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Biomedical subjects

J B Justice

Publications and source records attributed to J B Justice.

At least 73 records · Page 4Linked to original sources
PubMed1992

Naloxone reduces amphetamine-induced stimulation of locomotor activity and in vivo dopamine release in the striatum and nucleus accumbens.

This study tested the possibility that naloxone (NX), an opioid antagonist, reduces the behavioral effects of amphetamine (AMPH) in rats by attenuating the dopaminergic response to AMPH. In the first experiment, adult, male rats were injected SC with either NX (5.0 mg/kg) or saline and 30 min later received doses of AMPH (0.0, 0.1, 0.4, 1.6, and 6.4 mg/kg) cumulatively at 30-min intervals. Gross locomotor counts following AMPH administration were significantly lower for rats pretreated with NX than for rats pretreated with saline. In the second experiment, the same drug treatments were given while performing microdialysis in either the striatum (STR) or nucleus accumbens (NACC). STR rats treated with vehicle showed a larger percentage increase in DA levels following AMPH treatment than did NACC rats treated with vehicle. NX pretreatment did not affect dopamine concentrations in either brain region. However, compared to pretreatment with saline pretreatment with NX significantly decreased the dopaminergic response to AMPH in the STR. There was no difference between the two groups in the peak dopaminergic response to AMPH in the NACC, but there was a significant AMPH x treatment x time interaction due to differences between the groups during the later portion of the response to 6.4 mg/kg AMPH. There was also a difference in locomotor activity following AMPH treatment between NX- and saline-treated subjects during dialysis. These findings suggest that a decrease in the dopaminergic response to AMPH is the mechanism by which NX attenuates behavioral stimulant effects of AMPH. In addition, there is a difference between the STR and NACC in dopaminergic responsiveness to AMPH.

Animals↗
PubMed1992

Individual differences in amphetamine sensitization: dose-dependent effects.

Rats were screened for locomotor activity in a novel environment and divided into high (HR) or low (LR) responders based on whether their locomotor score for the first hour was above or below the median. In the first experiment, HR and LR rats were compared for their locomotor response following repeated administration of either 0.0, 0.5, 1.0, or 1.5 mg/kg d-amphetamine sulfate (AMPH). Injections of either 0.5 or 1.0 mg/kg AMPH produced higher locomotor activity in HR rats than in LR rats. Furthermore, there was a correlation between the locomotor response to novelty and the response to either 0.5 or 1.0 mg/kg AMPH. In addition, whereas both groups of rats developed the same degree of sensitization to 0.5 mg/kg AMPH, only the HR rats developed pronounced sensitization to repeated administration of 1.0 mg/kg AMPH. When both HR and LR were considered, there was a significant correlation between response to novelty and the extent of sensitization to the locomotor-stimulating properties of 1.0 mg/kg AMPH. There were no differences in locomotor activity or sensitization between HR and LR rats following the highest dose of AMPH (1.5 mg/kg). In a separate experiment, HR and LR rats were compared for locomotor activity following a series of intracranial infusions of AMPH. There were no overall differences in locomotor activity between the HR and LR groups following AMPH infusions into either the nucleus accumbens (NACC) or the anterior dorsal striatum (ADS). However, the locomotor activity scores in the novel environment significantly correlated with the locomotor response to 3.0 micrograms AMPH infused into either the NACC or ADS.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1992

Sensitization and individual differences to IP amphetamine, cocaine, or caffeine following repeated intracranial amphetamine infusions.

Rats that have a high locomotor response to novelty (HR) sensitize more readily to IP-administered amphetamine than rats with a low locomotor response (LR) to novelty. This experiment compared sensitization in HR and LR rats following amphetamine (3.0 micrograms/side for 5 days) infused bilaterally into either the nucleus accumbens (NACC), ventral tegmental area (VTA), or the medial frontal cortex (MFC). The subsequent locomotor response to IP-administered d-amphetamine sulfate (1 mg/kg), cocaine HCl (15 mg/kg), and caffeine benzoate (20 mg/kg) was also examined. No differences were observed between HR and LR rats following amphetamine infusion into either the MFC, NACC, or VTA. However, HR rats showed greater locomotor activity compared to LR rats following either IP amphetamine, cocaine, or caffeine for subjects cannulated in the NACC, MFC, or the VTA. Repeated infusions of amphetamine into the VTA increased the locomotor response to both IP amphetamine and cocaine, but not to IP caffeine, while repeated infusions of amphetamine into the NACC or MFC had no effect on locomotor response to any drug subsequently administered IP. The results support previous findings that changes induced by intra-VTA infusions, but not intra-NACC or MFC infusions, of amphetamine induce sensitization to IP-administered amphetamine and cocaine. Findings from the present experiment indicate the ability of the dopamine cell body region, but not the dopamine terminal fields, to produce locomotor sensitization to amphetamine and cocaine. The results from the present experiment also indicate the lack of localization to one of studied regions of individual differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1992

Quantitative microdialysis of dopamine in the striatum: effect of circadian variation.

Two quantitative microdialysis methods were used to determine the concentration of extracellular dopamine in the anterior striatum of the rat. In the first method, the slow perfusion flow rate method, perfusion was at 57 nl/min and dialysate samples were collected every 90 min for 18 h and assayed for dopamine (DA), DOPAC (3,4-dihydroxy-phenylacetic acid), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA). There was a significant increase in the concentration of dopamine during the dark cycle compared with the light cycle (14.7 +/- 1 nM vs. 9.3 +/- 0.7 nM; mean +/- SEM; P less than 0.0001), indicating possible circadian variations in the extracellular concentration of DA. There was a steady decrease in the level of DOPAC and HVA, and no change in the level of 5-HIAA. For the point of no-net-flux method, animals were perfused with 4 concentrations of DA or DOPAC, bracketing the extracellular concentrations. The extracellular concentrations of DA and DOPAC using this method were 10.2 +/- 1.7 nM and 17.4 +/- 2.6 microM, respectively. The in vivo recoveries for DA and DOPAC as derived from the slope of the linear regression curves were 72 +/- 3% and 43 +/- 5%. These values were shown to be significantly different (P less than 0.001). Both methods gave similar results for the level of DA in the striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Extracellular concentration and in vivo recovery of dopamine in the nucleus accumbens using microdialysis.

The present study compared two different in vivo microdialysis methods which estimate the extracellular concentration of analytes at a steady state where there is no effect of probe sampling efficiency. Each method was used to estimate the basal extracellular concentration of dopamine (DA) in the nucleus accumbens of the rat. In the first method, DA is added to the perfusate at concentrations above and below the expected extracellular concentration (0, 2.5, 5, and 10 nM) and DA is measured in the dialysate from the brain to generate a series of points which are interpolated to determine the concentration of no net flux. Using this method, basal DA was estimated to be 4.2 +/- 0.2 nM (mean +/- SEM, n = 5). The slope of the regression gives the in vivo recovery of DA, which was 65 +/- 5%. This method was also used to estimate a basal extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) concentration in the nucleus accumbens of 5.7 +/- 0.6 microM, with an in vivo recovery of 52 +/- 11% (n = 5). A further experiment which extended the perfusate concentration range showed that the in vivo recovery of DA is significantly higher than the in vivo recovery of DOPAC (p less than 0.001), whereas the in vitro recoveries of DA and DOPAA are not significantly different from each other. The in vivo difference is thought to be caused by active processes associated with the DA nerve terminal, principally release and uptake of DA, which may alter the concentration gradient in the tissue surrounding the probe.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens.

The reinforcing properties of cocaine are thought to be primarily mediated by the release of dopamine (DA) in the nucleus accumbens (N ACC). The extracellular concentration of DA in the N ACC was monitored with in vivo microdialysis procedures during ongoing cocaine self-administration to achieve a more detailed understanding of how DA mediates the reinforcing effects of cocaine. A dose-dependent decrease in lever pressing behavior occurred as the dose of cocaine was increased. The mean number of lever presses (in 20 min intervals) for 0.25, 0.50 and 0.75 mg/infusion doses was 5.6 +/- 0.7, 3.3 +/- 0.3 and 2.4 +/- 0.3, respectively. However, a simple inverse relationship did not occur between lever pressing behavior and the total amount of cocaine injected. Lever pressing behavior significantly increased cocaine intake as the dose of cocaine was increased. The total amount of cocaine intake that occurred during the 3 h self-administration period of the 0.25, 0.50 and 0.75 mg/infusion doses was 12.0 +/- 1.8 mg, 14.6 +/- 0.37 mg and 16.6 +/- 1.2 mg. Correspondingly, the extracellular concentration of DA in the N ACC was increased and maintained at significantly higher levels as the dose of cocaine was increased. The average concentration of DA that occurred during the self-administration of 0.25, 0.50 and 0.75 mg/infusion doses of cocaine was 269 +/- 26%, 381 +/- 21% and 464 +/- 49% of the basal DA concentration. As dose is increased, a corresponding increase occurs in both cocaine intake and in the extracellular concentration of DA in the N ACC.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Basal extracellular dopamine is decreased in the rat nucleus accumbens during abstinence from chronic cocaine.

Rats were treated for 10 days with cocaine (20 mg/kg, i.p.) followed by either 1 or 10 days of abstinence. On the test day a microdialysis method was performed in which dopamine (DA) was added to the perfusate at concentrations above and below the expected extracellular concentration (0, 2.5, 5, and 10 nM) to generate a series of points that can be interpolated to determine the concentration of no net flux, which represents the extracellular DA concentration. The slope of the line generated by this method is the in vivo recovery of the dialysis probe. After 1 day of abstinence, there was no significant difference in basal DA levels in the nucleus accumbens (N ACC) between cocaine treated (4.1 +/- 0.3 nM; mean +/- SEM) and saline-treated (3.9 +/- 0.2 nM) groups. However, there was a significant increase in the slope of the cocaine-treated group (0.91 +/- 0.04 vs. 0.67 +/- 0.08; P greater than 0.03). After 10 days of abstinence, there were reduced basal extracellular levels of DA in the N ACC of the cocaine-treated group as compared with saline-treated controls (P less than 0.002). The basal extracellular DA concentration in the N ACC was 2.1 +/- 0.3 nM for the cocaine group and 3.9 +/- 0.2 nM for the control group. The slopes of the curves were not significantly different for the cocaine (0.63 +/- 0.07) and saline (0.64 +/- 0.09) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine.

The relationship between a rat's locomotor response to a novel environment and its behavioral and dopaminergic responses to cocaine was examined. Subjects were divided into two groups based on their locomotor response to a novel environment. Subjects who had a novelty response above the median were classified as high responders (HR), while those with a novelty response below the median were classified as low responders (LR). Following administration of cocaine-HCl (0, 2.5, 5.0, 10.0, or 15.0 mg/kg), HR rats showed a greater locomotor response than LR rats. Moreover, there was a significant correlation between a subject's locomotor response to the novel environment and the locomotor response to either 10.0 (r = 0.65) or 15.0 (r = 0.92) mg/kg cocaine. In a separate experiment, the extracellular concentration of dopamine in the nucleus accumbens (NACC) was monitored using microdialysis procedures. Following cocaine administration (15.0 mg/kg) HR rats showed a larger NACC dopamine response and greater locomotor activity than LR rats. In addition, there was a threefold greater locomotor activity to dopamine ratio in HR rats than in LR rats. A correlation between a subject's locomotor response to a novel environment and the dopaminergic response to cocaine was also evident. These results suggest that differences in the locomotor response to cocaine can, to some degree, be predicted by a rat's locomotor response to a novel environment, and that variations in dopamine-dependent mechanisms of the NACC may underlie these individual differences.

Animals↗
PubMed1991

Individual differences in locomotor activity and sensitization.

Male rats were screened for locomotor activity in a novel environment and divided into high (HR) and low (LR) responders based on whether their locomotor activity score for the first hour was above or below the median locomotor activity for the subject sample. Subsequently, the locomotor response to repeated administration of either amphetamine (AMPH; 0.5 mg/kg), cocaine (10 mg/kg), scopolamine (0.5 mg/kg) or saline was monitored in separate groups of HR and LR rats. HR rats had significantly higher overall activity scores than LR rats for all 3 drugs. Both HR and LR rats developed tolerance at the same rate to repeated scopolamine administration. In contrast, only HR rats showed pronounced sensitization to the locomotor stimulating properties of AMPH and a direct correlation was evident between the locomotor response to novelty and the magnitude of sensitization. These results suggest that an individual's response to a novel environment can, to a certain extent, predict drug-induced locomotor activity and that individual differences in the response to novelty and sensitization to AMPH may result from individual variations in a common neural mechanism.

Amphetamine↗
PubMed1991

The in vivo microdialysis recovery of dopamine is altered independently of basal level by 6-hydroxydopamine lesions to the nucleus accumbens.

The present study was designed to test the hypothesis that the active neurotransmitter processes of release and uptake affect the in vivo microdialysis recovery of dopamine (DA) in the nucleus accumbens (N ACC) of the rat. The in vivo recovery for DA was established for rats which had received either unilateral infusions of the neurotoxin 6-hydroxydopamine (6-OHDA, 8 micrograms) or vehicle (0.2 micrograms ascorbate). In the quantitative dialysis method used (point of no net flux method), DA is added to the perfusate at concentrations above and below the expected extracellular concentration (0, 5, 10 and 20 nM) and DA is measured in the dialysate from the brain to generate a series of points. A linear fit is performed, the slope of which is the in vivo recovery of the dialysis probe. The in vivo recovery of the 6-OHDA group was 30 +/- 3% which was significantly lower (P less than 0.002) than the in vivo recovery of the control group which was 60 +/- 3% (mean +/- SEM; n = 6/group). The zero intercept of this regression is the point of no net flux, which is the extracellular concentration of DA independent of the probe sampling characteristics. The extracellular DA concentration for the 6-OHDA group was 7.8 +/- 1.1 nM, which was not significantly different than the control group which was 6.9 +/- 0.7 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Increased stimulated release and uptake of dopamine in nucleus accumbens after repeated cocaine administration as measured by in vivo voltammetry.

Electrically stimulated dopamine (DA) release (overflow) and uptake were measured with in vivo voltammetry in the nucleus accumbens (N ACC) of anesthetized rats that had previously received repeated cocaine treatments. Electrically stimulated DA release was induced by a 10-s stimulation in the medial forebrain bundle (2-ms, 200-microA, biphasic pulses at 100 Hz). DA overflow and uptake were measured with fast chronoamperometry using a Nafion-plated, carbon fiber electrode. Animals given repeated doses of cocaine (10 mg/kg s.c. from day 1 to 5, 20 mg/kg s.c. from day 6 to 10) showed marked increases in DA uptake (5.47 +/- 0.28 vs. 2.93 +/- 0.26 microM/s) and in stimulated DA overflow (27.3 +/- 1.1 vs. 18.9 +/- 1.3 microM) compared with DA uptake and stimulated overflow in saline control animals. The increased uptake was shown to be independent of the increased overflow. Uptake was monitored as a function of stimulation current, and the data were extrapolated to zero stimulation, resulting in calculated rates of uptake of 2.43 and 3.71 microM/s in the control and cocaine-treated groups, respectively. These effects were found to be temporary, as there were no significant differences in stimulated release or uptake between saline control animals and animals given 10 days of cocaine followed by a 10-day abstinence period. These alterations in the N ACC produced by repeated cocaine administration may be a compensatory response to prolonged uptake blockade of synaptic DA.

Animals↗
PubMed1991

Differences in the pharmacokinetics of cocaine in naive and cocaine-experienced rats.

Enhanced cocaine concentrations in brain and blood observed after an intraperitoneal challenge dose in rats exposed to cocaine for 10 days by subcutaneous administration are traced to a change in the absorption process from the site of an intraperitoneal injection to general circulation. This conclusion is reached by three sets of corroborating results: (a) Adipose tissue of rats treated for 10 days with repeat subcutaneous injections of cocaine did not reveal a buildup of cocaine in sufficient concentrations to account for the twofold increase in brain and blood concentrations seen during intraperitoneal administration; (b) administration of the drug by an intravenous route after 10-day cocaine treatment did not show a significant difference between treatment and control groups; (c) nonlinear regression on the intravenous and intraperitoneal data sets using a two-compartment open model indicated a difference in the absorption process but not in the metabolic and blood-brain transfer processes.

Absorption↗
PubMed1990

Effect of chronic cocaine on dopamine synthesis in the nucleus accumbens as determined by microdialysis perfusion with NSD-1015.

Reduced steady state formation of dihydroxyphenylalanine (DOPA) (47%) was found in the nucleus accumbens (N. ACC) of rats treated with ten days of repeated cocaine (10 mg/kg, i.p.) as compared to saline controls after NSD 1015 perfusion (10(-4) M) by microdialysis. In addition, prior to NSD 1015 perfusion, basal extracellular levels of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC) in the N. ACC were 33% lower in the chronic cocaine-treated animals. The results indicate the rate of dopamine synthesis in the N. ACC is significantly reduced by repeated cocaine administration.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

In vivo microdialysis and thermospray tandem mass spectrometry of the dopamine uptake blocker 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piper azine (GBR-12909).

Microdialysis in conjunction with thermospray tandem mass spectrometry was employed in following the time course of the experimental drug GBR-12909 in vivo. GBR-12909 is 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-3(phenylpropyl)-piperazine. An important feature of microdialysis exploited in the method is the elimination of sample cleanup procedures. The detection limit was determined to be 100 pg and the relative standard deviation of estimates for standard solution in the range of 50 nmol/L to 1 mumol/L concentrations was found to be 17%. Important factors in obtaining high sensitivity and reproducibility were carrier phase composition and operation in the flow injection mode. The maximum concentration of GBR-12909 in the brain for a dose of 100 mg/kg i.p. was determined to be 250 nmol/L with the maximal concentration occurring approximately 2 h postinjection. This represents a 40-fold lower concentration of GBR-12909 in the brain as compared to cocaine concentration obtained at a dose of 30 mg/kg, which was estimated earlier under similar experimental conditions. This observation could explain the discrepancy between relative in vivo and in vitro potencies of the two drugs.

Chemical Phenomena↗
PubMed1990

Extracellular concentrations of cocaine and dopamine are enhanced during chronic cocaine administration.

Chronic cocaine administration produces significant increases in cocaine-induced locomotor activity and stereotypy. In vivo microdialysis procedures were used to monitor extracellular dopamine (DA) and cocaine concentrations in the nucleus accumbens (N ACC) and cocaine concentrations in plasma of animals that received chronic or acute cocaine treatments. Following a cocaine challenge injection, concentrations of both cocaine and DA increased to significantly higher levels over time in animals that had received daily cocaine injections for 10 or 30 days than in control animals that received daily injections of saline. Concentrations of cocaine and DA in the N ACC reached maximum levels in the first 30 min following a challenge injection of cocaine. The maximum cocaine concentrations of 10- and 30-day chronic animals were, respectively, 186% and 156%, whereas the maximum DA concentrations were 264% and 216% above the maximum values observed in acute control animals. The results indicate that reverse tolerance effects observed following chronic cocaine administration may in part be accounted for by increased cocaine concentrations. Furthermore, chronic cocaine administration (over a 10- or 30-day period) increased the concentration of cocaine detected in plasma above control levels following a challenge injection. The increase in brain concentrations of cocaine in chronic animals is apparently due to increased concentrations of cocaine in plasma. A physiological change occurs in the periphery as a result of chronic cocaine administration that increases cocaine concentrations in plasma, increases extracellular cocaine levels in the brain, and increases the extracellular concentration of DA in the N ACC.

Animals↗
PubMed1989

Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis.

The extracellular dopamine (DA) concentration in the nucleus accumbens was measured following intravenous cocaine administration. The DA concentration increased in a dose-dependent manner following a single intravenous infusion of cocaine. The concentration of DA was observed to increase and stabilize in a schedule-dependent manner when cocaine was repeatedly administered 15-, 5- and 2.5-minute intervals. When cocaine was administered in regular intervals to animals by an experimenter or when animals self-administered cocaine. DA concentrations stabilized substantially above the basal level. These data support research that suggests that reinforcing properties of cocaine are primarily mediated by DA release in the nucleus accumbens. The data and pharmacokinetic calculations indicate that the DA concentration increases for a short period following each infusion. It then falls to a level until the animal again self-administers the drug. Animals may regulate self-administration responding for cocaine in order to maintain DA levels above a certain level, yet titrate responding so that aversive effects are not produced.

Animals↗
PubMed1988

Dopamine release at behaviorally relevant parameters of nigrostriatal stimulation: effects of current and frequency.

Released dopamine was monitored voltammetrically in the rat striatum in response to electrical stimulation of the nigrostriatal bundle. Stimulation parameters encompassed those typically used in behavioral studies. Dopamine released during intracranial self-stimulation (ICSS)-like stimulation reached a maximum within the first minute of stimulation, then rapidly decreased. The pattern of release obtained with continuous stimulation as a function of current and frequency supports the view that as the stimulation current is increased, a greater number of neurons are stimulated, while increasing the frequency of stimulation results in a fixed population of neurons being stimulated more intensely. Computer modeling of stimulated release from a population of dopaminergic nerve terminals was used to interpret effects of current and frequency and to predict ICSS release patterns as a function of schedule of reinforcement.

Animals↗