Biomedical subjects

P A Broderick

Publications and source records attributed to P A Broderick.

At least 19 recordsLinked to original sources

PubMed2001

Biogenic amines in the human neocortex in patients with neocortical and mesial temporal lobe epilepsy: identification with in situ microvoltammetry.

Biogenic amines in well defined subtypes of human temporal lobe epilepsy (TLE) have not been well characterized. Specimens from five patients with neocortical TLE (NTLE) and nine with mesial TLE (MTLE) were immediately placed in Ringer's lactate; stearate indicator microelectrodes were placed in temporal gray matter, Ag/AgCl reference microelectrodes and auxiliary microelectrodes were placed 3-7 mm contralaterally to the indicator microelectrode. Dopamine (DA), ascorbic acid (AA), norepinephrine (NE) and serotonin (5-HT) were identified by their characteristic oxidative potentials in vitro. Four of five patients with NTLE had NE depletion in temporal neocortex while eight of nine patients with MTLE had high concentrations of NE (chi-square P<0.01). Significant concentrations of DA were present in the temporal lobes of three of five NTLE patients but in only one of the nine MTLE patients (chi-square P<0.05). 5-HT was present in the neocortex of both NTLE and MTLE patients in similar concentrations. AA was found in the neocortex of one NTLE patient. These data support an association between NE depletion and NTLE. The relative NE deficiency along with the consistent presence of DA in NTLE patients suggest an impairment in the catecholamine pathway. The presence of AA, a co-factor in NE synthesis, in the neocortex of one NTLE patient may also be related since AA is a cofactor in NE synthesis.

Biogenic Amines↗

PubMed2001

Catastrophic antiphospholipid antibody syndrome.

The antiphospholipid antibody syndrome may be associated with connective tissue disorders. We describe a patient with catastrophic antiphospholipid antibody syndrome secondary to systemic lupus erythematosus who presented with recurrent abdominal symptoms. Our patient died, and autopsy revealed hemorrhagic infarction of bowel with numerous mesenteric hemorrhages. The treatment for antiphospholipid antibody syndrome ranges from aspirin, warfarin, and plasmapheresis to prednisone and hydroxychloroquine.

Adult↗

PubMed2000

Monoamine neurotransmitters in resected hippocampal subparcellations from neocortical and mesial temporal lobe epilepsy patients: in situ microvoltammetric studies.

It is known that epilepsy patients diagnosed with neocortical temporal lobe epilepsy (NTLE), differ from those diagnosed with mesial temporal lobe epilepsy (MTLE), e.g., in hippocampal (HPC) pathology. In the present studies, we tested the hypothesis that NTLE and MTLE subtypes of human epilepsy might differ in regards to their HPC monoamine neurochemistry. Monoamine neurotransmitters were studied in separate signals and within s with semiderivative microvoltammetry, used in combination with stearate indicator, Ag-AgCl reference and stainless steel auxiliary microelectrodes. Anterior HPC specimens from the patients' epileptogenic zone, defined by electrocorticography, were resected neurosurgically from 13 consecutive patients with intractable temporal lobe epilepsy. Four patients were diagnosed with NTLE and nine with MTLE. The criteria for the diagnosis of NTLE versus MTLE was absence versus presence of HPC sclerosis, respectively, based on MRI examination of resected tissue. In addition, NTLE patients demonstrated seizure onset in anterolateral temporal neocortex on electroencephalography (EEG). HPC subparcellations studied were: (a) Granular Cells of the Dentate Gyrus (DG), (b) Polymorphic Layer of DG and (c) Pyramidal Layer: subfields, CA1 and CA2. Dopamine (DA), serotonin (5-HT), norepinephrine (NE) and ascorbic acid (AA) (co-factor in DA to NE synthesis), exhibited separate and characteristic half-wave potentials in millivolts. Each half-wave potential, i.e., the potential at which maximum current was generated, was experimentally established in vitro. Concentrations of neurotransmitters found in HPC subparcellations were interpolated from calibration curves derived in vitro from electrochemical detection of monoamines and AA in saline phosphate buffer. Significant differences between subtypes in concentration of monoamines were analyzed by the Mann Whitney rank sum test and those differences in probability distribution of monoamines were analyzed by the Fisher Exact test; in each case, P<0.01 was the criteria selected for determining statistical significance. DA concentrations were higher in NTLE compared with MTLE in each HPC subparcellation [P=0.037, 0.024 and 0.007, respectively (P<0.01)] and DA occurred more frequently in NTLE in the Pyramidal Layer [P=0.077 (P<0.01)]. AA was present in one NTLE patient. NE concentrations were higher in MTLE vs. NTLE in each subparcellation [P=0.012, 0.067 and 0.07, respectively (P<0.01)] and NE occurred more frequently in MTLE in Granular Cells of DG and Pyramidal Layer [P=0.052 and 0.014, respectively (P<0.01)]. In MTLE, NE concentrations in the CA1 subfield of the Pyramidal Layer were decreased vs. the CA2 subfield [P=0.063 (P<0.01)]. Serotonin was found in every HPC subparcellation of each subtype but 5-HT concentrations were higher in NTLE vs. MTLE in the Granular Cells of DG and the Pyramidal Layer (CA1 subfield) [P=0.076 and 0.095, respectively (P<0.01)]. Thus, this preliminary study showed that marked differences in HPC monoamine neurochemistry occurred in NTLE patients as compared with MTLE patients.

Adult↗

PubMed1998

Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release.

With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D4/D2), haloperidol (D2) and the selective D4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A10 neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A9 neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT2 receptor antagonist properties, significantly (p < 0.001) increased DA release within A10 terminal fields, PFC and NAcc; DA release was not increased by clozapine within A9 terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A10 and A9 terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p < 0.05)]. The selective D4 antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased DA release within CPU, did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p < 0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D4 antagonist did not affect 5-HT release within either A10 or A9 terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles of clozapine and haloperidol, in order to provide comparative profiles for a selective D4 antagonist, PNU-101387G.

Animals↗

PubMed1998

Neurochemical and behavioral evidence supporting (+)-AJ 76 as a potential pharmacotherapy for cocaine abuse.

In vivo microvoltammetry was used to detect synaptic concentrations of dopamine (DA) and serotonin (5-HT) from nucleus accumbens (NAcc) in awake, freely moving, male, Sprague Dawley laboratory rats, while their locomotor behavior was monitored, simultaneously, in an open-field paradigm; the purpose was to evaluate the pharmacology of the D3-preferring, dopamine (DA) autoreceptor antagonist, (+)-AJ 76 [cis-(+)-1S, 2R-5-methoxy-1-methyl-2-(n-propylamino)-tetralin HCL] and its potential use as a pharmacotherapy for cocaine abuse. Results showed that (1). (+)-AJ 76 significantly increased synaptic concentration of DA above baseline (p < 0.001); a small but significant decrease in synaptic concentration of 5-HT was seen (p < 0.001), although a significant increase occurred during the time course, at the 20 minute mark (p < 0.05). Analysis of the two hour data also showed that both locomotor and central locomotor activity were not affected; however, temporally related increases in both behaviors were significant at 10, 20 and 30 minutes (p < 0.05). In a second and separate study, (2). cocaine increased synaptic concentrations of DA (p < 0.001) and 5-HT (p < 0.001), and locomotor activity (p < 0.001) above baseline, but central locomotion was not affected, except for specific temporal enhancements at 10, 20, 30, 50, 60 and 90 min. (p < 0.05). In a third and separate study, (3). an (+)-AJ 76/cocaine study, (+)-AJ 76 was administered five minutes before cocaine. The results showed that synaptic DA concentration was significantly increased over baseline values (p < 0.001) but that synaptic DA was lower than cocaine-induced synaptic DA (p < 0.001). No significant difference in synaptic 5-HT occurred after (+)-AJ 76/cocaine treatment, but temporally related increases over baseline occurred from 10 to 40 min. (p < 0.05). Synaptic 5-HT concentrations after (+)-AJ 76/cocaine were not significantly different from those induced by cocaine per se. (+)-AJ 76/cocaine treatment significantly increased locomotor activity (p < 0.001); central locomotor behavior was not affected, however, time course data showed significant increases at 10, 20, 40, 50 and 80 min. (p < 0.05). The major finding from the present studies, is that +(-) AJ 76/cocaine treatment produced synaptic concentrations of DA from NAcc which were lower than those due to cocaine per se, while no differential effect on synaptic 5-HT concentration, locomotor or central locomotor behavior occurred. Therefore, these data support the hypothesis that (+)-AJ 76 may be useful for the treatment of cocaine addiction or abuse.

Analysis of Variance↗

PubMed1998

Mechanism of triazolo-benzodiazepine and benzodiazepine action in anxiety and depression: behavioral studies with concomitant in vivo CA1 hippocampal norepinephrine and serotonin release detection in the behaving animal.

1. Real time, in vivo microvoltammetric studies were performed, using miniature carbon-based sensors, to concurrently detect norepinephrine (NE) release and serotonin (5-HT) release, in 2 separate electrochemical signals, within CA1 region of hippocampus in the freely moving and behaving, male, Sprague Dawley laboratory rat. 2. Concurrently, four parameters of open-field behavior, i.e. Ambulations, Rearing, Fine Movements and Central Ambulatory behavior (a measure of anxiety reduction behavior), were assayed by infrared photobeam detection. 3. Time course studies showed that the mechanism of action of the triazolobenzodiazepine (TBZD), adinazolam, (Deracyn) is dramatically different from that of the classical benzodiazepine (BZD), diazepam (Valium, i.e., adinazolam increased, whereas diazepam decreased, 5-HT release within CA1 region of hippocampus in the freely moving and behaving rat. 4. Adinazolam initially increased NE release and then decreased NE release in CA1 region of hippocampus in the freely moving and behaving rat whereas diazepam only decreased the electrochemical signal for NE; the decrease in NE produced by adinazolam was greater than the decrease in NE release produced by diazepam. 5. The Behavioral Activity Patterns, derived from same animal controls, simultaneously with detection of in vivo microvoltammetric signals for NE release and 5-HT release, showed that the BZD, diazepam, exhibited more potent sedative properties than did the TBZD adinazolam. 6. Hippocampal 5-HT and NE release effects of the TBZD, adinazolam, concomitant with behavioral effects lends explanation to the dual anxiolytic/antidepressant properties of the TBZDs.

Animals↗

PubMed1997

I. Serotonin (5-HT) within dopamine reward circuits signals open-field behavior. II. Basis for 5-HT--DA interaction in cocaine dysfunctional behavior.

Light microscopic immunocytochemical studies, using a sensitive silver intensification procedure, show that dopamine (DA) and serotonin (5-HT) axons terminate on neurons in the nucleus accumbens (NAcc) (A10) terminals and also in dorsal striatum (DSTr) (A9) terminals. The data demonstrate a prominent endogenous anatomic interaction at these distal presynaptic sites between the neurotransmitters 5-HT and DA; the pattern of the 5-HT-DA interaction differs between A10 and A9 terminals. Moreover, in distinction to the variance shown anatomically between 5-HT--DA interactions at distal A9 and A10 sites, the 5-HT--DA interactions at the level of DA somatodendrites, the proximal site, are similar, i.e. 5-HT terminals in the midbrain tegmentum are profuse and have a massive overlap with DA neurons in both ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). We suggest with reference to the DA neurons of A10 and A9 pathways, inclusive of somatodendrites (sites of proximal presynaptic interactions in the midbrain) and axons (sites of distal presynaptic interactions), that 5-HT--DA interactions in A10 terminals are more likely to exceed those in the DStr arrangement. Furthermore, our neuroanatomic data show that axonally released DA at A10 terminals may originate from proximal 5-HT somatodendrites, i.e. dorsal raphe (DR) or the proximal DA somatodendrites, VTA. In vivo microvoltammetric studies were done with highly sensitive temporal and spatial resolution; the studies demonstrate basal (endogenous) real time 5-HT release at distal A10 and distal A9 terminal fields and real time 5-HT release at proximal A10 VTA somatodendrites. In vivo microvoltammetric studies were performed concurrently and on line with studies of DA release, also at distal A10 and distal A9 terminal fields and at proximal A10 somatodendrites. Serotonin release was detected in a separate voltammetric peak from the DA voltammetric peak. The electrochemical signal for 5-HT release was detected within 10-12 s and that for DA release within 12-15 s, after each biogenic amine diffused through the synaptic environment onto the microelectrode surface. The electrochemical signal for 5-HT and a separate electrochemical signal for DA are detected on the same voltammogram within 22-27 s; each electrochemical signal represents current changes in picoamperes, within seconds of detection time. The amplitude of each electrochemical signal reflects the changes in diffusion of each biogenic amine to the microelectrode surface. Each neurotransmitter has a distinct potential at which oxidation occurs; this results in a recording which has a distinct peak for a specific neurotransmitter. The concentration of each neurotransmitter within the synaptic environment is directly related to the electrochemical signal detected via the Cottrell equation. Voltammograms were recorded every 5 min. At the time that basal 5-HT release and basal DA release were recorded within same animal control, open-field behavioral studies were performed, also concurrently, by infrared photocell beams. The frequency of each behavioral parameter was monitored every 100 ms; the number of behavioral events, were summated every 5 min during the time course of study. Thus, the detection of neurotransmitters occurs in real time, while simultaneously monitoring the animal's behavior by infrared photocell beams. The results from the in vivo microvoltammetric and behavioral data from this study show that basal 5-HT release at distal A10 and A9 terminals dramatically increased with DA release. Moreover, each increase in basal 5-HT release, at both A10 and at A9 terminal fields occurred consistently and at the same time as each increase in open-field locomotion and stereotypy occurred naturally during the animal's exploration in a novel chamber. Thus, the terminology 'synchronous and simultaneous' describes aptly the correlation between 5-HT release at distal A10 and A9 terminal fields and open-field locomo

Animals↗

PubMed1997

Alprazolam, diazepam, yohimbine, clonidine: in vivo CA1 hippocampal norepinephrine and serotonin release profiles under chloral hydrate anesthesia.

1. Although the GABA-A receptor complex has been the main focus of anti-anxiety therapy, the neural interaction in the septohippocampal circuit between GABA-A and the neurotransmitter, 5-HT, compels a study of the monoamine, 5-HT, in anxiety as well. 2. Neurochemistry for anxiety is also intimately involved with the neurotransmitter, NE. Indeed, 5-HT is a component of the dorsal ascending noradrenergic bundle and both neurotransmitters, NE and 5-HT, have been implicated in clinical depression. 3. In vivo microvoltammetric studies were performed using miniature carbon based sensors to detect NE release and concurrent 5-HT release, with 2 separate neural electrochemical signals, within CA1 region of hippocampus, in the chloral hydrate anesthetized rat. 4. Time course studies showed that both the triazolobenzodiazepine (TBZD), alprazolam, and the benzodiazepine (BZD), diazepam, decreased hippocampal NE release. 5. The in vivo and on line neurochemical profile of hippocampal 5-HT release for alprazolam differed from that of diazepam, i.e. alprazolam increased hippocampal 5-HT release, whereas diazepam decreased hippocampal 5-HT release. 6. Time course studies showed that the alpha 2-adrenergic antagonist, yohimbine, an anxiogenic agent, increased both NE and 5-HT release in CA1 region of hippocampus; the alpha 2-adrenergic agonist, clonidine, decreased NE release and increased 5-HT release in the same region. 7. Neither the profile for the TBZD, alprazolam, nor that of the BZD, diazepam, mimicked the neurochemical profile for the anxiogenic agent, yohimbine; the neurochemical profile for the TBZD, alprazolam, was similar to that of the alpha 2-adrenergic agonist, clonidine. 8. Interestingly, alprazolam's hippocampal 5-HT/NE interaction is similar to clonidine's 5-HT/NE action at alpha 2-adrenergic autoreceptors, resulting in enhanced 5-HT release. 9. Enhanced 5-HT release in hippocampus, exhibited by the atypical TBZD, alprazolam, and not by the typical BZD, diazepam, may be an underlying mechanism for the antidepressant activity exhibited by alprazolam.

Adrenergic alpha-Antagonists↗

PubMed1996

Neuropharmacological characterization of local ibogaine effects on dopamine release.

Local perfusion with ibogaine (10(-6) M-10(-3) M) via microdialysis probes in the nucleus accumbens or striatum of rats produced a biphasic dose-response effect on extracellular dopamine levels. Lower doses (10(-6) M-10(-4) M) produced a decrease while higher doses (5 x 10(-4) M-10(-3) M) produced an increase in dopamine levels. Dihydroxyphenylacetic acid (DOPAC) levels were not effected. Naloxone (10(-6) M) and norbinaltorphimine (10(-6) M-10(-5) M) did not affect dopamine levels, but when co-administered with ibogaine (10(-4) M) blocked the decrease in dopamine levels produced by ibogaine. Ibogaine (10(-3) M) stimulation of dopamine levels in the striatum was calcium independent and not blocked by tetrodotoxin (10(-5) M). Pretreatment with cocaine (15 mg/kg), reserpine (5 mg/kg) or alpha-methyl-para-tyrosine (250 mg/kg) given intraperitoneally significantly reduced ibogaine (10(-3)M) stimulation of striatal dopamine levels. In striatal synaptosomes, both ibogaine and harmaline (10(-7)-10(-4) M) produced dose-dependent inhibition of [3H]-dopamine uptake. These findings suggest that ibogaine has both inhibitory and stimulatory effects on dopamine release at the level of the nerve terminal. It is suggested that the inhibitory effect is mediated by kappa opiate receptors while the stimulatory effect is mediated by interaction with the dopamine uptake transporter.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Light microscopic immunocytochemical evidence of converging serotonin and dopamine terminals in ventrolateral nucleus accumbens.

The mesencephalic tegmentum contains monoaminergic neurons that project to the nucleus accumbens (NAcc). These monoaminergic neurons consist of the serotonergic (5-HT) neurons of the dorsal and median raphe and the dopaminergic (DA) neurons of the ventral tegmental area (VTA). Recent neurochemical reports describe cocaine-induced alterations in dopamine and serotonin release in NAcc that has coincidental occurrence both spatially and temporally, as shown by in vivo voltammetry. There is a functional role for 5-HT-DA interactions within the NAcc in the underlying mechanism of action of cocaine as well as for 5-HT in A10 DA neurons in the basal or endogenous state whether or not cocaine-relevant reward circuits are involved. Our objective was to study the neuroanatomic localization of tyrosine hydroxylase-containing (TH) and 5-HT-containing axons in the ventrolateral region of the rat NAcc, where codetection of monoamines had been assessed. The significance of this vINAcc is its reciprocal connectivity with VTA, which contains the somatodendritic portions of the mesoacumbens DA neurons. The results showed that, in the vINAcc, the core contained a dense terminal field of TH axons that had an extensive overlap with 5-HT axons in the periphery within the core. Because the in vivo electrochemical codetection of DA and 5-HT assessed in the ventral-most aspect of this overlap zone can be correlated with terminal release, a functional interaction of 5-HT and DA at postsynaptic sites in vINAcc is possible.

Animals↗

PubMed1994

Ibogaine modulates cocaine responses which are altered due to environmental habituation: in vivo microvoltammetric and behavioral studies.

Ibogaine, a serotonergic (5-HTergic) indole alkaloid, was studied for cocaine modulatory effects on four parameters of behavior by computerized infrared photocell beam detection. The behavioral parameters were: a) locomotor activity (ambulations), b) rearing, c) stereotypy (fine movements, primarily grooming), and d) agoraphobia [(thigmotaxis) a natural tendency to avoid the center of the behavioral chamber]. With each behavioral data point, dopamine (DA) release, and serotonin (5-HT) release were detected within seconds in nucleus accumbens (NAcc) of the same behaving male Sprague-Dawley rats, using in vivo electrochemistry (voltammetry). Ibogaine was administered (40 mg/kg IP) for 4 consecutive days. Importantly, the DAergic and the 5-HTergic responses to (SC) cocaine and two behavioral responses, ambulations and central ambulations, were reduced in intensity due to extended time spent in the novel behavioral chamber (habituated). Rearing and fine movement patterns were not habituated. The results show that ibogaine downmodulated the (SC) cocaine-induced increase in NAcc DA release (p < 0.0001) and potentiated the (SC) cocaine-induced decrease in NAcc 5-HT release (p < 0.0001). Concurrently, ibogaine downmodulated cocaine-induced ambulation (p < 0.0001) and central ambulation behavior (p < 0.0001). On the other hand, the behavioral parameters that did not exhibit habituation, i.e., rearing behavior and fine movement behavior, were not downmodulated by ibogaine (p < 0.1558) (p < 0.3763), respectively. Furthermore, ibogaine itself did not significantly alter NAcc DA release over the 2-h period studied (p < 0.9113) although individual time points were significantly affected bidirectionally. Concurrently ibogaine significantly increased 5-HT release (p < 0.0155). Behaviorally, ibogaine appears to be a weak psychostimulant. The data show a critical modulatory role for 5-HT in ibogaine-cocaine interactions. Also elucidated as critical is the efficacy of ibogaine when the response to (SC) cocaine is decreased due to the habituation of the animals to their environment.

Animals↗

PubMed1993

In vivo electrochemical studies of gradient effects of (SC) cocaine on dopamine and serotonin release in dorsal striatum of conscious rats.

Cocaine (20 mg/kg) was administered subcutaneously (SC) to conscious male Sprague-Dawley rats after exploration in a novel chamber. (SC) cocaine was studied for its influence on in vivo dopamine (DA) and serotonin (5-HT) release in dorsal striatum (STr), with a further study of an anterior-posterior dorsal subdivision in a range of +/- 400 microns. Semiderivative voltammetry, a circuit for in vivo electrochemical biotechnologies, was used in combination with a stearate microelectrode to concurrently detect in separate electrochemical signals the electroactive species for DA and 5-HT in dorsal STr. The temporal resolution for detection was in the order of seconds. Concomitantly, cocaine-induced psychostimulant behaviors were studied with infrared photo beam detection. Psychostimulant behaviors classically thought to depend on DA--that is, hyperactivity (increased locomotor activity or ambulations), rearing, and finally stereotypy (fine movements of grooming and head bob)--and a 5-HT-ergic behavior, central ambulations, were monitored. The results showed that (SC) cocaine significantly (p < 0.0001) increased DA release in dorsal STr, whereas the overall effect of (SC) cocaine on 5-HT release was a significant increase (p < 0.0001) followed by an overall small (13%) but statistically significant decrease (p < 0.05). A dramatic cocaine-induced gradient effect on 5-HT release was seen in anterior-posterior dorsal STr, where 5-HT release was significantly (p < 0.0001) increased throughout the entire time period of study. Classically DA-dependent behaviors were significantly and positively correlated with increased DA release in dorsal STr and anterior-posterior dorsal STr (p < 0.001) in the 4-h period of study. However, 5-HT release after cocaine in the anterior-posterior dorsal STr was significantly and positively correlated with the classically DA-dependent behaviors as well (p < 0.001), implicating a role for 5-HT in the effectuation of cocaine-induced psychostimulant behavior. Generally, the 5-HT-ergic response to cocaine was enhanced before the DA-ergic response. Therefore, the data show that 5-HT as well as DA plays a role in the underlying mechanism of action of cocaine in dorsal STr. The data suggest that 5-HT may play a compensatory or adaptive role in the modulation of cocaine-induced nigrostriatal DA-ergic regulation.

Animals↗

PubMed1993

Real time detection of acute (IP) cocaine-enhanced dopamine and serotonin release in ventrolateral nucleus accumbens of the behaving Norway rat.

Cocaine (10 mg/kg), administered intraperitoneal (IP), was studied for its effects on dopamine (DA) and serotonin (5-HT) release in ventrolateral nucleus accumbens (vlNAcc) of conscious and behaving male, virus-free, Sprague-Dawley rats with in vivo electrochemistry (voltammetry). Miniature stearate probes detected DA and 5-HT release, on line and within a temporal resolution of seconds. Psychostimulant behaviors, in the form of four behavioral components (i.e., the classically DA-dependent behaviors of locomotor activity [ambulations], rearing, and stereotypy, and a 5-HT-ergic behavior, central ambulations) were studied concurrently with infrared photobeam detection. The results show that (IP) cocaine significantly increased vlNAcc DA release (p < 0.0001) and 5-HT release (p < 0.0012). Each of the four parameters of cocaine-induced psychostimulant behavior was concurrently and significantly increased as well (ambulations: p < 0.0001); rearing p < 0.0008; stereotypy: p < 0.0004; central ambulations: p < 0.0082). Moreover, exactly coincident data points for DA and 5-HT release occurred 10 and 40 min after (IP) cocaine administration. Cocaine-induced DA and 5-HT release were highly and positively correlated during the first hour of study (p < 0.01). As expected, increased DA release in vlNAcc after cocaine administration was significantly and positively correlated with classically DA-dependent behaviors (first- and second-hour effects) (p < 0.01) and with the 5-HT-ergic behavior, central ambulations (p < 0.01). Also, cocaine-induced 5-HT release was significantly and positively correlated with 5-HT behavior (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Cocaine's colocalized effects on synaptic serotonin and dopamine in ventral tegmentum in a reinforcement paradigm.

The effect of subcutaneous (SC) cocaine (20 mg/kg) on synaptic concentrations of the biogenic amines, dopamine (DA), and serotonin (5-HT) in Ventral Tegmental Area, (VTA-[A10]) was studied in freely moving and behaving rats (rattus norvegicus) with in vivo voltammetry (in vivo electrochemistry). The actual detection of the biogenic amines was on-line and within a temporal resolution of seconds. Simultaneously, the psychostimulant behavior induced by cocaine was studied by infrared photocell beam detection. The results show that cocaine concurrently and significantly increased synaptic concentrations of DA (p less than 0.0001) and 5-HT (p less than 0.004) in VTA. Serotonin changes were accompanied by a notable oscillatory pattern. Importantly, DA and 5-HT changes in VTA were significantly and positively correlated (p less than 0.01). Moreover, psychostimulant behaviors induced by cocaine were significantly increased over control values (p less than 0.0001). Psychostimulant behaviors were significantly correlated with concurrently changing synaptic concentrations of DA (p less than 0.01) and also with 5-HT to a lesser degree. Additionally, behavioral data indicate that cocaine may exhibit an anxiolytic effect during acute administration because agoraphobic behavior, as shown by increased central ambulatory behavior, was dramatically reduced by cocaine. Summarily, the present findings show that cocaine increased synaptic concentrations of DA in VTA, an action that is correlated with cocaine-induced psychostimulant behavior. The DA-ergic effect appears to be tonically maintained. Furthermore, new findings demonstrate a colocalized, cocaine induced 5-HT-ergic effect in VTA, which keeps pace with cocaine-induced alterations in DA-ergic neurotransmission. Thus, 5-HT may be a relay or a gating mechanism for a DA reward signalling pathway for cocaine.

Animals↗

PubMed1992

Distinguishing effects of cocaine i.v. and SC on mesoaccumbens dopamineand serotonin release with chloral hydrate anesthesia.

The effect of i.v. cocaine (0.5 and 1.0 mg/kg) was studied on synaptic concentrations of dopamine (DA) and serotonin [5-hydroxytryptamine (5-HT)] in the mesoaccumbens nerve terminal, the nucleus accumbens (NAcc), in chloral hydrate-anesthetized, male Sprague-Dawley rats (Rattus norvegicus) with in vivo electrochemistry (voltammetry). In further in vivo voltammetric studies, the effects of SC cocaine on synaptic concentrations of DA and 5-HT were studied in the chloral hydrate-anesthetized paradigm in two neuroanatomic substrates, NAcc and mesoaccumbens somatodendrites, the ventral tegmental area (VTA-A10), in a dose-response fashion (10, 20, and 40 mg/kg) in six separate studies. Moreover, in two additional in vivo voltammetric studies, again using the chloral hydrate-anesthetized paradigm, the impulse flow blocker, gamma-butyrolactone (gamma-BL) (750 mg/kg, IP), was studied alone and in combination with SC cocaine (20 mg/kg) to determine whether or not cocaine can act by presynaptic releasing mechanisms for DA and 5-HT. The results show that IV cocaine concurrently and significantly increased DA and 5-HT release in the NAcc (p < 0.001, p < 0.0005, respectively) at both doses tested. Moreover, IV cocaine effects on DA and 5-HT release were significantly and positively correlated (p < 0.01). On the other hand, SC cocaine concurrently and significantly decreased DA and 5-HT release in NAcc (p < 0.0001) and VTA (p < 0.0001) at each separate dose tested. SC cocaine effects on DA and 5-HT release were significantly and positively correlated across dose and neuroanatomic substrate (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗

PubMed1991

Cocaine: on-line analysis of an accumbens amine neural basis for psychomotor behavior.

Dose-response studies on subcutaneous cocaine were done to ascertain its effects in nucleus accumbens in dopaminergic and serotonergic neuronal circuitry in the behaving rat with in vivo voltammetry. Simultaneously, and at each dose of cocaine, unconditioned psychomotor stimulant behavior induced by cocaine was studied in terms of multiple concurrent measures of spontaneous behavior and by activity pattern analysis, a study of spatial patterns of locomotion. Time course studies showed that the neurochemical effects of cocaine (10, 20, and 40 mg/kg SC) significantly (p less than 0.0001) increased accumbens synaptic concentrations of dopamine (DA) and concurrently and significantly (p less than 0.0001) decreased accumbens synaptic concentrations of serotonin (5-HT) in a dose response manner. Simultaneous behavioral time course studies showed that cocaine (10, 20, and 40 mg/kg SC) significantly (p less than 0.0001) increased ambulations (locomotor activity), fine movements (stereotypic movements of sniffing and grooming) and rearing behavior, while significantly decreasing agoraphobic behavior, as measured by a statistically significant increase in central ambulations (p less than 0.0001). The high dose of cocaine (40 mg/kg SC) significantly increased fine movements over those produced by the lower doses of cocaine (p less than 0.0002). One import of the findings is that the DA and 5-HT biogenic amine response occurs in a behavioral paradigm of psychomotor stimulation, which is a known measure of reinforcement. Another is that the biogenic amines DA and 5-HT are affected by cocaine in this reinforcement paradigm with exactly opposite directionality. Finally, acute cocaine administration is shown to produce a dose response inhibition of agoraphobia (fear), which is highly correlated (p = .983, p less than 0.01) with the opposing effects of cocaine on the accumbens biogenic amines, DA and 5-HT.

Animals↗

PubMed1991

In vivo voltammetric studies on release mechanisms for cocaine with gamma-butyrolactone.

The effect of cocaine (20 mg/kg SC) on presynaptic mechanisms of release for dopamine (DA) and for serotonin (5-HT) was studied in nucleus accumbens of unrestrained rats (Rattus norvegicus). The studies were done by assaying synaptic concentrations of DA and 5-HT in the presence of the neuronal impulse flow inhibitor, gamma-butyrolactone (gamma-BL). The results were compared with cocaine effects on accumbens DA and 5-HT in the freely moving rat, without gamma-BL treatment. A neurochemical time course profile showed that the cocaine-induced increase in accumbens synaptic concentrations of DA was significantly blocked (p less than 0.0001) after DA impulse flow was significantly inhibited (p less than 0.0038) by gamma-BL (35.8%). The neurochemical time course profile concurrently showed that the cocaine-induced decrease in accumbens synaptic concentrations of 5-HT was significantly blocked (p less than 0.0004) after impulse flow was significantly inhibited (p less than 0.025) by gamma-BL (50.6%). The findings show that cocaine's effects on synaptic concentrations for DA and for 5-HT in accumbens are dependent on neuronal impulse flow. The findings indicate that presynaptic releasing mechanisms, which may be different for DA vis-à-vis 5-HT, play a role in the mechanism of action of cocaine.

4-Butyrolactone↗

PubMed1991

Adinazolam affects biogenic amine release in hippocampal CA1 neuronal circuitry.

The new triazolobenzodiazepine, adinazolam, which has dual anxiolytic and antidepressant activities, was studied for its effects on hippocampal CA1 norepinephrine and serotonin release in chloral hydrate-anesthetized rats, with in vivo voltammetry. Norepinephrine signals were further characterized in vivo by the detection of a significantly increased norepinephrine signal (mean = 25.8%) (p less than 0.003) after intraperitoneal administration of the alpha 2 adrenoreceptor antagonist, yohimbine, and by the detection of a significantly decreased norepinephrine signal (mean = 20.1%) (p less than 0.037) after intraperitoneal administration of the alpha 2 adrenoreceptor agonist, clonidine. Time course studies showed that the anxiolytic-antidepressant drug adinazolam (10 mg/kg IP) significantly decreased hippocampal norepinephrine release (mean = 26.2%) (p less than 0.007). The norepinephrine signal was further significantly decreased by adinazolam (mean = 16.4%) (p less than 0.009) after an additional 2 mg/kg IP injection. Serotonin release, which was detected with norepinephrine in sequence, was also significantly decreased by adinazolam (10 mg/kg IP) (mean = 22.4%) (p less than 0.002). The supplemental dose of adinazolam (2 mg/kg IP), however, did not significantly alter serotonin release any further (p less than 0.307). The findings show that the mechanism of action of adinazolam occurs simultaneously on presynaptic release mechanisms for norepinephrine and for serotonin in CA1 region of hippocampus. These findings implicate that noradrenergic and serotonergic release mechanisms may be responsible in part for the dual anxiolytic-antidepressant efficacy of adinazolam.

Analysis of Variance↗