James R. Stellar

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.

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.

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.

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.

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.

Withdrawal duration differentially affects C-fos expression in the medial prefrontal cortex and discrete subregions of the nucleus accumbens in cocaine-sensitized rats

Intermittent administration of cocaine can result in behavioral sensitization, which is indicated by an augmented behavioral response to a subsequent administration of cocaine. This increase in behavior can be seen after various periods of abstinence from the drug, and is believed to model the cravings of drug users and the onset of drug addiction. It is believed that behavioral sensitization is mediated by activity of the mesocorticolimbic dopamine system. In particular, the nucleus accumbens and prefrontal cortex have been shown to play integral roles in this phenomenon. Recently, it has been demonstrated that the shell portion of the nucleus accumbens can no longer be considered a homogeneous structure, and can be subdivided into five separate regions. The present study was designed to assess the activation of key neuronal populations in subdivisions of the accumbens and subdivisions of the medial prefrontal cortex in cocaine-sensitized rats, using the expression of the immediate early gene, c-fos, as a marker of neuronal activation. Repeated cocaine administration resulted in robust sensitization that correlated with a significant decrease in the density of c-fos nuclei in all three subdivisions of the medial prefrontal cortex, and two subdivisions of the nucleus accumbens only in animals challenged after a 2-day withdrawal period. After a 2-week withdrawal period, sensitized animals no longer showed any differences in the density of c-fos nuclei in any of the areas examined, with the exception of a significant increase in the intermediate zone of the shell. The results indicate that distinct adaptations in neural activation take place in cocaine-sensitized rats that have been drug-free for various lengths of time. Furthermore, while specific subregions of brain areas known to play a role in drug abuse can be uniquely involved in the manifestations of cocaine sensitization, the functional roles of these subregions may differ depending on the time at which the behavior is assessed.

c-Fos and ΔFosB expression are differentially altered in distinct subregions of the nucleus accumbens shell in cocaine-sensitized rats

Repeated cocaine administration in rats can lead to sensitization as evidenced by an increased locomotor response to a subsequent exposure (challenge) dose of cocaine even after a drug-free period. Expression of the immediate early gene product, c-Fos, differs among distinct subregions of the nucleus accumbens shell. This would suggest that these subregions may be differentially involved in sensitization. The present study quantified c-Fos- and deltaFosB-immunoreactive nuclei in subterritories of the nucleus accumbens in animals behaviorally sensitized to cocaine. Rats received a sensitization-inducing regimen of cocaine (twice-daily injections of 15 mg/kg i.p. for five consecutive days). Fourteen days following the last injection, rats were given a challenge injection of cocaine (15 mg/kg i.p.), and killed 2 h later. Sections through the nucleus accumbens were processed for tyrosine hydroxylase and either c-Fos or deltaFosB. The number of immunoreactive nuclei was quantified in five subregions of the nucleus accumbens shell: the vertex, arch, cone, intermediate zone and ventrolateral zone, which can be identified by differential histological staining for tyrosine hydroxylase. Repeated cocaine administration resulted in robust sensitization that was associated with more deltaFosB in the vertex, arch, and cone compared with saline-treated controls. As previously reported, c-Fos immunoreactivity was increased in the intermediate zone in cocaine-sensitized rats. deltaFosB was significantly elevated in rats that did not receive a cocaine challenge, attesting to the long half-life of this transcription factor. These results provide further evidence suggesting distinct anatomical neuroadaptations within the nucleus accumbens shell that may play a functional role in psychomotor-stimulant sensitization.

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.

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.

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.