Biomedical subjects

J R Stellar

Publications and source records attributed to J R Stellar.

At least 37 records · Page 2Linked to original sources

PubMed1995

Reward shifts and motor responses following microinjections of opiate-specific agonists into either the core or shell of the nucleus accumbens.

Differences in pharmacology, anatomical connections, and receptor densities between the "core" and "shell" of the nucleus accumbens suggest that behavioral activity normally modulated by the accumbens, such as reward and motor functions, may be differentially regulated across the mediolateral axis. This study investigated the effects of opiate receptor-specific agonists on reward and motor functions in either the accumbens core or shell, using the intracranial self-stimulation (ICSS) rate-frequency curve-shift method. Microinjections of the mu opiate receptor-specific agonist, DAMGO (vehicle, 0.03 nmol, and 0.3 nmol), or the delta opiate receptor-specific agonist DPDPE (vehicle, 0.3 nmol, 3.0 nmol), were administered bilaterally in a random dose order with a minimum of 3 days between injections. Rats were tested over three consecutive 20-min rate-frequency curves immediately following a microinjection to investigate the time course of drug effects. Both opiate agonists decreased the ICSS frequency necessary to maintain half-maximal response rates when injected into the medial and ventral shell region of the accumbens. However, DAMGO microinjections into the lateral accumbens core or the control site of the caudate increased the frequency necessary to elicit half-maximal response rates, while DPDPE microinjections into these regions had no effect. Evaluation of motor effects show that administration of DAMGO resulted in a suppression of activity in all locations. In contrast, DPDPE microinjections resulted in little or no effect on lever pressing activity at any location.

Analgesics↗

PubMed1994

N-methyl-D-aspartic acid-induced lesions of the nucleus accumbens and/or ventral pallidum fail to attenuate lateral hypothalamic self-stimulation reward.

The role of ventral striatum in the maintenance and transmission of a hypothalamic intracranial self-stimulation (ICSS) reward signal was investigated using the rate-frequency multiple-curve shift paradigm. The excitotoxin N-methyl-D-aspartic acid (NMDA) was bilaterally administered into the nucleus accumbens (15 micrograms per side), the ventral pallidum (15 micrograms per side) or the juncture between the two structures (20 micrograms per side) creating three lesion groups. Both the nucleus accumbens (NAC) lesion group and the ventral pallidum (VP) lesion group displayed substantial NMDA-induced damage which was generally restricted to the intended limbic structure. The NMDA lesions in the third group displayed extensive damage to both the NAC and VP, as intended, but also typically diffused into adjacent medial structures. NMDA-induced lesions in all groups caused a suppression in motor/performance activity at all currents tested. Contrary to motor effects, reward efficacy was relatively unaffected for the NAC and VP groups. The lack of reward effects may be due to plasticity of neuronal systems and redundancy of circuit connections. However, this explanation is questionable given the fact that NMDA lesions which encompassed both the NAC and VP had little effect on reward efficacy. The above data suggests that the nucleus accumbens and the ventral pallidum are not critical for ICSS rewards stimulation and that hypothalamic ICSS reward signals are processed downstream from these limbic structures.

Animals↗

PubMed1994

Effects of accumbens DALA microinjections on brain stimulation reward and behavioral activation in intact and 6-OHDA treated rats.

The effects of bilateral nucleus accumbens microinjections of d-ala-met-enkephalinamide (DALA) were assessed in behavioral activation and lateral hypothalamic self-stimulation (LHSS) rate-frequency curve-shift paradigms in normal and accumbens 6-OHDA (4.0 micrograms) treated rats. Microinjections of DALA (2.5 micrograms/microliters) in the behavioral activation paradigm had little effect on normal activity; however, DALA administered to 6-OHDA treated rats produced a significant overall increase in locomotion. The 6-OHDA DALA-induced locomotion effect peaked at 2 weeks after 6-OHDA treatment and then returned to baseline levels by week 5 post-treatment. Using LHSS, DALA tested over a range of doses (2.5, 5, 10, 20 micrograms/microliters) displayed a weak biphasic reward effect only at the highest dose, which was characterized by an initial suppression followed by an elevation. DALA significantly depressed initial operant motor/performance in LHSS in a dose dependent fashion. Microinjections of the normally ineffective low dose of DALA (2.5 micrograms/microliters) following accumbens 6-OHDA treatment produced a significant LHSS reward decrease 2 weeks post-treatment, while LHSS motor/performance was relatively unaffected. Results are discussed in terms of opiate-dopamine and limbic-motor interactions.

Animals↗

PubMed1994

Effects of cocaine and GBR-12909 on brain stimulation reward.

Cocaine and GBR-12909, two dopamine reuptake blockers, were administered in a multiple current rate-frequency curve-shift test of intracranial self-stimulation (ICSS) reward in rats with medial forebrain bundle (MFB) electrodes. Acute injections of cocaine (0, 5, 15, 30 mg/kg, IP) increased ICSS reward at all currents (501, 316, 200 microAmps) as measured by decrease half-maximal frequency threshold. Cocaine also increased operant motor performance but only at the low current. In addition, cocaine increased dynamic interval at the highest dose at all currents. Similar treatment with GBR-12909 (0, 5, 10, 20 mg/kg, IP) significantly increased ICSS reward (decreased threshold) especially at the medium dose in all currents and had no significant effects on operant motor performance or dynamic interval. The major novel finding of the present study is that the rewarding effects of both drugs was not dependent on the choice of stimulation current, which is discussed as simplifying future psychophysical testing of psychostimulant drugs in the ICSS rate-frequency curve-shift paradigm.

Animals↗

PubMed1994

Comparison of delta opiate receptor agonist induced reward and motor effects between the ventral pallidum and dorsal striatum.

The role of the ventral pallidum and the dorsal striatum in mediating the rewarding effects of the delta receptor specific agonist [2-D-penicillamine, 5-D-penicillamine]enkephalin (DPDPE) were evaluated in the rat using the intracranial self-stimulation paradigm. Reward shifts were indicated by the change in frequency required to maintain half-maximal responding while motor/performance changes were identified by increases or decreases in the maximum responding. Each hour-long test session consisted of three identical, consecutive 20 min rate-frequency curves. In an effort to ascertain possible heterogeneity of function along the rostrocaudal axis, DPDPE (0.0 nmol = saline dose, 0.3 nmol = low dose, 1.0 nmol = medium dose, 3.0 nmol = high dose) was microinjected into either the rostral or caudal region of the two structures. Microinjections into the caudate were positioned directly above the ventral pallidum placements resulting in centromedial or caudomedial caudate placements. DPDPE microinjections into the rostral ventral pallidum resulted in a significant reward increase (28% increase or -0.14 log Hg shift) only at the high dose. In contrast, caudal ventral pallidal DPDPE microinjections showed a dose-response effect with reward increases of 19, 22 and 31% (-0.09, -0.11 and -0.16 log Hz) for the low, medium and high dose, respectively. DPDPE microinjections into the centromedial caudate resulted in a large reward increase (29% or -0.15 log Hz) at the high dose, while caudomedial caudate DPDPE microinjections had no effect on reward. Motor/performance effects tended to follow the pattern of reward effects, with most regions showing motor increases ranging from 25 to 75% over baseline activity. The only exception was found in the caudomedial caudate, where microinjections of the high dose of DPDPE resulted in an approximate 20% suppression of motor/performance activity. These results demonstrate that the ventral pallidum and the mediocentral caudate play a role in modulating opiate rewards, and adds to the growing body of literature regarding the regional heterogeneity within the caudate and ventral pallidum.

Animals↗

PubMed1993

Regional reward differences within the ventral pallidum are revealed by microinjections of a mu opiate receptor agonist.

The ventral pallidum receives a major projection from the nucleus accumbens, a heavily studied terminus of the mesolimbic dopamine system that is known to be involved in a variety of reward and behavioral functions. Recently, ventral pallidum microinjections of the mu opiate receptor agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol-enkephalin (DAMGO) have been shown to increase motor activity while ventral pallidum lesions have been shown to reduce opiate and cocaine self-administration behaviors. These results suggest a possible continuation of the mesolimbic reward/motor circuit from the nucleus accumbens into the ventral pallidum. This study investigated the effects of ventral pallidum DAMGO microinjections on reward and motor/performance through the use of the intracranial self-stimulation rate-frequency curve-shift paradigm. Microinjections of DAMGO (vehicle, 0.03 nmol, and 0.33 nmol) were administered bilaterally in a random dose order with a minimum of 3 days between injections. Rats were tested over three consecutive rate-frequency curves immediately following the opiate microinjections to investigate the time course of drug effects. DAMGO microinjections in the rostral ventral pallidum produced decreases in reward and motor/performance when compared to normal baseline activity or vehicle microinjections. In contrast, DAMGO microinjections into the caudal ventral pallidum produced increases in reward and motor/performance. These data confirm a role for the ventral pallidum in limbic function and extend it to intracranial self-stimulation reward. They also suggest reward modulation in the ventral pallidum is a regionally heterogeneous function and that the rostral ventral pallidum may be a transition area between the nucleus accumbens and the ventral pallidum.

Analgesics↗

PubMed1993

6-OHDA-treated weanling rats show normal neuroleptic sensitivity as adults on LHSS.

Weanling rats receiving 6-hydroxydopamine (6-OHDA) ICV on postnatal days 15-20 and tested as adults have normal lateral hypothalamic self-stimulation locus of rise (LOR) reward thresholds but significantly lower operant motor/performance (MAX) capacity when compared to vehicle-treated controls using the rate-frequency method. These results are comparable to those previously seen in adult rats treated with 6-OHDA on postnatal day 3. In a second test, day 15-20 6-OHDA treated rats were tested as adults with pimozide (0.125-1.0 mg/kg) and showed LOR shifts ranging from 0.06-0.32 log Hz and MAX shifts of 83-47% of baseline. These results were not significantly different at any dose when compared to day 15-20 vehicle-treated rats. This second result contrasts with the pimozide subsensitivity previously reported in day 3 6-OHDA treated rats and suggests that DA depletions made later in neonatal life may involve different forms of recovery than those seen with earlier dopamine depletions.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

The effects of excitotoxin lesions of the lateral hypothalamus on self-stimulation reward.

Unilateral microinjection into rat lateral hypothalamus (LH) of the excitotoxins ibotenic acid (IBO) and N-methyl-D-aspartic acid (NMDA) produced a local zone of neuronal death but also produced a zone of demyelination. The size of this demyelination zone was related to excitotoxin dose and was smaller than the zone of neuron killing. In behavioral testing, MFB self-stimulation reward and performance were measured with a rate-frequency curve-shift method before and after IBO or NMDA lesions of the LH. Excitotoxin lesions were made anterior or posterior to the LH electrode so that the zone of neuronal death, but not demyelination, extended to the electrode tip. These lesions produced small, temporary LH stimulation reward deficits, leading to the conclusion that intrinsic LH neurons are not a major substrate of MFB stimulation reward.

Animals↗

PubMed1990

Acute and chronic desipramine treatment effects on rewarding electrical stimulation of the lateral hypothalamus.

Two weeks of chronic desipramine HCl (DMI) (10 mg/kg, IP) treatment did not alter reward or motor/performance components of intracranial self-stimulation (ICSS) as assessed with the rate-frequency method. Acute DMI treatment produced an ICSS reward decrement relative to saline control treatment, which was similar in size on Day 1 and Day 15 of chronic testing. The failure to find a chronic DMI effect on ICSS reward suggests that ICSS in normal rats may not be a valid animal model of depression. A better paradigm may be to test the ability of antidepressants to reverse a chronic reduction in ICSS reward function that is first produced by some other method.

Animals↗

PubMed1989

Regional neuroleptic microinjections indicate a role for nucleus accumbens in lateral hypothalamic self-stimulation reward.

Bilateral microinjections of the neuroleptic, cis-flupenthixol, were made into 56 forebrain targets distributed across various dopamine (DA) terminal fields in the forebrain. Drug effects on medial forebrain bundle (MFB) stimulation-produced reward were assessed with a rate-frequency procedure implemented in a runway paradigm in a discrete-trial fashion. This method generated independent measures of drug-induced changes in the MFB stimulation reward and operant motor/performance capacity. Control experiments were run with the inactive isomer, trans-flupenthixol. Results indicate a major role for accumbens DA in MFB reward, but not for the DA in caudate and medial frontal cortex. Few drug-induced motor/performance deficits were found at any site. In 14 selected subjects, 6-OHDA-induced chronic DA lesions were made at the same site as neuroleptic microinjection. These results confirmed the reward effects of acute DA receptor blockade, but produced a greater associated motor/performance impairment. Both behavioral effects of the lesion recovered within 2 weeks in many, but not all subjects.

Animals↗

PubMed1988

Novel GABA agonists depress the reward effect of lateral hypothalamic stimulation in rats.

Rats were given systemic injections of one of a series of novel GABA compounds which can penetrate the blood-brain barrier to release GABA into the brain. They were then tested on lateral hypothalamic self-stimulation behavior using a rate-frequency paradigm to discriminate effects on reward from those on motor/performance. Both reward and, to a lesser extent, motor/performance impairments were found with all GABA compounds. In more extensive testing with one compound, LG2, no differences in the effects of three salts (acetate, ascorbate, and tartarate) were found except that the tartarate salt effects decayed more rapidly.

Animals↗

PubMed1988

Neonatal dopamine depletions spare lateral hypothalamic stimulation reward in adult rats.

Previous research has shown that adult rats sustaining near-total depletions of striatal dopamine (DA) as neonates exhibit few of the profound deficits in ingestion and sensory-motor behavior seen in comparably lesioned adults. This study extends these findings to another realm of DA-related behavior, reward function. In a rate-frequency curve-shift measurement paradigm, reward effectiveness of lateral hypothalamic brain stimulation was shown to be normal in adult rats depleted of brain DA as neonates. However, impairments were seen in rapid-initiation operant performance. Neonatally DA-depleted rats were also shown to be subsensitive to the DA receptor antagonist pimozide, suggesting that activity within undamaged DA neurons is not necessary for the elicitation of hypothalamic self-stimulation reward.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Reward saturation in medial forebrain bundle self-stimulation.

A rate-frequency curve in self-stimulation experiments plots the response rate as a function of the frequency of stimulation pulses, yielding a steeply rising, roughly sigmoidal curve. Altering stimulation reward efficacy results in lateral shifts of this curve, while altering the operant performance capacity of the rat results in primarily vertical shifts. One hypothesis explaining the lateral stability of the curve in the face of performance-altering manipulations is that the stimulation reward effect saturates at the frequency where the curve asymptotes. In the first experiment we determined the frequency of rate-frequency curve asymptote in two paradigms, runway and lever-pressing, and compared it to the reward saturation frequency determined in a discrete choice procedure. Results indicate that reward often saturates at frequencies above the rate-frequency asymptote point, which does not support the above hypothesis; levelling-off of the rate-frequency function is most likely a result of performance ceiling factors. In a second experiment, increases in stimulation current reduced the saturation frequency, indicating that saturation is not determined by an upper limit on the signal carrying capacity of the directly excited axons.

Action Potentials↗

PubMed1987

Effects of knife-cut lesions of the medial forebrain bundle in self-stimulating rats.

Unilateral frontal-plane knife-cut lesions were made in the anterior medial forebrain bundle ipsilateral to a lateral hypothalamic self-stimulation electrode. Behavioral effects of the knife cut on self-stimulation reward and operant performance capacity were measured via the reward summation function method. Knife cuts placed at the level of the anterior commissure were ineffective in altering reward or motor/performance capacity, whereas knife cuts just posterior in the caudal lateral preoptic area degraded reward and sometimes impaired motor/performance capacity. In a second experiment, knife cuts placed posterior to the ventral tegmental area were ineffective unless they intruded on the ventral tegmental area itself. Several small knife cuts placed just anterior to the ventral tegmental were effective in reducing self-stimulation reward. The results are discussed in terms of the anatomical substrate of lateral hypothalamic self-stimulation reward and as a first step in a larger mapping study.

Animals↗

PubMed1985

An investigation of the factors affecting development of frontal cortex self-stimulation.

Intracranial self-stimulation (ICSS) of the medial prefrontal cortex (MFC) is acquired gradually, taking 4 or more days to establish. One explanation for this finding is that the stimulation becomes more rewarding with repetition. Four experiments were conducted to test this hypotheses. In Experiment 1, the MFC ICSS frequency thresholds remained constant over the first 3 weeks of testing while the rate of lever pressing response increased. In Experiment 2, it was found that acquisition of MFC ICSS was much more rapid when a motorically simpler response (nose-poking) was employed. Similarly, Experiments 3 and 4 further demonstrated that response factors such as task complexity may ultimately determine the rate of development of frontal cortex ICSS. Overall, these data suggest that independent of the rewarding effects of MFC stimulation there are other effects that initially interfere with learning of complex operant responses.

Animals↗

PubMed1985

Reward, performance, and the response strength method in self-stimulating rats: validation and neuroleptics.

The response strength method consists of exposing the subject to a series of variable interval schedules of reinforcement at differing densities. Response rate is plotted against obtained reinforcement rate for each schedule. The data conform to a negatively accelerated curve that is fit well by an analytical representation which contains two parameters. The values of these parameters are obtained from the fitted curve, and are suggested to independently reflect reinforcement and performance functions. In a first experiment, two manipulations were conducted that validated these suggestions. First, lowering the frequency of brain stimulation pulses induced a relatively selective shift in the reinforcement parameter. Second, increasing the force required to press the lever primarily altered the performance parameter. In a second experiment, the effects of neuroleptic administration on these two parameters were noted and compared to the results of the first experiment. In general, neuroleptics were seen to produce both reward and motor/performance impairments in self-stimulating rats.

Animals↗

PubMed1983

Neurological reactivity during medial prefrontal cortex stimulation: effects of self-stimulation experience.

Electrical stimulation of the medial prefrontal cortex (MFC) induced a moderate behavioral suppression in a series of neurological tests that included measures of (1) open field activity (2) righting and climbing reflexes (3) somatosensory reactivity and (4) approach-withdrawal responsiveness to positive and negative stimuli. The same animals were trained to lever press for medial prefrontal cortex stimulation and after several days of self-stimulation were again tested for neurological reactivity during MFC stimulation. No habituation or lessening of behavioral suppression was evident as a result of self-stimulation experience. Therefore behavioral suppression, by itself, cannot account for the slow acquisition of MFC self-stimulation. Other data suggest that the stimulation interferes with the learning of complex operant responses and/or that the reward value of the stimulation is increased as a result of repetition.

Animals↗

PubMed1983

Effects of peripheral and central dopamine blockade on lateral hypothalamic self-stimulation: evidence for both reward and motor deficits.

The effects of dopamine receptor antagonists on lateral hypothalamic self-stimulation were analyzed using a reward summation function (RSF) technique. This paradigm relates running speed in a runway to the number of stimulation pulses received as a reward, and it is able to separately characterize changes in reward pulse effectiveness and motor performance. Pimozide, administered peripherally (0.125, 0.25, 0.5 mg/kg, IP), dose-dependently shifted the RSF toward higher values of number of pulses indicating reduced reward. Pimozide also reduced the asymptotic running speed of the RSF, indicating a deficit in motor performance. In a second experiment, alpha-flupenthixol infused directly into the nucleus accumbens (0.5 micrograms-0.5 micrograms, bilaterally) induced changes in the RSF similar to those obtained with peripheral neuroleptic treatment. These findings are discussed from the perspective that dopamine is involved both in the perception of reward value and in the performance of the response to obtain reward.

Animals↗