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

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

Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress

It has been suggested that physiological resistance to repeated stress is associated with increased 5-hydroxytryptamine (5-HT) release in the dorsal hippocampus and that dysregulation of this neuroadaptation may be implicated in the psychopathology of depression. This study used 5,7-dihydroxytryptamine lesions to investigate the role of 5-HT projections to the hippocampus in physiological responses to repeated stress and putative changes in corticosteroid receptor immunoreactivity in the brain. Repeated exposure to elevated open platform stress (1 h/day) caused regionally selective changes in glucocorticoid and mineralocorticoid receptor immunoreactivity in the dorsal hippocampus that were not observed in ventral hippocampus, frontal cortex, hypothalamus or parietal cortex. Glucocorticoid receptor immunoreactivity in the dorsal hippocampus was decreased after 5 days but increased after 20 days of stress. Mineralocorticoid receptor immunoreactivity was increased after 5 or 10 days of stress. The increases in glucocorticoid and mineralocorticoid receptor immunoreactivity, evoked by repeated stress, were abolished by lesions of the principal 5-HT projections to the hippocampus. The lesions abolished the increased defecation observed in stressed animals, but had no effects on the plasma corticosterone response to the stressor or the habituation of this response observed following repeated stress. The experiments have revealed a dissociation in the regulation of corticosteroid receptor expression in the dorsal and ventral hippocampus by repeated stress and 5-HT. The data suggest that adaptation to inescapable stress is associated with regionally selective changes in corticosteroid receptor expression in dorsal hippocampus that are largely 5-HT-dependent, although these changes do not mediate habituation of the pituitary adrenocortical response to the stressor.     

A thyrotropin-releasing hormone-containing system in the rat dorsal horn separate from serotonin

In this study, we report the identification of a thyrotropin-releasing hormone (TRH)-containing system in the dorsal horn of the rat spinal cord. This system is distinct from the TRH and serotonin (5-hydroxytryptamine, 5-HT) cotransmitter supraspinal system that has projections to the intermediolateral (IML) and ventral columns. Spinal cord sections from untreated rats, and those treated with colchicine or 5,7-dihydroxytryptamine (5,7-DHT) were processed using peroxidase-antiperoxidase (PAP) immunocytochemistry with nickel intensification. Results of the 5,7-DHT treatment were verified by quantifying TRH and 5-HT by radioimmunoassay (RIA) and high performance liquid chromatography (HPLC), respectively. Prominent immunocytochemical staining for TRH in the dorsal horn was seen in varicose fibers mainly in lamina II and superficial lamina III of the dorsal horn of the spinal cord of control rats. A few fibers were seen ascending into lamina I. A moderate number of fibers that were immunoreactive for 5-HT were primarily in laminae I and II. The distribution of TRH- and 5-HT-containing neurites in the IML and the ventral horn agreed with previously published reports. Rats treated with colchicine showed many small round TRH immunoreactive cells that were limited to laminae II/III of the dorsal horn. TRH immunoreactivity in the dorsal horn and IML was resistant to the effects of the selective serotonin neurotoxin, 5,7-DHT, while the ventral horn was depleted of TRH staining. Serotonin was almost completely eliminated in all spinal cord laminae. Quantitative biochemical studies showed significant, but non-parallel reductions of TRH and 5-HT in cervical, thoracic and lumbar spinal cord. These studies demonstrate the existence of TRH-containing cell bodies and terminals in the dorsal horn of the rat spinal cord. These findings provide evidence that a TRH-containing system exists in the dorsal horn of the rat and that it is distinct from the descending medullary raphe system that contains 5-HT; suggest that a population of TRH-containing fibers that project to the IML may not contain 5-HT; and confirm previously published results that 5-HT and TRH coexist in terminals in the ventral horn of the spinal cord.     

Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain

The sustained administration of the 5-HT1A agonist gepirone (15 mg/kg/day, s.c.) in the rat produced an initial decrease of the firing activity of dorsal raphe 5-HT neurons which was followed by a progressive recovery to normal after 14 days of treatment. At this point in time, the effect of intravenous lysergic acid diethylamide (LSD) on the firing activity of 5-HT neurons was markedly reduced, whereas those of 8-hydroxy-2-N,N-propylamino-tetralin (8-OH-DPAT) and of gepirone were unchanged; however, the responsiveness of 5-HT neurons to direct microiontophoretic application of 5-HT, LSD, 8-OH-DPAT, and gepirone, but not of GABA, was reduced. The responsiveness of postsynaptic dorsal hippocampus pyramidal neurons to 5-HT, 8-OH-DPAT, and gepirone was not altered by the 14-day gepirone treatment. The effectiveness of the electrical stimulation of the ascending 5-HT pathway in reducing pyramidal neuron firing activity was not significantly modified in rats treated with gepirone for 14 days. Furthermore, this treatment did not alter the function of the terminal 5-HT autoreceptor. It is concluded that the progressive restoration of the firing activity of 5-HT neurons, due to a desensitization of the somatodendritic 5-HT autoreceptor, combined with the direct activation of normosensitive postsynaptic 5-HT1A receptor by gepirone, should result in an augmented tonic activation of postsynaptic 5-HT1A receptors. The progressive appearance of this phenomenon would be consistent with the time course of the clinical anxiolytic, and possibly antidepressant, effects of gepirone.     

Temporal effects of intrahypothalamic 5,7-dihydroxytryptamine: relationship between serotonin levels and [H]serotonin binding

The relationship between serotonin (5-HT) levels and [³H]5-HT binding in discrete hypothalamic areas was examined in separate groups of animals at various times, following unilateral intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). Seven days post-5,7-DHT lesion, 5-HT levels were significantly decreased in both the ipsilateral and contralateral ventromedial and dorsomedial hypothalamic nuclei (VMN, DMN). In the lateral hypothalamic area (LHA), 5-HT levels were significantly decreased only ipsilaterally. Fifty days postlesion, 5-HT levels in the ipsilateral VMN remained significantly below sham, while the DMN and LHA returned to sham values. Seven days after 5,7-DHT there was a significant increase in [³H]5-HT labeling densities in the ipsilateral and contralateral ventromedial hypothalamic area as well as in the ipsilateral LHA. In contrast, in the dorsomedial hypothalamic area there was no increase in [³H]5-HT binding. Fifty days postlesion, no significant differences in [³H]5-HT binding between 5,7-DHT and sham were observed in any areas examined. This data provides further evidence for the regeneration of 5-HT fibers in the hypothalamus and demonstrates that the relationship between [³H]5-HT binding and 5-HT levels varies from one hypothalamic area to another.     

Serotonergic inhibition of the dorsal lateral geniculate nucleus

Electrophysiological studies were conducted on chloral hydrate-anesthetized rats to determine if the dorsal raphe nucleus (DR) exerts an inhibitory influence upon the dorsal lateral geniculate nucleus (dLGN), and if this inhibition is mediated by the release of serotonin (5-HT). Conditioning stimuli presented to the DR 100-400 ms before an optic tract (OT) shock significantly lowered the amplitude of OT shock-elicited, postsynaptic, field potentials of less than 3 ms latency. Rare, long-latency, field potentials (greater than 5 ms) were diminished in amplitude when preconditioning intervals were less than 15 ms. Six days after intracerebral injection of the 5-HT neurotoxin, 5,7-dihydroxytryptamine (8 micrograms), into the dLGN, significant reductions were observed in 5-HT and 5-hydroxyindole acetic acid in the dLGN. Field potentials recorded on the sixth day in indoleamine-depleted dLGN were significantly less inhibited by DR preconditioning. Intracerebral injections of a control solution neither altered monoamine levels nor the degree of inhibition by DR preconditioning. These data provide further evidence that inhibition of dLGN by DR is mediated by release of 5-HT.     

Effects of 5,7-dihydroxytryptamine on HRP retrograde transport from hippocampus to midbrain raphe nuclei in the rat

The combination of horseradish peroxidase (HRP) retrograde tracing and specific lesioning using 5,7-dihydroxytryptamine (5,7-DHT) was applied to the midbrain raphe-hippocampal system. Serotonergic fibers from the median raphe nucleus (MRN) of the rat reach the dorsal hippocampus (HIPP) through the cingulum bundle (CB) and the fornix-fimbria (FF). Intracerebral microinjections of 5,7-DHT in these two bundles were made at various times before HRP injections into the dorsal HIPP. After both CB and FF lesion, the number of labeled cells in MRN is reduced to 49.6% at zero time (HRP injected immediately after 5,7-DHT) and to 6.5% after 2 days. There was no significant effect on the number of labeled cells in the locus ceruleus. Selective lesioning of 5-HT fibers in the CB or the FF revealed that raphe-CB-HIPP neurons and raphe-FF-HIPP neurons have a similar distribution pattern in the MRN, but that a dorsal group of neurons at the junction of MRN and dorsal raphe nucleus took the CB route exclusively to innervate the HIPP. The CB pathway was used by more neurons (55% of total number of labeled neurons) than was the FF (21%). An appreciable number of fibers (23%) appear to have branches in both pathways. Our findings are discussed with regard to the recovery of HIPP function seen after long term destruction of 5-HT fibers in the CB.     

Effect of destruction of serotonin neurons on basal and fenfluramine-induced serotonin release in striatum

This study examined the relationship between the magnitude of tissue serotonin (5-HT)depletion produced by treatment with the neurotoxin 5,7-dihydroxytryptamine (5,7) and basal and fenfluramine-induced 5-HT release in the striatum. Separate groups of rats were treated with either vehicle or 5,7-DHT (100μ 76% striatal 5-HT depletion; or 200μ 93% styriatal 5-HT depletion). four weeks after treatment 5-HT release was measured in the ventral striatum using in vivo microdialysis in animals anesthetized with chloral hydrate. Basal 5-HT levels were not significantly altered in any lesion group, whereas basal 5-hydroxyindoleacetic acid levels were dosedependently reduced by 5,7-DHT. In contrast, the increase of 5-HT release produced by fenfluramine treatement (10 mg/kg) wa diminished significantly after 5-HT neuronal destruction in correlation with the reduction of striatal tissue 5-HT content. Fractional 5-HT efflux, a measure of the 5-HT release from surviving striatal nerve terminals, was also significantly elevated when tissue depletion of 5-HT exceeded 95%. This study suggests that compensatory mechanisms may enable surviving 5-HT terminals to maintain basal 5-HT levels in th striatum with as little as 5% of the terminals remaining, but those mechanisms are not sufficient to allow the damaged system to respond to a pharmacological challenge. © 1995 Wiley-Liss, Inc.     

Activation of the serotonin 5-HT3 receptor in the dorsal raphe nucleus suppresses REM sleep in the rat

The effects of the selective 5-HT₃ receptor agonist and antagonist m-chlorophenylbiguanide (m-CPBG) and ondansetron, respectively, were studied in adult male Wistar rats implanted for chronic sleep recordings. Microinjection of m-CPBG (2.0 and 4.0 mM) into the dorsal raphe nucleus (DRN) decreased rapid-eye-movement sleep (REMS) and the number of REM periods during the first, second, and third 2-h recording period. On the other hand, direct infusion of ondansetron (0.5–1.0 mM) into the DRN induced no significant changes in sleep variables over the 6 h of recording. Pretreatment with ondansetron (0.5 mM) antagonized the m-CPBG (2.0 mM)-induced reduction of REMS and of the number of REM periods. The data are consistent with the hypothesis that the 5-HT₃ receptor is involved in the effect of DRN serotonergic neurons on brainstem structures that act to promote and induce REMS.

It is suggested that the suppression of REMS after the microinjection of m-CPBG into the DRN is related, at least in part, to the stimulation of glutamatergic interneurons that express 5-HT₃ receptors. Activation of these receptors facilitates the release of glutamate, which, in turn, acts on postsynaptic N-methyl-d-aspartate and non-N-methyl-d-aspartate receptors expressed by serotonergic neurons of the DRN and increases the release of 5-HT at postsynaptic sites.     

Persistence of nonphotic phase shifts in hamsters after serotonin depletion in the suprachiasmatic nucleus

Serotonin-containing fibres (5-HT) project from the raphe complex to the suprachiasmatic nucleus (SCN). Previous studies have suggested that this pathway may be involved in nonphotic resetting of the circadian clock. For example, 5-HT agonists are capable of phase shifting the biological clock both in vivo and in vitro, producing phase response curves (PRCs) similar in shape to those of other nonphotic stimuli. Therefore we studied the role of the serotonergic projection to the SCN in nonphotic phase shifts by bilateral injection of the selective 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) onto the SCN of hamsters. About 50 days after the administration of the neurotoxin, the 5-HT and 5-HIAA (5-hydroxyindole acetic acid) levels were severely depleted in the SCN, as revealed by high performance liquid chromatography (HPLC), and immunocytochemistry (ICC). The average level of 5-HT depletion was 88% in Experiment 1 and 95% in Experiment 2. This treatment had no effect on the magnitude of phase shifts produced by 3 h of novelty-induced wheel-running starting at circadian time (CT) 4, the peak of the advance region of the PRC to this stimulus. The effect of 5-HT depletion on shifts produced by running at CT 22 were inconclusive because of changes in the behavior of control animals. No changes in the phase angle of entrainment of animals in a 14:10 light:dark (LD) cycle were detected in depleted animals. The results suggest that the 5-HT projection from the raphe to the SCN is not essential for activity-induced phase shifts in hamsters.     

Brain structures involved in the behavioral stimulant effect of central serotonin release

Drugs such as p-chloroamphetamine or a combination of tranylcypromine and tryptophan release serotonin in the central nervous system and produce a behavioral serotonin syndrome. However, in the presence of methysergide or following destruction of descending spinal serotonergic projections by 5,7-dihydroxytryptamine, central serotonin release produces hyperlocomotion. This supports the hypothesis that release of serotonin in the brain promotes locomotion but that the expression of this effect can be blocked by concomitant intraspinal effects of serotonin release. Hyperlocomotion induced by serotonin release is attenuated or blocked by: (a) pretreatment with p-chlorophenylalanine; (b) acute surgical lesions of the basal diencephalon; (c) chronic lesions of the ventromedial midbrain tegmentum by local injection of 5,7-dihydroxytryptamine; and (d) acute surgical decortication. Medial decortication tends to be more effective then lateral decortication. Hyperlocomotion produced by methamphetamine is also attenuated or blocked by acute basal diencephalic lesions or decortication. It is suggested that ascending serotonergic and dopaminergic projections collaborate in the generation of spontaneous voluntary motor activity.     

Heterogenous effects of serotonin in the dorsal horn of rat: the involvement of 5-HT1 receptor subtypes

The effect of ionophoretically applied serotonin (5-HT) was tested on cutaneous sensory responses of multireceptive dorsal horn neurones in the anaesthetized rat. Three types of 5-HT action were discerned: selective inhibition of nociceptive responses (10/18 cells), non-selective inhibition of responses to both noxious and innocous stimuli as well as to excitatory amino acids (4/18 cells) and non-selective excitation of evoked responses (1/18 cells). A few cells (3/18) were unaffected by 5-HT. The use of agonists, shown to discriminate between subtypes of 5-HT₁ receptor revealed that a 5-HT_1A receptor agonist mimicked the non-selective effects of 5-HT, whereas a 5-HT_1B receptor agonist mimicked the selective antinociptive effects of 5-HT. A 5-HT₂ receptor agonist, in contrast, was without effect. Both the selective and the non-selective effects were reversed by a 5-HT₁ receptor antagonist, but not a 5-HT₂ antagonist.     

The influence of neonatal serotonin depletion on emotional and exploratory behaviours in rats

Recent studies have shown that neurodevelopmental disturbances in the structure and function of the brain are significant factors in the onset of psychiatric disorders. Such deficits may also affect neurotransmission. Among the different neurotransmitter systems, serotonin (5-HT) plays an important role in the organisation and maturation of brain structures during development. The aim of the present study was to examine the influence of neonatal 5-HT depletion on emotional and exploratory behaviours in adult rats. Three-day-old Wistar male rats received intraventricular injections of the selective serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Littermates given saline injections acted as controls. After three months, rat behaviour was analysed in an open field test, a social interaction test and a novel object test. Moreover, contextual-conditioned freezing and ultravocalisation fear responses were studied. The pain reactivity was measured in a flinch-jump test. Biochemical analysis of 5,7-DHT-treated rats revealed a significant decrease in the concentration of 5-HT and its metabolite in the frontal cortex, hippocampus and striatum, with a decreased dopamine level in striatum. Early serotonin depletion reduced locomotor activity in the open field test and attenuated social interaction in non-aversive conditions and exploration of a novel object in adult rats. Ultravocalisation, but not freezing, was increased in the contextual fear-conditioning paradigm in 5-HT-depleted rats. There was no difference in the pain threshold between groups. These data demonstrate that neonatal 5-HT depletion resulted in subtle alterations in the locomotor, exploratory and conditioned fear response of adult animals.     

Different regulation of serotonin receptors following adrenal hormone imbalance in the rat hippocampus and hypothalamus

Summary Adrenal influence on serotonin (5-HT) transmission in the hippocampal and hypothalamic areas was studied in adrenalectomized rats receiving or not corticosterone replacement. After adrenalectomy, the 5-HT presynaptic receptors were desensitized both in hippocampus and hypothalamus: a significant increase in 5-HT 1 and 5-HT 2 receptor binding numbers took place in membranes from the hippocampus, but not in hypothalamus, while no changes in affinity of receptors to radioligands were observed in either brain area. Corticosterone treatment restored the adrenalectomy-impaired 5-HT autoreceptor sensitivity in hippocampus and hypothalamus and 5-HT density receptor sites in the hippocampus. Serotonin autoreceptor down-regulation following adrenalectomy may increase 5-HT release to maintain the constancy of serotonergic transmission in the brain and 5-HT modulated CRH-ACTH release to compensate the plasma corticosteroid drop. Corticosterone seems to display a distinct tonic control on serotonin transmission in both hippocampus and hypothalamus, the diversity being due to the different roles played by the hormone in these brain regions.     

Effect of central serotonin depletion on adrenocortical responses to neural stimuli

In view of the possible role of serotonin in adrenocortical regulation, basal plasma corticosterone concentrations and the response to ether stress, photic, acoustic, or sciatic nerve stimulation, were studied in rats with 5,7-dihydroxytryptamine or vehicle injected into the raphe nuclei. The neurotoxin inhibited the response to photic stimulation without affecting the other modalities. This may suggest that the depletion of brain serotonin has a differential effect on the transmission of neural impulses which activate the adrenal cortex.     

Stimulation of the rat dorsal raphe in vivo releases labeled serotonin from the parietal cortex

In vivo release of labeled serotonin ([³H]5-HT) from the parietal cortex was investigated by cortical cup technique and electrical stimulation of midbrain raphe in rats anesthetized with pentobarbital sodium. The spontaneous efflux of tritium from the parietal cortex preloaded with [³H]5-HT followed a multiphasic exponential course. After 120 min, the rate of efflux appeared to fit the single exponential function (slow phase). Imipramine (10⁻⁶−10⁻³ M) produced a dose-dependent increase in the spontaneous release. When pargyline in concentrations ranging from 10⁻⁴ to 10⁻³ M were added to the medium in the cup, the unchanged [³H]5-HT significantly increased in a dose-dependent manner and the slow declining coefficient of tritium efflux significantly decreased in the presence of 10⁻⁴ pargyline. Stimulation of the rostral two-thirds of the dorsal raphe and the lateral 5-HT bundle originating from the dorsal raphe significantly increased the release of [³H]5-HT and its metabolites while stimulation of the caudal one-third of the dorsal raphe did not produce a significant increase in the release of [³H]5-HT and its metabolites. Stimulation of the median raphe produced no or only a slight increase in the release of [³H]5-HT and its metabolites. These findings are a direct demonstration of the in vivo release of [³H]5-HT from the parietal cortex with stimulation of the dorsal raphe, particularly the rostral two-thirds of the nucleus and provide the neurochemical evidence for the dorsal raphe-cortical 5-HT pathway via the lateral 5-HT bundle.     

Effects of ovarian steroids on serotonin metabolism within grossly dissected and microdissected brain regions of the ovariectomized rat

Brain serotonin (5-HT) levels and accumulation rate within the dorsal raphe nucleus (DR) were elevated in ovariectomized (OVX) rats after ovarian steroid treatment, which consisted of estradiol benzoate (EB) followed by progesterone (P) 48 hr later. Some animals were also given the monoamine oxidase (MAO) inhibitor pargyline at designated times 10–40 min prior to sacrifice. Decapitation occurred 5 hr following the second steroid injection and 4–6 hr into the dark phase of a 14:10 light/dark cycle. Basal 5-HT levels and the rate of 5-HT accumulation (5-HT_r) following MAO inhibition were estimated by radioenzymatic assay of brain tissue punched from frozen sections or dissected freehand. Within the DR, 5-HT levels and 5-HT_r rates were respectively 13.8% (p < 0.001) and 23.2% (p < 0.025) higher in EB + P treated females compared with oil controls. Differences in basal 5-HT were found within the median raphe nucleus, but these were inconsistent from experiment to experiment. No differences were found in tissue immediately adjacent to these nuclear regions or within other brain regions including the ventral medial nucleus and suprachiasmatic nucleus of the hypothalamus. Increased levels of 5-HT were also found in grossly dissected tissue containing the mesencephalic raphe nuclei.     

Regional changes in neuropeptide levels after 5,7-dihydroxytryptamine-induced serotonin depletion in the rat brain

Summary The levels of five neuropeptides (substance-P, somatostatin, cholecystokinin octapeptide, methionin-enkephalin and dynorphin) were examined in the brain and the spinal cord of rats 2 weeks after intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT). 5,7-DHT injection caused a significant reduction of the serotonin level in all regions of the brain. The level of each neuropeptide except dynorphin significantly increased in specific regions of the brain after 5,7-DHT treatment without any decrease in their levels in any region. Since, coexistence and interaction between classical neurotransmitters and neuropeptides in the same neurons have been reported, both are indispensable for evaluating pathophysiological state of the brain function associated with abnormal neural transmission. The present findings together with previous reports suggest that neuropeptides act as neurotransmitters and compensate for the impaired function of the serotonergic systems.     

Cholinergic neurotransmission in the central nervous system of the Snell dwarf mouse

An unequal decrease in cholinergic activity has been evidenced in discrete brain areas in the growth hormone, thyroid-stimulating hormone and prolactin deficient Snell dwarf mouse. The effect of the mutation's pituitary deficit on central cholinergic mechanisms appears to be selective: Normally high cholinergic activity areas such as striatum, olfactory tubercles, and hippocampus show strong alterations in this neurotransmitter system. Structures which appear earlier in ontogenesis are less affected, if at all. The lack of pituitary hormones seems to have effects on choline acetyltransferase activity and/or synthesis as well as on the development of high affinity (H.A.) cholinergic uptake mechanisms, both strongly defective in hippocampus and striatum. Therefore, a lower density of cholinergic terminals can be inferred. Furthermore, our observations are consistent with a close functional coupling of the choline H.A. transport and of subsequent choline acetylation. Acetylcholinesterase activity does not seem to be affected. Moreover, a compensatory effect at the postsynaptic level may have occurred due to developmental or functional plasticity for cholinergic responsiveness. In conclusion, the dwarf mouse seems to be a useful model for a better understanding of the influences of growth hormone and thyroid hormones on the development of central cholinergic mechanisms. It also provides the possibility to attempt a functional restoration of the deficient cholinergic neurotransmission and the behavioral disturbances which may be linked to them, by hormone replacement.