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Biomedical subjects

R E See

Publications and source records attributed to R E See.

At least 37 records · Page 2Linked to original sources
PubMed1997

Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine.

This study investigated the ability of bilateral excitotoxic lesions of the basolateral amygdala (BLA) to disrupt cocaine self-administration, responding during extinction sessions, and stimulus cued recovery of extinguished responding in rats. BLA and sham lesions following 7 days of 3 h limited access cocaine self-administration sessions (0.33 mg/infusion) on a fixed ratio 1 (FR1) schedule of reinforcement failed to alter cocaine intake and responding on 7 subsequent days of self-administration. This lack of effect suggests that the BLA is not paramount for the maintenance of cocaine's reinforcing effects. In contrast, BLA lesions, but not sham lesions, following 7 to 14 days of cocaine self-administration attenuated responding on a lever associated with cocaine infusions on the first day of extinction sessions and blocked the ability of drug associated stimuli to reinstate extinguished responding following 20 daily extinction sessions. However, lesions of the BLA did not attenuate stimulus cued recovery of responding following 43 days of withdrawal. These results are consistent with the hypothesis that the BLA is important for the conditioned incentive properties of reinforcers, but not primary reinforcement itself.

Amygdala↗
PubMed1996

The neurotensin receptor antagonist SR 48692 decreases extracellular striatal GABA in rats.

Intracranial microdialysis was utilized to assess the effects of the novel neurotensin antagonist SR 48692 on extracellular gamma-amino-butyric acid (GABA) and glycine in the striatum. Subcutaneous injection of SR 48692 (0.2 mg/kg) significantly decreased extracellular striatal GABA levels, with peak decreases occurring 2-3 h post-injection. Injection of SR 48692 had no significant effect on glycine levels. These data suggest that endogenous neurotensin may modulate striatal GABA levels.

Analysis of Variance↗
PubMed1996

Duration-dependent increase in striatal glutamate following prolonged fluphenazine administration in rats.

Chronic neuroleptic administration has been shown to selectively increase striatal extracellular glutamate concentration. In the current study, age-matched female rats were administered chronic oral fluphenazime or no drug via their drinking water for 3 or 32 weeks. Microdialysis probes were inserted into the ventrolateral caudate putamen and the medial nucleus accumbens and dialysis samples were analyzed for glutamate and gamma-aminobutyric acid (GABA) concentrations Glutamate levels were significantly increased only in the ventrolateral caudate putamen after 32 weeks. No significant effects were seen for GABA levels. Neuroleptic-induced enhancement of striatal glutamate levels thus appears to increase with chronic exposure and this increase may relate to late onset motor side effects.

Animals↗
PubMed1996

Proposed animal neurosensitization model for multiple chemical sensitivity in studies with formalin.

A potentially promising line of animal research relevant to multiple chemical sensitivity (MCS) is that of sensitization in the central nervous system (CNS), particularly limbic pathways in the brain. Sensitization is the progressive and enduring enhancement in behavioral and neurochemical responses that occurs after repeated exposure to psychostimulants or environmental stressors. Since the onset and progression of sensitization has many parallels with that of MCS, it has been proposed that MCS may be initiated through a mechanism similar to the sensitization of CNS components occurring in the rodent. To test this hypothesis, female Sprague-Dawley rats were exposed to formalin vapors (FORM, 11 ppm) or water vapor (control) 1 h/day for 7 days. The next day, a saline injection was given followed by a cocaine injection (15 mg/kg, i.p.) 24 h later, and locomotor activity was monitored. Animals pretreated with repeated FORM inhalation demonstrated a significantly enhanced locomotor response to cocaine compared to controls, an indicator that specific limbic pathways may have been sensitized. At 4 weeks of withdrawal from FORM exposure, a subset of animals remained sensitized to a cocaine challenge. No differences were found between groups after a saline injection. In a second experiment, animals were screened prior to FORM or water exposure for their response to a novel situation, a measure believed to reflect an animal's general responsiveness to stimuli. Rats were divided into high responders (HR) or low responders (LR), based on their locomotion in a novel cage. Results from three behavioral tests demonstrated that HR and LR were differentially affected by exposure to FORM. In a passive avoidance test, HR and LR appeared to be different in their distribution of responses, while HR and LR responses in the FORM group were nearly identical. On the elevated plus maze test of anxiety, HR spent more time on the open arms than LR in both treatment groups, with significant differences between HR and LR in the FORM, but not water, treated group. On a hot plate test to measure nociceptive levels, no differences occurred between HR and LR in the control group, whereas nociception of LR tended toward an increase compared to HR in the FORM-exposed group. Results from the second experiment suggest that the effects of FORM exposure may be obscured by examining behavior in a heterogeneous population (HR and LR). This approach using animal models may help define neural substrates that mediate the amplification of responses of a subpopulation of individuals to chemicals in the environment.

Animals↗
PubMed1996

Subchronic administration of clozapine, but not haloperidol or metoclopramide, decreases dopamine D2 receptor messenger RNA levels in the nucleus accumbens and caudate-putamen in rats.

The effects of unique profile antipsychotic drugs on dopamine D2 receptors and D2 receptor messenger RNA were assessed following subchronic administration in rats. Male, Sprague-Dawley rats were administered oral haloperidol, clozapine, metoclopramide or no drug for three weeks via their drinking water. Tissue from the medial nucleus accumbens and dorsolateral caudate-putamen was dissected and analyzed by Northern blot analysis for levels of dopamine D2 receptor messenger RNA and binding assays conducted with [3H]spiperone for dopamine D2 receptors. Haloperidol and metoclopramide, but not clozapine, significantly increased [3H]spiperone in the caudate-putamen, but not the nucleus accumbens. Clozapine significantly decreased D2 messenger RNA levels in the caudate-putamen and the nucleus accumbens, while metoclopramide and haloperidol had no significant effect in either brain region. The finding of decreased D2 receptor messenger RNA levels produced by subchronic clozapine may account for the lack of striatal D2 receptor up-regulation, which was robustly observed after subchronic haloperidol and metoclopramide. Furthermore, since haloperidol and metoclopramide have a high liability for motor side effects, the current results relate favorably to the low motor side effect profile of clozapine.

Actins↗
PubMed1996

Differential effects of unique profile antipsychotic drugs on extracellular amino acids in the ventral pallidum and globus pallidus of rats.

The effects of antipsychotic drugs (APDs) on brain dopamine receptors in the striatum are ultimately expressed through efferent projections which primarily use amino acid transmitters, including gamma-aminobutyric acid and glutamate. The present study examined the effects of APDs on extracellular amino acid levels in the rat ventral pallidum (VP) and globus pallidus (GP), areas that receive projections from distinct striatal subregions. Clozapine, an APD with low motor side effect liability, and metoclopramide, a low-potency APD with high motor side effect liability, were compared with haloperidol, a widely used APD with high motor side effect liability. Drugs were administered subcutaneously and amino acid levels were monitored concurrently in the VP and GP by intracranial microdialysis. High doses of haloperidol and metoclopramide increased and clozapine decreased extracellular gamma-aminobutyric acid levels in the GP but not the VP. Low, but not high, doses of the three drugs tended to increase extracellular glutamate levels in both pallidal regions. Clozapine, but not the other two drugs, decreased extracellular threonine in the GP and glycine and threonine in the VP. Results indicate a correlation between increased gamma-aminobutyric acid levels in the GP and the propensity of the APDs tested to induce motor side effects. The novel effects of clozapine on extracellular glycine and threonine further distinguish this drug as a unique antipsychotic compound.

Amino Acids↗
PubMed1995

Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats.

Chronic neuroleptic administration has previously been shown to alter in vivo measures of dopaminergic function and lead to regionally selective increases in neurotensin levels. In the current study, female rats were administered chronic haloperidol for 6 months via subcutaneous silastic implants. After 24 weeks of administration, microdialysis probes were inserted into the lateral caudate putamen and the medial prefrontal cortex. Basal samples were collected prior to infusion of a high K+ concentration (100 mM KCl). Extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were assessed using HPLC. Chronic haloperidol-treated rats showed increased basal dopamine metabolite levels in the caudate putamen and an altered response to the effects of high K+ on 3,4-dihydroxyphenylacetic acid; no significant differences were seen with other analytes in the caudate putamen. Although basal concentrations were not different between groups in the prefrontal cortex, haloperidol-treated rats showed a significant attenuation of response to the effects of high K+ infusion on dopamine metabolite concentrations. Radioimmunoassay measurement of tissue neurotensin content showed highly significant elevations of neurotensin concentrations in the caudate putamen and nucleus accumbens, but not in other brain regions analyzed. These results suggest a confluence of altered dopamine and neurotensin function in the caudate putamen which may be related to motor side effects of haloperidol, whereas changes in prefrontal dopamine function are not associated with altered neurotensin levels.

Animals↗
PubMed1995

Chronic haloperidol potentiates stimulated glutamate release in caudate putamen, but not prefrontal cortex.

Rats were given haloperidol continuously for 6 months via subcutaneous implants. Extracellular concentrations of basal and high K(+)-stimulated GABA and glutamate in the lateral caudate putamen and the medial prefrontal cortex were then assessed using microdialysis. While there were no significant differences in basal extracellular concentrations in either brain region, chronic haloperidol-treated rats showed significantly greater increases in glutamate following stimulation with high K+ in the caudate putamen, but not the prefrontal cortex. This effect was accompanied by an attenuation of K(+)-stimulated GABA overflow in the caudate putamen. These results suggest regionally selective alterations in amino acid transmitter function which may be related to chronic neuroleptic-induced motor side effects.

Animals↗
PubMed1995

Tolerance-like attenuation to contingent and noncontingent cocaine-induced elevation of extracellular dopamine in the ventral striatum following 7 days of withdrawal from chronic treatment.

Time-dependent changes in mesolimbic dopamine (DA) function are believed to play a role in behavioral sensitization and drug craving experienced during withdrawal from chronic cocaine administration. The present study utilized intravenous (IV) cocaine self-administration coupled with intracranial microdialysis in rats to investigate time dependent changes during withdrawal from chronic cocaine exposure. Following 2 weeks of IV cocaine self-administration, rats were allowed contingent access to cocaine at 1 and 7 days of withdrawal while extracellular levels of DA were measured from the ventral striatum. A second group of animals received yoked, noncontingent cocaine for 2 weeks and were then administered noncontingent cocaine on days 1 and 7 of withdrawal. In addition, a third group of animals received 2 weeks of yoked saline followed by noncontingent cocaine 1 day after withdrawal. There were no significant differences between groups for the overall cocaine dosage or temporal pattern of infusions on days 1 and 7 of withdrawal. Basal extracellular DA concentrations did not differ between any treatment groups at either withdrawal time. Extracellular DA levels were increased throughout the session on both days; however, the increases at day 7 were significantly less than day 1 for both contingent and noncontingent conditions. DA overflow on day 1 did not differ between animals receiving chronic yoked cocaine or saline. These results suggest that tolerance-like attenuation to the DA-elevating effects of cocaine is not apparent early in withdrawal, but does develop by later time points.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Chronic haloperidol, but not clozapine, produces altered oral movements and increased extracellular glutamate in rats.

Rats administered chronic haloperidol or clozapine in their drinking water for 6 months were monitored for changes in oral movements using a computerized video analysis system. Haloperidol-treated animals exhibited late onset increases in small amplitude oral movements and an increase in the percentage of oral movements in the 1-2 Hz range, accompanied by a decrease in oral movements in the higher frequency range (> 6 Hz) as determined by fast fourier analysis. In contrast, clozapine-treated rats showed a decrease in medium-sized amplitude oral movements, but did not demonstrate significant changes in the distribution of oral movements across frequencies. Extracellular concentrations of gamma-aminobutyric acid (GABA) and glutamate in the ventrolateral striatum were then assessed by intracranial microdialysis during oral drug administration and 3 days after drug withdrawal. Extracellular GABA and glutamate levels were not significantly different between groups during drug administration. However, 3 days after drug withdrawal, there was a significant increase in glutamate in the haloperidol-treated rats. No changes were noted for glutamate levels in clozapine-treated rats or for GABA levels in either group following withdrawal. These results confirm the atypical profile of clozapine in an animal model of tardive dyskinesia and suggest that alterations in striatal glutamatergic function follow typical, but not atypical, antipsychotic drug administration.

Administration, Oral↗
PubMed1994

Differential effects of 3-PPP enantiomers on extracellular dopamine concentration in the caudate-putamen and nucleus accumbens of rats.

The ability of the enantiomers of 3-PPP (3-(3-hydroxyphenyl)-N-n-propylpiperidine) to modify the extracellular concentration of dopamine (DA) in the caudate-putamen and the nucleus accumbens of awake rats was assessed using intracranial microdialysis. The enantiomers and the racemate were directly infused at 3 incremental concentrations (1-100 microM) or systematically administered by subcutaneous injection (10 mg/kg). Both systemic administration and direct infusion of (-)3-PPP at the highest concentration (100 microM) significantly increased extracellular DA in both brain regions. This increase was also seen in the presence of higher extracellular DA levels following reuptake inhibition by nomifensine (10 microM). In contrast to the effects of (-)3-PPP, systemic administration of both (+)3-PPP and (+/-)3-PPP decreased DA levels. Infusion of (+/-)3-PPP led to slight increases in DA levels in both brain regions at the highest concentration (100 microM), while (+)3-PPP at 100 microM also produced a significant increase in the caudate-putamen, but not in the nucleus accumbens. However, in the presence of nomifensine-induced elevations in extracellular DA, (+)3-PPP produced a significant decrease in DA concentrations in both brain regions. These results support previous findings that the enantiomers of 3-PPP show unique profiles in their in vivo effects on DA terminal functions. Furthermore, these effects are dependent on the mode of 3-PPP administration, the brain region in which DA overflow is measured, and the level of basal extracellular DA.

Animals↗
PubMed1994

Single preexposure to fluphenazine produces persisting behavioral sensitization accompanied by tolerance to fluphenazine-induced striatal dopamine overflow in rats.

Single, previous exposure to a neuroleptic has been shown to produce long-lasting changes in various measures of behavior and neurochemistry upon subsequent drug exposure. The present study examined the effects of a single preexposure to fluphenazine (0.3 or 1.0 mg/kg) or vehicle on the effects of subsequent fluphenazine administration 15 or 30 days later. Intracranial microdialysis was used to assess changes in striatal extracellular dopamine concentrations. Animals were tested for catalepsy response on a horizontal bar test while concurrently collecting dialysis samples. Previous fluphenazine exposure produced a profound tolerance to the effects of subsequent fluphenazine at day 15 or day 30 on increasing extracellular dopamine levels. In addition, animals that had received fluphenazine on the first trial showed significant sensitization to the cataleptic effects of fluphenazine at both time points. Pretreatment with vehicle did not result in tolerance to dopamine overflow and there was only minimal evidence of cataleptic sensitization to a subsequent fluphenazine challenge. Although the tolerance to dopamine overflow may only indirectly relate to behavioral sensitization, these results support the hypothesis that significant behavioral and neurochemical alterations persist for prolonged time periods following single neuroleptic exposure.

Animals↗
PubMed1994

The consequences of long-term antipsychotic drug administration on basal ganglia neuronal function in laboratory animals.

Antipsychotic drugs (APDs) have been widely utilized in the treatment of a variety of psychiatric disorders, most prevalently for schizophrenia. In addition to their desired therapeutic effects, repeated administration of APDs often produces various motor side effects. Experimental evidence has implicated alterations in the nuclei of the basal ganglia as the basis for the motor dysfunctions that may arise during APD treatment. Because APDs are invariably administered for extended periods of time, a great deal of research has focused on the effects of prolonged drug exposure. Animal models have been a particularly valuable tool for studying APD effects on basal ganglia function following several weeks (subchronic) to months or years (chronic) of administration. The present paper reviews the scope of studies that have assessed various aspects of basal ganglia function in laboratory animals treated with APDs for prolonged period of time. Possible mechanisms of action are reviewed regarding subchronic and chronic APD effects on basal ganglia function as well as directions for future research.

Animals↗
PubMed1993

Chronic haloperidol does not alter G protein alpha-subunit levels in rats.

Female Sprague-Dawley rats were administered continuous haloperidol or no drug for 32 weeks via subcutaneous silastic implants. Three days after drug withdrawal, animals were rapidly decapitated and tissue samples were analyzed for levels of G alpha subunits for Gi and Gs using immunoblotting procedures. No significant differences were seen between groups in the dopaminergic terminal regions of the medial prefrontal cortex, nucleus accumbens, or dorsolateral caudate-putamen. These results suggest that haloperidol administered in a regimen known to produce alterations in several parameters of dopamine function fails to alter the amount of receptor-linked G protein subunits in rat brain.

Animals↗
PubMed1993

Assessment of striatal extracellular dopamine and dopamine metabolites by microdialysis in haloperidol-treated rats exhibiting oral dyskinesia.

Rats that had received continuous, chronic haloperidol (HAL) for 32 weeks were mentioned for changes in oral movements as determined by Fast Fourier analysis of jaw movements recorded with a computerized video analysis system. Beginning at 24 weeks of administration, HAL-treated animals exhibited a pattern of significant increases in oral movement activity in the 1 to 3 Hz range and decreases in the 5 to 8 Hz range when compared to control animals. The release and metabolism of dopamine (DA) in the striatum of these animals was then assessed using intracranial microdialysis during week 32 of HAL administration and 3 days after withdrawal of HAL. Basal extracellular concentrations of the DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid were significantly increased in the HAL-treated rats during continuous HAL administration. Three days after withdrawal from HAL, no difference was seen in basal extracellular concentrations of any of the analytes. No difference in the magnitude of DA release was seen between groups following local application of amphetamine (10 microM) through the dialysis probe during or after chronic HAL administration. These results confirm previous findings that long-term HAL administration produces increased DA turnover during HAL administration, but that this increase does not persist following HAL withdrawal. The increased striatal DA turnover seen during chronic HAL administration may have relevance to the development of late-onset neuroleptic-induced dyskinesia in rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Chronic neuroleptic administration decreases extracellular GABA in the nucleus accumbens but not in the caudate-putamen of rats.

The extracellular levels of gamma-aminobutyric acid (GABA) in the caudate-putamen and the nucleus accumbens of rats following administration of haloperidol decanoate, fluphenazine decanoate, or vehicle for 8 months were assessed using intracranial microdialysis. Basal levels of extracellular GABA were significantly decreased in the nucleus accumbens of both neuroleptic-treated groups while levels of GABA in the caudate-putamen were not significantly different between groups. These results provide evidence for selective chronic neuroleptic-induced effects on in vivo GABA function in different terminal regions containing dopamine receptors.

Animals↗
PubMed1992

Changes in striatal dopamine release and metabolism during and after subchronic haloperidol administration in rats.

The release and metabolism of dopamine (DA) in the striatum of rats during and after subchronic haloperidol (HAL) administration (3 weeks) was assessed using in vivo microdialysis. Basal extracellular levels of DA, DA metabolites (homovanillic acid and 3,4-dihydroxyphenylacetic acid) and the serotonin metabolite (5-hydroxyindoleacetic acid) were not significantly different from control values at 3 weeks of HAL administration and 3 days after drug withdrawal. The specific DA D2 receptor antagonist, raclopride (0.5 mg/kg, i.p.), significantly increased DA release and metabolism in control animals, but decreased DA release in the HAL-treated groups at 3 weeks of drug treatment. This effect was not significant following drug withdrawal. These results contrast with our previous finding that chronic HAL treatment (32 weeks) increases basal DA metabolism and further support the possibility that changes in DA function differ following short term vs. long term neuroleptic exposure.

3,4-Dihydroxyphenylacetic Acid↗