Prolonged medial forebrain bundle unit responses to rewarding and aversive intracranial stimuli.

In unanesthetized cerveau isolé rats, brief medial forebrain bundle (MFB) and dorsal midbrain reticular (RET) stimulus trains elicited prolonged MFB unit responses lasting up to ten or more seconds. On the MFB unit responses studied, the effects of MFB and RET stimuli were basically similar, although the stimulations were probably rewarding and aversive respectively. These data agree with the previously reported anatomical localization, in medial regions of thalamus and pallidum, of opposite single cell responses to the behaviorally opposite inputs, and suggest that unit responses to rewarding stimuli should not be characterized as reward-related when aversive stimuli elicit similar responses in the same unit.     

Unit responses in the medial forebrain bundle to rewarding stimulation in the hypothalamus

The effects of different intensities of stimulation were studied on self-stimulation behavior and on the neural responses in the medial forebrain bundle correlated with it. Of the two neural responses observed, an excitatory type was more diffusely distributed throughout this pathway than an inhibitory type, and its properties varied more as a function of the rate of self-stimulation at the various intensities tested than the properties of the inhibitory responses did. The latter were more localized to the caudal portion of the medial forebrain bundle studied, and their threshold was generally lower than the threshold of self-stimulation behavior. Also, the inhibitory responses appeared to be more sensitive indicators of stimulation applied to the medial forebrain bundle, whereas the excitatory responses were more sensitive indicators of variations in the rate of responding for brain reward. The neural responses in the MFB to rewarding stimulation are evaluated in terms of the possibility that they are specific to the positive reinforcement mechanism in the diencephalon.     

Opposite responses to aversive stimuli in lateral habenula neurons

Appropriate behavioural strategies to cope with unexpected salient stimuli require synergistic neuronal responses in diverse brain regions. Among them, the epithalamic lateral habenula (LHb) plays a pivotal role in processing salient stimuli of aversive valence. Integrated in the complex motivational circuit, LHb neurons are indeed excited by aversive stimuli, including footshock (Fs). However, whether such excitation is a common feature represented throughout the LHb remains unclear. Here, we combined single‐unit extracellular recordings in anaesthetized mice with juxtacellular labelling to describe the nature, location and pharmacological properties of Fs‐driven responses within the LHb. We find that, along with Fs‐excited cells, about 10% of LHb neurons display Fs‐mediated inhibitory responses. Such inhibited neuronal population, in contrast to Fs‐excited neurons, display regular and high frequency activity at baseline and is clustered in the medial portion of the LHb. Juxtacellular labelling of Fs‐excited and inhibited neurons unravels that both populations are of glutamatergic type, as they co‐localized with the EAAC1 glutamatergic transporter but not with the GAD67 GABAergic marker. Moreover, while the excitatory responses to Fs require both AMPA and NMDA receptors, the inhibitory responses rely instead on GABA_A channels. Taken together, our results indicate that two functionally and partly segregated LHb neuronal ensembles encode Fs in an opposite fashion. This highlights the neuronal complexity in the LHb for processing aversive external stimuli.     

Periaqueductal gray and cerebral cortex modulate responses of medial thalamic neurons to noxious stimulation

The response of medial thalamic neurons to noxious peripheral stimulation were studied with intracellular recording methods in the cat. Electrical stimulation of the contralateral forepaw produced an EPSP-IPSP sequence followed by rebound excitation in these medial thalamic neurons. Action potentials appeared with the initial EPSP or with the rebound excitation. The mean latency to onset was 15 ms for the EPSP and 33 ms for IPSP. In contrast, electrical stimulation of the PAG or of the pericruciate cerebral cortex produced large IPSPs in the medial thalamic neurons. When PAG or cortex stimulation were paired with noxious stimulation, both the PAG and cortex responses predominated over the noxious response. This shows that the PAG and the cerebral cortex have the capabilities of influencing the responses of the medial thalamus to noxious stimulation. The medial thalamus is part of the relay system which sends information about noxious stimulation to the cerebral cortex where the noxious information reaches conscious awareness, so influencing the message at the level of the medial thalamus would probably alter the conscious perception of pain. The data suggest the existence of an ascending pain modulation system from the midbrain to the thalamus and also suggests a mechanism of cortical control over pain perception.     

Opioids and rewarding brain stimulation

Studies are reviewed which demonstrate opioid-induced facilitative effects on self-stimulation to a number of different neuroanatomical sites in the rat brain. Tolerance has not been demonstrated to this facilitation. Evidence is presented to support the contention that these behavioral effects reflect an increase in sensitivity of the neuronal pathways subserving brain stimulation reward. It is proposed that these actions are directly related to the hedonic subjective effects and addiction liability associated with human use of this class of compounds.     

Effects of naloxone on rewarding and aversive brain sites

The effects of naloxone on the rewarding and aversive properties of brain stimulation derived from the ventral tegmental area and the nucleus reticularis gigantocellularis, respectively, were assessed in rats, based on the following measures-the current threshold for latency to escape aversive nucleus reticularis gigantocellularis stimulation, the frequency threshold for rewarding ventral tegmental area stimulation, and the frequency threshold for self-stimulation obtained from delivery of concurrent ventral tegmental area and nucleus reticularis gigantocellularis stimulation, before and after three systemic doses of naloxone (0, 10, and 20mg/kg); in the latter case, the stimulation trains were interdigitated with an interpulse interval of 2 ms. Initially, thresholds for concurrent stimulation were elevated relative to the values obtained for ventral tegmental area stimulation alone, returning to baseline values only when the nucleus reticularis gigantocellularis stimulation no longer induced escape. After each pairing of the two sites, the current threshold for escape gradually increased until the maximum value administered, 700 microA, at which point aversive responses were no longer observed. This required very few pairings, between one and five trials across animals. Drug tests were then begun and produced a significant dose-response threshold increase across animals, without reinstating the latency to escape nucleus reticularis gigantocellularis stimulation. These findings are discussed in terms of a dissociation between the analgesic and rewarding properties of ventral tegmental area stimulation.     

Opiate antagonists and rewarding brain stimulation

This review examines the literature on the effects of opiate antagonists on brain stimulation (ICSS) reward. Antagonists should have predictable effects if endogenous opioids modulate ICSS. Naloxone is the antagonist most often used, and it has produced inconsistent results in some ICSS paradigms. When schedules of intermittent reinforcement are used, however, naloxone reliably reduces the rate of responding. It reverses the effects of opiate agonists on ICSS behavior, and it also attenuates the effects of psychomotor stimulants, such as amphetamine. The results produced by naloxone are consistent with a modulatory effect of endogenous opioid systems on reward, and suggest that the opiate and dopamine systems together exert significant control over ICSS. Further research is needed to characterize better the actions of the antagonists on ICSS behavior, and productive research directions are proposed. Data obtained in future studies might suggest how the endogenous opioid systems modulate both natural and brain stimulation reward.     

Interactions between rewarding lateral hypothalamic and aversive nucleus reticularis gigantocellularis stimulation

The interaction between rewarding and aversive consequences of brain stimulation were assessed in two studies. In the first, the frequency threshold for 300 ms trains of combined lateral hypothalamic (LH) and nucleus reticularis gigantocellularis (Gi) stimulation, in which each LH pulse was followed 2 ms later by the Gi one, was determined for one month. Compared to the threshold for trains of single LH pulses, combined LH-Gi stimulation initially increased the frequency threshold; however, this effect reversed within one session and was subsequently maintained for the duration of the study. The aversion produced by Gi stimulation, as measured by latency to escape, was abolished following a single session of LH-Gi pairs. In the second study, a subset of animals received both presentations of combined pulses, LH followed by Gi, and the reverse; the interval between pulses was varied from 0.2 to 6.4 ms. The effectiveness of combined stimulation, determined by the ratio of LH frequency thresholds to that of the LH-Gi ranged from 0 to 50% across animals but the individual effectiveness functions within animals did not vary with different intervals. In addition, the order of presentation of pulses was of no consequence. Thus, not only did exposure to LH stimulation appear to obliterate Gi aversion, but the combination of LH and Gi pulses added to the rewarding effect produced by LH stimulation alone.     

Current-distance relation for rewarding brain stimulation

A novel approach to estimating the current density required to directly activate axons involved in the reinforcing effect of brain stimulation is described. Self-stimulating rats received trains of cathodal pulse pairs via two adjacent, stimulating electrodes which were positioned in the lateral hypothalamus and oriented to lie in a plane transverse to the medial forebrain bundle. The first pulse of each pair was delivered through one electrode and, after varied delays, the second was applied to the other electrode in an attempt to detect a loss of stimulation effectiveness attributable to refractoriness of axons that penetrated the intersection of the two stimulation fields. In low-current tests, no change in the psychophysically scaled effectiveness was observed as the interval separating the pulses was varied but, at higher currents, the stimulation effectiveness rose when the delay between the pulses surpassed the refractory periods of these cells. Our inference was that greater currents produced progressively overlapping stimulation fields. Moreover, evidence of overlap was seen at lower currents in rats that had been prepared with smaller separations between the electrodes. Our estimate of the threshold current density for the most sensitive of the reward units is 1300 microA/mm2 when 0.1 ms pulses are used.     

Task difficulty increases thresholds of rewarding brain stimulation

The effect of increasing task difficulty on the threshold of rewarding, electrical brain stimulation was evaluated. Rats were trained to press a lever to obtain a brief burst of pulses to the lateral hypothalamus. The threshold was psychophysically scaled using a descending method of limits in which the pulse frequency was varied to yield a maximum to minimum range of self-stimulation rates. As expected, weighting the lever with 0, 15, 30, or 45 g produced progressive decreases in maximal rates, but it also caused a weight-related shift to the right of the rate-frequency ogives in each of the 7 rats. Although the degree of shift varied from rat to rat, it did not matter whether criterion performance was defined as half-maximum rate or as a constant rate of 5 responses. These results suggest that the effort required to make the operant response contributes to the position of rate-frequency curves and, further, that shifts in rate-frequency functions must be interpreted with caution when such shifts are obtained by CNS lesions or drug injections.     

Haloperidol modulates noradrenergic responses to aversive stimulation depending on treatment duration

Antipsychotic drugs are widely used in the treatment of schizophrenia. While their effects are considered to be due to a modulation of dopaminergic and serotonergic signaling, little is known about their effects on noradrenergic (NA) activity in the brain. In this study, rats received either a 6 d or 14 d treatment with haloperidol using osmotic minipumps. Noradrenaline responses to novelty, appetitive food and to an aversive tail pinch were measured in the prefrontal cortex, nucleus accumbens and caudate putamen (CPu) using in vivo microdialysis. Haloperidol significantly decreased baseline NA levels after short and long term treatment. A tail pinch significantly increased NA activity in the CPu. This effect was attenuated by haloperidol in a treatment duration-dependent way. This study suggests that haloperidol modulates NA baseline activity and reduces NA responses to mildly aversive stimuli depending on treatment duration.     

Cholinergic involvement in lateral hypothalamic rewarding brain stimulation

Rats were implanted with stimulating electrodes in the lateral hypothalamus, and cannulae for chemical injections in the ventral tegmentum. Injections of atropine, a muscarinic antagonist, increased thresholds for self-stimulation in a dose-dependent fashion, without slowing bar pressing rates. Thresholds increased less for a self-stimulation site contralateral to the atropine injection. In a conditioned place preference test, the rats preferred compartments in which they received carbachol, a cholinergic agonist. Muscarinic receptors in ventral tegmentum therefore seem critical for medial forebrain bundle (MFB) reward. The possible cholinergic cells of origin are discussed.     

Consistent rewarding or aversive effects of the electrical stimulation of the lateral parabrachial complex

Electrical stimulation of the external lateral parabrachial subnucleus (LPBe) may induce rewarding or aversive behaviors in animals subjected to two different learning discrimination tasks. Statistical analysis found no significant differences between the group receiving electrical stimulation of the brain and the non-stimulated control group. However, rewarding or aversive behaviors were consistent and positively correlated between the two discrimination tasks in the stimulated group. Thus, these tests differed in the gustatory stimuli used, in the right/left position of stimulation-associated/non-associated flavors, and in the cage in which experiments were performed. This behavioral consistency and corresponding correlation were not observed in the non-stimulated control group. These results suggest the existence of aversive and reward systems that are differentiated but anatomically very close. Therefore, the activation of aversive or rewarding systems may depend on the precise location of the electrode implanted in the LPBe of each animal.     

Unilateral subthalamic nucleus deep brain stimulation contralateral to thalamic stimulation in Parkinson disease

The effects of unilateral subthalamic nucleus (STN) stimulation contralateral to thalamic stimulation in Parkinson disease (PD) have not been previously reported. We are reporting a patient who developed left arm tremor in 1994, at age 62, as her first PD symptom. She underwent right thalamic DBS surgery in 1999 that resulted in complete resolution of left arm tremor. Her PD symptoms progressed and she developed severe motor fluctuations and disabling dyskinesias. In 2003, she underwent left STN electrode implantation. Left STN stimulation improved contralateral motor scores in the medication OFF state, and allowed for reduced medication doses and less dyskinesia. However, there was no significant improvement in activities of daily living (ADL), motor scores in the medication ON state, gait, or postural stability.