Multisecond oscillations in the subthalamic nucleus: effects of apomorphine and dopamine cell lesion.

Clinical and preclinical data indicate that the subthalamic nucleus (STN) plays a critical role in mediating the hyper- and hypoactive behavioral states associated with increases and decreases in dopamine receptor stimulation in the basal ganglia. The present study investigates effects of dopamine receptor stimulation on slow multisecond oscillations in firing rates in STN neurons. Extracellular, single-unit recordings were performed in locally anesthetized and immobilized rats which were either intact or had received unilateral 6-OHDA lesions of the medial forebrain bundle. The majority (64%) of spike trains recorded from STN neurons exhibited periodic oscillations in firing rate within the range of 2-60 sec, with an average period of 24 sec. The distribution of these baseline periodicities was not altered by unilateral 6-OHDA lesion, but periods were significantly shortened by systemic administration of the D1/D2 agonist apomorphine. This effect was observed in a greater proportion of neurons recorded from 6-OHDA-lesioned rats as compared to intact rats, was notably diminished in rats systemically anesthetized with chloral hydrate, and did not correlate with drug-induced changes in firing rate. These oscillations are similar to slow periodicities in firing rate recently reported in other basal ganglia nuclei. The possibility that these periodic oscillations in firing rate play a significant role in basal ganglia function was supported by the observation that the time of onset of apomorphine induced alterations in amplitude and periodicity of slow oscillations in STN spike trains is coincident with the onset of behavioral effects of this drug in 6-OHDA-lesioned animals. Synapse 38:38-50, 2000. Published 2000 Wiley-Liss, Inc.

The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson's disease.

Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson's disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway (a model of Parkinson's disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine and L-3, 4-dihydroxyphenylalanine (L-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (+/-)- 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson's disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei.

The present study investigated alterations of the regulation of serotonin (5-hydroxytryptamine; 5-HT) release by 5-HT1A autoreceptors following single and repeated treatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). Rats were pretreated with 8-OH-DPAT (1.0 mg/kg, s.c.) for 1, 7, or 14 days. The ability of an acute challenge administration of 8-OH-DPAT (1.0 mg/kg, i.p.) to decrease 5-HT release in the ventral striatum and the ventral hippocampus of rats maintained under chloral hydrate anesthesia was examined 24 h after the last pretreatment injection using in vivo microdialysis. The decrease of 5-HT release in the striatum produced by the challenge dose of the 5-HT1A receptor agonist was diminished following 7 and 14 days of pretreatment, but not after 1 day of pretreatment, with 8-OH-DPAT. In contrast, decreases of 5-HT release in the hippocampus by the 8-OH-DPAT challenge were not altered after 1 or 7 days of pretreatment, and only a trend for attenuation appeared after pretreatment for 14 days. The results of the present study indicate that desensitization of 5-HT1A autoreceptors regulating 5-HT release in different brain regions by repeated treatment with 8-OH-DPAT occurs at different rates.

Apomorphine and dopamine D(1) receptor agonists increase the firing rates of subthalamic nucleus neurons.

The present study investigated the regulation of spontaneous neuronal activity in the subthalamic nucleus by dopamine receptors using in vivo extracellular single unit recording techniques. Subthalamic nucleus neuronal firing rates were doubled by systemic administration of the nonselective dopamine receptor agonist apomorphine. The response to apomorphine was attenuated in animals anesthetized with chloral hydrate or ketamine. The dopamine D(2)/D(3) receptor agonist quinpirole did not alter subthalamic nucleus neuronal firing rates. Firing rates were increased by the D(1) receptor agonists SKF 38393 and SKF 82958 two- to three-fold; these increases were reversed by the D(1) receptor antagonist, SCH 23390. Autoradiographic studies using [(125)I]SCH 23982 indicated that D(1) family receptors were located along the ventral edge of the subthalamic nucleus and the dorsal aspect of the cerebral peduncle. Local administration of SKF 82958 into the subthalamic nucleus doubled neuronal firing rates; these increases were reversed by systemic administration of SCH 23390. Infusion of SCH 23390 into the subthalamic nucleus prevented systemic SKF 38393 from increasing the firing rates of subthalamic nucleus neurons. These results indicate that apomorphine and D(1) receptor agonists exert an excitatory influence on subthalamic nucleus neuronal activity. In addition, the excitation induced by D(1) receptor agonists appears to be mediated, at least in part, by D(1) receptors located in the vicinity of the subthalamic nucleus. The data suggest that basal ganglia output under conditions of increased dopamine receptor stimulation is influenced by the activation of excitatory subthalamic efferent pathways, as opposed to suppression of these pathways as predicted by current models of basal ganglia function.

Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo.

Extracellular levels of serotonin (5-HT) and the regulation of 5-HT release by the 5-HT1A receptor were examined after single and repeated treatment with different types of antidepressant drugs: the selective 5-HT uptake inhibitor fluoxetine, the selective norepinephrine uptake inhibitor desipramine and the 5-HT2A/2C/alpha 2 receptor antagonist mianserin (each at 15.0 mg/kg). Extracellular levels of 5-HT were measured using in vivo microdialysis in the striatum and hippocampus of rats anesthetized with chloral hydrate. Acute administration of fluoxetine transiently elevated the levels of 5-HT in the striatum and hippocampus; desipramine did not change 5-HT levels, and mianserin slightly decreased 5-HT levels in the hippocampus. Rats were administered these antidepressant drugs for either 1 or 14 days and studied 48 hr after the final injection. Repeated treatment with fluoxetine increased base-line levels of 5-HT in the striatum and hippocampus; repeated treatment with desipramine increased base-line 5-HT levels in the striatum only, and repeated treatment with mianserin did not alter base-line 5-HT levels. Repeated fluoxetine treatment attenuated the ability of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to decrease 5-HT release in both the striatum and hippocampus. Repeated desipramine treatment did not significantly alter the effects of 8-OH-DPAT on 5-HT release, but there was a hint of a decreased effect in the hippocampus. Repeated mianserin treatment did not significantly alter the effects of 8-OH-DPAT on 5-HT release, but there was a hint of an increased effect in the striatum. The results of the present study suggest that repeated treatment with antidepressant drugs alters extracellular levels of 5-HT and the ability of 5-HT1A receptors to regulate the release of 5-HT in a regionally selective manner. These changes in the regulation of 5-HT release produced by antidepressant drugs may be associated with their therapeutic effects, because they are caused by repeated rather than acute treatment.

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-DHT) and basal and fenfluramine-induced 5-HT release in the striatum. Separate groups of rats were treated with either vehicle or 5,7-DHT (100 micrograms: 76% striatal 5-HT depletion; or 200 micrograms: 93% striatal 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 dose-dependently reduced by 5,7-DHT. In contrast, the increase of 5-HT release produced by fenfluramine treatment (10 mg/kg) was 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 the 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.

Dopamine receptor agonist potencies for inhibition of cell firing correlate with dopamine D3 receptor binding affinities.

The potencies for in vivo inhibition of substantia nigra pars compacta dopamine single cell firing were determined for apomorphine, BHT 920, N-0923, (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), pramipexole, quinelorane, quinpirole, RU 24926, U-86170, and U-91356. Significant correlation was obtained between the potencies of these 11 highly efficacious dopamine receptor agonists and the in vitro binding affinities at dopamine D3 receptors, but not at dopamine D2L receptors. These results support a functional role for the dopamine D3 receptor subtype in the autoreceptor-mediated regulation of dopamine cell activity, while a role for dopamine D2 receptors awaits further analysis. In addition, the results demonstrate the limitations of using currently available dopamine receptor agonists to delineate relative in vivo roles for the dopamine D2 and D3 receptor subtypes.

Differential regulation of serotonin (5-HT) release in the striatum and hippocampus by 5-HT1A autoreceptors of the dorsal and median raphe nuclei.

The present study characterized the pharmacological mechanisms and regional selectivity of the regulation of serotonin (5-HT) release by 5-HT1A autoreceptors. 5-HT release was measured simultaneously in the striatum and ventral hippocampus by using in vivo microdialysis in rats maintained under chloral hydrate anesthesia. Systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) produced complete reductions of 5-HT release. The effects of systemic 8-OH-DPAT on 5-HT release were blocked completely by systemic administration of the 5-HT/beta adrenergic receptor antagonist, (-)-propranolol, but not by the beta-1 adrenergic receptor antagonist betaxolol or the beta-2 adrenergic receptor antagonist ICI-118,551. Local administration of 8-OH-DPAT into the striatum or hippocampus through the microdialysis probe did not alter 5-HT release. Local administration of 8-OH-DPAT into the dorsal raphe nucleus reduced 5-HT release in the striatum, but not in the hippocampus. Conversely, administration of 8-OH-DPAT into the median raphe nucleus reduced 5-HT release in the hippocampus, but not in the striatum. The effects of systemic 8-OH-DPAT on striatal 5-HT release were selectively blocked by concurrent administration of (-)-propranolol into the dorsal raphe nucleus, whereas effects of systemic 8-OH-DPAT on hippocampal 5-HT release were selectively blocked by concurrent administration of (-)-propranolol into the median raphe nucleus. The present study suggests that somatodendritic 5-HT1A receptors regulate the release of 5-HT in a regionally dependent manner.

Antidepressant-like behavioral effects of serotonin receptor agonists.

The clinical discoveries that drugs that stimulate 5-HT neurotransmission, either by inhibiting 5-HT uptake or by stimulating postsynaptic receptors directly, have antidepressant properties has stimulated interest in defining the role of the 5-HT receptor system in the clinical effects of antidepressant drugs. Two approaches are reviewed in this paper that address the neurochemical mediation of the therapeutic effects of antidepressant drugs from the standpoint of animal behavior. The first approach utilizes a behavioral response in rats, the forced swimming test, that correlates well with predicting antidepressant drugs in humans. Studies are reviewed that examined serotonergic compounds in the forced swimming test, from the standpoint of identifying better serotonergic mechanisms involved in the antidepressant response. Both 5-HT uptake inhibitors and 5-HT1A receptor agonists produce effects in the forced swimming test that are similar to those of other classes of antidepressant drugs. In contrast, agonists at other 5-HT receptors or 5-HT receptor antagonists do not produce antidepressant-like behavioral effects. Evidence for an important role of 5-HT1A receptors in the antidepressant response is supported by findings that antagonists of 5HT1A receptors prevent the ability of 5-HT1A receptor agonists to reduce immobility in the forced swimming test. The results of studies interfering with 5-HT neurotransmission, either by inhibition of 5-HT synthesis or by the destruction of 5-HT neurons, favor the idea that the effects of 5-HT1A receptor agonists are produced by the stimulation of postsynaptic 5-HT1A receptors. The second approach for studying the behavioral effects of antidepressant drugs employs drug discrimination studies, conducted using a discriminated taste aversion procedure, to provide a method for studying the discriminative stimulus effects of the antidepressant 5-HT uptake inhibitor sertraline. Rats were trained to discriminate the effects of sertraline (10 mg/kg) from saline. Other 5-HT uptake inhibitors, such as fluoxetine, fluvoxamine and paroxetine, substituted for the sertraline stimulus. High doses of norepinephrine uptake inhibitors, such as desipramine or maprotiline, were required to produce similar effects. These two behavioral approaches promise to be useful for defining the important pharmacological effects associated with the behavioral effects of antidepressant drugs.

The presence of a serotonin uptake inhibitor alters pharmacological manipulations of serotonin release.

The present study investigated the effects of the presence of the serotonin uptake inhibitor citalopram in the perfusion medium on pharmacological manipulations which increased and decreased striatal serotonin release using in vivo microdialysis. A high performance liquid chromatography detection system equipped with a microbore column was used which reduced the detection limit to 0.5 fmol serotonin/5 microliters sample and enabled basal striatal serotonin release to be measured without the addition of a serotonin uptake inhibitor to the perfusion medium. Although serotonin uptake inhibitors have frequently been used to enhance the serotonin content of dialysate samples, the effects of the presence of serotonin uptake inhibitors on pharmacological manipulations which increased and decreased the release of serotonin have not yet been characterized. Serotonin release was reduced by the systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Although 5-HT release was reduced by 8-OH-DPAT after the addition of citalopram, the 5-HT1A receptor agonist did not reduce absolute levels of extracellular serotonin below basal values of serotonin measured in the absence of citalopram. In addition, citalopram dramatically prevented the four-fold increase in the release of serotonin produced by the systemic administration of the serotonin-releasing agent fenfluramine. The blockade of fenfluramine's effects by citalopram supports the hypothesis that transport of fenfluramine into serotonergic neurons is necessary to increase serotonin release. This study demonstrates that the use of an HPLC detection system equipped with a microbore column can reliably measure basal serotonin release using in vivo microdialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Desensitization of 5-HT1A autoreceptors by chronic administration of 8-OH-DPAT.

The function of 5-HT1A autoreceptors was examined by measuring the ability of the 5-HT1A receptor agonist 8-OH-DPAT to reduce 5-HT release in the striatum using in vivo microdialysis. 8-OH-DPAT reduced the release of 5-HT in the striatum. Chronic treatment with 8-OH-DPAT (1.0 mg/kg s.c.) for 7 days, but not 1 day, attenuated the effect of an acute challenge dose of 8-OH-DPAT. The results of the present study indicate that in vivo microdialysis can be used to study the effects of activation of 5-HT1A autoreceptors on 5-HT release and the regulation of 5-HT release by chronic administration of psychoactive drugs.

Human odor intensity perception: correlation with frog epithelial adenylate cyclase activity and transepithelial voltage response.

Although a number of odorants are hypothesized to depolarize frog olfactory receptor cells by binding to ciliary glycoproteins which activate membrane-bound G-proteins to induce adenylate cyclase-mediated increases in intracellular cAMP (cyclic adenosine 3',5'-monophosphate), it is not known whether these odorants influence human odor perception via similar mechanisms. In this paper we present evidence derived from odor attribute ranking and multidimensional scaling procedures that the perceived intensity of such odorants to humans is correlated with (a) the amount of adenylate cyclase activity they induce in an in vitro frog olfactory cilia preparation and (b) the magnitude of their influence on the frog transepithelial voltage response or electro-olfactogram (EOG). These observations are in accord with the hypothesis that the perception of the intensity of some odors by humans is associated with cAMP-related epithelial processes and imply that remarkable homologies exist between the intensity-related olfactory receptor mechanisms of frog and man.