Brain stimulation reward is altered by affecting dopamine-glutamate interactions in the central extended amygdala.

This work compares the effects on brain stimulation reward (BSR) when combining D2 dopamine receptor and AMPA glutamate receptor manipulations in the sublenticular central extended amygdala (SLEAc) and the nucleus accumbens shell (NAc shell). Thirty-seven male Long Evans rats received medial forebrain bundle (MFB) stimulation electrodes and bilateral injection guide cannulae aimed at either the SLEAc or the NAc shell. The rate-frequency paradigm was used to assess drug-induced changes in stimulation reward effectiveness and in response rate following 0.5 µl infusions of 0.50 µg of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) (AMPA receptor antagonist), 10.0 µg of quinpirole (D2 receptor agonist), 0.25 µg of AMPA (AMPA receptor agonist), 3.0 µg of eticlopride (D2 receptor antagonist), 0.50 µg of NBQX with 10.0 µg of quinpirole, and 0.25 µg of AMPA with 3.0 µg of eticlopride. The drugs were injected both ipsi- and contralateral to the stimulation site. AMPA blockade and D2 stimulation synergized to reduce BSR's reward efficacy when directed at the SLEAc contralateral to the stimulation site whereas changes in reward efficacy were primarily D2-dependent following injections into the ipsilateral SLEAc. When injected into the NAc shell the drugs had only one significant effect on the frequency required to maintain half-maximal responding: injections of NBQX with quinpirole ipsilateral to the stimulation site increased required frequency significantly more than did injections of saline. Contrary to expectations, stimulating AMPA receptors with and without co-blockade of D2 receptors also decreased the stimulation's reward efficacy, although these effects may reflect general behavioral disruption more than effects on reward per se. These results indicate a role for the SLEAc in BSR and also suggest that SLEAc neurons ipsi- and contralateral to the stimulated MFB play their roles in BSR through different mechanisms.

Temporary inactivation of the retrorubral fields decreases the rewarding effect of medial forebrain bundle stimulation.

Prior studies indicate that lesioning the retrorubral fields (RRF) decreases the rewarding effect of medial forebrain bundle (MFB) stimulation, although these studies did not make the RRF their primary target. This study directly investigates the role of the RRF in MFB self-stimulation using transient lidocaine-induced inactivation of target tissue rather than permanent lesioning. In 18 rats with MFB stimulation electrodes, inactivation of the RRF via 0. 5 and 1.0 microl of 4% lidocaine produced immediate, substantial upward shifts in the frequency required to maintain half-maximal self-stimulation response rates whereas injecting comparable volumes of saline did not. Bilateral inactivation was particularly effective, especially at medium and high stimulation currents, although unilateral inactivation ipsilateral to the stimulation site was also effective. Contralateral inactivation alone did not substantially change the stimulation's reward value, although contralateral inactivation appeared to contribute to the effectiveness of bilateral inactivation. The frequency required to maintain half-maximal responding returned to baseline levels by 15-20 min after lidocaine infusion. In seven rats whose infusion sites were not in the RRF, lidocaine inactivation did not consistently degrade the stimulation's reward value. These results indicate that some neural elements located in the RRF contribute to the rewarding effect of MFB stimulation. Possible roles for these elements in the anatomical substrate for MFB self-stimulation are discussed.

Lesions and inactivation implicate dorsolateral hindbrain in MFB self-stimulation.

Two experiments explored the role of the motor nucleus of the trigeminal nerve (Mo5) and surrounding area in the rewarding effects of medial forebrain bundle (MFB) stimulation. In the first, eight rats received serial bilateral lesions of the target region. The reward value of MFB stimulation was assessed at 200, 400, and 800 microA using the rate-frequency curve shift paradigm. In five rats, no lesions affecting the motor nucleus or its surrounding area affected the frequency required to maintain half-maximal response rate at any current. One rat with a relatively ventrally placed lesion showed substantial enhancement of stimulation reward value at two currents, while two rats with lesions affecting the area around the descending fibers of the superior cerebellar peduncle (scp) showed substantial increases in required frequency. In the second experiment, six rats received uni- and bilateral injections of lidocaine to temporarily inactivate the target area. Two rats with injections centered near the descending fibers of the scp showed substantial increases in required frequency, as great as 0.30 log(10) units. Two rats with injections slightly rostral to these showed little change in required frequency. Two rats with injections in the ventral cerebellum, just lateral to the fastigial nucleus, showed increases in required frequency, particularly following injections contralateral to the MFB stimulation site. These data are interpreted to imply a role for the area around the lateral pole of the scp, perhaps including axons arising from the cerebellum, in MFB stimulation reward.

Lesions of midline midbrain structures leave medial forebrain bundle self-stimulation intact.

Previous work with psychophysically-based collision methods and pharmacological manipulation suggests a role in medial forebrain bundle (MFB) self-stimulation for neurons lying along the midline between the cerebral hemispheres, in the mid- and/or hindbrain. Also, recently-proposed models of the anatomical substrate for medial forebrain bundle stimulation reward suggest that at least part of the directly-activated axons of this substrate arise from mid- and/or hindbrain somata, bifurcate, and send bilateral projections to the MFB of each hemisphere. Branches of these axons are thought to cross the midline at some point near the ventral tegmental area. This study examines the effects on MFB stimulation reward of lesioning midbrain structures that lie along the midline between hemispheres. In 13 rats, lesions of the median raphe, the decussation of the superior cerebellar peduncle, or the interpeduncular nucleus were all ineffective in altering the stimulation frequency required to maintain half-maximal levels of operant responding for stimulation reward. These results are discussed in terms of implications for recent models of the anatomical substrate for brain stimulation reward.

Midbrain periaqueductal lesions do not degrade medial forebrain bundle stimulation reward.

To investigate the possible role of the midbrain central grey and dorsal raphe in medial forebrain bundle (MFB) self-stimulation, 12 rats received monopolar stimulation electrodes in both the lateral hypothalamic and ventral tegmental MFB and an ipsilateral lesioning electrode in either the central grey or dorsal raphe. Baseline rate-frequency data were collected at several currents at each stimulation site until the frequency required to maintain half-maximal responding stabilized and then an electrolytic lesion was made by passing either 20 or 60 s of anodal constant current through the lesioning electrode. Post-lesion rate-frequency data indicated that lesions of the central grey and dorsal raphe had little appreciable effect on the rewarding nature of MFB stimulation. One rat's lesion damaged the median raphe and produced sustained downward shifts in required frequency, suggesting post-lesion enhancement of the stimulation's rewarding effect.

Lesions of pontomesencephalic cholinergic nuclei do not substantially disrupt the reward value of medial forebrain bundle stimulation.

This study examines the effects of lesioning the pedunculopontine tegmentum (PPTg) and laterodorsal tegmentum (LDTg) on the reward effectiveness of medial forebrain bundle (MFB) stimulation. Although the focus is on the effects of unilateral lesions made ipsilateral to stimulation sites in the hypothalamic and ventral tegmental MFB, the effects of contralateral lesions of both targets are also investigated. Reward effectiveness was assessed using the rate-frequency curve shift paradigm. In nine rats with unilateral PPTg lesions and five rats with unilateral LDTg lesions, the frequency required to maintain half-maximal response rats was generally not changed by more than 0.1 log units relative to prelesion baseline mean. In three rats with contralateral PPTg lesions and four rats with contralateral LDTg lesions, required frequency was also not substantially changed. The results are interpreted in terms of a previously proposed hypothesis regarding the role in MFB self-stimulation of ascending cholinergic input from the pontomesencephalon to ventral tegmental dopaminergic neurons.

Destruction of the medial forebrain bundle caudal to the site of stimulation reduces rewarding efficacy but destruction rostrally does not.

Rats with an electrode in the medial forebrain bundle (MFB) in or near the ventral tegmental area and another at the level of the rostral hypothalamus sustained large electrolytic lesions at either the rostral or the caudal electrode. The rewarding efficacy of stimulation through the other electrode was determined before and after the lesion. Massive damage to the MFB in the rostral lateral hypothalamus (LH) generally had little effect on the rewarding efficacy of more caudal stimulation, whereas large lesions in the caudal MFB generally reduced the rewarding efficacy of LH stimulation by 35-60%. Similar reductions were produced by knife cuts in the caudal MFB. These results appear to be inconsistent with the hypothesis that the reward fibers consist either of descending or ascending fibers coursing in or near the MFB. It is suggested that the reward fibers are collaterals from neurons with both their somata and their behaviorally significant terminals located primarily in the midbrain.

Effects of excitotoxic lesions of the basal forebrain on MFB self-stimulation.

Electrolytic lesions of the anterior medial forebrain bundle (MFB) have been shown to attenuate the rewarding impact of stimulating more caudal MFB sites. In the present study, excitotoxic lesions were employed to determine the relative contribution of somata or fibers of passage contributing to that effect. Changes in reward efficacy were inferred, at three currents, from lateral displacements of the curve relating the rate of responding to the number of stimulation pulses per train. After baseline data were collected from stimulation sites in the lateral hypothalamus (LH) and the ventral tegmental area (VTA), 70 nmol of N-methyl-D-aspartic acid was injected via cannulae aimed at basal forebrain sites. Three subjects were injected with vehicle and served as controls. In 5 out of 15 cases, lesions encompassing the lateral preoptic area, anterior LH, and substantia innominata resulted in long-lasting, large increases (0.2-0.47 log10 units) in the number of pulses required to maintain half-maximal rates of self-stimulation for low currents delivered via the LH electrode; smaller increases (0.08-0.33 log10 units) were noted at moderate and high currents. Seven rats with similar or more dorsally located damage showed moderate or transient increases in the number of pulses required to maintain half-maximal rates of LH or VTA self-stimulation. Vehicle injections did not affect behaviour. Varying degrees of demyelination were seen, mostly removed from the electrode tip, and in locations that varied substantially across subjects manifesting similar changes in self-stimulation. These results support the notion that somata in the basal forebrain give rise to some of the directly activated fibers subserving self-stimulation of the MFB.

Self-stimulation of the MFB following parabrachial lesions.

It has been reported previously that the parabrachial region supports robust self-stimulation. In the present study, we determined whether lesions of the parabrachial nucleus (PBN) influence the rewarding effect of medial forebrain bundle (MFB) stimulation. In 10 rats, stimulation electrodes were aimed at the lateral hypothalamus and/or ventral tegmental area and a lesioning electrode aimed at the PBN. Rate-frequency curves were collected at each of three stimulation currents at each electrode, before and after lesioning. Four rats showed virtually no change in the frequency required to sustain half-maximal performance following lesioning, and two showed some postlesion decreases. Only two rats showed substantial postlesion increases in required frequency; the lesions in these subjects damaged the region ventral to the superior cerebellar peduncle, just caudal to the decussation of the peduncle, but spared the PBN. Thus, the reward effectiveness of MFB stimulation does not appear to be altered substantially following PBN lesions but may decrease following damage to the neighboring pedunculopontine region.

Rewarding effectiveness of caudal MFB stimulation is unaltered following DMH lesions.

The dorsomedial hypothalamus (DMH) has been proposed to be a major part of the neural substrate for self-stimulation of the medial forebrain bundle (MFB). In this report, rate-frequency and rate-current curves were collected from 19 rats with lesions in or around the DMH and stimulation electrodes in or near the caudal MFB. Thirteen rats with lesions of the DMH showed little or no postlesion change in the rewarding effectiveness of caudomedial MFB stimulation. Six other lesions, affecting the anterior, dorsal, and/or ventromedial hypothalamus, were also ineffective in changing rewarding effectiveness. The one lesion that was followed by a substantial decrease in rewarding effectiveness, invaded the medial MFB at the level of the lateral hypothalamus but produced little DMH damage. These data do not support the notion that neurons arising in, terminating in, or projecting through the DMH play an important role in MFB self-stimulation.

Effect of current on the maximum possible reward.

Using a 2-lever choice paradigm with concurrent variable interval schedules of reward, it was found that when pulse frequency is increased, the preference-determining rewarding effect of 0.5-s trains of brief cathodal pulses delivered to the medial forebrain bundle of the rat saturates (stops increasing) at values ranging from 200 to 631 pulses/s (pps). Raising the current lowered the saturation frequency, which confirms earlier, more extensive findings showing that the rewarding effect of short trains saturates at pulse frequencies that vary from less than 100 pps to more than 800 pps, depending on the current. It was also found that the maximum possible reward--the magnitude of the reward at or beyond the saturation pulse frequency--increases with increasing current. Thus, increasing the current reduces the saturation frequency but increases the subjective magnitude of the maximum possible reward.

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.

Failure of amygdaloid lesions to increase the threshold for self-stimulation of the lateral hypothalamus and ventral tegmental area.

It has been proposed that the directly stimulated axons underlying the rewarding effect of medial forebrain bundle (MFB) stimulation originate in the forebrain and descend at least as far as the ventral tegmentum. However, little is known about the location of the somata that give rise to these axons. Among the nuclei that contribute fibers to the descending component of the MFB and project past the lateral hypothalamus (LH) and ventral tegmental area (VTA) are cell groups within the amygdaloid complex. In this study, the rewarding effectiveness of stimulating the LH and VTA was measured before and after the amygdaloid complex was damaged by electrolytic lesions. Changes in rewarding effectiveness were inferred from shifts in the frequency required to sustain a half-maximal rate of lever-pressing at each of 3 currents. Following the lesions, there was no clear evidence of substantial, sustained decreases in rewarding effectiveness at the 14 stimulation sites, although one subject ceased to self-stimulate reliably. Given that the lesions damaged the principal amygdaloid sources of descending MFB fibers, these results suggest that the amygdaloid complex is not a major source of the directly activated fibers responsible for the rewarding effect of MFB stimulation.

Frequency-response characteristics provide a functional separation between stimulation-bound feeding and self-stimulation.

Many lateral hypothalamic electrodes that support self-stimulation also elicit feeding. Refractory period and conduction velocity estimates for the axons supporting these behaviors appear identical, suggesting that these behaviors may be elicited by stimulation of a common directly activated substrate. However, it is not known if the substrate(s) for the two behaviors integrate activity in directly stimulated axons similarly in controlling their respective behaviors. This study generates rate-frequency curves for a range of current intensities for self-stimulation and stimulation-bound feeding, using bar press rate and ingestion rate, respectively, as behavioral measures. For self-stimulation, as is well established, increases in intensity shift rate-frequency curves toward lower frequencies. For stimulation-bound feeding, increases in intensity raise asymptotic ingestion rate, but do not always appreciably change the location of the curve along the frequency axis. The different parametric profiles obtained for the two behaviors suggest different processes of integrating neural activity in the directly activated substrates.

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.

Basal forebrain knife cuts and medial forebrain bundle self-stimulation.

Current autoradiographic and electrophysiological data suggest that fibers coursing from the diagonal band/medial septum and lateral preoptic area through the medial forebrain bundle (MFB) to the midbrain may carry the reward signals generated by lateral hypothalamic stimulation. To test this hypothesis, 40 rats were given a unilateral lateral hypothalamic stimulating electrode and an ipsilateral guide cannula for knife cut transection. In baseline self-stimulation testing, both the animal's capacity to respond for the stimulation and the reward efficacy of the stimulation were measured. A coronal plane knife cut transection was given following stabilization of baseline behavior, and any changes in response capacity and stimulation reward efficacy were observed for up to two weeks, beginning 24 h after transection. Cuts to the diagonal band/medial septal region or the outflow therefrom did not permanently or significantly alter stimulation reward effectiveness. Cuts in the lateral preoptic area or in the MFB just anterior to the stimulating electrode decreased stimulation reward effects only if considerable concomitant rostrocaudal tissue damage was apparent around the knife cut. Even in these cases, reward degradation was rarely permanent. These results suggest that the majority of reward-relevant fibers probably do not arise in forebrain nuclei rostral to the stimulating electrode. A possible role of neurons endemic to the lateral hypothalamus in stimulation reward effects is discussed.

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.

Self-control choice with electrical stimulation of the brain as a reinforcer.

In a discrete-trials procedure, rats chose between a small reinforcer (a low frequency of electrical stimulation of the brain) and a larger reinforcer (a higher frequency of stimulation). The small reinforcer was delivered after a delay that was constant within a condition but varied across conditions. The delay for the large reinforcer was increased or decreased many times a session in order to estimate an indifference point--a delay at which the two alternatives were chosen about equally often. When the indifference points from several conditions were plotted as a function of the delay for the small reinforcer, the resultant "indifference curves" had positive y-intercepts and slopes greater than 1.0. These results are similar to those obtained in previous studies with pigeons as subjects and food as the reinforcer, and they suggest that a hyperbolic equation describes the relation between a reinforcer's delay and its value or effectiveness. The fact that a large reinforcer delayed several seconds was chosen over a small reinforcer delivered almost immediately after a response provides further evidence against a simple reciprocal relation between delay and value.