Intracranial self-stimulation in the parafascicular nucleus of the rat

A behavioral analysis of intracranial self-stimulation was provided for parafascicular nucleus. To evaluate whether intracranial self-stimulation in this nucleus could be site-specific and to determine if the positive sites are the same parafascicular areas that facilitate learning when stimulated, rats were tested via monopolar electrodes situated throughout the parafascicular nucleus. Animals were trained to self-stimulate by pressing a lever in a conventional Skinner box (1-5 sessions). Twenty-two of the 42 animals included in the study, had the electrode at the parafascicular nucleus. Only two of them showed intracranial self-stimulation. Histological analyses indicated that the latter rats had the electrode implanted at the anterior area of the medial parafascicular. Other two animals also showed intracranial self-stimulation but they had the electrode in a more posterior brain region, between the Dark-schewitsch nucleus and the red nucleus. The animals implanted at the parafascicular showed higher response rates than the other two rats. These results confirm that: (a) the anterior region of the medial parafascicular is a positive site for stable and regular intracranial self-stimulation behavior, and (b) these positive sites do not coincide with the parafascicular regions related to learning improvement.     

Monoamine involvement in hippocampal self-stimulation.

The roles of noradrenergic and serotonergic projections to the hippocampus were investigated with respect to their involvement in the intracranial self-stimulation of this structure. In the first study, 6-hydroxydopamine-induced lesions of the dorsal tegmental noradrenergic bundle, which depleted hippocampal NE by 97%, had no effect on hippocampal self-stimulation in rats. In the second study, intragastric administration of para-chlorophenylalanine (PCPA) decreased hippocampal self-stimulation, suggesting the importance of a serotonin input in maintaining this behavior. Identical PCPA treatments resulted in temporary depletions of brain serotonin which paralleled the changes in hippocampal self-stimulation. The maximal decreases in both the biochemical and behavioral measures occured at 4 days post-drug. Interpretations of this deficit in hippocampal self-stimulation in terms of gross sensory and/or motor changes were ruled out as animals with lateral hypothalamic electrodes showed increases in self-stimulation paralleling the post-drug serotonin changes. An intra-sessional analysis of the PCPA-induced behavioral changes revealed that lateral hypothalamic self-stimulation was facilitated mainly during the first hour of the two-hour test sessions, whereas the depression in hippocampal self-stimulation occurred primarily in the last hour of the sessions. The differential effects of PCPA on lateral hypothalamic and hippocampal self-stimulation provide evidence against simple monoamine theories of reinforcement.     

Increased dopamine and serotonin metabolism in rat nucleus accumbens produced by intracranial self-stimulation of medial forebrain bundle as measured by in vivo microdialysis

In the present study, we have used a newly developed microdialysis system to perfuse the nucleus accumbens (NAC) of conscious rats during spontaneous intracranial self-stimulation of the medial forebrain bundle (MFB). Chromatographic (HPLC-ECD) analysis of the perfusates showed that dopamine (DA) release increased, but with an unstable pattern during the actual period of self-stimulation. On the other hand, the main DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and a serotonin metabolite 5-hydroxyindoleacetic acid, were all markedly enhanced by self-stimulation, but with different time courses. These findings indicate that self-stimulation of the MFB in rats induces increases in both DA and serotonin activities in the NAC. Such changes may be involved in mediating self-stimulation of the MFB.     

Post-training intracranial self-stimulation facilitates a hippocampus-dependent task

Previous research has shown that post-training intracranial self-stimulation facilitates implicit or procedural memory. To know whether it can also facilitate explicit memory, post-training intracranial self-stimulation was given to Wistar rats immediately after every daily session of a delayed spatial alternation task that seems to depend on the integrity of the hippocampal memory system. We tested the effects of intracranial self-stimulation in three consecutive learning phases which tried to make the task progressively more difficult: 10 s delay (D10 phase), 30 s delay (D30 phase), and inverting the starting position of the animals to make their response more dependent on allocentric cues (INV phase). Every phase finished when each rat achieved a fixed learning criterion. Intracranial self-stimulation facilitated the flexible expression of the learned response (INV phase). That is, when the starting position was randomly inverted, only the rats that received intracranial self-stimulation maintained the performance level acquired in the previous training phases. Changing the starting position reduced the correct performance of the non-treated subjects, which need more training sessions to achieve the learning criterion and made less correct responses than treated rats. These findings show that post-training intracranial self-stimulation can facilitate hippocampus-dependent memories.     

Responses of ventral tegmental area GABA neurons to brain stimulation reward

Dopamine neurons in the ventral tegmental area (VTA) have been implicated in rewarded behaviors, including intracranial self-stimulation (ICSS). We demonstrate, in unrestrained rats, that the discharge activity of a homogeneous population of presumed VTA GABA neurons, implicated in cortical arousal, increases before ICSS of the medial forebrain bundle (MFB). These findings suggest that VTA GABA neurons may be involved in the attentive processes related to brain stimulation reward (BSR).     

Behavioral intervention for self-stimulatory, attending and seizure behavior in a cerebral palsied child

This study evaluated the effects of a behavioral treatment package and anti-convulsant medication for reducing self-stimulation and seizure activity, and for improving attention in a 7-yr-old white male. During baseline (A), no direct contingencies for the target behaviors were applied. In the B phase, hand overcorrection for self-stimulation and differential reinforcement of attentional responses and behaviors incompatible with self-stimulation were arranged. Carbamazepine (tegretol) was added to the behavioral program in the BC phase. Medication was later withdrawn while behavioral strategies remained in effect. The results showed rapid and significant improvements in all target symptoms during all phases of behavioral treatment, while introduction and withdrawal of medication did not result in any significant changes. Effects were maintained at 8 months' follow-up.     

Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation

The ability of chronic treatment with the atypical neuroleptic clozapine to induce functional dopaminergic hypersensitivity in laboratory rats was assessed. The intracranial electrical self-stimulation paradigm, known to be sensitive to changes in functional dopaminergic sensitivity, was used. Animals with electrodes in the ventral tegmental nucleus (mesolimbic dopamine cell body area) showed a marked increase in self-stimulation rate following 3 weeks of chronic clozapine. This increase was similar in magnitude and duration to that shown by animals given 3 weeks of chronic haloperidol. In contrast, animals with electrodes in the substantia nigra (nigrostriatal dopamine cell body area) showed no change in self-stimulation rate following 3 weeks of chronic clozapine. These data are interpreted in the light of previous suggestions that clozapine and other atypical neuroleptics may possess functional selectivity for the mesolimbic dopamine system.     

Lack of glucocorticoids attenuates the self-stimulation-induced increase in the in vivo synthesis rate of dopamine but not serotonin in the rat nucleus accumbens

Our previous study demonstrated that intracranial self-stimulation of the medial forebrain bundle can increase the in vivo synthesis turnover rate of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of adrenal-intact rats. The present study examined using microdialysis whether such increases in DA and 5-HT syntheses are influenced by adrenal hormones, which are also activated following intracranial self-stimulation. A decarboxylase inhibitor, NSD-1015, was perfused through reversed microdialysis which enabled the simultaneous measurement of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) as an index of the in vivo turnover rate of DA and 5-HT syntheses. Adrenalectomy (ADX) attenuated significantly the self-stimulation-induced increase in dialysate levels of DOPA but not 5-HTP. Corticosterone (Cort) replacement reversed the attenuation in DOPA levels in adrenalectomized rats. The finding indicates that activation of DA synthesis in vivo in the nucleus accumbens during intracranial self-stimulation is dependent on, whereas that of 5-HT synthesis is independent of glucocorticoid modulation.     

Evaluation of stressor effects on intracranial self-stimulation from the nucleus accumbens and the substantia nigra in a current intensity paradigm

The effect of uncontrollable footshock was evaluated in animals responding for intracranial self-stimulation from the nucleus accumbens and the substantia nigra (pars compacta) in a descending current intensity paradigm. Responding for brain stimulation from the nucleus accumbens was found to be affected by the stressor at the upper end of the rate-intensity curve. In contrast, responding for brain stimulation from the substantia nigra was unaffected by the stressor at any of the current intensities employed. The variations of responding for self-stimulation from the nucleus accumbens were unrelated to alterations of locomotor activity or rearing. It is suggested that stressor-provoked reductions of responding for intracranial self-stimulation are not a result of the brain stimulation taking on aversive properties, but rather reflect a reduction in the reinforcing or motivational value associated with the stimulation.     

Adaptations in reward-related behaviors and mesolimbic dopamine function during motherhood and the postpartum period

Initiation and maintenance of maternal behavior is driven by a complex interaction between the physiology of parturition and offspring stimulation, causing functional changes in maternal brain and behavior. Maternal behaviors are among the most robust and rewarding motivated behaviors. Mesolimbic dopamine (DA) system alterations during pregnancy and the postpartum enable enhanced reward-related responses to offspring stimuli. Here, we review behavioral evidence demonstrating postpartum rodents exhibit a bias towards pups and pup-related stimuli in reward-related tasks. Next, we provide an overview of normative adaptations in the mesolimbic DA system induced by parturition and the postpartum, which likely mediate shifts in offspring valence. We also discuss a causal link between dopaminergic dysfunction and disrupted maternal behaviors, which are recapitulated in postpartum depression (PPD) and relevant rodent models. In sum, mesolimbic DA system activation drives infant-seeking behavior and strengthens the mother-infant bond, potentially representing a therapeutic target for reward-related deficits in PPD.     

Voltammetry of extracellular dopamine in rat striatum during ICSS-like electrical stimulation of the medial forebrain bundle

Fast-scan voltammetry cyclic in the striatum of anesthetized rats has been used to monitor extracellular dopamine during forced electrical stimulation of the media forebrain bundle using parameters that mimic intracranial self-stimulation. The temporal resolution provided by microelectrodes positioned very near sites of dopamine release allows resolution of the response to individual 500-ms stimulation trains separated by 500-ms intervals. Uptake inhibition by Nomifensine alters the resolution obtained at short times after initiation of stimulation.     

Differences in sensitivity to neuroleptic blockade: medial forebrain bundle versus frontal cortex self-stimulation

The effects of systemic injections of the dopamine receptor antagonist, cis-flupenthixol were tested on intracranial self-stimulation at electrode sites in the medial forebrain bundle and the medial prefrontal cortex. Changes in the reward effectiveness of the brain stimulation were assessed using a curve-shift paradigm. Low to moderate doses of cis-flupenthixol (0.05, 0.1 and 0.15 mg/kg) consistently produced larger upward shifts in the rate-frequency function for medial forebrain bundle than for medial prefrontal self-stimulation. At the highest doses of cis-flupenthixol (0.15 and 0.2 mg/kg), some of the medial forebrain bundle rats failed to respond, whereas all medial prefrontal rats responded at these doses. These results demonstrate that medial forebrain bundle self-stimulation is much more dependent on dopamine systems than is prefrontal cortex self-stimulation.     

Type 1 5α-reductase may be required for estrous cycle changes in affective behaviors of female mice

There are estrous cycle differences in affective behaviors of rodents that are generally attributed to cyclic variations in estradiol, progesterone (P) and its metabolites. A question is the role of the steroid metabolism enzyme, 5α-reductase, for these estrous cycle differences. To address the requirement of 5α-reductase, estrous cycle variations in the behavior of wildtype mice and their littermates that are deficient in the 5α-reductase type 1 enzyme (5αRKO mice) were examined. The hypothesis was that if some of the estrous cycle differences in exploratory (open field) and anxiety (elevated plus maze) are due to P's 5α-reduction to 5α-pregnan-3α-ol-20-one (3α,5α-THP), then wildtype mice will have estrous cycle differences in the expression of these behaviors, but 5αRKO mice will not. Mice were tested in these tasks and then had plasma and brains collected so that steroid levels (estradiol, P, 3α,5α-THP, corticosterone) could be measured in these tissues. Results supported this hypothesis. There were estrous cycle differences among wildtype, but not 5αRKO, mice. Proestrous wildtype mice made more central entries in the open field and spent more time on the open arms of the plus maze, coincident with higher 3α,5α-THP levels in plasma and brain regions important for these behaviors, such as the hippocampus and cortex, compared to their diestrous counterparts. Variability in the open field and elevated plus maze could be explained by circulating and hippocampus levels of 3α,5α-THP, respectively. Thus, 5α-reductase may be required for the estrous cycle variations in affective behavior and 3α,5α-THP levels of female mice.     

Chronic brain stimulation rewarding experience ameliorates depression-induced cognitive deficits and restores aberrant plasticity in the prefrontal cortex

Background

Major depressive disorder (MDD) is a multifactorial disease which often coexists with cognitive deficits. Depression-induced cognitive deficits are known to be associated with aberrant reward processing, neurochemical and structural alterations. Recent studies have shown that chronic electrical stimulation of brain reward areas induces a robust antidepressant effect. However, the effects of repeated electrical self-stimulation of lateral hypothalamus - medial forebrain bundle (LH-MFB) on depression-induced cognitive deficits and associated neurochemical and structural alterations in the prefrontal cortex (PFC) are unknown.

Site of rewarding action of morphine in the mesolimbic system determined by intracranial electrical self-stimulation

Systemic treatment with morphine has been shown to facilitate intracranial electrical self-stimulation reward elicited from the ventral tegmental area (VTA) as was determined using a response rate-insensitive threshold measurement. In the present experiment graded doses of morphine were microinjected into the mesolimbic system to determine the site of this morphine action. Morphine injected into the nucleus accumbens did not affect the threshold and response rate of self-stimulation by electrodes in the VTA, while relatively high doses of morphine injected into the VTA produced a long-lasting decrease of the threshold of self-stimulation by electrodes in the nucleus accumbens. It is concluded that morphine can facilitate self-stimulation when injected into the VTA, and that a concerted action of morphine on multiple brain sites may be involved in the interaction of the drug with brain reward.     

Electrical self-stimulation in the parabrachial area is depressed after ibotenic acid lesion of the lateral hypothalamus

The involvement of lateral hypothalamic intrinsic neurons on electrical self-stimulation of the parabrachial area was analyzed. Rats were bilaterally implanted in the parabrachial area and with a guide cannula located above each lateral hypothalamus. They were subsequently tested for intracranial self-stimulation. Then, the lateral hypothalamus on one side of the brain was injected with ibotenic acid. The effect of the induced lesion was tested 8 days later on self-stimulation of the ipsilateral and contralateral parabrachial areas. The intrinsic neurons of the non-lesioned lateral hypothalamus were then destroyed with ibotenic acid. Self-stimulation was then tested 8, 12 and 30 days later. The unilateral lesion produced a significant decrease of self-stimulation using the electrode ipsilateral to the lesion, without any modification of the stimulation using the contralateral electrode. After bilateral lesion, self-stimulation was greatly reduced bilaterally. The results suggest that the main effect of the lesion was to increase the self-stimulation threshold. Given that the parabrachial area is a relay station for the gustatory inputs and that the intrinsic neurons of the lateral hypothalamus project back to the parabrachial area, the present results are tentatively interpreted as an indication that self-stimulation in this pontine area results from the activation of feedback loops between the lateral hypothalamus and the parabrachial area.     

Intracranial self-stimulation in relation to the ascending noradrenergic fiber systems of the pontine tegmentum and caudal midbrain: A moveable electrode mapping study

Chronically implanted moveable electrodes were used to map the pontine tegmentum and caudal midbrain for intracranial self-stimulation in relation to the ascending noradrenergic systems as revealed by fluorescence histochemistry. In no area tested was there a consistent correlation between the quality or the presence of self-stimulation and the degree of noradrenergic fiber density or cellular aggregation. Of particular importance was the failure to obtain self-stimulation from the locus coeruleus, despite repeated testing and extensive attempts at behavioral shaping. Those areas supporting self-stimulation included the dorsal raphe nucleus, the superior cerebellar peduncle and the mesencephalic and motor nuclei of the trigeminal nerve. These data appear to rule out activation of the ascending noradrenergic systems as an explanation of the rewarding effects of stimulation in these areas. A gustatory-visceral fiber system is suggested as an alternative possible substrate.     

Spatial firing properties of lateral septal neurons

The present study describes the spatial firing properties of neurons in the lateral septum (LS). LS neuronal activity was recorded in rats as they performed a spatial navigation task in an open field. In this task, the rat acquired an intracranial self-stimulation reward when it entered a certain place, a location that varied randomly from trial to trial. Of 193 neurons recorded in the LS, 81 showed place-related activity. The majority of the tested neurons changed place-related activity when spatial relations between environmental cues were altered by rotating intrafield (proximal) cues. The comparison of place activities between LS place-related neurons recorded in the present study and hippocampal place cells recorded in our previous study, using identical behavioral and recording procedures, revealed that spatial parameters (spatial information content, coherence, and cluster size) were smaller in the LS than in the hippocampus. Of the 193 LS neurons, 86 were influenced by intracranial self-stimulation rewards; 31 of these 86 were also place-related. These results, together with previous anatomical and behavioral observations, suggest that the spatial information sent from the hippocampus to the LS is modulated by and interacts with signals related to reward in the LS.     

The effects of ventral tegmental administration of GABA(A), GABA(B), NMDA and AMPA receptor agonists on ventral pallidum self-stimulation

The ventral pallidum (VP) is a basal forebrain structure that is interconnected with motor and limbic structures and may be considered as an interface between motivational and effector neural signals. Results from a considerable number of studies suggest that this structure is critically involved in reward-related behavior. The VP shares reciprocal connections with other reward-implicated regions, such as the ventral tegmental area (VTA). This anatomy predicts that drug-induced neuronal alterations in the VTA could profoundly alter the function of the VP. Here, using the curve-shift intracranial self-stimulation method, we studied the effects of muscimol (GABA(A) agonist), baclofen (GABA(B) agonist), NMDA and AMPA, microinjected bilaterally into the VTA on the rewarding efficacy of VP self-stimulation. Central injections of the highest dose of muscimol (0.128 microg) resulted in significant elevations in VP self-stimulation thresholds, indicating a reduction in the rewarding efficacy of the stimulation. Elevations in VP self-stimulation thresholds were also evident after intrategmental injections of higher doses of baclofen (0.12, 0.48 microg). By contrast, intrategmental activation of NMDA and AMPA receptors did not affect reward thresholds. These findings suggest that GABAergic and glutamatergic transmission in the VTA activate different circuits that may mediate different functions. Thus, the VTA--VP projection activated by GABA modulates VP stimulation reward, while the projection activated by glutamate may be involved in reward-unrelated effects, rather than in the processing of reward. The decreased rewarding efficacy of VP self-stimulation following intrategmental injections of muscimol and baclofen may be due to GABAergic modulation of ventral tegmental dopaminergic and nondopaminergic neurons projecting to the VP.     

Effects of opiate antagonists and their quaternary analogues on nucleus accumbens self-stimulation

Naloxone and naltrexone were compared with their quaternary analogues naloxone methobromide and naltrexone methobromide for efficacy in suppressing intracranial self-stimulation behavior. These quaternary analogues effectively block opiate receptors in the periphery, but since they do not readily cross the blood-brain barrier they have little effect on central receptors. Rats with electrodes in the nucleus accumbens were trained to self-stimulate in daily 60-min sessions. Naloxone (0.2, 2.0 and 20 mg/kg) and naltrexone (20 mg/kg) potently suppressed self-stimulation behavior. In contrast, neither naloxone methobromide (0.2 and 20 mg/kg) nor naltrexone methobromide (20mg/kg) had any significant effects on this behavior. These results suggest that blockade of peripheral opiate receptors alone is insufficient to suppress self-stimulation, and therefore support the idea that opiate antagonists suppress self-stimulation by blockade of central receptors that mediate reinforcement.