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P A Garris

Publications and source records attributed to P A Garris.

At least 19 recordsLinked to original sources
PubMed2001

Partial, graded losses of dopamine terminals in the rat caudate-putamen: an animal model for the study of compensatory adaptation in preclinical parkinsonism.

Procedures to lesion dopamine (DA) neurons innervating the rat caudate-putamen (CP) in a partial, graded fashion are described in this study. The goal is to provide a lesion model that supports intra-animal comparisons of voltammetric recordings used to investigate compensatory adaptation of DA neurotransmission. Lesions exploited the topography of mesostriatal DA neurons, microinjections of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial and lateral edges of the ventral mesencephalon containing DA cell bodies and microdissection of the CP into six regions. Analysis of tissue DA content in these regions by HPLC-EC demonstrated that 6-OHDA injected into the lateral substantia nigra results in a significantly greater loss of DA in lateral versus medial regions of the CP. The direction of the graded loss of DA was reversed (i.e. a medial to lateral lesion gradient) by the injection of 6-OHDA into the ventral tegmental area near the medial SN. Extracellular concentrations of electrically evoked DA could be measured across the mediolateral axis of the CP in a single animal using the technique of in vivo voltammetry. More importantly, graded decreases in the amplitude of evoked DA levels generally followed the direction of the tissue DA gradient in lesioned animals. These results suggest that the graded loss of DA terminals in the CP, coupled to a spatially and temporally resolved technique for monitoring extracellular DA, is a viable tool for investigating compensatory adaptation in the mesostriatal DA system.

Adrenergic Agents↗
PubMed1999

Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation.

Mesolimbic dopamine-releasing neurons appear to be important in the brain reward system. One behavioural paradigm that supports this hypothesis is intracranial self-stimulation (ICS), during which animals repeatedly press a lever to stimulate their own dopamine-releasing neurons electrically. Here we study dopamine release from dopamine terminals in the nucleus accumbens core and shell in the brain by using rapid-responding voltammetric microsensors during electrical stimulation of dopamine cell bodies in the ventral tegmental area/substantia nigra brain regions. In rats in which stimulating electrode placement failed to elicit dopamine release in the nucleus accumbens, ICS behaviour was not learned. In contrast, ICS was acquired when stimulus trains evoked extracellular dopamine in either the core or the shell of the nucleus accumbens. In animals that could learn ICS, experimenter-delivered stimulation always elicited dopamine release. In contrast, extracellular dopamine was rarely observed during ICS itself. Thus, although activation of mesolimbic dopamine-releasing neurons seems to be a necessary condition for ICS, evoked dopamine release is actually diminished during ICS. Dopamine may therefore be a neural substrate for novelty or reward expectation rather than reward itself.

Animals↗
PubMed1999

Utility of a tripolar stimulating electrode for eliciting dopamine release in the rat striatum.

The present study evaluated tripolar stimulating electrodes for eliciting dopamine release in the rat brain in vivo. Stimulating electrodes were placed either in the medial forebrain bundle or in the ventral mesencephalon associated with the ventral tegmental area and substantia nigra. The concentration of extracellular dopamine was monitored in dopamine terminal fields at 100-ms intervals using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. To characterize the stimulated area, recordings were collected in several striatal regions including the caudate putamen and the core and shell of the nucleus accumbens. The tripolar electrode was equally effective in stimulating dopamine release in medial and lateral regions of the striatum. In contrast, responses evoked by a bipolar electrode were typically greater in one mediolateral edge versus the other. The added size of the tripolar electrode did not appear to cause complications as signals were stable over the course of the experiment (3 h). Subsets of mesostriatal dopamine neurons could also be selectively activated using the tripolar electrode in excellent agreement with previously described topography. Taken together, these results suggested that the tripolar stimulating electrode is well suited for studying the regulation of midbrain dopamine neurons in vivo.

Animals↗
PubMed1997

Dopamine release and uptake rates both decrease in the partially denervated striatum in proportion to the loss of dopamine terminals.

The present study tested the hypothesis that normal concentrations of extracellular dopamine are preserved in the partially denervated striatum without active compensatory changes in dopamine uptake or release. One to four weeks after adult rats were unilaterally lesioned with 6-hydroxydopamine, fast-scan cyclic voltammetry at Nafion-coated, carbon-fiber microelectrodes was used to monitor extracellular dopamine levels in vivo, under urethane anesthesia. Simultaneous voltammetric recordings were collected in the lesioned and contralateral control striata. Extracellular dopamine was elicited by bilateral electrical stimulation of the medial forebrain bundle. A 20 Hz stimulation evoked similar concentrations of extracellular dopamine in both lesioned and control striata, although tissue dopamine was decreased 30-70% in lesioned striata, as determined subsequently by HPLC-EC. However, kinetic analysis of the voltammetric recordings revealed that the concentration of dopamine released per stimulus pulse and Vmax for dopamine uptake decreased in proportion to the magnitude of the lesion. These data support the hypothesis that normal extracellular dopamine levels can be generated in the partially lesioned striatum in the absence of active neuronal compensation. These results also suggest that passive mechanisms involved in the regulation of extracellular dopamine play an important role in maintaining function during the preclinical or presymptomatic phase of Parkinson's disease.

Animals↗
PubMed1997

Real-time measurement of electrically evoked extracellular dopamine in the striatum of freely moving rats.

The real-time measurement of electrically evoked dopamine was established in brain extracellular fluid of freely moving rats. Dopamine was monitored by fast-scan cyclic voltammetry at carbon fiber microelectrodes lowered into the striatum by means of a detachable micromanipulator. A stimulating electrode, previously implanted in the substantia nigra, was used to evoke striatal dopamine efflux. Evoked extracellular dopamine was both current and frequency dependent. When low current intensities (+/-125 microA) and frequencies (10-20 Hz) were applied, detectable levels of dopamine were elicited without a perceptible behavioral response. Reproducible concentrations of extracellular dopamine could be evoked in the same rat for at least 2 months. These concentrations, moreover, were significantly higher in freely moving rats compared with rats anesthetized with Equithesin. Analysis of measured curves for dopamine uptake and release rates revealed that anesthesia inhibits release but does not affect uptake. It is concluded that (a) fast-scan cyclic voltammetry at carbon fiber microelectrodes is a viable technique for the measurement of electrically evoked dopamine in brain extracellular fluid of freely moving rats, (b) it is possible to determine in situ rate constants for dopamine release and uptake from these temporally and spatially resolved measurements of levels of dopamine, and (c) transient changes in extracellular dopamine levels elicited by electrical stimulation are affected by anesthesia.

Anesthesia↗
PubMed1995

Distinct pharmacological regulation of evoked dopamine efflux in the amygdala and striatum of the rat in vivo.

The pharmacological regulation of evoked extracellular dopamine was compared in the basolateral amygdaloid nucleus (BAN) and caudate-putamen (CP) of the urethane-anesthetized rat. The effects of drugs, which alter dopamine uptake, release or degradation, were examined. Dopamine efflux was elicited by electrical stimulation of ascending dopamine fibers and was monitored by fast-scan cyclic voltammetry at Nafion-coated, carbon-fiber microelectrodes. Dopamine uptake inhibitors, nomifensine (25 mg/kg) and cocaine (20 mg/kg), and the dopamine receptor antagonist, haloperidol (0.5 mg/kg), robustly increased evoked extracellular dopamine in the CP. In sharp contrast, these drugs were much less effective in the BAN. The relative potencies of the uptake inhibitors varied between the two regions. Nomifensine was more potent than cocaine in the CP, whereas cocaine was more potent that nomifensine in the BAN. The monoamine oxidase inhibitor, pargyline (75 mg/kg), and the catechol-O-methyltransferase (COMT) inhibitor, Ro 40-7592 (40 mg/kg), had small or negligible effects in either region. No electrochemical evidence was found for the formation of 3-methoxytyramine, the dopamine metabolite formed by the action of COMT on released dopamine, on the time scale of the measurements in control or after pharmacological manipulation of the degradative enzymes for dopamine. The conclusions reached are: (1) potent mechanisms for uptake and autoreceptor inhibition of release, which exist in the CP to tightly control the concentration of extracellular dopamine, are considerably weaker in the BAN; (2) the extracellular clearance of evoked dopamine in the BAN and CP is the result of cellular uptake and not degradation; and (3) these results support the view that the pharmacological regulation of extracellular dopamine is regionally distinct in the brain.

Amygdala↗
PubMed1995

Comparison of dopamine uptake in the basolateral amygdaloid nucleus, caudate-putamen, and nucleus accumbens of the rat.

Regional differences in the kinetics and pharmacological inhibition of dopamine uptake were investigated with fast-scan cyclic voltammetry in both the intact rat brain and a brain slice preparation. The regions compared were the basolateral amygdaloid nucleus, caudate-putamen, and nucleus accumbens. The frequency dependence of dopamine efflux evoked in vivo by electrical stimulation of the medial forebrain bundle was evaluated by nonlinear curve fitting with a Michaelis-Menten-based kinetic model. The Km for dopamine uptake was found to be significantly higher in the basolateral amygdala (0.6 microM) than in the other two regions (0.2 microM), whereas the Vmax value for dopamine uptake in the basolateral amygdala was significantly lower (0.49 microM/s vs. 3.8 and 2.4 microM/s in the caudate and accumbens, respectively). Similar kinetics were also obtained in brain slices. Addition of a dopamine uptake inhibitor, cocaine or nomifensine (10 microM), to the perfusion buffer increased the apparent Km value > 25-fold in slices of both the caudate-putamen and nucleus accumbens. In contrast, neither uptake inhibitor had an observable effect in the basolateral amygdaloid nucleus. Thus, dopamine uptake in the rat brain is regionally distinct with regard to rate, affinity, and sensitivity to competitive inhibition.

Amygdala↗
PubMed1995

Different effects of cocaine and nomifensine on dopamine uptake in the caudate-putamen and nucleus accumbens.

The effects of cocaine and nomifensine on the uptake of dopamine have been compared in the caudate-putamen and nucleus accumbens of rat brain slices. Electrical stimulation of brain slices was used to evoke dopamine efflux and the changes in dopamine concentration in the extracellular fluid were monitored with fast-scan cyclic voltammetry with Nafion-coated, carbon-fiber electrodes. The disappearance of extracellular dopamine after the stimulation fit Michaelis-Menten kinetics in both regions. Cocaine and nomifensine were found to competitively inhibit dopamine uptake in both regions. The competitive mechanism of action was apparent in the primary data because the initial uptake rates were unchanged by low doses of inhibitor, but dopamine uptake was slowed at concentrations near the Km value. In both regions, the apparent Km value increased with higher concentrations of cocaine (0.01-60 microM) or nomifensine (0.01-30 microM) in the perfusion buffer. The apparent Km values were used to obtain inhibition constants (Ki values) for the uptake inhibitors in each region. This analysis showed that cocaine had a Ki of 0.29 microM in both regions. Nomifensine, however, had a significantly higher potency in the caudate-putamen (Ki = 0.09 microM) than in the nucleus accumbens (Ki = 0.21 microM). These results show that there are differential effects of uptake inhibitors in different brain regions, and suggest that the dopamine transporter exhibits cell-specific regulation.

Animals↗
PubMed1994

In vivo voltammetric measurement of evoked extracellular dopamine in the rat basolateral amygdaloid nucleus.

1. The in vivo measurement of evoked extracellular dopamine was established in the basolateral amygdaloid nucleus (BAN) using fast-scan cyclic voltammetry at carbon-fibre microelectrodes. 2. The identification of evoked extracellular dopamine in the BAN was based on anatomical, electrochemical and pharmacological criteria. Electrochemical and pharmacological evidence indicated that the species was a catecholamine. Mesencephalic sites eliciting overflow and amygdaloid sites supporting overflow correlated well with the mesoamygdaloid dopamine innervation. 3. Marked differences in the dynamics and magnitude of evoked dopamine overflow were observed in the BAN, caudate-putamen and amygdalo-striatal transition area. The results underscore the importance of making spatially resolved measurements of extracellular dopamine in the amygdala. 4. Mesoamygdaloid dopamine neurons have similar release characteristics as mesostriatal dopamine neurons but share with mesoprefrontal cortical dopamine neurons the ability to use a greater percentage of intraneuronal dopamine stores for release.

Amygdala↗
PubMed1994

Heterogeneity of evoked dopamine overflow within the striatal and striatoamygdaloid regions.

The heterogeneity of evoked dopamine overflow in vivo was examined and compared in striatal and striatoamygdaloid regions of the rat. The characteristics of appearance and disappearance rates and the maximum concentration elicited were determined from overflow curves measured by fast-scan cyclic voltammetry. Overall, the characteristics of evoked dopamine overflow were quite variable in the striatum compared to the relative uniformity of overflow in the basolateral amygdaloid nucleus. In addition, there was a significant decrease in the extracellular disappearance rate of evoked dopamine with depth in the striatum. This gradient did not alter with passage from the caudate-putamen to the nucleus accumbens and no change was observed for the appearance rate or maximum concentration. In contrast, differences in evoked dopamine overflow within the striatoamygdaloid region were sharply defined dorsoventrally and appeared to be region-specific. Dopamine terminal fields in the striatum are not clearly demarcated into the caudate-putamen and nucleus accumbens, but may exist as a continuum. The uptake of dopamine appears to be the distinguishing characteristic for the regulation of extracellular dopamine levels in the striatum and the basolateral amygdaloid nucleus.

Amygdala↗
PubMed1994

Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain.

Synaptic release of dopamine in the nucleus accumbens of the intact rat brain elicited by a single electrical impulse applied to ascending dopaminergic fibers results in extracellular concentrations sufficient to bind the known dopamine receptors. The dopamine concentration observed after four rapid, sequential pulses is exactly four times greater and is unaffected by pharmacological antagonism of dopamine uptake and receptor sites at supramaximal concentrations. Thus, dopamine efflux from the synaptic cleft is not restricted by binding to intrasynaptic proteins on the time scale of the measurements (50-100 msec). The extracellular concentration, as a result of a single stimulus pulse, is 0.25 microM and is rapidly removed by extrasynaptic uptake. This maximal, transient concentration of dopamine is 60 times higher than steady-state concentrations reported previously using dialysis techniques, illustrating that dopamine extracellular concentrations are spatially and temporally heterogenous. In contrast to ACh transmission at the neuromuscular junction, the dopamine synapse in the telencephalon is designed for the effective efflux of dopamine from the synaptic cleft to the extrasynaptic compartment during neurotransmission.

Animals↗
PubMed1994

Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study.

The regulation of extracellular dopamine (DA) concentrations was examined and compared in vivo in four projection fields of mesotelencephalic dopaminergic neurons with fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Transient electrical stimulation of ascending DA fibers in a near physiological range of frequencies (10-20 Hz) elicited similar levels of extracellular DA in the medial prefrontal cortex (MPFC), basal lateral amygdaloid nucleus (BAN), caudate-putamen (CP), and nucleus accumbens (NAc) despite the documented 90-fold disparity in DA tissue levels and terminal density. However, marked differences were observed in the dynamics and overall frequency dependence of the evoked synaptic overflow of DA. These differences are due to the significantly different rates of release and uptake found in each of the four regions. For example, rate constants for the release of the four regions. For example, rate constants for the release and uptake of DA were similar in the MPFC and BAN but approximately 8 and 50 times less, respectively, than that in the CP and NAc. When the parameters were normalized to endogenous DA tissue content, a unique picture emerged: compared to all other regions, relative release was 10-fold greater in the MPFC while relative uptake was at least 10 times less in the BAN. The results further differentiate the functional characteristics of mesotelencephalic dopaminergic systems and demonstrate the regiospecific nature of DA neural transmission in the brain. In addition, the regulation of extracellular DA levels in the MPFC and BAN is suitable for the "long-range" transfer of chemical information in the brain and is consistent with a hypothesis of extrasynaptic neurotransmission.

Amygdala↗
PubMed1993

A compartmentalized chamber for studying dopamine neurons in an hypothalamo-pituitary explant.

UNLABELLED: An in vitro technique was developed which could be used to study whole neurons of the tuberohypophyseal dopaminergic (THDA) tract. Explants containing the medial basal hypothalamus (MBH; THDA cell bodies), pituitary stalk (THDA axons) and posterior pituitary (PP; THDA nerve terminals) were carefully dissected and placed in specially designed chambers. The chambers consist of separate compartments for the incubation of the MBH and PP while maintaining an intact pituitary stalk which traverses through a notched barrier. Dopamine (DA) synthesis in the explants was constant for 3 h and was significantly elevated by electrical stimulation. Electrical stimulation of both the PP and MBH increased endogenous DA release from the PP. DA release in response to potassium depolarization and dopaminergic drugs was significantly lower in explants than in the isolated PP even though spontaneous release was similar. CONCLUSIONS: (1) this method is suitable for studying intact THDA neurons in vitro, and (2) intact THDA neurons respond differently to various stimuli than their excised terminals.

Animals↗
PubMed1993

Evoked extracellular dopamine in vivo in the medial prefrontal cortex.

The measurement of evoked extracellular dopamine in the medial prefrontal cortex by using fast-scan cyclic voltammetry with carbon-fiber microelectrodes was established and release characteristics of mesoprefrontal dopamine neurons were examined in vivo in anesthetized rats. Despite the sparse dopaminergic innervation and the presence of more dense noradrenergic and serotonergic innervations overall in the medial prefrontal cortex, the measurement of extracellular dopamine was achieved by selective recording in dopamine-rich terminal fields and selective activation of ascending dopamine neurons. This was confirmed by electrochemical, pharmacological, and anatomical evidence. An increased release capacity for mesoprefrontal dopamine neurons was also demonstrated by the slower decay of the evoked dopamine response after inhibition of catecholamine synthesis and the maintenance of the evoked dopamine response at higher levels in the medial prefrontal cortex compared with the striatum during supraphysiological stimulation.

Animals↗
PubMed1992

Regulation of transient dopamine concentration gradients in the microenvironment surrounding nerve terminals in the rat striatum.

Synaptic overflow of dopamine in the striatum has been investigated during electrical stimulation of the medial forebrain bundle in anesthetized rats. Dopamine has been detected with Nafion-coated, carbon-fiber electrodes used with fast-scan voltammetry. In accordance with previous results, dopamine synaptic overflow is a function of the stimulation frequency and the anatomical position of the carbon-fiber electrode. In some positions the concentration of dopamine is found to respond instantaneously to the stimulus when the time-delay for diffusion through the Nafion film is accounted for. In these locations the measured rates of change of dopamine are sufficiently rapid such that extracellular diffusion is not apparent. The rate of dopamine overflow can be described by a model in which each stimulus pulse causes instantaneous release, and cellular uptake decreases the concentration between stimulus pulses. Uptake is found to be described by a constant set of Michaelis-Menten kinetics at each location for concentrations of dopamine from 100 nM to 15 microM. The concentration of dopamine released per stimulus pulse is found to be greatest at low frequency (< or = 10 Hz) with stimulus trains, and with single-pulse stimulations in nomifensine-treated animals. The frequency dependence of release is not an effect of dopamine receptor activation; haloperidol (2.5 mg/kg) causes a uniform increase in release at all frequencies. The absence of diffusional effects in the measurement locations means that the constants determined with the electrode are those operant inside intact striatal tissue during stimulated overflow. These values are then extrapolated to the case where a single neuron fires alone. The extrapolation shows that while the transient concentration of dopamine may be high (200 nM) at the interface of the synapse and the extrasynaptic region, it is normally very low (< 6 nM) in the bulk of extracellular fluid.

Animals↗
PubMed1992

Effect of chronic haloperidol treatment on stimulated synaptic overflow of dopamine in the rat striatum.

In vivo voltammetry was used to assess the change in stimulated striatal dopamine overflow in response to various treatments with the dopamine receptor antagonist haloperidol. Dopamine overflow was induced with stimulating electrodes implanted in the medial forebrain bundle of anesthetized rats while dopamine concentrations were monitored with Nafion-coated, carbon-fiber microelectrodes implanted in the striatum. An acute challenge of haloperidol (0.5 mg kg-1, i.p.) given to naive animals caused stimulated overflow to increase at all stimulation frequencies (10-60 Hz), with the greatest change, 5-fold, occurring at 30 Hz. These results have been compared to those obtained in a different group of rats given daily injections of haloperidol (0.5 mg kg-1, s.c.) for 30 consecutive days. On the 30th day, dopamine striatal tissue levels and uptake kinetics were not altered by this treatment, but 3,4-dihydroxyphenylacetic acid tissue levels were elevated almost 2-fold. A challenge dose of haloperidol (0.5 mg kg-1, i.p.) administered to the animals treated with chronic haloperidol did not elicit a change in stimulated dopamine overflow. In two other groups, rats were withdrawn from 30-day haloperidol treatment for 3 days or 14 days before experimentation. Stimulated dopamine overflow concentrations in both groups were not significantly different from naive animals. When the withdrawn animals were given a haloperidol challenge (0.5 mg kg-1, i.p.), 15- and 12-fold increases in overflow for 3-day and 14-day withdrawal groups, respectively, were observed at a stimulation frequency of 30 Hz. Thus, chronic treatment with haloperidol induces long-lasting effects on the capacity of dopamine receptors to modulate dopamine release.

Animals↗
PubMed1991

Effects of reuptake inhibitors on dopamine release from the stalk-median eminence and posterior pituitary in vitro.

Similar to other dopaminergic systems, the dopaminergic neurons innervating the stalk-median eminence (SME) and posterior pituitary (PP) possess an uptake mechanism for dopamine (DA). However, the extent of DA reuptake in these tissues and its physiological significance are debated since much of the released DA is removed by the hypophysial portal vasculature before recapture. The objectives of this study were: (1) to establish in vitro conditions for examining the effects of reuptake inhibitors on DA release from the PP and SME; (2) to compare the effects of nomifensine, diclofensine and amphetamine on DA release from the SME and PP; and (3) to distinguish between reuptake and releasing properties of these drugs. Individual SME and PP were dissected from ovariectomized rats and incubated in either a static or perifusion system. Media DA was extracted with alumina and quantitated by high performance liquid chromatography with electrochemical detection. The reuptake inhibitors, nomifensine, dichlofensine and amphetamine, in the presence of pargyline, a monoamine oxidase inhibitor, stimulated both basal and K(+)-evoked release of DA from the SME and PP under static incubation conditions. The drugs elicited a 2-3-fold higher increase in basal DA release from the SME as compared to the PP. Only amphetamine stimulated DA release in the perifusion system whereas nomifensine and diclofensine were without effects. We concluded that: (1) a mechanism for the reuptake of DA is operable in both the SME and PP; (2) the reuptake of DA appears to be more active in the SME than the PP; and (3) unlike amphetamine, nomifensine and diclofensine are pure reuptake inhibitors devoid of direct DA releasing activities.

Amphetamine↗