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Restless legs syndrome (RLS) is a disorder characterized by an irresistible urge to move the legs during rest, usually accompanied by uncomfortable sensations in the affected extremity or extremities. RLS can manifest at any age but prevalence increases with advancing age. This article describes the symptoms of RLS, associated comorbidities, and how to diagnose and manage RLS.

Movement disorders such as Parkinson's disease (PD) and dystonia are associated with alterations of basal ganglia motor circuits and abnormal neuronal activity in the output nucleus, the globus pallidus internus (GPi). This study aims to compare the electrophysiological hallmarks for PD and dystonia in the linear and non-linear time stamp domains in patients who underwent microelectrode recordings during functional stereotactic surgery for deep brain stimulation (DBS) or pallidotomy. We analyzed single-unit neuronal activity in the posteroventral lateral region of the GPi in awake patients prior to pallidotomy or the implantation of DBS electrodes in 29 patients with PD (N = 83 neurons) and 13 patients with dystonia (N = 41 neurons) under comparable conditions. The discharge rate and the instantaneous frequency of the GPi in dystonia patients were significantly lower than in PD patients (P < 0.001), while the total number of bursts, the percentage of spikes in bursts and the mean duration of bursts were higher (P < 0.001). Further, non-linear analysis revealed higher irregularity or entropy in the data streams of GPi neurons of PD patients compared to the dystonia patients group (P < 0.001). This study indicates that both linear and non-linear features of neuronal activity in the human GPi differ between PD and dystonia. Our results may serve as the basis for future studies on linear and non-linear analysis of neuronal firing patterns in various movement disorders.

Meta-analysis based techniques are emerging as powerful, robust tools for developing models of connectivity in functional neuroimaging. Here, we apply meta-analytic connectivity modeling to the human caudate to 1) develop a model of functional connectivity, 2) determine if meta-analytic methods are sufficiently sensitive to detect behavioral domain specificity within region-specific functional connectivity networks, and 3) compare meta-analytic driven segmentation to structural connectivity parcellation using diffusion tensor imaging. Results demonstrate strong coherence between meta-analytic and data-driven methods. Specifically, we found that behavioral filtering resulted in cognition and emotion related structures and networks primarily localized to the head of the caudate nucleus, while perceptual and action specific regions localized to the body of the caudate, consistent with early models of nonhuman primate histological studies and postmortem studies in humans. Diffusion tensor imaging (DTI) revealed support for meta-analytic connectivity modeling's (MACM) utility in identifying both direct and indirect connectivity. Our results provide further validation of meta-analytic connectivity modeling, while also highlighting an additional potential, namely the extraction of behavioral domain specific functional connectivity., (Published by Elsevier Inc.)

Previous electrophysiological studies of the basal ganglia in Parkinson's disease (PD) patients have utilized linear analyses in time-or-frequency domains to characterize neuronal discharge patterns. However, these measures do not fully describe the non-linear features of discharge rates and oscillatory activities of basal ganglia neurons. In this original research, we investigate whether non-linear temporal organizations exist in the inter-spike interval series of neurons recorded in the globus pallidus or the subthalamic nucleus in PD patients undergoing surgery for the implantation of deep brain stimulating electrodes. Our data indicate that in approximately 80% of globus pallidus and subthalamic neurons, the raw inter-spike interval sequences have lower entropy values than those observed after shuffling of the original series. This is the first report establishing non-linear temporal organization as a common feature of neuronal discharge in the basal ganglia of PD patients.

We report a patient with Parkinson's disease whose whole body drenching sweats were completely alleviated by stimulation of the subthalamic nucleus and/or adjacent structures. Sweating reappeared 4h after the pulse generator (stimulation) was turned off and ceased when stimulation was resumed. Imaging studies with reconstruction indicated that stimulation of, or spread of stimulation from, the caudal medial aspect of the right subthalamic nucleus and/or the caudal aspect of the ventral thalamus/zona incerta may be responsible for alleviating the drenching sweats.

High-frequency stimulation of the subthalamic nucleus is a neurosurgical procedure for the alleviation of motor symptoms of Parkinson's disease and debilitating medication-induced dyskinesias. Stimulation is achieved with electrodes implanted stereotactically in the subthalamic nucleus by a neurosurgeon specializing in stereotactic surgery and a team composed of an anesthesiologist, a neurophysiologist, certified nurses and nurse practitioners and, at some centers, a neurologist. The teamwork continues in the recovery room and the intensive care unit, where the patient may experience transient adverse behavioral effects. Two weeks after surgery, the neurostimulator is activated and programmed. The medications also are adjusted to complement stimulation to maximize the therapeutic effects and minimize the stimulation-induced side effects. For those patients who are deconditioned or have major speech, gait, or balance problems, rehabilitation therapy is employed.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder affecting more than 1.2 million people in the United States. Genetic and environmental toxins are believed to be risk factors in acquiring the disease. PD is characterized by tremors, rigidity, bradykinesia, poor gait, and postural instability. These cardinal symptoms improve with medication such a levo-dopa (L-dopa). However, over time, as the disease progresses, the patient becomes refractory to medication, or medication produces debilitating side effects. When this occurs or when there are worsening of symptoms, neurosurgical treatment is recommended, particularly deep brain stimulating (DBS) electrodes implanted in the subcortical subthalamic nucleus (STN). Over the last 5 years STN DBS has gained acceptance and become the neurosurgical treatment of choice for PD. To achieve maximum beneficial effects with minimum adverse effects from the surgery, the expertise of an integrated team of physicians and nurses is essential. A clear understanding of the different aspects of the procedure, including the risks and benefits of the treatment, assists neuroscience nurses in communicating with the PD patient, and providing the most appropriate, knowledge-based pre- and postoperative care.

Objective: Basal ganglia neuronal activity in patients undergoing posteroventral pallidotomy (PVP) for the treatment of primary genetic, secondary, or idiopathic dystonia (DYS) was studied to gain a better understanding of the pathophysiology of DYS., Methods: Intraoperative neurophysiological data recorded from 15 DYS patients were compared with those from 78 patients with Parkinson's disease (PD) who underwent PVP., Results: Putamen neurons in both DYS and PD patients had low discharge rates. Globus pallidus externa (GPe) and globus pallidus interna (GPi) neurons in DYS patients had significantly lower discharge rates and more irregular discharge patterns than in PD patients. GPe and GPi neurons displayed similar discharge rates and patterns in DYS, whereas in PD, the discharge rate of GPe neurons was lower than that of the GPi neurons. The discharge rate and pattern of GPe and GPi neurons in patients whose DYS was ameliorated by PVP were similar to those in DYS patients who did not benefit from PVP. No significant differences in the rate or pattern of neuronal discharge in patients with DYS of different causes were discernible. PVP was most beneficial in patients with primary genetic DYS. Anesthesia with desflurane depressed the discharge rate of the GPe and GPi neurons, particularly in patients with PD., Conclusion: Significant differences in the rates and patterns of discharge of GPe and GPi neurons exist in DYS and PD. The findings are discussed with reference to the current model of the functional connections of the basal ganglia.

The neurotoxin MPTP kills only certain midbrain dopaminergic (DA) neurons to produce a model of Parkinson's disease. The dopamine transporter (DAT) is important to MPTP toxicity because to be neurotoxic, an MPTP metabolite must first gain access to the DA neuron via the DAT. Also, MPTP is less toxic to DA neurons that contain the putative neuroprotective calcium-binding protein calbindin-D28k (CB). The present study examined the relative importance of DAT activity and CB for cellular vulnerability to MPTP-induced degeneration in the C57BL/6 mouse. Cells that were vulnerable to MPTP were found to contain high levels of DAT mRNA, whereas cells that were not vulnerable contained low levels. Also, the few substantia nigra cells remaining after a toxic dose of MPTP contained only low levels of DAT mRNA. However, there was not a strong relationship between cellular resistance to MPTP toxicity and cells containing CB. These data provide in vivo evidence for a direct correlation between midbrain cellular vulnerability to MPTP toxicity and the activity of the DAT.

Calbindin-D28k is a calcium-binding protein that protects nerve cells from degeneration. It is located in the midbrain dopaminergic neurons that are relatively invulnerable to degeneration in Parkinson's disease. Because the hypothalamic dopaminergic neurons do not degenerate in Parkinson's disease, the present study sought to determine whether these neurons also contain calbindin-D28k. Using immunocytochemical staining with antibodies against calbindin-D28k and tyrosine hydroxylase, and computer imaging techniques, the distributions of calbindin-D28k and tyrosine hydroxylase-containing neurons were mapped. Both neuronal populations were present throughout the rostral-caudal extent of the hypothalamus. However, only in the periventricular region, at the preoptic and anterior hypothalamic levels, was there an overlap in the two cellular distributions. Using the presence of neuromelanin pigment as a marker for dopaminergic neurons, approximately 30% of the dopaminergic neurons contain calbindin-D28k in the periventricular region. These data indicate that a sub-population of hypothalamic dopaminergic neurons contain calbindin-D28k. This finding is discussed in terms of why hypothalamic dopaminergic neurons are resistant to degeneration in Parkinson's disease.

The dopamine transporter (DAT) is the site at which the neurotoxic metabolite of MPTP gains access to midbrain dopaminergic (DA) neurons. However, not all midbrain DA neurons degenerate following MPTP treatment. The midbrain DA neurons that contain the calcium-binding protein, calbindin-D28k (CALB), are relatively invulnerable to MPTP toxicity, compared with DA neurons that lack CALB. Using in situ hybridization and immunocytochemical staining techniques in the rat and mouse, we now report that there is as much as 10 fold less DAT mRNA in regions where DA neurons contain CALB compared with regions where DA neurons lack CALB. These data suggest that specific midbrain DA neurons are invulnerable to MPTP toxicity not only because they contain CALB, but also because they have relatively low DAT activity.

Estrogen formation is catalyzed by the aromatase cytochrome P450 (P450AROM) enzyme. Aromatase activity has been detected in several regions in the rat brain. In the present study, we used peptide-generated polyclonal antibodies raised against a 20-amino acid synthetic fragment of the rat P450AROM protein (as deduced from the nucleic acid sequence of the rat P450AROM complementary DNA), to determine the location of this enzyme in rat brain sections. Immunoreactive antisera were titered by means of an enzyme-linked immunosorbent assay and purified by diethylaminoethyl-Affigel Blue chromatography. Specific immunoreactivity was confirmed by Western blot analysis using known aromatase-containing tissue (rat ovary homogenates and microsomal fractions). Evaluation of the distribution of P450AROM immunoreactivity in brain sections of male and female rats (30 and 60 days of age) was performed using the avidin biotin peroxidase immunocytochemical technique and light microscopy. P450AROM immunoreactivity appeared to be localized to neurons, and was present in brain regions and nuclei where enzymatic activity has been reported. For example, intense immunoreactivity was observed in the amygdaloid structures and supraoptic nucleus, whereas moderate to light immunoreactivity was evident in the paraventricular and arcuate nuclei and hippocampus. Surprisingly, neurons in the bed nucleus stria terminalis, medial basal hypothalamic, and preoptic areas displayed little aromatase immunoreactivity. However, P450AROM immunoreactivity was detected in specific brain regions not previously recognized to contain the enzyme (i.e. intense staining was seen in the reticular thalamic nucleus, olfactory tract and piriform cortex, as well as other brain structures). The pattern, distribution, and intensity of P450AROM immunoreactivity was similar regardless of sex or age. In this study, microsomal preparations derived from a new brain area (i.e. the reticular thalamic nucleus; Rt) displaying P450AROM immunoreactivity were observed to contain detectable levels of aromatase enzymatic activity, as determined by the 3H2O-release assay. The activity in the Rt was inhibited by a known aromatase inhibitor, 4-hydroxyandrostenedione. These results confirm histologically the localization of P450AROM to brain regions where aromatase enzymatic activity has been detected and extend the knowledge of its location to areas previously unknown as sites of aromatase activity, which may be involved in the modulation of neuroendocrine function and reproductive behavior.

Bilateral electrolytic lesions of the incertohypothalamic A13 dopamine (DA) system were made on the morning of proestrus in female rats with regular estrous cycles under ether anesthesia. Hourly blood samples were withdrawn, via a jugular catheter from conscious, freely moving rats, between 14.00 h and 18.00 h on the afternoon of proestrus. Plasma LH, FSH and prolactin levels were determined by RIA. The preovulatory surges of LH and prolactin were blocked in animals in which the A13 DA nucleus was destroyed by more than 70%. Levels of FSH were not significantly different from those of control of sham-lesioned groups. Lesions that were dorsal, ventral or caudal to the A13 DA systems did not affect the preovulatory surges of LH and prolactin whereas anterior lesions caused variable changes in the level of all three hormones. These data suggest that the A13 DA region may have a role in the control of the preovulatory surges of LH and prolactin.

In this study the effect of gonadectomy and steroid treatment on the dorsal component of the incertohypothalamic dopamine system or nucleus A13 was assessed by immunocytochemistry using an antibody raised to tyrosine hydroxylase (TH). A computer graphic system interfaced to a microscope was used to count and measure the diameters of TH-positive neurons and display the data in the three-dimensional space of the nucleus. In males, castration resulted in a dramatic decrease in the reaction product representative of TH. The number of TH-positive cells in the A13 DA nucleus decreased to 25% of intact levels. In females, ovariectomy also caused an impressive loss in the TH-immunostainable material, but this was not indicated by a change in the total number of TH-positive neurons. In both sexes the loss in TH immunostain was confined mainly to the mid-portion of the nucleus. Hormone treatment restored the TH immunostain (cell number and size) to and/or above intact levels in both sexes. These data suggest that A13 TH immunostain is stimulated by gonadal steroids in male and female rats.

High performance liquid chromatography with electrochemical detection and differential pulse voltammetry were used to provide a direct measurement of tissue content of dopamine and its metabolites and extracellular dopamine levels, respectively, in the striata of BALB/c and CBA inbred strains of mice. We found that levels of striatal dopamine and its metabolite, dihydroxyphenylacetic acid, were significantly higher in the CBA strain than in the BALB/c strain, whereas levels of homovanillic acid were not significantly different between the strains. Levels of the dopamine metabolite 3-methoxytyramine, on the other hand, were higher in the BALB/c mice. Dopamine turnover rates were significantly higher in the CBA strain when the homovanillic acid/dopamine ratio was used as an index of dopamine activity. Voltammetric recording showed that the local infusion of K+ in pargyline-treated mice resulted in the immediate appearance of a peak at +85 mV, which has been shown to correspond to extracellular dopamine in the rat. The mean height of this peak detected in vivo following K+ stimulation corresponds to in vitro dopamine concentrations of 25 +/- 8 microM for BALB/c mice and 7 +/- 2 microM for CBA mice. K(+)-stimulated dopamine release in the BALB/c mice could be evoked every 10-15 min with similar magnitude. In contrast, very little dopamine release in CBA mice could be evoked after the first stimulation. Since striatal dopamine levels are higher in CBA mice, these data suggest that (a) BALB/c strain may have more dopamine in the readily releasable pool, whereas the CBA mice have a larger storage pool of dopamine, and/or (b) that dopamine uptake in the CBA mice is much more avid than in BALB/c.

The effects of systemically administered ipsapirone, an aryl-piperazine compound, and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), on locus coeruleus (LC) noradrenergic activity was investigated. On an equimolar basis both ipsapirone and 1-PP were approximately equipotent in increasing LC neuronal activity. However, pretreatment with 1-PP caused a significantly greater parallel shift to the right of the dose response curve for the inhibitory action of the LC alpha 2-receptor agonist clonidine compared to ipsapirone. Biochemically, pretreatment with SKF 525A, a compound which prevents the formation of 1-PP from ipsapirone, diminished the ipsapirone-induced increase in MOPEG-SO4 levels in the brainstem and cortex. These data, together with the findings that 1-PP is more potent than ipsapirone in displacing 3H-clonidine from cerebral cortical membranes, suggest that the parent drug influences LC neuronal activity via the action of I-PP on LC alpha 2-adrenoceptors.

The present experiments were conducted to determine the electrophysiological and pharmacological properties of substantia nigra neurons in the mouse. These cells were studied using extracellular single unit recording and microiontophoretic techniques in both chloral hydrate anesthetized mice and in vitro mouse slices. In the in vivo preparation the substantia nigra zona compacta neurons had long duration action potentials (greater than 4 ms), fired from 1 to 7 impulses/s, and the cells discharged with either a decremental burst pattern or with a regular pattern. The dopamine agonists apomorphine and d-amphetamine, given systemically, decreased the firing rate of these neurons and the dopamine receptor blocker, haloperidol, reversed these effects. The zona compacta neurons were inhibited by the micro-iontophoretic application of dopamine and gamma-aminobutyric acid, and systemic haloperidol selectively attenuated the effects of dopamine. In vitro recordings from substantia nigra zona compacta and zona reticulata neurons were generally similar to those found in vivo, both in terms of the electrophysiological and pharmacological properties. However, the zona compacta cells fired faster in vitro than in vivo, and the firing pattern in vitro tended to be pacemaker-like, especially when recordings were made in an incubation medium which blocks synaptic transmission (e.g. low Ca2+/high Mg2+). Our data indicate that: (a) in vivo mouse zona compacta neurons exhibit the same electrophysiological and pharmacological properties as rat dopamine-containing neurons; (b) in vitro mouse dopaminergic neurons fire with pacemaker regularity when in a low Ca2+/high Mg2+ environment; and (c) in vitro studies offer an approach to examine the basic properties of dopaminergic neurons exclusive of feedback pathways and other afferent inputs.

Two theories have been put forth concerning the anxiolytic actions of the anti-anxiety drugs. One theory maintains that these drugs decrease locus coeruleus output, and the other maintains that they facilitate gamma-aminobutyric acid (GABA) neurotransmission at benzodiazepine (BZ)-linked GABA receptors. The BZ-anxiolytic diazepam does decrease locus coeruleus neuronal impulse flow. However, this decrease is not due to effects on BZ-linked GABA receptors in the locus coeruleus. Furthermore, the non-BZ anxiolytic buspirone, its metabolite and its analog all slightly increase locus coeruleus neuronal impulse flow. This increase, in the case of the metabolite, appears to be due, in part, to blockade of alpha 2-adrenoceptors. Finally, buspirone, unlike diazepam, did not potentiate GABA inhibition at BZ-linked GABA receptor sites (i.e. cerebellar Purkinje cells). These data suggest that the non-BZ anxiolytic buspirone produces its anti-anxiety effects by unconventional mechanisms.

Amfonelic acid (AFA), a potent non-amphetamine CNS stimulant, has been shown previously to have marked effects on dopamine (DA) metabolism and DA neuronal activity, but no effect on norepinephrine (NE) metabolism. AFA is known to inhibit the NE neuronal uptake mechanism. Other NE uptake inhibitors, such as desipramine (DMI), have been shown to decrease the firing rate of NE-containing locus coeruleus (LC) neurons. The purpose of the present study was to compare the actions of AFA and DMI electrophysiologically on LC neurons, and biochemically on NE metabolism in whg rate, with DMI being more potent. Brain NE metabolism was not influenced by either AFA or DMI at doses considerably higher than those which were effective in reducing NE neuronal impulse flow. Thus, NE uptake inhibition coupled with a decrease in impulse flow results in no net change in NE metabolite formation. The effects of AFA on LC unit activity do not seem to be due to its marked effects on brain DA, since DA receptor blockade with haloperidol had little effect on LC unit responsiveness to AFA (or amphetamine). Whereas AFA has dramatic effects on DA metabolism via enhanced release per impulse, the drug has minimal effects on NE metabolism, and this specificity of action may be related to differences in NE and DA transmitter storage mechanisms. It is concluded that the effects of AFA on NE neuronal firing rate are likely due to the drug's DMI-like action and not to enhanced NE release per impulse.

The effects of zoxazolamine (ZOX) and related centrally acting muscle relaxants on striatal dopamine (DA) metabolism and turnover, and substantia nigra zona compacta DA neuronal impulse flow were studied in rats. ZOX, chlorzoxazone and mephenesin, but not meprobamate, chloral hydrate, diazepam, pentobarbital, ethanol or dantrolene, decreased striatal DA metabolism without affecting striatal DA concentrations. More specifically, ZOX, as a representative muscle relaxant, was shown to decrease striatal DA turnover without directly affecting DA synthesis, catabolism, reuptake, or release. ZOX decreased nigral DA neuronal firing rates and dramatically decreased firing rate variability (normally many of the cells fire with bursting firing patterns but after ZOX the cells often fired with a very regular pacemaker-like firing pattern). ZOX and related centrally acting muscle relaxants appear to decrease striatal DA turnover by decreasing both neuronal firing rate and firing rate variability. The possible relationships between DA neuronal activity and muscle tone are discussed.

The present study compares the effects of d-amphetamine (d-AMP) and the potent non-amphetamine CNS stimulant, amfonelic acid (AFA), on the firing rate of single midbrain dopaminergic (DA) neurons and on neostriatal DA metabolism (dihydroxyphenylacetic acid--DOPAC). The results indicate that AFA, like d-AMP, reduces the firing rate of DA neurons, although unlike d-AMP, AFA does not cause a decrease in neostriatal DOPAC content and, in fact, enhances that produced by haloperidol (HALO). The AFA-induced decrease in firing rate, like d-AMP, is reversed by the DA receptor blocker HALO, but again unlike d-AMP, the decrease in firing rate is not prevented by catecholamine synthesis inhibition with alpha-methyl-para-tyrosine. Thus, both amphetamine and amfonelic acid have identical electrophysiological effects on DA neurons but act by different mechanisms.

Reserpine depletes dopamine (DA) levels and increases tyrosine hydroxylase (TH) activity in the rat corpus striatum. TH is activated not only by enhancement of DA neuronal impulse flow, but also by cessation of impulse flow. To assist in the understanding of the relative contribution of impulse flow to the regulation of TH activity in the DA depleted neuron, we examined the consequences of severe DA depletion on substantia nigra DA neuronal impulse flow and on in vivo TH activity in the rat corpus striatum. One day after reserpine or 30 min after the reversible reserpine-like compound, Ro4-1284, striatal DA levels were severely depleted and in vivo TH activity was enhanced about three-fold. DA depletion was found to significantly increase DA neuronal impulse flow. Although the DA neuron is firing faster than normal in the DA depleted rat, because there is no DA being released it is still not clear whether the elevation in TH activity is due to the enhancement of impulse flow or to the lack of DA at presynaptic receptor sites, or both. gamma-Butyrolactone (GBL), causes a cessation of DA neuronal impulse flow and activates TH by a presynaptic autoreceptor mechanism. GBL inhibited by over 50 percent the elevation in TH activity produced by severe DA depletion. This finding suggests that the enhanced TH activation after DA depletion in in large part due to increased DA impulse flow. Furthermore, the TH activity seen with GBL in DA depleted rats was significantly less than that seen after GBL administration in normal rats. This finding is consistent with the hypothesis that the DA storage granule also plays a role in TH regulation.

A13 incertohypothalamic dopamine (DA) neurons were labelled with antibodies raised to tyrosine hydroxylase in the male rat. Electrophysiologically, these neurons could be distinguished from their neighboring non-DA cells by their wide action potentials (greater than 2 ms), slow firing rates (0-3.8 impulses/s) and by the ability of iontophoresed DA and systemically administered apomorphine to inhibit impulse flow. Low doses of the antipsychotic drug haloperidol attenuated DA's response and reversed the apomorphine-inhibition of impulse flow.

Low doses of d-amphetamine (d-AMP) produced a 50% or greater decrease in the firing rates of both dopamine (DA) neurons (substantia nigra zone compacta) and norepinephrine (NE) neurons (locus coeruleus). However, pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MT) blocked the d-AMP-induced reduction in DA neuron firing rate, but had no effect on the d-AMP-induced reduction in NE cell firing rate. Similarly, alpha-MT administered subsequent to d-AMP readily reversed the d-AMP-induced decrease in the firing rates of DA cells, but caused no significant reversal in NE cell firing rates. These electrophysiological findings, in conjunction with biochemical and behavioral data, support the hypothesis that there is a difference in the DA and NE neurotransmitter storage mechanism. In the DA neuron, there appears to be a slow transfer between stored and readily-releasable (newly synthesized) amine pools so that, following synthesis inhibition, there is little DA available for release. However, in the NE neuron, there is a more rapid mobilization of stored amine to readily releasable sites, such that d-AMP continues to cause the release of NE even though synthesis of transmitter is blocked.

Differential pulse voltammetry (DPV) combined with carbon fibre electrodes allows selective detection of electroactive dopamine and serotonin metabolites in vivo. While usually employed in rats, we have now applied this in vivo technique in two inbred strains of mice: BALB/c and CBA. Three distinct oxidation peaks were recorded in vivo in the striatum of either BALB/c or CBA mice with a small shoulder occurring after the third peak at approximately +400 mV. Pargyline (150 mg/kg i.p.) potentiated this voltammetric shoulder into an easily measurable peak (Peak 4). In addition, Peak 4 was 2-3 times larger in BALB/c than in CBA mice. Homovanillic acid (HVA) and 3-methoxytyramine (3-MT), both catabolites of dopamine, oxidised at approximately +400 mV in vitro. Brain tissue levels of HVA and 3-MT, measured by high-performance liquid chromatography (HPLC) with electrochemical detection, demonstrated that pargyline treatment reduced striatal HVA, but increased 3-MT. These results support the view that Peak 4 recorded in the striatum of pargyline-treated mice in vivo is due to the oxidation of extracellular 3-MT. Thus, Peak 4 may be a useful index of dopamine release in situations where dopamine itself cannot be detected. Local infusion of KCl (2 microliters, 0.1 M) further increased the size of Peak 4 in the striatum of both BALB/c and CBA mice. However, the increase was approx. 3 times greater in BALB/c mice, supporting previous evidence of greater dopaminergic function of BALB/c compared with CBA mice. In addition these two inbred strains of mice provide model systems for investigating the comparative functional roles of nigrostriatal pathways.

The activity of neurones in the inferotemporal cortex of the alert rhesus monkey was recorded while the monkey was shown visual stimuli, which included both food and non-food objects for comparison with the activity of neurones in the lateral hypothalamus and substantia innominata. In the anteroventral part of the inferotemporal cortex, neurones were found with visual responses which were sustained while the animal looked at the appropriate visual stimuli. The latency of the responses was 100 msec or more. The majority (96/142 or 68%) of these neurones responded more strongly to some stimuli than to others. These units usually had different responses when objects were shown from different views, and physical factors such as shape, size, orientation, colour and texture appeared to account for the responses of some of these units. Association of visual stimuli with a food reward (glucose solution) or an aversive taste (5% saline solution) did not affect the magnitude of the responses of the neurones to the stimuli either during the learning or after the period of learning. Nor did feeding the monkey to satiety affect the responses of the neurones to their effective stimuli.

The Met-enkephalin content in tissue micropunches of the substantia nigra zona compacta, ventral tegmental area and the caudate nucleus in BALB/c and CBA mouse strains was measured by radioimmunoassay. The CBA strain had significantly higher Met-enkephalin levels in all 3 regions than the BALB/c strain. These differences should be taken into account when relating the intensity of dopamine-induced behaviors to the number of dopamine neurons.

It has been hypothesized that treatments which increase locus coeruleus (LC) noradrenergic neuronal activity produce anxiety, whereas treatments which decrease LC neuronal activity are anxiety-reducing. Although the benzodiazepine anxiolytic diazepam decreases LC neuronal impulse flow and norepinephrine metabolism, the non-benzodiazepine anxiolytic buspirone does the opposite. These data suggest that a reduction in LC output is not a necessary prerequisite for anxiolytic activity.

Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-5HT from the 5HT1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-5HT from both 5HT1a and 5HT1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.

To investigate whether the responses of neurones in the lateral hypothalamus and substantia innominata associated with the sight of food could control the responses of the hungry monkey to the food, the latency of activation of these neurones by food was measured. It was found that when an electromagnetically operated wide-aperture shutter opened to reveal food or non-food objects, these hypothalamic neurones responded with a latency of 150--200 msec to the food objects, and did not respond to the non-food objects. To measure the latency of the monkey's responses to the food, a visual discrimination task was set in which the monkey could lick a tube to obtain fruit juice if a food-realted visual stimulus was shown, but obtained hypertonic saline, which was aversive, if a different visual stimulus was shown. In this situation the typical latencies of the neuronal responses to the food were 150--200 msec, of the lick responses 350--500 msec, and of the EMG activity associated with these lick responses 250--400 msec. Thus the responses of these hypothalamic neurones precede the monkey's responses to the food, and could mediate the feeding and other responses of the animal to the food. It was also shown that a different population of hypothalamic neurones with responses associated with the sight of aversive visual stimuli had response latencies of 150--200 msec.