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Biomedical subjects

J R Stellar

Publications and source records attributed to J R Stellar.

At least 19 recordsLinked to original sources
PubMed2001

Electrophysiological and behavioral output of the rat basal ganglia after intrastriatal infusion of d-amphetamine: lack of support for the basal ganglia model.

Dopamine, by acting upon D1 and D2 dopamine receptors located on striatonigral and striatopallidal neurons, respectively, has been postulated to inhibit output from the substantia nigra pars reticulata (SNpr) and internal pallidal segment (GPi). The inhibition of the SNpr/GPi should, in turn, disinhibit the thalamus to facilitate movement. The present study tests this prediction in intact (unlesioned) rats by attempting to correlate changes in the single unit activities of SNpr neurons with motor (i.e. behavioral) responses in the 20-30 min after infusions of d-amphetamine into the striatum. Unilateral injections of amphetamine (20 microg/microl) into either the dorsal-rostral, central, or ventral-lateral striatum failed to appreciably alter behavior and, in parallel electrophysiological studies, failed to consistently or significantly alter the activities of SNpr neurons in either chloral hydrate-anesthetized rats or awake locally anesthetized rats. However, when amphetamine was infused bilaterally into the ventral-lateral striatum (VLS; 20 microg/microl per side), a robust behavioral activation ensued (increased locomotor activity, oral movements, and sniffing) with an onset ranging from immediate to 20 min post-infusion and persisting for at least 40 min. In parallel studies, bilateral amphetamine infusions into VLS also caused changes in the firing frequency of a majority of SNpr neurons. However, the changes in firing were extremely variable and, contrary to expectation, the net population response of SNpr neurons was an increase in firing which corresponded in time with the period of peak behavioral activation. These results show that (i) bilateral but not unilateral activation of striatal dopamine receptors is needed to elicit behavioral and electrophysiological output from the basal ganglia, and (ii) motor activation is apparently not signaled by a generalized inhibition of SNpr firing, as is predicted by the basal ganglia model.

Animals↗
PubMed2001

Effects of repeated GBR 12909 administration on brain stimulation reward.

Male rats were trained at three separate currents to bar press for intracranial self-stimulation. On days 1 and 15, all subjects were given 1-(2-bis(4-fluorophenyl)-methoxy)-ethyl-4-(3-phenylpropyl) piperazine, also known as GBR 12909 (10 mg/kg, i.p.), prior to test session. Between these days, the paired Chronic-before group was injected (every other day) with GBR 12909 prior to intracranial self-stimulation, while unpaired, Chronic-after group was given the drug just after the end of the session. A third group (Control) received saline injections (i.p.) 20 min following the session. Although GBR 12909 was found to be reward enhancing, neither sensitization nor tolerance developed to the rewarding and performance/motor effects regardless of the injection regimen. In addition, the rewarding effects of intracranial self-stimulation were found to be independent of both current and environment-specific pairing. The present data obtained for GBR 12909 agree with previous observations of the effects of repeated administration of drugs of abuse on intracranial self-stimulation.

Animals↗
PubMed2001

Novel monoamine transporter ligands reduce cocaine-induced enhancement of brain stimulation reward.

Six novel monoamine reuptake inhibitors were screened for their intrinsic effects on brain stimulation reward (BSR), as well as for their potential to reduce cocaine-induced reward-enhancement in that paradigm. Two of the compounds, nocaine-3B and 5-ara-74A (disubstituted piperidines) significantly reduced locus of rise (LOR), threshold measure of reward, at some doses. One compound, 1-RV-96A (a hybrid of the GBR and WIN-like agents) significantly reduced reward (increased LOR), but only at the highest dose tested. No effect of dose was found for MC9-20 (a GBR-like acyclic analogue of the N-bisarylmethoxyethyl-N'-phenylpropyl piperazine), nocaine-250B or 4-ara-42C (disubstituted piperidines). When cocaine (10 mg/kg, ip) and selected, hedonically neutral doses of novel compounds were combined, the following findings were obtained: MC9-20 (2.5 mg/kg, ip) showed a significant increase in cocaine-induced reward enhancement (0.2 log units or 53%). In contrast, nocaine-250B and 1-RV-96A (both at 10 mg/kg, ip) demonstrated a significant reduction (0.13 log units or 41%) in cocaine-induced reward enhancement (P<.01 and P<.05, respectively), as measured by changes in LOR. There were no differences in the maximum behavioral output (MAX) at either dose of each of the six drugs, or when selected doses were combined with cocaine. These results indicate that nocaine-250B and 1-RV-96A constitute two potential anticocaine compounds worthy of further behavioral and biochemical evaluation.

Animals↗
PubMed2001

Repeated exposure to rewarding brain stimulation downregulates GluR1 expression in the ventral tegmental area.

There is considerable evidence that drug reward and brain stimulation reward (BSR) share common neural substrates. Although it is known that exposure to drugs of abuse causes a variety of molecular changes in brain reward systems, little is known about the molecular consequences of BSR. We report that repeated exposure to rewarding stimulation of the medial forebrain bundle (MFB) selectively decreases expression of GluR1 (an AMPA receptor subunit) in the VTA, without effect on expression of several other proteins (GluR2, NMDAR1, tyrosine hydroxylase). This effect of BSR on GluR1 expression is opposite of that caused by intermittent exposure to cocaine and morphine, which are known to elevate GluR1 expression in the VTA. Considering that elevated GluR1 expression in the VTA has been associated with increased sensitivity to drug reward, the finding that BSR and drugs of abuse have opposite effects on GluR1 expression in this region may provide an explanation for why the reward-related effects of many drugs (cocaine, morphine, amphetamine, PCP, nicotine) do not sensitize with repeated testing in BSR procedures that quantify reward strength.

Animals↗
PubMed2000

Assessment of tyrosine hydroxylase immunoreactive innervation in five subregions of the nucleus accumbens shell in rats treated with repeated cocaine.

To explore the effects of behavioral sensitization on the anatomy of the nucleus accumbens shell, we employed a typical cocaine dosing paradigm and assessed tyrosine hydroxylase immunoreactive varicosities in five different areas of the shell, as well as the core of the nucleus accumbens. Rats were given bidaily injections of either saline (1 ml/kg i.p.) or cocaine (15 mg/kg i.p.) for 5 consecutive days, and sacrificed either 2 or 14 days from the last injection. Sections of the nucleus accumbens were processed for tyrosine hydroxylase immunoreactivity and the number of immunoreactive varicosities in contact with neuronal cell bodies was quantified in each of the subregions of the shell, as well as the core of the nucleus accumbens. Compared to saline controls, the cocaine-treated animals showed a significant augmentation in tyrosine hydroxylase immunoreactivity in two of the five subregions after 2 days of withdrawal in the shell, but not in the core. No differences were found in any region tested after 14 days of withdrawal. These data are the first to suggest that increases in nucleus accumbens presynaptic tyrosine hydroxylase may play a role in the development of behavioral sensitization, but not in the long-term expression of this phenomenon.

Animals↗
PubMed2000

Repeated cocaine treatment alters tyrosine hydroxylase in the rat nucleus accumbens.

To determine whether repeated exposure of cocaine affects the dopaminergic innervation of the nucleus accumbens, we employed a typical cocaine-dosing regimen in adult male Sprague-Dawley rats followed by an immunocytochemical analysis of tyrosine hydroxylase (TH). Treatment consisted of bi-daily injections of saline or 15 mg/kg cocaine for 5 consecutive days. After 2 or 14 days of withdrawal, sections of the nucleus accumbens (NAc) were processed for tyrosine hydroxylase and the number of immunoreactive varicosities in the core and shell were quantified. Two days after treatment, the core demonstrated a decrease, while after 14 days of treatment, the shell was found to contain significantly more TH immunoreactive varicosities. Additionally, 2 days post-cocaine treatment, core-shell differences were found, however moderate differences were also found in the saline treatment group, making the absolute effects of cocaine difficult to separate from injection and handling effects at this time point. These results suggest that the shell of the NAc may undergo alterations that could be involved with behavioral sensitization that typically results from such cocaine treatment regimens.

Animals↗
PubMed2000

An examination of glutamate decarboxylase(65) immunoreactive puncta with respect to rat ventral pallidum neurons after repeated cocaine administration.

The ventral pallidum is known to have topographically organized reciprocal gamma-aminobutyric acid-ergic projections with the nucleus accumbens, and changes in these connections may play a role in mediating the behavioral sensitizing effect of repeated exposure to cocaine. The present study investigated glutamate decarboxylase-65 (GAD(65)) immunoreactivity in the rat ventral pallidum after repeated cocaine administration. Male Sprague-Dawley rats were administered bi-daily injections of 15 mg/kg cocaine or saline vehicle for 5 consecutive days. After 2 or 14 days of withdrawal, ventral pallidal sections were immunocytochemically processed for GAD(65) immunoreactive puncta and counts were made. In both groups, there were no statistically significant differences in the number or density of GAD(65) puncta in medial or lateral portions either in contact with neuronal cell bodies or in the neuropil after 2 or 14 days of withdrawal. The results suggest that there is no alteration in the number of GABAergic boutons expressing GAD(65) immunoreactivity in the ventral pallidum after repeated exposure to cocaine.

Animals↗
PubMed1997

A simple design for a small fixed four-electrode brain stimulation array.

Anatomical studies of intracranial self-stimulation (ICSS) reward in rats often use the lesion method and, therefore, require repeated behavioral testing before and after the lesion. Other anatomical studies on unlesioned rats use a moveable electrode to permit testing at a number of ICSS sites. Combining these methods would yield still more information, but repeated testing is not possible due to the damage created by lowering the electrode. To meet this need, an array of 4 fixed vertically-spaced electrodes was devised. Electrodes are constructed from strands of 0.14-mm (0.0045'') Teflon-insulated stainless-steel wire, 4 of which are glued into an implantable bundle. A 4-channel IC rotary switch is implanted on the rat's head to permit the use of an inexpensive 2-channel electrode lead and commutator. In our laboratory, electrodes were vertically spaced at 0.3 mm, spanning the dorsoventral extent of the lateral hypothalamus and yielded stable rate-frequency curves over the usual 3-4 month period of behavioral testing.

Animals↗
PubMed1996

NMDA-induced lesions of the nucleus accumbens or the ventral pallidum increase the rewarding efficacy of food to deprived rats.

The role of the nucleus accumbens (NAC) and ventral pallidum (VP) in food reward modulation was investigated using Heyman's [24] curve fitting approach in food deprived rats. All rats were maintained at 80% normal body weight, and trained to lever press for food reinforcement. Each rat was tested daily with a series of four variable-interval (VI) reinforcement schedules (80, 40, 20, and 10 s) designed to approximate an exponential distribution, and randomly administered in ascending or descending order. The maximum response rate (Rmax) and the reinforcement rate required to maintain half-maximal responding (Re50) were recorded for each rat's daily test session. Following the establishment of baseline responding, the excitotoxin N-methyl-D-aspartic acid (NMDA) was bilaterally administered into the NAC (30 micrograms per side) or VP (20 micrograms per side) over a 10 min period. Both groups displayed substantial damage to the intended structure, with the lateral regions typically sustaining more damage than medial regions, and minor damage to surrounding areas. When tested at three weeks post-lesion, a suppression of motor activity was evident in all animals when compared to pre-lesion baseline. Moreover, in almost all rats, Re50 decreased, suggesting that the rewarding efficacy of food had increased. These data are surprising, given the extensive literature on the relationship between damage in the NAC and loss of reward efficacy. However, based on pharmacological and anatomical findings, both brain regions have been divided into several subregions. Behavioral studies suggest that these subregions may differentially regulate reward and motor functions. The results from the present study suggest that (1) both the NAC and VP are involved in the modulation of food reward, (2) that lateral subregions in each structure may function to dampen food reward efficacy, and (3) that medial subregions may enhance food reward.

Animal Feed↗
PubMed1996

Measurement issues in curve-shift analysis of apomorphine effects on rewarding brain stimulation.

The direct dopamine agonist apomorphine has been reported to reduce the rewarding efficacy of lateral hypothalamic (LH) self-stimulation. This effect has been claimed to support the notion that dopamine mediates the rewarding effects of LH self-stimulation. Using a standard rate-frequency curve-shift paradigm with ascending order of frequency presentation, we also found that apomorphine (0.1-0.8 mg/kg, SC) appeared to decrease LH self-stimulation reward. These apparent rightward curve shifts were exacerbated by shortening the test duration, which also produced a number of sessions in which the subjects did not respond at all. When the presentation order of stimulation frequencies was reversed, apomorphine did not produce large reward decreases. These results suggest that the previously reported effects of apomorphine on LH self-stimulation were the result of artifact, perhaps related to apomorphine-induced stereotypical behavior combined with rapid pharmacological recovery.

Animals↗
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↗