Electrochemical Recordings Research Articles

Medial Dorsal Striatum Is More Sensitive Than Lateral Dorsal Striatum to Cocaine Inhibition of Exogenous Dopamine Clearance: Relation to [ 3H]Mazindol Binding, but Not Striosome/Matrix

Previous studies have shown that acute systemic cocaine inhibits dopamine (DA) transport and thereby produces dose-dependent changes in exogenous DA clearance in the brain. This measure reflects the dynamic activity of the DA transporter. There are also differential effects of cocaine on DA clearance in dorsal and ventral striatum, and evidence from many studies suggests that even within the dorsal striatum, the interaction of cocaine with the DA transporter may not be homogeneous. A greater understanding of how cocaine interacts with the striatal DA transporter will help clarify the role of the striatum in mediating effects of cocaine. In these studies we used in vivo electrochemical recording to examine the effect of ip cocaine on exogenous DA clearance in the medial and lateral dorsal striatum with respect to both DA transporter binding sites and electrode localization to striosomes or matrix. Baseline exogenous DA clearance was different in medial and lateral dorsal striatum in the absence of cocaine. Systemic cocaine produced a more pronounced inhibition of DA clearance in medial dorsal striatum than in lateral dorsal striatum. [ 3H]Mazindol binding to DA transporters was lower in medial dorsal striatum, but was not in register with striosome or matrix compartments. There was no notable difference between cocaine's effects on DA clearance in striosome or matrix that was due to this compartmentalization. Others have demonstrated that medial dorsal striatum receives proportionally more innervation from the mesolimbic, as opposed to the nigrostriatal, DA system. Taken together, these and previous in vivo results suggest that this differential sensitivity to cocaine reflects the unique properties of the ascending mesolimbic DA projection and the lower density of DA transporters associated with it.

Neurobiological correlates of masculine sexual behavior

The experimental analysis of the neuroendocrine interactions regulating sexual behavior has traditionally relied on studying the effects of CNS lesions and pharmacological treatments with hormones or drugs purportedly acting through specific neurotransmitter systems. New methodological developments have allowed the assessment of several indices of neural function in experimental animals, particularly the rat, as they relate to behavioral changes. In the field of sexual behavior, ex vivo analyses have been used to measure markers of energy metabolism, such as 2-deoxyglucose uptake and Na,K-ATPase activity, the tissue content of neurotransmitters and metabolites, the levels of steroid receptors and neurosteroids, and immediate-early gene expression products in different areas of the CNS. In vivo studies have monitored brain electrical activity and temperature, as well as the extracellular levels of neurotransmitters and metabolites by cerebrospinal fluid sampling, push-pull perfusion and, especially, electrochemical recordings and microdialysis, in the course of mating and exposure to various relevant stimuli. The findings with the different methodologies are generally consistent and agree with those of previous surgical and pharmacological manipulations. They provide data on temporal relationships between neurobiological and behavioral events and suggest new interpretations for different aspects of the male copulatory pattern.

Evidence that activation of the hypothalamo-pituitary-adrenal axis by electrical stimulation of the noradrenergic A1 group is not mediated by noradrenaline.

The paraventricular nucleus (PVN) of the hypothalamus, where the CRF-containing neurosecretory cells controlling the hypothalamo-pituitary-adrenal (HPA) axis are located, receives a dense noradrenergic innervation from the A1 group of the caudal ventrolateral medulla. In the present study we studied the relationship between release of noradrenaline (NA) in the PVN and activation of the HPA axis in response to electrical stimulation of the A1 region. In the urethane-anesthetized male rat, extracellular NA in the PVN was monitored on line by electrochemical recording while the activity of the HPA axis was estimated by measurement of ACTH in blood samples. A 1 min, 10 Hz stimulation evoked a significant increase of extracellular NA in the PVN as well as an ACTH surge in blood. The NA and ACTH response evoked by stimulation in the 3- to 14-Hz range were found to be frequency dependent. However, whilst the NA response increased in an exponential manner with respect to frequency, the ACTH response appeared to plateau between 10 and 14 Hz. Specific lesions of the noradrenergic terminals in the PVN, by bilateral local administration of 6-hydroxydopamine, markedly reduced the ACTH response to stimulation. Intracerebroventricular injection of desmethylimipramine, a NA uptake inhibitor, enhanced the increase in extracellular NA evoked by submaximal stimulation about 2.5-fold but did not modify the corresponding ACTH response. Combined intracerebroventricular injection of alpha- and beta-adrenergic antagonists, phentolamine and propanolol respectively, did not prevent the ACTH response evoked by stimulation. Following stimulation of the caudal ventrolateral medulla, the ACTH response thus appears to result from the stimulation of the A1 noradrenergic group projecting to the PVN. However, the inability of pharmacological manipulations which enhance or block central noradrenergic transmission to influence the ACTH response suggests that the noradrenergic endings in the PVN originating from the A1 group use a transmitter other than NA to activate the HPA axis at the PVN level.

Reduced Clearance of Exogenous Dopamine in Rat Nucleus Accumbens, but Not in Dorsal Striatum, Following Cocaine Challenge in Rats Withdrawn from Repeated Cocaine Administration

We investigated whether changes in the dopamine transporter in the nucleus accumbens or striatum are involved in cocaine-induced behavioral sensitization by using in vivo electrochemistry to monitor the clearance of locally applied dopamine in anesthetized rats. Rats were injected with cocaine-HCl (10 mg/kg i.p.) or saline daily for 7 consecutive days and then withdrawn for 7 days. Pressure ejection of a finite amount of dopamine at 5-min intervals from a micropipette adjacent to the electrochemical recording electrode produced transient and reproducible dopamine signals. After a challenge injection of cocaine (10 mg/kg i.p.), the signals in the nucleus accumbens of cocaine-treated animals became prolonged and the clearance rate of the dopamine decreased, indicating significant inhibition of the dopamine transporter. In contrast, simultaneous measurements in the dorsal striatum indicated a transient increase in both the amplitude of the signals and the clearance rate of the dopamine. The signals in both brain regions in the saline-treated animals given the cocaine challenge were similar to those in untreated animals given an acute injection of cocaine (10 mg/kg i.p.) or saline. Behaviorally, not all of the cocaine-treated animals were sensitized; however, both sensitized and nonsensitized animals displayed similar changes in dopamine clearance rate. Quantitative autoradiography with [3H]mazindol revealed that the affinity of the dopamine transporter for cocaine and the density of binding sites were similar in cocaine- and saline-treated rats. The decrease in dopamine clearance rate observed in the nucleus accumbens of the cocaine-treated rats after a challenge injection of cocaine is consistent with increased dopaminergic transmission, but does not appear to be sufficient in itself for producing behavioral sensitization.

Human fetal xenografts of brainstem tissue containing locus coeruleus neurons: Functional and structural studies of intraocular grafts in athymic nude rats

Fetal human brainstem tissue including the nucleus locus coeruleus was transplanted to the anterior eye chamber of athymic nude rats. Most transplants survived and grew in the anterior chamber of the eye. After 9–15 months, the host animals were anesthetized and electrophysiological or in vivo electrochemical recordings were performed. The brainstem transplants contained spontaneously active neurons with regular single-spike firing patterns. The neurons responded to ipsilateral light stimulation with an increase in firing rate and to the α 2-receptor agonist clonidine with significantly decreased firing rates. In vivo electrochemical studies demonstrated reproducible noradrenergic overflow after local application of potassium. Immunohistochemical evaluation of the brainstem transplants showed an abundance of tyrosine hydroxylase-positive neurons and neurites in all transplants and a dense network of neurofilament-, synapsin-, and glial fibrillary acidic protein-positive profiles throughout the grafts. Taken together, the present physiological and histochemical data indicate that it is possible to obtain transplants containing a specific monoaminergic population within the brainstem from human fetal fragments and to maintain these transplants in oculo in athymic nude rats for at least 15 months, during which time noradrenergic neurons develop.

Regional effects of aging on dopaminergic function in the Fischer-344 rat

To examine the consequences of aging on nigrostriatal (A9) and mesolimbic (A 10) dopamine (DA) function, neurochemical and behavioral measurements were performed in male Fischer-344 rats 6, 12, 18, 24, and 30 months old. Regional analyses of dopaminergic overflow and uptake processes were examined using high-speed (5 Hz) in vivo electrochemical recordings and local drug application techniques. When potassium was used to elicit the presynaptic overflow of dopamine (DA) in striatal areas predominantly innervated by the substantia nigra, the amplitude of DA overflow was significantly lower in 24- and 30-month-old rats ( p < 0.05 and p < 0.01 vs. 6 months, respectively). Furthermore, in ventral striatum (including the nucleus accumbens) which is innervated primarily by A 10 DA cell bodies, potassium-evoked DA overflow release amplitudes were significantly lower in the 18, 24, and 30 month groups ( p < 0.01 vs. 6 months). In addition, age-related differences between the dorsal and ventral striatum were found in a preliminary investigation of DA diffusion and clearance. Local application of nomifensine, a DA uptake inhibitor, significantly increased ( p < 0.05 vs. control) the amplitude of the signal recorded after local application of 25–30 pmol DA in the ventral striatum of 6 month-old but not 24-month-old rats. High-performance liquid chromatography coupled with electrochemical detection (HPLC-EC) was used to analyze whole striatal DA levels, DA metabolite levels and turnover indices. However, no age-related differences in any of these variables were observed. Finally, a rod walking test was used to measure motor coordination and balance in animals prior to in vivo electrochemical recording. Rats in the 24- and 30-month-old age groups were found to be impaired in this task. In summary, this study identified regional age-dependent changes in presynaptic DA overflow and uptake.

In vivo electrochemical studies of dopamine diffusion and clearance in the striatum of young and aged Fischer-344 rats

Dopaminergic neurons are vulnerable to the degenerative effects of the aging process. Age-dependent functional changes which occur in nigrostriatal and mesolimbic DA pathways may decrease the ability of these systems to effectively communicate with postsynaptic targets, thereby impairing the normal flow of motor information through the basal ganglia. In order to overcome these effects, the brain relies on homeostatic mechanisms which act to balance neurochemical changes. In this study we have tested the hypothesis that dopamine neurons compensate for age-related decreases in depolarization-induced transmitter overflow by altering the rate of DA clearance from the extracellular space. The diffusion and clearance of DA was directly measured in urethane anesthetized Fischer 344 rats using high-speed (5 Hz) in vivo electrochemical recordings and local drug application techniques. The results show that aged rats (24 and 30 months old) are as effective in removing exogenously applied dopamine from the striatum as young rats (6 months old). However, the uptake sites in the aged animals were less responsive to nomifensine, a competitive inhibitor of DA uptake. This drug did not modulate the amplitude of DA signals in the dorsal striatum of 30-month-old rats nor in the ventral striatum of 24-and 30-month-old rats. We can conclude that there are changes in the high affinity uptake carrier based on the different pharmacological actions of nomifensine in the young and aged striatum. If this is the case, then more studies are necessary to determine if drugs used in the treatment of depression (which have the same mechanism of action as nomifensine) are less effective in elderly patients. This research may also lead to the understanding of mechanisms which compensate for age-related deficits in chemical signalling.

Electrically-evoked release of norepinephrine in the rat cerebellum: an in vivo electrochemical and electrophysiological study

Norepinephine (NE) release from the locus coeruleus (LC) afferents to the cerebellar cortex of urethane anethetized rats was achieved by electrical stimulation of the locus coeruleus or by local administration of potassium into the cerebellum. Both methods evoked an overflow of NE-like electroactive species. Electrically-evoked and potassium-induced overflow of NE-like responses were found to be reversible and reproducible. Releases were not observed in cerebellar white matter, an area which is relatively devoid of monoamine containing terminals. Systemic administration of desipramine, a potent and selective norepinephrine re-uptake blocker, significantly augmented the electrically-evoked electrochemical responses. Measurements of evoked release tajen using high-speed chronoamperometry support the idea that a predominant contributor to electrically-induced signals was NE. Electrophysiological recordings of single Purkinje cells were performed with the same Nafion-coated single carbon fiber electrodes used for electrochemical recordings. Electrical stimulation of the LC was seen to depress Purkinje cell firing rates; an increase in electroactive species was detected at the same site that paralleled the time course of the electrophysiological response. These studies provide further direct evidence that the LC norepinephrine-containing cells have a direct inhibitory effect on Purkinje cells in the cerebellum, and that both pre- and postsynaptic events can be measured with the same recording sensor.

Electrochemical characterization of stimulated norepinephrine overflow in locus coeruleus-hippocampus double brain grafts grown in oculo

Rat locus coeruleus-hippocampus double in oculo brain grafts were studied with high-speed electrochemical techniques to characterize stimulus-evoked overflow of norepinephrine. Local pressure ejections of KC1 into the locus coeruleus (LC) portion of the double graft elicited electrochemical signals in the hippocampal portion that had NE-like reduction/oxidation current ratios. In contrast, electrical stimulation of the LC part of the double graft did not lead to consistently detectable signals in the hippocampal portion of the transplant. These data demonstrate that LC graft neurons are able to release NE in target tissues when stimulated in an appropriate manner, and that the time course and magnitude of the overflow of NE can be detected with sensitive high-speed electrochemical recording techniques.

The effects of cholecystokinin (CCK-8) on dopamine-containing nerve terminals in the caudate nucleus and nucleus accumbens of the anesthetized rat: an in vivo electrochemical study

The action of cholecystokinin (CCK) on presynaptic function of dopaminergic nerve terminals has been the subject of much debate in the literature. In efforts to resolve some of the reported ambiguities, high speed in vivo electrochemical recordings were carried out in the caudate nucleus and nucleus accumbens of the urethane anesthetized rat, to determine effects of locally applied sulfated (CCK-8S) and unsulfated (CCK-8US) CCK octapeptide. Locally-applied CCK-8S and CCK-8US caused no increase in the baseline electrochemical signals recorded from either brain region. However, locally applied CCK-8S potentiated the potassium-evoked overflow of dopamine (DA) into the extracellular space in both the caudate and nucleus accumbens. In contrast, pressure ejection of CCK-8US produced no significant effects on the potassium-evoked overflow of DA in either structure. These data support a facilitatory effect of CCK-8S on potassium-evoked overflow from DA-containing nerve terminals in the urethane anesthetized rat that is likely mediated through a peripheral type CCK receptor.

Changes in neurotransmitter turnover in locus coeruleus produced by changes in arterial blood pressure

The effect of drug-induced hypertension and hypotension on neurotransmitter metabolism in the locus coeruleus (LC) of urathen anesthetized rats ws studied using in vivo electrochemical methods. Peaks were seen at +0.15 V and +0.28 V. Studies with alpha-methylparatyrosine, fusaric acid and pargyline showed the first peak was produced by extracellular fluid dihydroxyphenylacetic acid (DOPAC) while the second peak was 5-hydroxyindoleacetic acid (5-HIAA). Phenylephrine was infused intravenously to raise the blood pressure by 50 mmHg, nitroprusside IV was used to reduce the blood pressure by 20 mmHg. During phenylephrine hypertension, the electrochemical signal for DOPAC showed an initial small reduction followed by a later significant increase which persisted even after the infusion was stopped. The signal for 5-HIAA rose with the onset of hypertension and remained elevated. Nitroprusside hypotension did not change the DOPAC peak but did lead to an immediate and persistent increase in the electrochemical 5-HIAA peak. To confirm the electrochemical findings, other groups of rats were decapitated during and after hypertensive and hypotensive drug infusions and the LC was assayed for norepinephrine, dopamine, DOPAC, serotonin, and 5-HIAA using HPLC with electrochemical detection. Changes in tissue DOPAC and 5-HIAA concentrations supported the electrochemical electrode observations. The effect of clonidine on the electrochemical recordings from LC was also studied. Clonidine reduced the catechol peak. No change was observed in the 5-HIAA peak during the infusion, but the 5-HIAA peak went up after the infusion was stopped. These experiments show that hypertension, hypotension, and alpha-2 agonists lead to changes in catecholamine and indoleamine metabolism in LC.

Baroreflex-linked variations of catecholamine metabolism in the caudal ventrolateral medulla: an in vivo electrochemical study

In vivo electrochemical recordings of the metabolism of catecholamines were obtained in the caudal ventrolateral medulla in anesthetized rats submitted to various experimental changes in systemic arterial pressure. Hypertension induced with phenylephrine and reversal of hypovolemia decreased the catechol metabolic activity. In contrast, controlled or hypovolemic hypotension, induced respectively with sodium nitroprusside or blood withdrawal (30% of blood volume), reversibly elicited the opposite pattern. This was suppressed by deafferentation. The changes in 3atechol metabolic activity in response to hypovolemia were accompanied by similar trends of variations of plasma vasopressin levels. By contrast with the increased catechol metabolic activity secondary to hypotension induced by either prazosin, sodium nitroprusside or hypovolemia, clonidine elicited a decrease in catechol metabolic activity. These data show a dynamic and specific involvement of the metabolism of catecholamines themselves promoted by changes in systemic arterial pressure. This pattern of functioning of catechol metabolism in the caudal ventrolateral medulla appears to be negatively related to systemic arterial pressure changes, a finding which does not fit with the proposed vasodpressor role of the A1-group.

Nucleus tractus solitarus: An evaluation by [formula omitted] voltammetry

Nucleus tractus solitarius (NIS) is a brainstem nucleus known to play an important role in baroreceptor mediated cardiovascular regulation. As part of our study of the role of monoamines in the function of NTS, we have characterized pharmacologically the in vivo electrochemical signal recorded from the nucleus using carbon paste electrodes and linear sweep voltammetry with semiderivative signal processing in awake, freely moving rats. Two peaks were recorded by these techniques, one at 0.14 V and a second at 0.28 V. The tyrosine hydroxylase inhibitor α-methyl-p-tyrosine led to a significant reduction in the peak recorded at 0.14 V whereas it had no effect on the higher potential peal at 0.28 V. The dopamine-β-hydroxylase inhibitor fusaric acid resulted in a large reduction in the 0.14 V peak and led to a 30% increase in the 0.28 V peak height. Pargyline, a monoamine oxidase inhibitor, did not change the low potential peak but did significantly reduce the 0.28 V peak. Tissue assays provided further support for the interpretation of in vivo electrochemical recordings. Norepinephrine concentration was reduced with fusaric acid. Tissue serotonin was not affected by any of the drugs while the 5-HIAA content was increased with fusaric acid and reduced with pargyline. These experimental findings lead to the conclusion that the first peak in the voltammogram most likely represents norepinephrine with a possible contribution by dopamine but not by DOPAC. The second peak appears to be 5-HIAA.

In vivo electrochemical demonstration of potassium-evoked monoamine release from rat cerebellum

In vivo electrochemical methods were employed to study the potassium (K +-evoked release of monoamines from the cerebellum of the chloral hydrate anesthetized rat. K +-evoked releases were elicited using micropipette-Nafion-coated graphite epoxy electrode arrays in the granule/Purkenje cell layer, molecular layer, and white matter. These recorded releases were generally found to be reversible, moderately dose-dependent, and reproducible. However, the temporal dynamics of the releases were different for the cell layer versus molecular layer records. Releases were infrequently observed in cerebellar white matter, an area which is relatively devoid of monoamine containing terminals. The signals recorded from the cell and molecular layers were significantly attenuated by pretreatment with nomifensine, a potent catecholamine reuptake blocker, significantly prolonged the K +-evoked signals observed in both the granule/Purkenje cell and molecular layers. These data, taken together with earlier reports on the electrophysiological responses to activation of cerebellar noradrenergic inputs, support the conjecture that in vivo electrochemical recording methods have the sensitivity and spatial resolution for studies of functional monoamine release from brain regions that have a diffuse or laminated monoamine innervation.

Formula omitted][formula omitted] electrochemical recording of acetaminophen in non human primate brain

In vivo electrochemical recordings were obtained from the caudate nucleus of three young adult pigtail monkeys ( M. nemestrina ) following the oral administration of acetaminophen (APAP) (75 mg/kg). Using linear sweep voltammetry, electrodes in the right and left caudate were scanned alternately every five minutes. The electrochemical peak resulting from the APAP was monitored for at least 140 minutes following drug administration. Maximum APAP levels were detected in the monkey caudate 40 minutes following drug administration. Both right and left caudate displayed an identical time course, with oxidation potentials (E ox) similar on both sides of the brain. Blood samples were collected from one monkey by means of an intravenous catheter. Samples were obtained at approximately 5-minute intervals and over a period of 140 minutes following oral administration of APAP. Concentration of APAP in serum peaked 25 minutes after administration. In this animal the maximum electrochemical peak height was detected 40 minutes following APAP administration. These findings demonstrate the ability to measure APAP in the caudate nucleus of awake monkeys by means of electrochemical detection. This method may be useful for calibrating electrochemical electrodes in vivo , and it also provides a model system for studying drug kinetics in the brain.

Variations in 3,4-dihydroxyphenylacetic acid concentration are correlated to single cell firing changes in the rat locus coeruleus

The purpose of this study is to see whether variations in the catechol oxidation peak in the locus coeruleus would be closely related with variations in single cell firing, and would be independent of the mechanism triggering the variation of neuronal activity. Single unit and electrochemical (differential pulse voltammetry) recordings were performed, respectively on the left and right locus coeruleus of anaesthetized rats. The variations in single unit activity were induced using well known stimulatory mechanisms (yohimbine, hypovolemia, indirect activation using a 5-hydroxytryptamine central agonist RU 24969, RU 24722 known to activate noradrenergic metabolism), or inhibitory (clonidine, morphine) models. This was done in addition to successive activation or inhibition (reversal of oxotremorine with scopolamine, antagonism of clonidine by piperoxane). In all the experimental conditions, variations in the catechol oxidation current followed variations in single cell activity. Furthermore, the catechol oxidation current variations correlated significantly to changes in the firing rate. Such a close correlation between a catechol oxidation peak, and the electrical activity of the locus coeruleus cell bodies supports the use of catechol oxidation current variations as a good indirect index of functional activity in noradrenergic locus coeruleus perikarya. This suggests a close relationship between dopamine metabolism and electrical activity in locus coeruleus cell bodies.

Catecholamine metabolism in the rat locus coeruleus as studied by in vivo differential pulse voltammetry. III. Evidence for the existence of an α2-adrenergic tonic inhibition in behaving rats

One of the various regulations controlling the noradrenergic (NA) locus coeruleus (LC) activity has been proved to be α 2 adrenergic specific, on the basis of electrophysiological data obtained in anesthetized preparations. To assess, under rigorously chronic conditions, the existence of such an inhibition, recordings of LC catechol metabolic activity were performed with in vivo differential pulse voltammetry. A guiding cannula and appropriate wires were implanted under anesthesia. After 48 h of recovery a carbon fiber electrode was threaded to the LC through this cannula to monitor the LC catechol oxidation current. Piperoxane 60 mg/kg i.p. and yohimbine 10 mg/kg i.p. induced an increase in catechol oxidation current to approximately 300% of baseline (100%) values. Graded doses of piperoxane (1–100 mg/kg i.p.) induced a dose dependent increase in LC catechol metabolic activity (ED 50 = 29.7mg/kg). These changes in catechol oxidation current were confirmed either by combined electrophysiological and electrochemical recordings in the LC of an anesthetized preparation, or by postmortem HPLC catechol determinations on LC microdissections. By contrast, guanfacine 1 mg/kg and clonidine (10–200 μg/kg i.p.) induced a dose dependent decrease in catechol peak height. Clonidine 50 μg/kg reversed the effect of piperoxane 30 mg/kg i.p. On the other hand, a highly selective α 1 antagonist, such as prazosin (1 mg/kg i.p.), evoked only a small increase in catechol peak (11% above saline effect). This data is consistent with previously reported electrophysiological, biochemical and autoradiographic data. They confirm the presence of a tonic α 2 adrenergic inhibition on NA-LC cell activity, in behaving rats.

Intracerebral injection of ascorbate oxidase - effect on in vivo electrochemical recordings

The electrochemical oxidation peak of ascorbic acid in vitro, recorded using differential pulse voltammetry, was abolished by addition of the enzyme ascorbate oxidase while it had no effect on the dopamine or DOPAC oxidation peaks. Micro-infusion of the enzyme into the striatum or nucleus accumbens selectively reduced an oxidation peak recorded in vivo at between +0.22 and +0.24 V, but did not alter a peak recorded at about +0.35 V. The results suggest ascorbate oxidase should be a useful tool for the intracerebral manipulation of ascorbic acid.

Behavioral observation and intracerebral electrochemical recording following administration of amphetamine in rats

Intracerebral electrochemistry (chronoamperometry) was performed on rats that were administered 1, 4, and 8 mg/kg doses of amphetamine. Graphpoxy working electrodes were implanted bilaterally in nucleus accumbens (ACC) and ventral anterior striatum (VAS). Following drug injection, locomotor and stereotyped behaviors were observed. Intracerebral electrochemical signals reliably increased following injection of amphetamine. The magnitude of these increases did not change significantly across the dose range tested for VAS electrodes. ACC electrodes had increases similar in magnitude to VAS electrodes at 1 and 4 mg/kg. At 8 mg/kg increases obtained from ACC electrodes were significantly lower than those recorded from VAS. Onset of the change in electrochemical signal paralleled the onset of activity or stereotypy but the subsequent declines in signal and behavior were only loosely correlated. At the 4 mg/kg dose, the magnitude of signal increase from striatum was negatively correlated with indices of stereotypy and positively correlated with locomotor counts.

Involvement of 5-hydroxytryptamine and dopamine neurones in the behavioural effects of α-methylytryptamine

α-Methyltryptamine (10 mg/kg) produced a two-phased behavioural response in the rat. The first phase consisted of responses such as hind limb abduction, forepaw treading, lateral head weaving and Straub tail and lasted up to 90 min. The second phase of the behavioural response lasted up to 4 hr and consisted of marked running and exploratory activity. p-Chlorophenylalanine (150 mg/kg), which depletes brain 5-hydroxytryptamine, prevented both phases of the behavioural response. α-Flupenthixol (0.4 mg/kg) a dopamine receptor antagonist also attenuated both phases of the response. Metergoline (2 mg/kg), a 5-hydroxytryptamine receptor antagonist, abolished the initial phase of the response but had no effect on the second phase and the animals showed well co-ordinated exploratory behaviour throughout the experimental period. Fluoxetine (10 mg/kg), which probably inhibited the uptake of α-methyltryptamine into 5-hydroxytryptamine neurones, prevented the initial response and reduced the second phase. Pimozide (0.3 mg/kg), another dopamine receptor anatgonist, had no effect on the first part of the response but significantly reduced the second exploratory phase. There was no significant change in brain 5-hydroxytryptamine and 5-hydroxyindoleaetic acid during the time course of the initial behavioural response. In vivo electrochemical recordings, from the striatum and hippocampus, indicated an increase in extraneuronal amine, probably mainly 5-hydroxytryptamine, during the initial phase. The results indicate that the initial behavioural response is primarily due to a pre-synaptic action of α-methyltryptamine on 5-hydroxytryptamine neurones but with the participation of dopamine neurones. The second phase involved more general stimulation of dopamine neurones, but an intact 5-hydroxytryptamine neuronal system appears essential.