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R E See

Publications and source records attributed to R E See.

At least 19 recordsLinked to original sources
PubMed2005

Dopamine D1 or D2 receptor antagonism within the basolateral amygdala differentially alters the acquisition of cocaine-cue associations necessary for cue-induced reinstatement of cocaine-seeking.

The basolateral amygdala complex has been implicated in the formation and utilization of cocaine-cue associations in rat models of cue-induced reinstatement to cocaine-seeking behavior. We have previously demonstrated the importance of dopamine inputs to the basolateral amygdala complex in the reinstatement of cocaine-seeking behavior following chronic cocaine self-administration. Here we show that selective blockade of amygdalar dopamine D1 and D2 receptors during acquisition of cocaine-cue associations has distinctive effects on subsequent conditioned-cued cocaine-seeking behavior. Male, Sprague-Dawley rats were first trained to self-administer i.v. cocaine on a fixed ratio 1 schedule for 5 days. Subjects then received bilateral, intra-basolateral amygdala complex infusions of a dopamine D1 receptor antagonist (SCH23390, 0.25-2.0 microg/side; experiment 1), a dopamine D2 receptor antagonist (raclopride, 0.625-5.0 microg/side; experiment 2), or vehicle just prior to a single classical conditioning session, during which a light+tone cue was discretely paired with passive infusions of cocaine in the absence of lever responding. Following five additional days of cocaine self-administration and 7-10 days of extinction training, animals underwent multiple tests for cue-induced reinstatement. SCH23390 (2.0 microg/side), administered at the time of cocaine-cue association only, produced an attenuation of reinstatement to cue-induced cocaine-seeking behavior. In contrast, low doses of raclopride potentiated, while a higher dose of raclopride attenuated cue-induced reinstatement. These results demonstrate unique contributions of D1 vs. D2 receptors in mediating dopamine inputs within the basolateral amygdala complex during the formation of cocaine-stimulus associations that are critical for cue-induced reinstatement.

Amygdala↗
PubMed2003

Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in rats.

Recent evidence has demonstrated a critical role for the basolateral amygdala complex in the reinstatement of extinguished drug-seeking behavior produced by drug-paired cues. In the current study, we utilized a model of the acquisition and expression of cocaine-stimulus associative pairing in order to study the role of cholinergic input to the basolateral amygdala in mediating conditioned-cued reinstatement. Male, Sprague-Dawley rats were first trained daily to self-administer i.v. cocaine on a fixed ratio 1 schedule of reinforcement. The muscarinic acetylcholine receptor antagonist, scopolamine, was directly infused into the basolateral amygdala prior to: a) classically conditioned pairing of a tone+light stimulus with cocaine infusions (acquisition), or b) testing of conditioned-cued reinstatement following a period of withdrawal from cocaine and extinction of cocaine-paired lever responding. Infusion of scopolamine just prior to the classical conditioning trial produced a dose-dependent disruption of cocaine-seeking behavior maintained by cocaine-paired cues during the reinstatement test. In contrast, infusion of scopolamine prior to the reinstatement test had no effect on conditioned-cued reinstatement of cocaine-seeking behavior. These results indicate a crucial role for cholinergic innervation of muscarinic acetylcholine receptors in the basolateral amygdala during the formation, but not the expression, of stimulus-reward associations that mediate cue-induced cocaine-seeking behavior.

Amygdala↗
PubMed2001

Decreased pallidal GABA following reverse microdialysis with clozapine, but not haloperidol.

Changes in striatopallidal GABA are believed to play a significant role in the motor side effects produced by antipsychotic drugs (APDs). In the current study, we measured extracellular GABA in the globus pallidus (GP) of rats. GABA release was partially impulse- and Ca2+-dependent, as evidenced by decreased efflux following tetrodotoxin (TTX) or removal of Ca2+. In addition, GABA release was significantly increased by high K+ (100 mM KCl) stimulation. Reverse dialysis of the atypical APD, clozapine (1-100 microM), produced a concentration dependent decrease in extracellular GABA. In contrast, the typical APD, haloperidol (1-100 microM), had no significant effect on GABA levels. These results suggest that clozapine has direct actions within the GP, while the effects of haloperidol are most likely mediated through its effects in the striatum. The clozapine-induced decrease in pallidal GABA may account for its low motor side effect liability.

Animals↗
PubMed2001

Differential contributions of the basolateral and central amygdala in the acquisition and expression of conditioned relapse to cocaine-seeking behavior.

The amygdala is known to be a critical mediator of emotional learning in aversive and appetitive conditioning. Here we show for the first time that distinct subregions of the amygdala play unique roles in the acquisition and expression of cocaine-seeking behavior maintained by drug-paired cues in a model of relapse. Reversible inactivation of the basolateral amygdala with the sodium channel blocker tetrodotoxin disrupted both the acquisition and expression of the conditioned reinforcing effects maintained by drug-paired stimuli. However, inactivation of the central amygdala disrupted only the expression, but not the acquisition, of the conditioned reinforcing effects of drug-paired stimuli. Our results demonstrate that these nuclei participate as components of an amygdalar circuit to drive cocaine-seeking behavior produced by stimulus-reinforcement associations.

Amygdala↗
PubMed2001

Decreased choline acetyltransferase immunoreactivity in discrete striatal subregions following chronic haloperidol in rats.

Neuronal loss within the basal ganglia has been hypothesized to play a role in movement disorders (e.g., tardive dyskinesia) that often occur following chronic neuroleptic treatment. Previous studies in animal models have provided some support to this possibility, but have not assessed regionally specific changes after chronic neuroleptic administration. The present study examined whether counts of neurons containing acetylcholine, described as large aspiny type II neurons, were altered in subregions of the corpus striatum and nucleus accumbens following chronic haloperidol administration in rats. Rats were administered haloperidol decanoate (21 mg/kg, i.m.) or vehicle every third week for 24 weeks. Following 4 weeks of withdrawal from the drug, predefined regions were examined for choline acetyltransferase (ChAT) immunoreactive (ir) cells. Compared to the vehicle group, the haloperidol group showed significant reductions in ChAT-ir cell counts in the ventrolateral striatum, nucleus accumbens core, and nucleus accumbens lateral shell. No significant differences were found in the other regions examined: dorsolateral striatum, dorsomedial striatum, ventromedial striatum, nucleus accumbens medial shell, and horizontal limb of the diagonal band. These findings indicate that there may be regionally specific alterations in ChAT-ir cells following chronic haloperidol treatment, supporting previous hypotheses of striatal cholinergic cell loss resulting from chronic neuroleptic treatment. More importantly, the regions affected (ventrolateral striatum and nucleus accumbens) are critical in the regulation of oral movements, thus suggesting that alterations in cholinergic cell activity, and perhaps actual loss of cholinergic cells in these regions, may be important in the manifestation of late-onset oral dyskinesia.

Acetylcholine↗
PubMed2001

Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior.

RATIONALE: Following chronic cocaine self-administration and extinction, lesions of the basolateral amygdala (BLA) will significantly attenuate responding for secondary reward (tone + light previously paired with cocaine), without disrupting lever responding for primary reward. However, the specific neurotransmitters involved in conditioned reinstatement remain to be determined. OBJECTIVE: In the present study, we examined possible receptor substrates of amygdalar regulation of conditioned reinstatement after chronic cocaine self-administration. METHODS: Rats were allowed 2 weeks of 3-h daily sessions of cocaine self-administration along a fixed ratio (FR) 1 schedule. After 1 week of daily 3-h extinction sessions in which no programmed consequences occurred, selective antagonists of glutamate or dopamine (DA) receptors were bilaterally infused at single doses into the BLA prior to testing for a cocaine-conditioned reward (tone + light). Following three more days of extinction trials, receptor antagonist effects on reinstatement of cocaine self-administration in the absence of the conditioned stimulus were determined. RESULTS: Infusion of an NMDA receptor antagonist (AP-5, 1.97 micrograms/side), a kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (CNQX, 0.83 microgram/side), or both drugs together had no significant effects on conditioned reward or reinstatement of cocaine self-administration. In contrast, infusion of a DA D1 receptor antagonist (SCH-23390, 2 micrograms/side) or a combination of SCH-23390 and a DA D2/D3 receptor antagonist (raclopride, 5 micrograms/side) significantly reduced responding for conditioned reward, but did not affect cocaine self-administration. Raclopride alone was without effect on either test day. CONCLUSIONS: These results suggest that conditioned reinstatement of drug-seeking behavior is dependent on amygdalar D1 receptors.

2-Amino-5-phosphonovalerate↗
PubMed2001

Conditioned reinstatement of drug-seeking behavior with a discrete compound stimulus classically conditioned with intravenous cocaine.

The present study investigated the ability of a light and tone (LT) compound stimulus paired with cocaine infusions to reinstate cocaine-seeking behavior. Rats were trained to self-administer cocaine in the presence or absence of the LT during daily 3-hr sessions (maintenance). During Maintenance Days 5 and 10, rats underwent classical conditioning, whereby passive cocaine infusions were paired with either short-delayed, random, or no presentations of an LT. After extinction sessions, rats underwent test sessions in which the LT was presented in a noncontingent or response-contingent manner to measure conditioned cocaine-seeking behavior. The results demonstrated that response-contingent LT presentations significantly increased cocaine-seeking behavior and that the LT trained in a classical conditioning format transferred to an operant secondary reinforcer.

Animals↗
PubMed2000

An evaluation of the role of 5-HT(2) receptor antagonism during subchronic antipsychotic drug administration in rats.

A widely postulated mechanism of action for the atypical profile of many novel antipsychotic drugs (APDs) is their relatively high affinity for 5-HT(2) receptors. The present study investigated motor function and striatal dopamine (DA) efflux and metabolism in rats given 21 daily injections of drugs that differed in 5-HT(2) affinity. These drugs included: risperidone (high 5-HT(2A/2C)/high D(2)), clozapine (high 5-HT(2A/2C)/low D(2)), haloperidol (low 5-HT(2A/2C)/high D(2)), haloperidol+ritanserin (selective 5-HT(2A/2C)), or vehicle. Rats injected with haloperidol (0.5 mg/kg) or haloperidol+ritanserin (0.5 mg/kg and 1.0 mg/kg, respectively) showed extreme catalepsy on day 1, but significantly decreased catalepsy when tested again on days 7 and 21. Acute or subchronic risperidone (0.05 or 0.5 mg/kg), clozapine (20 mg/kg), or vehicle did not induce significant catalepsy. Microdialysis performed 24 h after the last injection demonstrated that rats treated with risperidone, clozapine, or vehicle showed similar increases in DA efflux and metabolism following an acute injection of a selective DA D(2/3) antagonist (raclopride, 0.5 mg/kg). DA efflux showed an attenuated response to raclopride in the haloperidol alone group; this effect was less apparent in the haloperidol+ritanserin group. However, both of these groups showed a similar tolerance effect to the raclopride-induced increase in DA metabolites. These results suggest that the profile seen after subchronic risperidone more closely resembles clozapine than haloperidol. While ritanserin reduced the tolerance-like effects of haloperidol on striatal DA efflux, the overall results demonstrate that potent 5-HT(2) blockade alone may not entirely account for the distinctive profile of novel APDs.

Animals↗
PubMed2000

Chronic haloperidol-induced alterations in pallidal GABA and striatal D(1)-mediated dopamine turnover as measured by dual probe microdialysis in rats.

Using dual probe microdialysis, assessment of extracellular neurotransmitter levels in the corpus striatum and globus pallidus was performed in ovariectomized and gonadally intact female, Sprague-Dawley rats following chronic (24 weeks) oral haloperidol administration. Vacuous chewing movements, an animal analog of orofacial dyskinesia, were also recorded at several time points during haloperidol administration and throughout the dialysis sampling session. Basal GABA levels were significantly elevated in the globus pallidus of haloperidol-treated rats compared with vehicle animals. Injection of the dopamine D(1) agonist dihydrexidine (3mg/kg, s.c.) decreased striatal dopamine levels in both vehicle and haloperidol-treated rats, with a larger decrease seen in haloperidol-treated rats. Furthermore, dihydrexidine reduced striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid levels only in haloperidol-treated rats. Gonadal status had no effect on any neurochemical measure. Vacuous chewing movements were significantly elevated in haloperidol-treated groups by the sixth week of treatment, with higher counts seen in gonadally intact rats. Vacuous chewing movements were significantly elevated above baseline in all groups following dihydrexidine, with no differential effect of prior haloperidol treatment or gonadal status. These results indicate a tonic increase in pallidal GABA levels and a hypersensitivity of D(1)-mediated striatal dopamine and dopamine metabolite decreases following chronic haloperidol treatment. While not found to be correlated with neurochemical measures, the heightened vacuous chewing movements in gonadally intact vs ovariectomized rats may serve as a model of hormone-mediated differences in neuroleptic-induced oral dyskinesia.

Animals↗
PubMed2000

Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse.

The neural substrates underlying relapse to drug-seeking behavior after chronic drug abuse may differ from those underlying immediate drug-taking behavior. In a model of relapse to drug-seeking behavior following chronic cocaine self-administration and prolonged extinction, we have previously shown that rats will significantly reinstate lever responding for either primary reward (cocaine) or secondary reward (tone + light stimulus previously paired with cocaine). In the present study, we utilized reversible inactivation of discrete brain nuclei with tetrodotoxin (TTX) in order to examine the neural substrates mediating primary and secondary cocaine reward in rats allowed two weeks of cocaine self-administration. After one week of daily extinction sessions, bilateral inactivation of the basolateral amygdala resulted in significant attenuation of lever pressing for a cocaine-conditioned reward (tone + light). Following three more days of extinction, bilateral TTX inactivation of the basolateral amygdala had no effect on the reinstatement of cocaine self-administration. In contrast, TTX inactivation of the nucleus accumbens produced the exact opposite effects, with significant blockade of primary reward (cocaine alone), but not secondary reward (tone + light). Thus, cocaine-conditioned reward is neuroanatomically dissociated from primary cocaine reward.

Amygdala↗
PubMed1999

The importance of a compound stimulus in conditioned drug-seeking behavior following one week of extinction from self-administered cocaine in rats.

Previous studies have demonstrated that conditioned stimuli can increase responding on a drug-associated lever after extinction from drug self-administration. The present study investigated singular stimuli (tone or light) or a compound stimulus (tone + light) for their ability to increase extinguished responding following chronic cocaine self-administration. Rats self-administered cocaine for 2 weeks on a fixed ratio (FR1) schedule of reinforcement, in which lever responding resulted in varied presentation of a tone, light, or tone + light combination. The rats were then exposed to 1 week of daily extinction sessions. Presentation of the tone + light on day 8 of extinction in the absence of cocaine reinforcement resulted in a significant increase in responding, while either stimulus component alone was much weaker or failed to produce any changes from extinction rates of responding. In addition, changing the duration of the single elements of the compound did not affect the magnitude of increased responding to the compound. Following three final extinction sessions, robust lever responding for cocaine infusions on day 12 of extinction was seen across all groups. These findings suggest that compound stimuli may be critical to fully activate drug-seeking behavior in conditions of craving and relapse following prolonged extinction.

Acoustic Stimulation↗
PubMed1999

Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia.

BACKGROUND: Previous studies have shown an increase in plasma levels of norepinephrine (NE) after clozapine treatment of schizophrenia. This effect has been suggested to relate to improvement in symptoms. METHODS: To test whether other novel antipsychotic drugs have such an effect, the present experiment examined schizophrenic symptoms and plasma levels of NE before and after 5 weeks of treatment with risperidone or haloperidol. RESULTS: Risperidone, but not haloperidol, significantly increased plasma NE; however, there was no correlation of this effect with clinical improvement on any symptom scale. CONCLUSIONS: This finding suggests that risperidone shares similar properties with clozapine in enhancing peripheral NE, but that these changes in plasma NE may not be a consistent indicator of atypical antipsychotic drug efficacy.

Adult↗
PubMed1999

Predicting relapse to cocaine-seeking behavior: a multiple regression approach.

Recovery of previously extinguished responding to stimuli paired with the administration of drugs of abuse is becoming a widely utilized animal model of relapse to drug-seeking behaviors. While this approach is useful for identifying factors such as conditioned stimuli that are associated with drug-seeking, it has not directly identified behaviors that might predict susceptibility to relapse. In this study, rats were initially screened for locomotor activity in response to a novel environment. Rats were then trained to self-administer cocaine. A stimulus light and tone were paired with each infusion of cocaine. After 14 days of self-administration (maintenance) rats underwent 7 days of extinction trials (extinction phase 1), in which responding yielded neither cocaine nor the presentation of the conditioned stimulus. After extinction phase 1, rats responded for presentations of the compound stimulus in the absence of cocaine (test day 1). Rats then underwent 3 more days of extinction (extinction phase 2). After extinction phase 2, rats were once again allowed to self-administer cocaine (test day 2) and received presentations of the compound stimulus. Hierarchical regression equations, utilizing data from locomotor screening and the average responding during maintenance and extinction phases 1 and 2, were then constructed in order to predict the magnitude of responding on test days 1 and 2. A model utilizing locomotor activity, maintenance responding and extinction phase 1 responding accounted for over 76% of the variance associated with responding on test day 1, with extinction phase 1 as best predictor. A further model indicated that locomotor activity was the best predictor of propensity to self-administer cocaine on test day 2. These regression models provide a novel approach to determining factors that may predict relapse to drug-seeking behaviors.

Animals↗
PubMed1998

Unique activation of extracellular striato-pallidal neurotransmitters in rats following acute risperidone.

The present study investigated the effects of the putative atypical antipsychotic drug (APD), risperidone, on striatal monoamine and pallidal gamma-aminobutyric acid (GABA) function using dual probe in vivo microdialysis. Risperidone (0.03, 0.3, 3 mg/kg) or vehicle was injected (s.c.) into female, Sprague-Dawley rats fitted with dual microdialysis probes in the striatum and the globus pallidus (GP). In the striatum, risperidone increased extracellular levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) at all doses and the serotonin (5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA), at the highest dose. The increase in striatal DA was most pronounced at the lowest dose of risperidone; however, DOPAC showed a dose dependent increase. Risperidone at the medium and high doses significantly reduced extracellular GABA levels in the GP. Simultaneous measurement of limb rigidity during microdialysis showed that risperidone dose-dependently produced significant increases in horizontal bar test catalepsy and fore- and hindlimb paw retraction latencies. The current results suggest novel effects of risperidone on striatal DA release, while the pallidal GABA changes are similar to previous results obtained with the atypical antipsychotic drug, clozapine. Additionally, the behavioral results predict the clinical expression of extrapyramidal motor side effects at high doses. Overall, these results support an atypical profile of risperidone when compared with typical APDs, yet one with unique neurochemical and behavioral properties.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Emergence of oral and locomotor activity in chronic haloperidol-treated rats following cortical N-methyl-D-aspartate stimulation.

Neuroleptic-induced orofacial movements in rats have been widely utilized as an animal model of tardive dyskinesia (TD). The present study investigated the role of the oral motor cortex in these movements by applying direct cortical stimulation in rats exposed to chronic haloperidol. Rats received depot i.m. injections of haloperidol decanoate or sesame oil vehicle every 3 weeks (10 rats per group). After 24 weeks of injections and a 3-week withdrawal period, bilateral guide cannulae were implanted into the primary oral motor cortex. After a 1-week recovery, bilateral microinfusions of saline vehicle followed by 1, 3, and 10 mM N-methyl-D-aspartate (NMDA) were given and observations of oral activity, locomotion, rearing, and grooming were recorded. Haloperidol-treated rats displayed a significant emergence of NMDA stimulated oral activity (nondirected oral movements, oral tremor, audible teeth grinding, and directed oral movements). In addition, rearing and locomotion were significantly elevated in these animals. In contrast to haloperidol-treated rats, sesame oil-treated rats showed no significant emergence of any motor activity. These results suggest that chronic haloperidol administration alters primary motor cortex efferents, and that this effect may be a factor in the manifestation of chronic neuroleptic induced motor side effects, such as TD.

Animals↗
PubMed1998

Repeated low-level formaldehyde exposure produces cross-sensitization to cocaine: possible relevance to chemical sensitivity in humans.

Sensitivity to chemicals in humans has been proposed to be an acquired disorder in which individuals become increasingly sensitive to chemicals in the environment. A possible link between the manifestation of psychiatric symptoms in individuals claiming sensitivity to chemicals was investigated based on a leading hypothesis put forth by Bell and co-workers (1992) to explain the amplification of symptoms after chemical exposure. The hypothesis is that chemical sensitivities may be akin to sensitization observed in rodents after repeated psychostimulants. Repeated exposure to psychostimulants enhances behavioral activity and the underlying neurochemical responses in specific limbic pathways; a similar sensitization of limbic pathways has been proposed to occur in individuals who become sensitive to chemicals. To test this hypothesis, female Sprague-Dawley rats were exposed to either air or formaldehyde (Form) for 1 h/day for 7 days or 20 days (5 days/week x 4 weeks). Two to 4 days after the last exposure, rats were given a cocaine challenge (= early withdrawal) followed by an additional cocaine challenge 4-6 weeks later (= late withdrawal). No differences in cocaine-induced locomotor activity were noted between groups after 7 days of exposure. However, after 20 days of exposure to Form, vertical activity was significantly elevated at both early and late withdrawal times. These studies demonstrate that behavioral sensitization occurs after long-term, but not short-term, low-level exposure to Form, and lends support to the limbic system sensitization hypothesis of sensitivity to chemicals in humans.

Anesthetics, Local↗
PubMed1997

Cocaine self-administration in ovariectomized rats is predicted by response to novelty, attenuated by 17-beta estradiol, and associated with abnormal vaginal cytology.

Parameters of cocaine self-administration behavior and vaginal cytological changes were assessed in ovariectomized rats during and after chronic self-administration. Response to novelty as measured by locomotor activity was found to correlate with cocaine self-administration on both fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. Chronic 17-beta estradiol (E2) replacement did not affect cocaine self-administration on FR or PR schedules of reinforcement. Acute E2 administration decreased cocaine self-administration on a PR schedule of reinforcement on the day of and on the two days following hormone treatment. Finally, the proliferation of vaginal epithelia following acute E2 was potentiated in rats both during cocaine self-administration and 30 days into withdrawal when compared with non-drug-exposed animals. These results identify response to novelty as a behavioral index predictive of cocaine self-administration liability in female rats and additionally provide evidence of psychostimulant-hormonal interactions highly relevant to female behavior and physiology.

Animals↗