Is GABA Involved in the Development of Caffeine Tolerance?

Caffeine (10 or 20 mg/kg per day, po)-induced stimulation of locomotor activity (LA) reached its peak following 4 consecutive days of caffeine administration. Caffeine-induced stimulation of LA was restored to the control values following caffeine tolerance after 16 or 12 consecutive days of caffeine treatment at a dose of 10 or 20 mg/kg per day, po. Biochemical studies showed that caffeine in the nontolerant condition reduced GABAergic activity in cerebral cortex, corpus striaturn, cerebellum, hypothalamus and pons-medulla; but tolerance to caffeine (10 or 20 mg/kg per day, po) pushed up the GABAergic activity to the control value in all these regions of brain. Further, it was found that muscimol reduced the LA while bicuculline stimulated LA in the caffeine tolerant condition. Thus, from the present study it may be concluded that: (a) caffeine-induced stimulation of LA is dependent on dose and duration of caffeine treatment, (b) development of tolerance to caffeine is dependent on the dosage of caffeine, and (c) the reduction of central GABAergic activity in the caffeine-nontolerant condition pushed up and restored the LA to the control level on the development of tolerance to caffeine.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Differential effects on morphine analgesia and naloxone antagonism by biogenic amine modifiers.

The stimulation of dopaminergic receptors, inhibition of serotonin synthesis or blockade of muscurinic receptors by various modifiers led to inhibition of morphine analgesia in mice. Blockade of dopaminergic receptors or the increase in serotonergic or cholinergic activity resulted in the enhancement of morphine analgesia. Serotonergic and cholinergic systems are proposed as positive and the dopaminergic system as negative modulators of morphine analgesia. The modulation of naloxone antagonism was much more complicated than that of morphine analgesia and often the effect of biogenic amine-modifiers on antagonism differed from that on analgesia. The fact that biogenic amine-modifiers do not affect morphine analgesia and naloxone antagonism by a similar pattern suggest that interaction of narcotics and narcotic antagonists with analgesic receptors may not be exactly the same.     

Effect of acute and chronic cholinesterase inhibition with diisopropylfluorophosphate on muscarinic, dopamine, and GABA receptors of the rat striatum

The effects of acute and chronic administration of diisopropylfluorophosphate (DFP) to rats on acetylcholinesterase (AChE) activity (in striatum, medulla, diencephalon, cortex, and medulla) and muscarinic, dopamine (DA), and gamma-aminobutyric acid (GABA) receptor characteristics (in striatum) were investigated. After a single injection of (acute exposure to) DFP, striatal region was found to have the highest degree of AChE inhibition. After daily DFP injections (chronic treatment), all brain regions had the same degree of AChE inhibition, which remained at a steady level despite the regression of the DFP-induced cholinergic overactivity. Acute administration of DFP increased the number of DA and GABA receptors without affecting the muscarinic receptor characteristics. Whereas chronic administration of DFP for either 4 or 14 days reduced the number of muscarinic sites without affecting their affinity, the DFP treatment caused increase in the number of DA and GABA receptors only after 14 days of treatment; however, the increase was considerably lower than that observed after the acute treatment. The in vitro addition of DFP to striatal membranes did not affect DA, GABA, or muscarinic receptors. The results indicate an involvement of GABAergic and dopaminergic systems in the actions of DFP. It is suggested that the GABAergic and dopaminergic involvement may be a part of a compensatory inhibitory process to counteract the excessive cholinergic activity produced by DFP.     

Paradoxical REM sleep promoting and permitting neuronal networks

Since its electrophysiological identification in the 1950's, the state of REMS or PS has been shown through multiple lines of evidence to be generated by neurons in the oral pontine tegmentum. The perpetration of this paradoxical state that combines cortical activation with the most profound behavioral sleep occurs through interplay between PS-promoting (On) and PS-permitting (Off) cell groups in the pons. Cholinergic cells in the LDTg and PPTg promote PS by initiating processes of both forebrain activation and peripheral muscle atonia. Bearing alpha1-adrenergic receptors, cholinergic cells, which likely project to the forebrain, are excited by NA and active during both W and PS (W/PS-On), when they promote cortical activation. Bearing alpha2-adrenergic receptors, other cholinergic cells, which likely project to the brainstem, are inhibited by NA and thus active selectively during PS (PS-On), when they promote muscle atonia. Noradrenergic, together with serotonergic, neurons, as PS-Off neurons, thus permit PS in part by lifting their inhibition upon the cholinergic PS-On cells. The noradrenergic/serotonergic neurons are inhibited in turn by local GABAergic PS-promoting neurons that may be excited by ACh. Other similarly modulated GABAergic neurons located through the brainstem reticular formation become active to participate in the inhibition of reticulo-spinal and raphe-spinal neurons as well as in the direct inhibition of motor neurons. In contrast, a select group of GABAergic neurons located in the oral pontine reticular formation and possibly inhibited by ACh turn off during PS. These GABAergic PS-permitting neurons release from inhibition the neighboring large glutamatergic neurons of the oral pontine reticular formation, which are likely concomitantly excited by ACh. In tandem with the cholinergic neurons, these glutamatergic reticular neurons propagate the paradoxical forebrain activation and peripheral inactivation that characterize PS.     

Effects of luteolin on learning acquisition in rats: involvement of the central cholinergic system

The study was conducted to investigate the ameliorating effects of luteolin on memory acquisition in rats. The effects of luteolin on scopolamine-induced impairment of passive avoidance response were evaluated primarily, as well as the role of the central nervous system through the use of central neurotoxins and central nervous antagonists. Luteolin was not reversed by scopolamine N-methylbromide (M-SCOP) but blocked the impairment of learning acquisition induced by cholinergic neurotoxin (ethylcholine aziridinium, AF64A) and muscarinic (scopolamine hydrobromide, SCOP) and nicotinic (mecamylamine, MECA) receptor antagonists. However, it did not block dopaminergic neurotoxin (6-hydroxydopamine, 6-OHDA)-induced and serotonergic neurotoxin (5,7-dihydroxytryptamine, 5,7-DHT)-induced impairments. From these results, we suggest that the attenuating effect of luteolin (10 mg/kg, i.p.) on the deficits of passive avoidance performance induced by SCOP may be related to the increases in the activities of central muscarinic and nicotinic receptors.     

Dopaminergic acceleration and GABAergic inhibition in extrinsic neural control of the hermit crab heart

The acceleratory and inhibitory cardio-regulatory nerves of hermit crabs (Aniculus aniculus, Dardanus crassimanus) were studied using histochemical, immunocytochemical and pharmacological tests. Glyoxylic acid-induced fluorescence was observed in two of three axons of the dorsal cardiac nerve. One axon of the nerve showed gamma-aminobutyric acid-like immunoreactivity. Effects of stimulation of cardio-acceleratory axons were blocked by the dopaminergic antagonists, haloperidol and chlorpromazine, but not by cholinergic, adrenergic or serotonergic blockers, suggesting that dopamine is the primary potential candidate for the neurotransmitter of cardio-accelerator neurons. Picrotoxin antagonized inhibition of the cardiac ganglion induced by gammaam-inobutyric acid and by cardio-inhibitory axons. Both small and large ganglionic cells may receive dopaminergic and GABAergic extrinsic neural control.Abbreviations ACh acetylcholine - CA cardio-accelerator - CA1 and CA2 first and second cardio-accelerators - CI cardio-inhibitor - EJP excitatory junction potential - GABA gamma-aminobutyric acid - EPSP excitatory postsynaptic potential - IPSP inhibitory postsynaptic potential - LGC large ganglionic cell - SGC small ganglionic cell - 5-HT serotonin     

Specific Neurochemical Derangements of Brain Projecting Neurons in Apolipoprotein E-Deficient Mice

Abstract: Apolipoprotein E (apoE)-deficient mice provide a useful system for studying the role of apoE in neuronal maintenance and repair. Previous studies revealed specific memory impairments in these mice that are associated with presynaptic derangements in projecting forebrain cholinergic neurons. In the present study we examined whether dopaminergic, noradrenergic, and serotonergic projecting pathways of apoE-deficient mice are also affected and investigated the mechanisms that render them susceptible. The densities of nerve terminals of forebrain cholinergic projections were monitored histochemically by measurements of acetylcholinesterase activity, whereas those of the dopaminergic nigrostriatal pathway, the noradrenergic locus coeruleus cortical projection, and the raphe-cortical serotonergic tract were measured autoradiographically using radioligands that bind specifically to the respective presynaptic transporters of these neuronal tracts. The results obtained revealed that synaptic densities of cholinergic, noradrenergic, and serotonergic projections in specific brain regions of apoE-deficient mice are markedly lower than those of controls. Furthermore, the extent of presynaptic derangement within each of these tracts was found to be more pronounced the further away the nerve terminal is from its cell body. In contrast, the nerve terminal density of the dopaminergic neurons that project from the substantia nigra to the striatum was unaffected and was similar to that of the controls. The rank order of these presynaptic derangements at comparable distances from the respective cell bodies was found to be septohippocampal cholinergic > nucleus basalis cholinergic > locus coeruleus adrenergic > raphe serotonergic ? nigrostriatal dopaminergic, which interestingly is similar to that observed in Alzheimer's disease. These results suggest that two complementary factors determine the susceptibility of brain projecting neurons to apoE deficiency: pathway-specific differences and the distance of the nerve terminals from their cell body.     

Development of the nervous system of the pluteus larva of Strongylocentrotus droebachiensis

Summary Development of the nervous system of the pluteus larva of Strongylocentrotus droebachiensis was investigated using indirect immunofluorescence with antibodies against dopamine, GABA, and serotonin, and glyoxylic acid-induced fluorescence of catecholamines. Serotonergic cells first appear in full gastrulae; dopaminergic and GABAergic cells are present in early four-arm plutei. The number of neurons and the complexity of the nervous system increases through development of the pluteus. In the pluteus the dopaminergic component of the nervous system includes a ganglion in the lower lip of the mouth and a pair of ganglia at the base of the post-oral arms which extend axons along the base of the circumoral ciliary band. The distribution of cells visualized by glyoxylic acid-induced fluorescence is similar to that of dopaminergic cells. GABAergic neurons occur in the upper lip and in the wall of the esophagus. Serotonergic neurons are present in the lower lip; the pre-oral hood contains an apical ganglion which extends axons along the base of the epidermis overlying the blastocoel. The dopaminergic and GABAergic components of the nervous system are associated with effectors involved in feeding and swimming. The serotonergic component is not associated with any apparent effectors but may have a role in metamorphosis.     

Overnight Fasting Regulates Inhibitory Tone to Cholinergic Neurons of the Dorsomedial Nucleus of the Hypothalamus

The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis.     

Interaction between GABA agonists and the cholinergic muscarinic system in rat corpus striatum

Chronic treatment with γ-acetylenic GABA(GAG), a GABA transaminase inhibitor, causes an increase in striatal dopamine receptor binding and function in rat brain suggesting that extrapyramidal side effects may accompany the use of these agents. In the present investigation it was found that chronic administration of THIP, a direct acting GABA receptor agonist, induced a similar increase in dopamine receptor binding. In addition, co-administration of atropine, a cholinergic muscarinic antagonist, was found to completely prevent the GABA-induced dopamine receptor increase. Furthermore, high affinity choline uptake, a measure of cholinergic activity, in striatal synaptosomes is enhanced after the acute administration of either GAG or THIP. Taken together these results support the notion of an interaction between dopaminergic, cholinergic and GABA-ergic neurons in the extrapyramidal system and indicate that co-administration of an anticholinergic agent may be of benefit in preventing the extrapyramidal side effects which may accompany the use of GABAergic agonists.     

Effects of the serotonin agonist, quipazine, on luteinizing hormone and prolactin release: evidence for serotonin-catecholamine interactions

The present study tested whether administration of the serotonin agonist, quipazine maleate, affects the secretion of luteinizing hormone (LH) and prolactin (PRL) and concomitantly, the activity of central noradrenergic and dopaminergic systems. Quipazine (15 mg/kg, ip) significantly reduced LH and increased PRL when administered to ovariectomized rats. Associated with these changes, the depletion of dopamine seen after synthesis inhibition with alpha-methyl tyrosine was reduced by quipazine in the caudate nucleus and median eminence, suggesting a depression of dopaminergic activity. The depletion of norepinephrine in the median eminence was unaffected. In a second experiment, quipazine (1 microM) diminished the potassium-induced release of both norepinephrine and dopamine from fragments of medial basal hypothalamus, in vitro. Release from preoptic area was unaffected. These results suggest that central serotonergic systems may interact with noradrenergic and dopaminergic systems that regulate LH and PRL secretion, respectively.     

Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain

Gamma-hydroxybutyrate (GHB) is both a therapeutic agent and a recreative drug. It has sedative, anxiolytic and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral GABAergic and dopaminergic activities, but the serotonergic system might also be involved. In this study, we examine the effects of pharmacological doses of GHB on the serotonergic activity in rat brain. Administration of 4.0 mmol/kg i.p. GHB to rats induces an accumulation of tryptophan and 5-HIAA (5-hydroxyindole acetic acid) in the frontal cortex, striatum and hippocampus without causing significant change in the tissue serotonin content. In the extracellular space, GHB induced a slight decrease in serotonin release. The tryptophan and 5-HIAA accumulation induced by GHB is mimicked by the GHB receptor agonist para-chlorophenyl-transhydroxycrotonate (NCS-356) and blocked by NCS-382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene acetic acid) a selective GHB receptor antagonist. GHB induces the accumulation of either a derivative of or [3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. Some of the effect of GHB could be reproduced by baclofen and reduced by the GABAB antagonist CGP 35348. Taken together, these results indicate that the GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.     

The effects of some porphyrinogenic drugs on the brain cholinergic system.

In central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyse acetylcholine. Diminished cholinesterase activity is known to alter several mental and psychomotor functions. The symptoms of cholinergic crisis and those observed during acute attacks of acute intermittent porphyria are very similar. The aim of this study was to investigate if there could be a link between the action of some porphyrinogenic drugs on brain and the alteration of the cholinergic system. To this end, AChE and BuChE activities were assayed in whole and different brain areas. Muscarinic acetylcholine receptor (mAChR) levels were also measured. Results obtained indicate that the porphyrinogenic drugs tested affect central cholinergic transmission. Quantification of mAChR gave quite different levels depending on the xenobiotic. Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced. Acute and chronic isoflurane anaesthesia diminished BuChE activity by 70-90% in whole brain instead cerebellum and hippocampus mAChR levels were only altered by chronic enflurane anaesthesia. Differential inhibition of cholinesterases in the brain regions and their consequent effects may be of importance to the knowledge of the mechanisms of neurotoxicity of porphyrinogenic drugs.     

Inhibitory deficit in schizophrenia is not necessarily a GABAergic deficit

1. Current evidence strongly supports the idea of an inhibitory deficit as a central pathophysiological mechanism in schizophrenia. This deficit has been well documented in sensory gating and paired-pulse studies and may be related to decreases in inhibitory interneurons found in schizophrenic patients.2. The GABAergic system has been repeatedly postulated to mediate this deficit, but the findings are controversial, at least in some areas, and mostly negative regarding treatment with drugs enhancing GABAergic activity. Therefore, the scope of mediators of this inhibitory deficit should be widened and the neuromodulator adenosine is proposed as a candidate to be further studied.3. A state of adenosinergic hypoactivity in schizophrenia is compatible not only with the inhibitory deficit but also with symptoms, clinical response to antipsychotics, impaired sensory gating, deteriorating course, increased smoking, and sleep alterations reported in schizophrenia.4. It is concluded that although the GABAergic system should be further studied, especially in sensory gating model in humans, emphasis on other inhibitory mechanisms may prove useful and provide more effective treatment.     

Effects of Fetal Methylazoxymethanol Acetate Lesion on the Synaptic Neurochemistry of the Adult Rat Striatum

Abstract We used the cytotoxic properties of methylazoxymethanol acetate (MAM), which ablates mitotically active neuroblasts, to eliminate neurons in the fetal striatum to define the factors that regulate the development of the synaptic circuitry of this region. Adult rats whose mothers received a single intraperitoneal injection of 20 mg/kg of MAM on gestational days (DG) 14-17 were used in this study. MAM treatment at 14 DG caused a 49% decrease in striatal mass whereas treatment at 17 DG reduced the striatal weight by only 16%; MAM treatment on 15 or 16 DG gave intermediate results. Histologic analysis of Nissl-stained sections did not reveal an obvious disruption of striatal organization, although the region was clearly hypoplastic. The hypoplasia was associated with significant increases in the specific activities of choline acetyltransferase and tyrosine hydroxylase, although total activities of these enzymes per striatum were significantly depressed with the 14 or 15 DG treatments. In contrast, the specific activity of glutamate decarboxylase was unaffected by MAM treatment whereas the total activity of this enzyme was reduced commensurate with the degree of striatal hypoplasia. In rats lesioned at 15 DG, there was a similar 30% increase in the specific activities of all presynaptic dopaminergic markers studied. In contrast, the specific activity of the synaptosomal uptake process for [³H]choline was elevated by 60%, the specific activity of choline acetyltransferase was increased by only 30%, and the concentration of acetylcholine in the striatum was unchanged. Whereas the specific activities of glutamate decarboxylase and of the synaptosomal uptake process for [³H]γ-aminobutyric acid ([³H]GABA) were unaffected by the 15 DG MAM treatment, the concentration of GABA was increased significantly by 20%. The specific binding of [³H]spiroperidol, [³H]quinuclidinyl benzilate ([³H]QNB). and [³H] muscimol to, respectively, dopamine, muscarinic, and GABA receptors was unchanged by the 15 DG MAM lesion. The nigral dopaminergic perikarya appeared unaffected by the 15 DG MAM lesion in that the tyrosine hydroxylase activity remained normal. Consistent with the loss of striatal GABAergic perikarya, the specific activities of glutamate decarboxylase and of the synaptosomal uptake process for [³H]GABA were significantly reduced in the substantia nigra; however, the concentration of endogenous GABA was twofold greater than in control in this terminal region. The results of these studies indicate that the nigro-striatal dopaminergic pathway only partially compensates for the loss of neurons in its terminal field within the hypoplastic striatum. Striatal cholinergic and GABAergic neurons differ considerably in their responses to the MAM lesion, suggesting that they are derived from different neuroblast pools. Finally, the altered synaptic relationships induced by the fetal lesion may affect neurotransmitter turnover as evidenced by disparities in GABA and acetylcholine levels when compared with other presynaptic markers for the GABAergic and cholinergic neurons.     

Neuronal background of activation of estivated snails,with special attention to the monoaminergic system: a biochemical,physiological, and neuroanatomical study

Osmotic stimulation activates both estivated and inactivated specimens of Helix pomatia and increases their central arousal. High-pressure liquid chromatography has shown that, during activation, the level of both serotonin and dopamine decreases in the central nervous system (CNS) but increases in the foot and heart, organs that are involved in the eversion of the body. In isolated CNS from activated animals, the firing frequency of the heart-modulator serotonergic (RPas) neurons is significantly higher than that in the CNS of estivated or inactivated animals. These neurons innervate both the heart and the anterior aorta. In semi-intact preparations, distilled water (an osmotic stimulus) applied to the mantle collar increases their firing frequency, whereas tactile stimulation evokes their inhibition. Extracellularly applied monoamines mimic the effect of peripheral stimuli: serotonin (0.1–10 μM) increases the activity of the RPas neurons, whereas dopamine (0.1–10 μM) inhibits their activity. Tyrosine-hydroxylase immunocytochemistry and retrograde neurobiotin tracing have revealed similar bipolar receptor cells in the mantle collar and tail, organs that are exposed to environmental stimuli in estivated animals. Serotonin immunocytochemistry carried out on the same tissues does not visualize receptor cells but labels a dense network of fibers that appear to innervate neurobiotin-labeled receptor cells. The combination of neurobiotin-labeling of RPas neurons and immunolabeling suggests that RPas neurons receive direct dopaminergic inputs from receptor cells and serotonergic inputs from central serotonergic neurons, indicating that central serotonergic neurons are interconnected. Thus, the RPas neurons may belong to neuronal elements of the arousal system. This work was supported by Hungarian OTKA grants T037389, T046580, T037505, and K63451.     

Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit

Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non cell-autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson's disease. Variable Shh signaling results in graded inhibition of muscarinic autoreceptor- and glial cell line-derived neurotrophic factor (GDNF)-expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson's disease.     

A specialized subclass of interneurons mediates dopaminergic facilitation of amygdala function

The amygdala is under inhibitory control from the cortex through the activation of local GABAergic interneurons. This inhibition is greatly diminished during heightened emotional states due to dopamine release. However, dopamine excites most amygdala interneurons, suggesting that this dopaminergic gate may be mediated by an unknown subpopulation of interneurons. We hypothesized that this gate is mediated by paracapsular intercalated cells, a subset of interneurons that are innervated by both cortical and mesolimbic dopaminergic afferents. Using transgenic mice that express GFP in GABAergic interneurons, we show that paracapsular cells form a network surrounding the basolateral complex of the amygdala. We found that they provide feedforward inhibition into the basolateral and the central amygdala. Dopamine hyperpolarized paracapsular cells through D1 receptors and substantially suppressed their excitability, resulting in a disinhibition of the basolateral and central nuclei. Suppression of the paracapsular system by dopamine provides a compelling neural mechanism for the increased affective behavior observed during stress or other hyperdopaminergic states.     

Possible destruction of cholinoceptive neurons by overstimulation of cholinergic tracts

It is well established that intracerebral injections of kainic acid may cause not only neuronal cell destruction at the injection site, but also losses in some distant regions. The mechanisms are different. The distant, but not the local, destruction can be produced by folic as well as by kainic acid and prevented by pretreatment of the animal with diazepam. Overexcitation of excitatory projections is believed responsible for the distant damage and evidence is presented that in some instances the projections involved are cholinergic. Thus, for example, injections of kainic acid or folic acid into the substantia innominata of rats destroy neurons in areas such as the pyriform cortex and amygdala which receive cholinergic projections from the injected area. Some of the destroyed neurons are GABAergic. That the distant toxicity in these areas can be partially blocked by scopolamine and is accompanied by decreases in the number of muscarinic binding sites is consistent with a cholinergic mechanism. Distant damage also occurs in the thalamus but this appears to be mediated by a noncholinergic projection. Similar injections of folic acid or kainic acid into the rostral pontine tegmentum, another area with cholinergic cells, cause destruction of both dopaminergic and GABAergic neurons in the substantia nigra. The effect on the GABAergic but not that on the dopaminergic cells is blocked by scopolamine. The results are discussed in relation to possible mechanisms of epilepsy and of selective neuronal losses in diseases such as Parkinson's disease.