the serotonergic neurotoxin, 5,7-dihydroxytryptamine(5,7-DHT). The injection of 5,7-DHT (11 micrograms free base dissolved in 10 microliters of isotonic saline containing 0.01% ascorbic acid) in rats produced an reduction by about 74% in frontoparietal cortical 5-HT content at 1 and 3 weeks after injection. These changes were associated with a significant decrease by about 30% in the total number of specific SS receptors in the frontoparietal cortex at both times studied without influencing the apparent affinity of the receptors. Together, these results suggest that a portion of the frontoparietal cortex SS receptors may be localized presynaptically on the serotonergic nerve terminals. The 5,7-DHT did not affect SS-like immunoreactivity (SSLI) levels suggesting that SS and 5-HT are not colocalized within the same neuronal elements in the rat frontoparietal cortex.     

Relationship of dietary fat and lysine level with body composition in broiler chickens

Recent evidence indicates that neocortical electrocorticographic (ECoG) activation depends critically on cholinergic (ACh) inputs from the basal forebrain and serotonergic (5-hydroxytryptamine, 5-HT) inputs from the midbrain raphe to the neocortex. It appears that ACh and 5-HT block synchronized ECoG activity and induce cortical activation by a direct, local action in the neocortex that is not mediated by secondary systems. Concurrent blockade of cholinergic and serotonergic inputs to the cortex abolishes all ECoG activation, suggesting that: (a) together, ACh and 5-HT are essential for cortical activation to occur; and (b) other systems cannot maintain cortical activation in the absence of the cholinergic and serotonergic inputs. Nevertheless, additional neural systems (amygdala, locus coeruleus-noradrenaline (-NA), superior colliculus, orbitofrontal cortex, dopamine, histamine, glutamate) also modulate the ECoG and can produce cortical activation. In contrast to ACh and 5-HT, however, none of these systems are essential for the maintenance of cortical activation. Further, rather than producing activation via direct inputs to the neocortex, these systems appear to produce cortical activation by stimulating the cholinergic or serotonergic inputs to cortex. Thus, neocortical activation is maintained by multiple, parallel systems; cholinergic and serotonergic pathways are essential for activation and produce activation directly and locally in the neocortex, whereas additional pathways are not essential and contribute to activation indirectly by acting through these two direct activating inputs to the cortex.     

Comparison of the effects of serotonin in the hippocampus and the entorhinal cortex

Among the molecular, cellular, and systemic events that have been proposed to modulate the function of the hippocampus and the entorhinal cortex (EC), one of the most frequently cited possibilities is the activation of the serotonergic system. Neurons in the hippocampus and in the EC receive a strong serotonergic projection from the raphe nuclei and express serotonin (5-HT) receptors at high density. Here we review the various effects of 5-HT on intrinsic and synaptic properties of neurons in the hippocampus and the EC. Although similar membrane-potential changes following 5-HT application have been reported for neurons of the entorhinal cortex and the hippocampus, the effects of serotonin on synaptic transmission are contrary in both areas. Serotonin mainly depresses fast and slow inhibition of the principal output cells of the hippocampus, whereas it selectively suppresses the excitation in the entorhinal cortex. On the basis of these data, we discuss the possible role of serotonin under physiological and pathophysiological circumstances.     

Specificity of amphetamine induced release of norepinephrine and serotonin from rat brain in vitro

Incubation of normal rat cortical or brain stem tissue with 3H-NE or 3H-5-HT and subsequent exposure to amphetamine produced a concentration-related release of the transmitters from tissue stores into the incubation media. Although pretreatment with the catecholamine neurotoxin in 6-hydroxydopamine (6-OHDA) reduced the retention of 3H-NE in both of these tissues, the proportion of 3H-NE released by amphetamine was attenuated only in cortical tissue. Pretreatment with the serotonergic neurotoxin, 5,6-dihydroxytryptamine (5,6-DHT) had no effect on the retention or release of 3H-NE in cortical or brain stem tissue. Pretreatment with 5,6-DHT reduced the retention of 3H-5-HT in the cortex and brain stem, but the release of 3H-5-HT was significantly attenuated only in the latter tissue. 6-OHDA pretreatment increased the retention and proportion of cortical 3H-5-HT released by amphetamine but reduced the release of brain stem 3H-5-HT in the absence of an effect on retention. It appears that the in vitro release of 3H-NE from the cerebral cortex occurs primarily from catecholamine and not serotonergic neurons whereas the cortical release of 3H-5-HT is not an event specific to serotonergic nerve terminals. The release of 3H-5-HT from brain stem does not appear to be restricted to the serotonergic cell bodies since its release was attenuated by 5,6-DHT and 6-OHDA.     

Differential effects of serotonin (5-HT) lesions and synthesis blockade on neuropeptide-Y immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C receptor binding sites in the rat cerebral cortex

The present study was aimed at comparing the effects of serotonin (5-HT) synthesis blockade using chronic administration of p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine injections of variable volume (3 vs. 6 microl) on the density of NPY immunoreactive (Ir) neurons and binding of [3H]8-OH-DPAT, S-CM-G[125I]TNH2 and [125I]DOI to 5-HT1A, 5-HT1B/1D, and 5-HT2A/2C receptors in rat cortical regions. Three weeks after large but partial (89% depletion in 5-HT tissue concentration) lesions of 5-HT neurons no changes in neither NPY immunoreactivity nor 5-HT receptor binding were detected. The complete 5,7-DHT lesions produced increases in the number of NPY-Ir neurons in the upper regions of the cingular (134%), frontal (140%) and parietal cortex (48%) and corresponding decreases in 5-HT2A/2C binding (16-26%). No changes in 5-HT1A and 5-HT1B/1D binding were observed after lesions of this kind. After PCPA treatment, decreases in NPY-Ir neurons density (22-40%) and increases in 5-HT1A and 5-HT1B/1D receptor binding sites (20-50%) were distributed in both upper and deeper cortical regions. The lack of effect of the partial lesion suggests that spared 5-HT neurons may exert compensatory mechanisms up to a large extent. The changes in NPY immunoreactivity and 5-HT2A/2C binding detected in the upper regions of the cortex after complete 5-HT lesions probably result from local cellular rearrangements, whereas blocking 5-HT synthesis has more widespread influence on NPY neurons and on 5-HT1A and 5-HT1B/1D receptor subtypes. Moreover, decreases in DOPAC concentrations detected only after complete lesions suggest that the involvement of catecholaminergic transmission may also differentiate 5,7-DHT and PCPA treatments. Altogether, these data suggest that different receptor subtypes might be involved in 5-HT-NPY relationships.     

Increased food intake, body weight, and adiposity in rats after regional neurochemical depletion of serotonin.

Assessed long-term changes in food and water intake, body weight (BW), and skeletal growth following bilateral hypothalamic microinfusions of 5,7-dihydroxytryptamine (DHT; 6 or 12 μg) in 16 female hooded rats. The analysis of ingestive behavior included assessment of photoperiodic effects and responsivity to alterations in dietary composition. The neuroanatomical and neurochemical selectivity of the serotonergic depletion was documented by regional spectrofluorometric analysis for serotonin (5-hydroxytryptamine, 5-HT), dopamine, and norepinephrine. Results indicate that, substantial depletion of 5-HT occurred in the septum, hippocampus, and hypothalamus of the DHT (12 μg) group. During feeding of a high-fat diet, the 5-HT-depleted Ss exhibited a long-lasting and stable hyperphagia that led to an increase in BW. Because BW increased in the absence of increased skeletal growth or intestinal weight, it is concluded that the increased BW reflected increased adiposity. Overall results provide evidence of an inhibitory role of 5-HT in food intake and point to the importance of maximizing both neurochemical and neuroanatomical selectivity. (46 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin and alcohol intake, abuse, and dependence: findings of animal studies

Despite a relatively large body of literature on the role of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) in the regulation of alcohol intake, the functional significance of serotonergic neurotransmission and its relationship to alcohol intake, abuse, and dependence remains to be fully elucidated. In part two of this review, the experimental (animal) data is summarized along two lines: the effects of serotonergic manipulations on the intake of alcohol, and the effects of acute and chronic alcohol intake, as well as the withdrawal of chronic alcohol, on the serotonergic system. It is concluded that serotonin mediates ethanol intake as a part of its larger role in behavior modulation, such that increases in serotonergic functioning decrease ethanol intake, and decreased serotonergic functioning increases ethanol intake. Ethanol produces transient increases in serotonergic functioning that activate the mesolimbic dopaminergic reward system. The results are discussed in light of recent theories describing the regulatory role of serotonin in general behavior.     

Comparative analysis of ribonuclease P RNA structure in Archaea

The relationship between central serotonergic activities and voluntary alcohol consumption was studied in Sprague-Dawley rats, which normally have low alcohol preference. After initial screening for an evenly matched baseline alcohol preference, selective central serotonergic lesioning was induced by intracisternal injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Control rats received injections of vehicle only. Both 5,7-DHT and vehicle-treated rats were further divided into two subgroups, which either had continued free access to ethanol (alcohol-drinking) or were deprived of it (alcohol-free). All rats were then tested again for alcohol preference. All rats were then killed, and the levels of monoamines in the brains were determined by high performance liquid chromatography with electrochemical detection. Behavioral results indicated that all 5,7-DHT-treated rats had significantly higher alcohol preference and consumption than the corresponding sham controls. Except in the cerebellum, the 5,7-DHT-treated rats had significantly lower levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in most brain regions compared with those in the corresponding sham controls. Treatment with 5,7-DHT also resulted in a decrease in serotonin turnover in all brain regions in the alcohol-free rats, except in the cerebellum. In alcohol-drinking rats, however, 5,7-DHT treatment only reduced serotonin turnover in the pons. The levels of norepinephrine and dopamine in several brain regions were not significantly different. Thus, it appeared that in the Sprague Dawley rats, 5,7-DHT treatment depleted 5-HT and 5-HIAA levels in most brain regions while increasing alcohol consumption. Chronic alcohol-drinking attenuated the increase in alcohol consumption associated with serotonergic lesions. Voluntary alcohol consumption seemed more associated with 5-HT turnover than with tissue 5-HT levels. Our data also suggested that tolerance to alcohol-induced hypothermia was primarily attributable to long-term alcohol drinking rather than serotonergic lesioning.     

Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma

In the present study, we examined denervation-induced changes in the sensitivity of hypothalamic postsynaptic serotonin1A (5-HT1A) receptor function with respect to changes in the dose-dependent elevation in plasma hormones [adrenocorticotropic hormone (ACTH), corticosterone, prolactin, oxytocin, prolactin, renin and vasopressin] by the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT). Rats received intracerebroventricular (i.c.v.) injections of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or vehicle (0.1% ascorbate in saline) 3 weeks before challenge with increasing doses of 8-OH-DPAT (0, 10, 50 or 200 micrograms/kg s.c.). The effectiveness of 5,7-DHT-induced destruction of serotonergic neurons was confirmed by a 93% reduction in [3H]paroxetine-labeled 5-HT uptake sites in the hypothalamus. No changes in basal levels of ACTH, corticosterone, oxytocin, prolactin, renin and vasopressin were observed in rats that received i.c.v. 5,7-DHT injections. The dose-response curves for 8-OH-DPAT-induced elevations of plasma corticosterone and prolactin levels were shifted to the left in rats treated with 5,7-DHT, whereas no significant difference in the ACTH dose-response curve was observed between rats treated with vehicle and rats treated with 5,7-DHT. In contrast, the maximal oxytocin response to 8-OH-DPAT was attenuated in rats treated with 5,7-DHT. A 5,7-DHT-induced decline in the synthesis of oxytocin could explain this phenomenon. Although 8-OH-DPAT did not increase plasma levels of renin or vasopressin in rats treated with vehicle, 8-OH-DPAT produced an elevation (75%) in plasma renin concentration but not in vasopressin levels in rats that received i.c.v. injections of 5,7-DHT. No change was observed in [3H]8-OH-DPAT labeled 5-HT1A receptors in the hypothalamus. In summary, denervation of hypothalamic serotonergic nerve terminals produces supersensitivity of some neuroendocrine responses to 8-OH-DPAT independent of changes in the density of hypothalamic 5-HT1A receptors.     

Modulation of intrinsic circuits by serotonin 5-HT3 receptors in developing ferret visual cortex

Serotonergic projections are widespread in the developing neocortex, but their functions are obscure. The effects of 5-HT3 receptor agonists on cortical circuit response properties were studied in slices of ferret primary visual cortex using high-speed optical imaging of voltage-sensitive dye signals and whole-cell patch-clamp recording. Activation of the 5-HT3 receptor decreased the amplitude and lateral extent of excitation throughout postnatal development. This effect peaks after eye opening, which indicates a function for serotonergic modulation of circuit responses during the period of refinement of cortical connections. Whole-cell patch-clamp recordings from single neurons revealed that synaptic responses evoked by white matter stimulation were reduced by 5-HT3 receptor agonists, whereas the frequency of spontaneous GABAergic synaptic currents was enhanced dramatically. This indicates that the modulation of spontaneous synaptic activity by fast-acting serotonin receptors is reflected in an inhibition of the circuit response, in line with the notion of background synaptic activity altering the spatiotemporal integration properties of cortical cells by changing their membrane potential and their electrotonic structure. These mechanisms may regulate the response properties of intrinsic circuits in both the adult and developing neocortex.     

Auditory-evoked potentials as indicator of brain serotonergic activity--first evidence in behaving cats

Due to the increasing importance of the central serotonergic neurotransmission for pathogenetic concepts and as a target of pharmacotherapeutic interventions in psychiatry, reliable indicators of this system are needed. Several findings from basic and clinical research suggest that the stimulus intensity dependence of auditory evoked potentials (AEP) may be such an indicator of behaviorally relevant aspects of serotonergic activity (Hegerl and Juckel 1993, Biol Psychiatry 33:173-187). In order to study this relationship more directly, epidural recordings over the primary and secondary auditory cortex were conducted in chronically implanted cats under intravenous (i.v.) administration of drugs influencing the serotonergic and other modulatory systems (8-OH-DPAT, m-CPP, ketanserin, DOI, apomorphine, atropine, clonidine). The intensity dependence of the cat AEP component with the highest functional similarity to this of the N1/P2-component in humans was significantly changed by influencing 5-HT1a and 5-HT2 receptors, but not 5-HT1c receptors. This serotonergic modulation of the intensity dependence was only found for the primary auditory cortex which corresponds to the known different innervation of the primary and secondary auditory cortex by serotonergic fibers. Our study supports the idea that the intensity dependence of AEP could be a valuable indicator of brain serotonergic activity; however, this indicator seems to be of relative specificity because at least cholinergic effects on the intensity dependence were also observed.     

Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway

The superficial cells of the entorhinal cortex (EC), main input to the hippocampus, receive a serotonergic input from the raphe nuclei and express 5-hydroxytryptamine creatine sulfate complex (5-HT) receptors at high density. With the use of intracellular recordings, we investigated the effects of serotonin on synaptic inhibition of layer II and III neurons of the EC. Serotonin reduced both polysynaptic fast and slow inhibitory postsynaptic potentials (IPSPs) in projection neurons of the superficial EC. Polysynaptic fast and slow IPSPs were depressed by serotonin in a dose-dependent manner (0.1-100 microM). Serotonin in a concentration of 1 microM reduced the amplitudes of polysynaptic fast and slow IPSPs by approximately 40 and 50%, respectively. To identify the subtype of the 5-HT-receptor mediating the effects on polysynaptic IPSPs, we applied various 5-HT-receptor agonists and antagonists. Although the serotonin agonists for the 5-HT1B,2C,3 receptors were ineffective, the effects were mimicked by the 5-HT1A-receptor agonists (8-OH-DPAT, 5-CT) and prevented by the 5-HT1A-receptor antagonist NAN-190. To look at the direct effects of 5-HT on inhibitory interneurons, we elicited monosynaptic IPSPs in the absence of excitatory synaptic transmission. In contrast to the polysynaptic IPSPs, monosynaptic IPSPs were not significantly affected by serotonin. Recordings from putative inhibitory interneurons revealed that their excitatory postsynaptic potentials (EPSPs) were reversibly reduced by serotonin. We conclude that serotonin suppresses polysynaptic inhibition in projection neurons of layers II and III of the EC by depression of EPSPs on inhibitory interneurons via 5-HT1A receptors.     

In vivo chronoamperometric measurements of the clearance of exogenously applied serotonin in the rat dentate gyrus

The present study evaluated high-speed chronoamperometry as a method for measuring the clearance of serotonin (5-HT) from extracellular space in vivo. Male Sprague-Dawley rats were anaesthetized and a Nafion-coated, carbon fiber electrode, attached to a multibarrel pipette, was lowered into the subgranular layer of the dentate gyrus, a region which receives dense serotonergic innervation, or the corpus callosum, a fiber tract relatively devoid of the 5-HT transporter (SERT). Serotonin, pressure ejected into these regions, produced replicable electrochemical signals. The amplitude and time course of the signals were significantly prolonged in the corpus callosum compared to the dentate gyrus. Similarly, signals produced by locally applied 5-HT in the dentate gyrus of rats following destruction of hippocampal serotonergic innervation with 5,7-dihydroxytryptamine (5,7-DHT), were significantly enhanced compared to those observed in control animals. The time course of the 5-HT signal was significantly prolonged by local application of the selective 5-HT reuptake inhibitor, fluvoxamine, into the dentate gyrus. By contrast, fluvoxamine did not modify the clearance of 5-HT when locally applied into the dentate gyrus of 5,7-DHT lesioned rats or into the corpus callosum of intact rats. Taken together, these data demonstrate that in intact rats, the SERT contributes to the clearance of exogenously applied 5-HT from the extracellular space. Under the experimental conditions used in this study, high-speed chronoamperometry proved to be a reliable method for directly measuring extracellular 5-HT and appears to be a valuable tool for the study of 5-HT clearance by the SERT in vivo.     

Effect of acetylsalicylic acid on formalin test and on serotonin system in the rat brain

1. Acetylsalicylic acid (ASA; 400 mg/kg, i.p.) increased serotonin (5-HT) content in rat brain but did not modify the number or the affinity of 5-HT1A receptors in the pons and the cerebral cortex, whereas the number of cortical 5-HT2 receptors decreased significantly. 2. Pretreatment with parachlorophenylaline (100 mg/kg/day for 4 days) depleted 5-HT brain content but modified neither the serum levels of salicylates nor the 5-HT2 cortical receptor characteristics, and it abolished the antinociceptive effect of ASA, 400 mg/kg, in the first phase of the formalin test. 3. These data support the involvement of the central serotonergic system in the antinociceptive activity of ASA.     

Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors

5-HT1A autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5-HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5-HT (5-HT(ext)) induced by the 5-HT uptake inhibitor paroxetine in forebrain were potentiated by the 5-HT1A antagonist WAY-100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5-HT(ext) during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY-100635. The perfusion of 50 micromol/L citalopram in the dorsal or median raphe nucleus reduced 5-HT(ext) in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5-HT(ext) induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY-100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self-inhibition mediated by 5-HT1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5-HT1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.     

Facilitation of acetylcholine release in rat frontal cortex by indeloxazine hydrochloride: involvement of endogenous serotonin and 5-HT4 receptors

Effects of indeloxazine hydrochloride, an inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake with a facilitatory effect on 5-HT release, on acetylcholine (ACh) output in frontal cortex of conscious rats were characterized using an in vivo microdialysis technique. Systemic administration of indeloxazine (3 and 10 mg/kg, i.p.) increased ACh and 5-HT output in a dose-dependent manner. Depletion of endogenous monoamines by reserpine and of 5-HT by p-chlorophenylalanine, but not that of catecholamines by alpha-methyl-p-tyrosine, significantly attenuated the facilitatory effect of indeloxazine on ACh release. When applied locally by reverse dialysis, indeloxazine (10 and 30 microM) and the selective 5-HT reuptake inhibitor citalopram (10 microM), but not the NE reuptake inhibitor maprotiline (30 microM), increased cortical ACh output. Indeloxazine (10 mg/kg)-induced increase in ACh release was significantly inhibited by local application of the 5-HT4 receptor antagonists RS23597 (50 microM) and GR113803 (1 microM), while the 5-HT1A antagonist WAY-100135 (100 microM), 5-HT1A/1B/beta-adrenoceptor antagonist (-)propranolol (150 microM), 5-HT2A/2C antagonist ritanserin (10 microM) and 5-HT3 antagonist ondansetron (10 microM) failed to significantly modify this effect. Neither depletion of monoamines nor treatment with serotonergic antagonists significantly changed the basal ACh level, indicating that endogenous monoamines do not tonically activate ACh release. These results suggest that indeloxazine-induced facilitation of ACh release in rat frontal cortex is mediated by endogenous 5-HT and involves at least in part cortical 5-HT4 receptors.     

Fast synaptic signaling by nicotinic acetylcholine and serotonin 5-HT3 receptors in developing visual cortex

Cholinergic and serotonergic fiber systems invade the developing visual cortex several weeks before eye opening; both transmitters have been implicated in plasticity of neocortical circuits. These transmitters have been presumed to act predominantly through second messenger-coupled receptors, because fast cholinergic or serotonergic neurotransmission has never been observed in neocortex. However, acetylcholine and serotonin also act on ligand-gated ion channels; the nicotinic acetylcholine receptor and the serotonin 5-HT3 receptor, respectively. Here, using whole-cell patch-clamp techniques in developing ferret visual cortex, we pharmacologically isolated fast, spontaneous, and evoked cholinergic and serotonergic synaptic events in pyramidal cells and interneurons of all cortical layers. The number of cells receiving such inputs increased with the ingrowth of thalamic afferents, and the frequencies of the spontaneous events increased at eye opening. Thus, both acetylcholine and serotonin can mediate fast synaptic transmission in the visual cortex; the early onset of these mechanisms suggests a role during initial stages of circuit formation and during subsequent experience-dependent remodeling of cortical connections.     

Evidence that an OX-2-positive cell can inhibit the stimulation of type 1 cytokine production by bone marrow-derived B7-1 (and B7-2)-positive dendritic cells

The present study was designed to compare the effects of typical and atypical antipsychotic drugs on extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis with dual probe implantation in awake, freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical antipsychotics, produced greater increases in extracellular DA levels in the mPFC than in the NAC. Olanzapine (1 mg/kg), risperidone (0.1 and 1 mg/kg), also an atypical antipsychotic, and S-(-)-sulpiride (25 mg/kg), a typical antipsychotic, produced comparable increases in extracellular DA levels in the mPFC and the NAC. S-(-)-sulpiride (10 mg/kg) and haloperidol (0.1 and 1 mg/kg), another typical antipsychotic, significantly increased extracellular DA levels in the NAC but not in the mPFC. The effects of the six antipsychotic drugs to increase extracellular DA levels in the mPFC relative to those in the NAC was positively correlated with the difference between their pKi values for serotonin (5-hydroxytryptamine, 5-HT2A) and DA-D2 receptors and was inversely correlated to their pKi values for D2 or D3 receptors, but was not for 5-HT2A receptors alone. These results are consistent with the hypothesis that the ability of antipsychotic drugs to produce a greater increase in prefrontal compared with NAC extracellular DA levels may be related, in part, to weak D2 and D3 receptor affinity relative to 5-HT2A receptor antagonism.     

Modulation of in vivo neuronal sprouting by serotonin in the adult CNS of the snail

1. During in situ recovery from a lesion to the cerebrobuccal connective (CBC) in the snail Achatina fulica, neurons of the buccal ganglia undergo extensive regeneration and sprouting as assessed by axonal dye-fillings of the CBC. 2. These changes are preceded by the distal degeneration of severed fibres from the serotonergic metacerebral giant neuron (MCG), which results in the depletion of serotonin (5-HT) in the ipsilateral buccal ganglion. We have investigated the potential role of this depletion in causing some of the ensuing neuroplastic events. 3. Pharmacological depletion of 5-HT using either 5,7-dihydroxtryptamine or p-chlorophenylalanine in normal, unlesioned animals was found to produce supernumerary neuronal labelling similar to that seen following a lesion. 4. Systemic daily injections of 5-HT were found to partly suppress the sprouting response following the CBC lesion. For example, the contralateral, uninjured MCG which is normally induced by the lesion to sprout novel projections into the denervated ganglion, is suppressed from doing so by the 5-HT treatment. 5. These growth inhibiting effects of 5-HT upon the contralateral MCG could be antagonized by the prior administration of the 5-HT receptor blocker cyproheptadine, suggesting a specific receptor mediated action. 6. We suggest that 5-HT may play a role in governing the state of neuronal outgrowth in vivo in the CNS of the adult snail, as has been suggested by early development and neuronal cultural studies.