Role of 5-HT2C receptors in the enhancement of c-Fos expression induced by a 5-HT2B/2C inverse agonist and 5-HT2 agonists in the rat basal ganglia

Some non-selective serotonin2C (5-HT_2C) agonists or inverse agonists enhance the product of the proto-oncogene c-Fos within the basal ganglia, a group of brain regions involved in motor behavior and in the ability of these drugs to promote abnormal movements. The role of 5-HT_2C receptors in these effects is unclear. The 5-HT_2C antagonist SB243,213 (1 mg/kg), which enhanced Fos per se in the striatum and the subthalamic nucleus (STN) only, was used to study the implication of 5-HT_2C receptors. The agonists Ro 60-0175 (3 mg/kg) and m-CPP (1 mg/kg) and the inverse agonist SB206,553 (10 mg/kg) enhanced Fos expression in the STN and faintly in the entopeduncular nucleus (EPN, the internal globus pallidus in primate). The effects of these drugs differed mainly in the striatum regarding the magnitude (m-CPP > Ro 60-0175> SB243,213 > SB206,553) or the striatal quadrants (faint to no labeling in lateral striatum) and in the substantia nigra. None of these compounds enhanced Fos expression by themselves in the globus pallidus or in the EPN when combined with SB243,213. Their Fos effect in the STN was reduced significantly by SB243,213 only in the case of m-CPP. In the ventromedial striatum, SB243,213 reduced the effects of m-CPP while SB206,553 reduced the effects of SB243,213. The results show that opposite pharmacological agents alter similarly Fos expression in the EPN or the STN. Although some of the effects of 5-HT agents are related to targets other than 5-HT_2C receptors, the study confirms the existence of multiple 5-HT_2C receptor-dependent controls recruited by these drugs upon basal ganglia activity.     

Selective blockade of serotonin2C receptor enhances Fos expression specifically in the striatum and the subthalamic nucleus within the basal ganglia

Serotonin_2C (5-HT_2C) receptors are widely expressed in the basal ganglia, a group of brain regions involved in the control of motor behavior. However, it remains unclear whether their tonic influence on neuronal activity is distributed in these regions. We have addressed this question by measuring the product of the proto-oncogene c-Fos in rats after peripheral administration of the non-selective 5-HT antagonist mianserin, the 5-HT_2C/2B antagonist SER-082 or the selective 5-HT_2C antagonist SB 243213. The intraperitoneal administration of 1 mg/kg of SB 243213 or SER-082, but not mianserin, enhanced Fos-immunoreactive cells in the subthalamic nucleus and the striatum, primarily its medial portion. None of these treatments significantly affected Fos expression in the external globus pallidus, the entopeduncular nucleus (the internal globus pallidus in primate) or the substantia nigra pars reticulata. The data suggest that selective blockade of 5-HT_2C receptors is necessary to unmask a tonic regulation of neuronal activity by this receptor in the basal ganglia and that this effect is restricted to the two structures receiving cortical entries, the striatum and the subthalamic nucleus.     

The enhanced oral response to the 5-HT2 agonist Ro 60-0175 in parkinsonian rats involves the entopeduncular nucleus: electrophysiological correlates

Lesions of nigrostriatal dopaminergic neurons as seen in Parkinson’s disease (PD) increase orofacial responses to serotonergic (5-HT) agonists in rodents. Although this response to 5-HT agonists has been related to aberrant signalling in the basal ganglia, a group a subcortical structures involved in the control of motor behaviours, it deserves additional studies with respect to the specific loci involved. Using measurements of orofacial activity, as well as single-cell recordings in vivo, we have studied the role of the entopeduncular nucleus (EPN; equivalent to the internal globus pallidus of primates), an output structure of basal ganglia, in the hypersensitized responses to a 5-HT agonist in sham- or unilaterally dopamine-depleted rats. Intra-EPN injections of Ro 60-0175 (0.3 and 1 μg/100 nl) promoted robust oral movements in 6-OHDA rats without affecting oral activity in sham-depleted rats. Peripheral administration of Ro 60-0175 (3 mg/kg ip) decreased EPN neuronal firing rate in 6-OHDA rats compared to sham-depleted rats. Such an effect was also observed when the agonist (0.2 μg/20 nl) was locally applied onto EPN neurons. These data demonstrate the contribution of EPN to hypersensitized responses to 5-HT agonists in a rat model of PD.     

Multiple controls exerted by 5-HT2C receptors upon basal ganglia function: from physiology to pathophysiology

Serotonin2C (5-HT_2C) receptors are expressed in the basal ganglia, a group of subcortical structures involved in the control of motor behaviour, mood and cognition. These receptors are mediating the effects of 5-HT throughout different brain areas via projections originating from midbrain raphe nuclei. A growing interest has been focusing on the function of 5-HT_2C receptors in the basal ganglia because they may be involved in various diseases of basal ganglia function notably those associated with chronic impairment of dopaminergic transmission. 5-HT_2C receptors act on numerous types of neurons in the basal ganglia, including dopaminergic, GABAergic, glutamatergic or cholinergic cells. Perhaps inherent to their peculiar molecular properties, the modality of controls exerted by 5-HT_2C receptors over these cell populations can be phasic, tonic (dependent on the 5-HT tone) or constitutive (a spontaneous activity without the presence of the ligand). These controls are functionally organized in the basal ganglia: they are mainly localized in the input structures and preferentially distributed in the limbic/associative territories of the basal ganglia. The nature of these controls is modified in neuropsychiatric conditions such as Parkinson’s disease, tardive dyskinesia or addiction. Most of the available data indicate that the function of 5-HT_2C receptor is enhanced in cases of chronic alterations of dopamine neurotransmission. The review illustrates that 5-HT_2C receptors play a role in maintaining continuous controls over the basal ganglia via multiple diverse actions. We will discuss their interest for treatments aimed at ameliorating current pharmacotherapies in schizophrenia, Parkinson’s disease or drugs abuse.     

Selective activation of 5-HT(2C) receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: a combined in vivo electrophysiological and neurochemical study

In vivo electrophysiology and microdialysis were used to investigate the physiological role of 5-HT(2C) receptors in the control of substantia nigra pars reticulata (SNr) function. Extracellular single-unit recordings were performed from putative GABA-containing neurons in the SNr of anesthetized rats, and local GABA release was studied by in vivo microdialysis in the SNr of awake freely-moving rats. Systemic administration of the selective 5-HT(2C) receptor agonist (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C(4)H(4)O(4) (RO 60-0175) caused a dose-dependent excitation of about 30% of the SNr neurons recorded. However, the remaining neurons were either inhibited or unaffected by systemic RO 60-0175, in similar proportion. Local application of RO 60-0175 by microiontophoresis caused excitation in the majority of SNr neurons tested (48%), whereas a group of neurons was inhibited (16%) or unaffected (36%). Both the excitatory and the inhibitory effects of systemic and microiontophoretic RO 60-0175 were completely prevented by pretreatment with SB 243213 [5-methyl-1-({2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl}carbamoyl)-6-trifluoromethylindoline], a selective and potent 5-HT(2C) receptor antagonist. Consistent with these electrophysiological data, both systemic and intranigral administration of RO 60-0175 and m-chlorophenylpiperazine (mCPP), a non-selective 5-HT(2C) agonist, markedly increased extracellular GABA levels in the SNr. The stimulatory effect of systemic and local RO 60-0175 on GABA release was completely prevented by systemic administration of SB 243213, whereas local application of SB 243213 into the SNr only partially blocked RO 60-0175-induced GABA release. It is concluded that selective activation of 5-HT(2C) receptors stimulates GABA-ergic function in the SNr, and the clinical relevance of these data is discussed.     

Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement

Previously, we reported that stimulation of selective serotonin (5-HT) receptor subtypes in the nucleus accumbens shell differentially affected consumption of freely available food. Specifically, activation of 5-HT₆ receptors caused a dose-dependent increase in food intake, while the stimulation of 5-HT_1/7 receptor subtypes decreased feeding [34]. The current experiments tested whether similar pharmacological activation of nucleus accumbens serotonin receptors would also affect appetitive motivation, as measured by the amount of effort non-deprived rats exerted to earn sugar reinforcement. Rats were trained to lever press for sugar pellets on a progressive ratio 2 schedule of reinforcement. Across multiple treatment days, three separate groups (N = 8–10) received bilateral infusions of the 5-HT₆ agonist EMD 386088 (at 0.0, 1.0 and 4.0 μg/0.5 μl/side), the 5-HT_1/7 agonist 5-CT (at 0, 0.5, 1.0, or 4.0 μg/0.5 μl/side), or the 5-HT_2C agonist RO 60-0175 fumarate (at 0, 2.0, or 5.0 μg/0.5 μl/side) into the anterior medial nucleus accumbens prior to a 1-h progressive ratio session. Stimulation of 5-HT₆ receptors caused a dose-dependent increase in motivation as assessed by break point, reinforcers earned, and total active lever presses. Stimulation of 5-HT_1/7 receptors increased lever pressing at the 0.5 μg dose of 5-CT, but inhibited lever presses and break point at 4.0 μg/side. Injection of the 5-HT_2C agonist had no effect on motivation within the task. Collectively, these experiments suggest that, in addition to their role in modulating food consumption, nucleus accumbens 5-HT₆ and 5-HT_1/7 receptors also differentially regulate the appetitive components of food-directed motivation.     

5-HT1B receptor regulation of serotonin (5-HT) release by endogenous 5-HT in the substantia nigra

Axonal release of serotonin (5-hydroxytryptamine, 5-HT) in the CNS is typically regulated by presynaptic 5-HT autoreceptors. Release of 5-HT in substantia nigra pars reticulata (SNr), a principal output from the basal ganglia, has seemed an interesting exception to this rule. The SNr receives one of the highest densities of 5-HT innervation in mammalian brain and yet negative feedback regulation of axonal 5-HT release by endogenous 5-HT has not been identified here. We explored whether we could identify autoregulation of 5-HT release by 5-HT_1B receptors in rat SNr slices using fast-scan cyclic voltammetry at carbon-fiber microelectrodes to detect 5-HT release evoked by discrete stimuli (50 Hz, 20 pulses) paired over short intervals (1–10 s) within which any autoreceptor control should occur. Evoked 5-HT release exhibited short-term depression after an initial stimulus that recovered by 10 s. Antagonists for 5-HT_1B receptors, isamoltane (1 μM) or SB 224-289 (1 μM), did not modify release during a stimulus train, but rather, they modestly relieved depression of subsequent release evoked after a short delay (≤2 s). Release was not modified by antagonists for GABA (picrotoxin, 100 μM, saclofen, 50 μM) or histamine-H₃ (thioperamide, 10 μM) receptors. These data indicate that 5-HT release can activate a 5-HT_1B-receptor autoinhibition of subsequent release, which is mediated directly via 5-HT axons and not via GABAergic or histaminergic inputs. These data reveal that 5-HT release in SNr is not devoid of autoreceptor regulation by endogenous 5-HT, but rather is under modest control which only weakly limits 5-HT signaling.     

Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction

The present study is designed to elucidate how basal ganglia afferents from the substantia nigra pars reticulata (SNr) to the mesopontine tegmental area of the brainstem contribute to gait control and muscle-tone regulation. We used unanesthetized and acutely decerebrated cats (n=27) in which the striatum, thalamus and cerebral cortex were removed but the SNr was preserved. Repetitive stimulation (50 Hz, 10-60 microA, for 5-20 s) applied to a mesencephalic locomotor region (MLR), which corresponded to the cuneiform nucleus, and adjacent areas, evoked locomotor movements. On the other hand, stimulation of a muscle-tone inhibitory region in the pedunculopontine tegmental nucleus (PPN) suppressed postural muscle tone. An injection of either glutamatergic agonists (N-methyl-D-aspartic acid and kainic acid) or GABA antagonists (bicuculline and picrotoxin) into the MLR and PPN also induced locomotion and muscle-tone suppression, respectively. Repetitive electrical stimuli (50-100 Hz, 20-60 microA for 5-20 s) delivered to the SNr alone did not alter muscular activity. However stimulating the lateral part of the SNr attenuated and blocked PPN-induced muscle-tone suppression. Moreover, weaker stimulation of the medial part of the SNr reduced the number of step cycles and disturbed the rhythmic alternation of limb movements of MLR-induced locomotion. The onset of locomotion was delayed as the stimulus intensity was increased. At a higher strength SNr stimulation abolished the locomotion. An injection of bicuculline into either the PPN or the MLR diminished the SNr effects noted above. These results suggest that locomotion and postural muscle tone are subject to modulation by GABAergic nigrotegmental projections which have a partial functional topography: a lateral and medial SNr, for regulation of postural muscle tone and locomotion, respectively. We conclude that disorders of the basal ganglia may include dysfunction of the nigrotegmental (basal ganglia-brainstem) systems, which consequently leads to the production of abnormal muscle tone and gait disturbance.     

C-Fos identification of neuroanatomical sites associated with haloperidol and clozapine disruption of maternal behavior in the rat

Rat maternal behavior is a complex social behavior. Most antipsychotic drugs disrupt active maternal responses (e.g., pup retrieval, pup licking and nest building). Our previous work shows that typical antipsychotic haloperidol disrupts maternal behavior by blocking dopamine D₂ receptors, whereas atypical clozapine works by blocking 5-HT_2A/2C receptors. The present study used c-Fos immunohistochemistry technique, together with pharmacological tools and behavioral observations, and delineated the neuroanatomical bases of the disruptive effects of haloperidol and clozapine. Postpartum female rats were treated with haloperidol (0.2 mg/kg sc) or clozapine (10.0 mg/kg sc), with or without pretreatment of quinpirole (a selective dopamine D₂/D₃ agonist, 1.0 mg/kg sc) or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 2.5 mg/kg sc). They were then sacrificed 2 h later after a maternal behavior test was conducted. Brain regions that have been previously implicated in the regulation of rat maternal behavior and/or in the antipsychotic action were examined. Behaviorally, both haloperidol and clozapine disrupted pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, reversed the clozapine-induced deficits. Neuroanatomically, the nucleus accumbens (both the shell and core), dorsolateral striatum and lateral septum showed increased c-Fos expression to the treatment of haloperidol. In contrast, the nucleus accumbens shell showed increased expression of c-Fos to the treatment of clozapine. More importantly, pretreatment of quinpirole and DOI produced opposite response profiles in the brain regions where haloperidol and clozapine had an effect. Based on these findings, we concluded that haloperidol disrupts active maternal behavior primarily by blocking dopamine D₂ receptors in a neural circuitry involving the nucleus accumbens, dorsolateral striatum and lateral septum. In contrast, clozapine appears to disrupt maternal behavior mainly by blocking serotonin 5-HT_2A/2C receptors in the nucleus accumbens shell.     

The effects of 5-HT1A and 5-HT2C receptor agonists on behavioral satiety sequence in rats

The present study examined the effects of 5-HT1A and 5-HT2C receptor agonists on behavioral satiety sequence (BSS) in rats. The 5-HT1A receptor agonist, 8-OH-DPAT (0.5 microg), and the 5-HT2C receptor agonist, Ro-60-0175 (3.0 microg), were injected into the paraventricular nucleus (PVN) of rats. The animals were maintained on an ad libitum feeding paradigm with access to water and individual sources of protein, carbohydrate, and fat. Intra-PVN administration of each agonist was associated with decreased carbohydrate consumption. The effect was enhanced by the administration of both agonists together. Behavioral analysis indicated that co-administration of 8-OH-DPAT and Ro-60-0175 interrupted the natural BSS with an increase in non-feeding behavior, whereas the 8-OH-DPAT alone promoted early development of the natural BSS. In conclusion, the 5-HT receptor agonists affected serotonergic modulation of feeding behavior in a functionally selective way.     

Substantia nigra pars reticulata GABA is involved in the regulation of operant lever pressing: pharmacological and microdialysis studies

Substantia nigra pars reticulata (SNr) is an important mesencephalic nucleus that functions as a relay area for basal ganglia output. SNr receives GABAergic inputs from the neostriatum and globus pallidus, and in turn sends projections to a variety of motor areas. Although a large number of studies have focused upon the behavioral functions of basal ganglia dopamine, much less is known about the behavioral functions of SNr GABA. The present studies were undertaken to investigate the role of SNr GABA in lever pressing behavior. In the first experiment, the GABA(A) antagonist bicuculline was infused locally into SNr to determine if blockade of GABA receptors interfered with the performance of lever pressing on a fixed ratio 5 schedule. SNr injections of bicuculline produced a dose-related suppression of operant responding. Analysis of interresponse time bins showed that SNr bicuculline produced a response slowing characterized by a relative reduction in the number of fast interresponse times, and an increase in the relative number of pauses. In an additional experiment, microdialysis methods were used to determine if extracellular GABA is elevated during the performance of fixed ratio five lever pressing. During the 30 min lever pressing session, extracellular GABA showed a significant and substantial increase relative to baseline levels.These data support the hypothesis that SNr GABA is involved in the regulation of motor output, and indicate that GABA release in this structure is increased during behavioral stimulation.     

Discharge rate of substantia nigra pars reticulata neurons is reduced in non-parkinsonian monkeys with apomorphine-induced orofacial dyskinesia

Involuntary movements (dyskinesia) are a common symptom of dopamine-replacement therapy in parkinsonian patients, neuroleptic drug treatment of mental patients, and tic disorders. Levodopa-induced dyskinesia has been shown to be associated with substantial reduction of firing rate in the internal part of the globus pallidus. This study characterizes the changes that occur in the activity of the substantia nigra pars reticulata (SNr) of non-parkinsonian (normal) monkeys with apomorphine (APO)-induced orofacial dyskinesia. We conducted extracellular recordings of SNr neurons of two monkeys before and after induction of orofacial dyskinesia by systemic administration of APO. Involuntary orofacial movements appeared a few minutes after the injections and lasted 20-40 min. Almost all recorded neurons changed their firing rate after APO injection (96%), and most declined (70%). The mean amplitude of decreases was also larger than that of increases (40 vs. 21% of the control rate). Changes in firing pattern were not significant on average. Pairs of SNr neurons were uncorrelated before APO injection, similar to the normal pallidum. However, unlike the increased correlations in the pallidum that accompany parkinsonism, orofacilal dyskinesia in non-parkinsonian monkeys was not associated with changes in correlation between SNr neurons. We conclude that normal monkeys treated with APO can model orofacial dyskinesia and tic disorders that are a consequence of dopaminergic over-activity. These symptoms appear to be more related to reduced firing rate of SNr neurons and thus to disinhibition of their targets, than to changes in pattern and synchronization.     

5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with L-DOPA

Long-term L-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease (PD) is associated with motor complications such as dyskinesia. There are clear functional interactions between dopaminergic and serotonergic type 2A receptors (5-HT_2A)-mediated neurotransmission. Moreover, 5-HT_2A receptor antagonists can reduce L-DOPA-induced dyskinesia (LID). We hypothesized that enhanced 5-HT_2A-mediated neurotransmission may be involved in the genesis of L-DOPA-induced dyskinesia. Radioligand binding autoradiography, using [³H]-ketanserin, was performed to define 5-HT_2A receptor levels in brain tissue from macaques: 6 normal; 5 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, parkinsonian macaques, without exposure to L-DOPA; 6 MPTP-lesioned, parkinsonian macaques, receiving a single administration of L-DOPA, and exhibiting no dyskinesia; and 6 MPTP-lesioned, parkinsonian, macaques chronically treated with L-DOPA, and exhibiting dyskinesia. 5-HT_2A receptor binding was increased in the caudate, putamen, and middle layers of the motor cortex in chronically L-DOPA-treated animals, by 50%, 50%, and 45% respectively, compared with normal macaques. 5-HT_2A binding was not significantly altered in parkinsonian, untreated, or parkinsonian, single treatment, nondyskinetic macaques, compared with normal. These data provide an anatomical basis for mechanisms to explain the efficacy of 5-HT_2A antagonists against dyskinesia.     

Blockade of 5-HT<Subscript>2A/2C</Subscript>-Type Receptors Impairs Learning in Female Rats in the Course of Estrous Cycle

Were studied the effects of chronic administration (14 days) of agonist of 5-HT_2B/2C serotonin receptors m-CPP (0.5 mg/kg subcutaneously) and agonist of 5-HT_2A/2C serotonin receptors ketanserin (0.1 mg/kg intraperitoneally) on conditioned reactions in female rats in different phases of the estrous cycle. Passive avoidance (PA) paradigm and Morris water maze were used as behavioral tests. Chronic administration of m-CPP did not affect PA retrieval during the proestrus and estrus phases, but improved the dynamics of spatial learning in Morris water maze in comparison with control rats. Chronic administration of ketanserin uniformly impaired processes of spatial and nonspatial learning in female rats irrespective to the phase of the estrous cycle. A modulating role of 5-HT_2A/2C and 5-HT_2B/2C serotonin receptors in process of learning in female rats during the key phases of the estrous cycle was demonstrated.     

Dopamine agonist-mediated rotation in rats with unilateral nigrostriatal lesions is not dependent on net inhibitions of rate in basal ganglia output nuclei.

Current models of basal ganglia function predict that dopamine agonist-induced motor activation is mediated by decreases in basal ganglia output. This study examines the relationship between dopamine agonist effects on firing rate in basal ganglia output nuclei and rotational behavior in rats with nigrostriatal lesions. Extracellular single-unit activity ipsilateral to the lesion was recorded in awake, locally-anesthetized rats. Separate rats were used for behavioral experiments. Low i.v. doses of D1 agonists (SKF 38393, SKF 81297, SKF 82958) were effective in producing rotation, yet did not change average firing rate in the substantia nigra pars reticulata or entopeduncular nucleus. At these doses, firing rate effects differed from neuron to neuron, and included increases, decreases, and no change. Higher i.v. doses of D1 agonists were effective in causing both rotation and a net decrease in rate of substantia nigra pars reticulata neurons. A low s.c. dose of the D1/D2 agonist apomorphine (0.05 mg/kg) produced both rotation and a robust average decrease in firing rate in the substantia nigra pars reticulata, yet the onset of the net firing rate decrease (at 13-16 min) was greatly delayed compared to the onset of rotation (at 3 min). Immunostaining for the immediate-early gene Fos indicated that a low i.v. dose of SKF 38393 (that produced rotation but not a net decrease in firing rate in basal ganglia output nuclei) induced Fos-like immunoreactivity in the striatum and subthalamic nucleus, suggesting an activation of both inhibitory and excitatory afferents to the substantia nigra and entopeduncular nucleus. In addition, D1 agonist-induced Fos expression in the striatum and subthalamic nucleus was equivalent in freely-moving and awake, locally-anesthetized rats. The results show that decreases in firing rate in basal ganglia output nuclei are not necessary for dopamine agonist-induced motor activation. Motor-activating actions of dopamine agonists may be mediated by firing rate decreases in a small subpopulation of output nucleus neurons, or may be mediated by other features of firing activity besides rate in these nuclei such as oscillatory firing pattern or interneuronal firing synchrony. Also, the results suggest that dopamine receptors in both the striatum and at extrastriatal sites (especially the subthalamic nucleus) are likely to be involved in dopamine agonist influences on firing rates in the substantia nigra pars reticulata and entopeduncular nucleus.     

Opposite functions of histamine H1 and H2 receptors and H3 receptor in substantia nigra pars reticulata

The substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus. Inhibitory outputs from SNr are encoded in spike frequency and pattern of the inhibitory SNr projection neurons. SNr output intensity and pattern are often abnormal in movement disorders of basal ganglia origin. In Parkinson's disease, histamine innervation and histamine H3 receptor expression in SNr may be increased. However, the functional consequences of these alterations are not known. In this study, whole cell patch-clamp recordings were used to elucidate the function of different histamine receptors in SNr. Histamine increased SNr inhibitory projection neuron firing frequency and thus inhibitory output. This effect was mediated by activation of histamine H1 and H2 receptors that induced inward currents and depolarization. In contrast, histamine H3 receptor activation hyperpolarized and inhibited SNr inhibitory projection neurons, thus decreasing the intensity of basal ganglia output. By the hyperpolarization, H3 receptor activation also increased the irregularity of the interspike intervals or changed the pattern of SNr inhibitory neuron firing. H3 receptor-mediated effects were normally dominated by those mediated by H1 and H2 receptors. Furthermore, endogenously released histamine provided a tonic, H1 and H2 receptor-mediated excitation that helped keep SNr inhibitory projection neurons sufficiently depolarized and spiking regularly. These results suggest that H1 and H2 receptors and H3 receptor exert opposite effects on SNr inhibitory projection neurons. Functional balance of these different histamine receptors may contribute to the proper intensity and pattern of basal ganglia output and, as a consequence, exert important effects on motor control.     

Regulation of cortical and striatal 5-HT1A receptors in the MPTP-lesioned macaque

Serotonergic 1A (5-HT_1A) receptor agonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in Parkinson's disease (PD), though the mechanism(s) and site(s) of action remain unclear. We employed [³H]-WAY 100,635 autoradiographic receptor binding to measure 5-HT_1A receptor levels in 4 groups of macaques: normal (vehicle-vehicle); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, without exposure to L-DOPA, i.e., untreated parkinsonian (MPTP-vehicle); MPTP-lesioned, receiving a single administration of L-DOPA to alleviate parkinsonism (MPTP-L-DOPA-acute); and MPTP-lesioned, chronically treated with L-DOPA, parkinsonism alleviated but exhibiting dyskinesia (MPTP-L-DOPA-chronic). We demonstrate that 5-HT_1A receptor binding decreases (by 10%-20%, p < 0.05) in the external layers, but increases (by 80%-100%, p < 0.05) in the middle layers, of the premotor and motor cortex of all MPTP-lesioned macaques. In the striosomes of the caudate nucleus, 5-HT_1A receptor binding increases in MPTP-vehicle macaques (by 50%, p < 0.05), compared with normal macaques. While 5-HT_1A receptor binding is low in the matrix of the caudate nucleus in normal macaques, it increases (by 200%, p < 0.05) in MPTP-L-DOPA-chronic macaques. These data suggest that 5-HT_1A receptors are involved in the pathophysiology of both parkinsonism and complications of L-DOPA therapy.     

Effect of 5-HT2C receptor antagonist RS 102221 on mouse behavior

Injection of RS 102221 (selective antagonist of serotonin 5-HT_2C receptors) in a dose of 2 mg/kg reduced anxiety of mice in the light-darkness test and decreased the amplitude of the startle reflex. RS 102221 in a dose of 1 mg/kg reduced prestimulus inhibition of the startle reflex. No behavioral changes in Porsolt test and motor activity in the open field test were detected. Hence, RS 102221 is characterized by selective anxiolytic activity, and 5-HT_2C receptors are involved in the mechanisms of anxiety and startle reflex formation. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 7, pp. 86–89, July, 2006     

Directional analysis of coherent oscillatory field potentials in the cerebral cortex and basal ganglia of the rat

Population activity in cortico-basal ganglia circuits is synchronized at different frequencies according to brain state. However, the structures that are likely to drive the synchronization of activity in these circuits remain unclear. Furthermore, it is not known whether the direction of transmission of activity is fixed or dependent on brain state. We have used the directed transfer function (DTF) to investigate the direction in which coherent activity is effectively driven in cortico-basal ganglia circuits. Local field potentials (LFPs) were simultaneously recorded in the subthalamic nucleus (STN), globus pallidus (GP) and substantia nigra pars reticulata (SNr), together with the ipsilateral frontal electrocorticogram (ECoG) of anaesthetized rats. Directional analysis was performed on recordings made during robust cortical slow-wave activity (SWA) and 'global activation'. During SWA, there was coherence at ∼1 Hz between ECoG and basal ganglia LFPs, with much of the coherent activity directed from cortex to basal ganglia. There were similar coherent activities at ∼1 Hz within the basal ganglia, with more activity directed from SNr to GP and STN, and from STN to GP rather than vice versa. During global activation, peaks in coherent activity were seen at higher frequencies (15–60 Hz), with most coherence also directed from cortex to basal ganglia. Within the basal ganglia, however, coherence was predominantly directed from GP to STN and SNr. Together, these results highlight a lead role for the cortex in activity relationships with the basal ganglia, and further suggest that the effective direction of coupling between basal ganglia nuclei is dynamically organized according to brain state, with activity relationships involving the GP displaying the greatest capacity to change.     

Adenosine A(2A) receptor-mediated modulation of GABA and glutamate release in the output regions of the basal ganglia in a rodent model of Parkinson's disease

A target neuron of adenosine A(2A) receptor antagonists to exert anti-parkinsonian activities has been currently identified to be, at least in part, striatopallidal medium spiny neurons (MSNs). In the present study, we determine whether A(2A) receptor-mediated modulation is associated with changes in the release of GABA and glutamate in the substantia nigra pars reticulata (SNr), an output structure of the whole basal ganglia network, using in vivo microdialysis in a rat Parkinson's disease (PD) model. In 6-hydroxydopamine (OHDA)-lesioned rats compared with normal rats, basal extracellular GABA levels in the SNr show no change, whereas basal glutamate levels are significantly increased. Oral administration of the A(2A) receptor-selective antagonist (E-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1-H-purine-2,6-dion (KW-6002) to 6-OHDA-lesioned rats at 1 mg/kg caused a marked and sustained increase of GABA and glutamate levels in the SNr. The increase of nigral glutamate by KW-6002 was abolished by a kainic acid-induced lesion of the globus pallidus (GP) or subthalamic nucleus (STN) in 6-OHDA-lesioned rats, whereas the increase of nigral GABA was completely blocked by the GP-lesion but only partially blocked by the STN-lesion. These results indicate that changes in neurotransmitter release in the SNr brought about by KW-6002 are largely attributable to blockade of A(2A) receptor-mediated modulation of striatopallidal MSNs. Thus, these actions of KW-6002 on striatopallidal MSNs may be the main mechanism for ameliorating PD by A(2A) antagonists.