Intracranial reward after 5,6-dihydroxytryptamine: further evidence for serotonin's inhibitory role

One intraventricular injection of 50 μg of 5,6-dihydroxytryptamine produced, 24 hr later, a marked increase in rates of medial forebrain bundle self-stimulation. Whole brain serotonin levels were selectively depressed at this time, presumably because of the destructive effect on serotonin-containing neuron terminals. When whole brain serotonin levels had recovered fairly close to normal, the excitatory effect had disappeared. In rats having self-stimulation electrodes positioned at slight distances from the medial forebrain bundle, the excitatory effect never appeared. These results further support the theory that serotonergic neurons in the medial forebrain bundle are part of an inhibitory system subserving reward and motivational mechanisms. The results also again show the great importance of electrode placement as a determinant of a drug's effect on self-stimulation.     

Effect of intraventricular oxytocin and vasopressin on self-stimulation in rats.

Oxytocin (500 mu u) and vasopressin (50 mu u) were injected into the lateral ventricle and its effect on hypothalamic self-stimulation has been studied. Oxytocin increased, while vasopressin decreased the self-stimulation rate tested 10-20 min following application. The hypothalamic and mesencephalic serotonin content decreased slightly while plasma corticosterone content did not change 20 min after oxytocin and vasopressin administration compared to the injected control animals. The data suggest that vasopressin and oxytocin have an opposite effect on self-stimulation and this action is not mediated through the brain serotoninergic or pituitary-adrenocortical axis.     

Participation of brain stimulation reward substrates in memory: anatomical and biochemical evidence.

On the basis of the pioneering leads provided by James Olds, brain stimulation reward has been shown to be a) derived from specific anatomical locations, b) influenced by psychotropic drugs, and c) functionally related to feeding behavior and sexual activity. These results recommend the view that it is worthwhile to understand, not necessarily the curious intracranial self-stimulation behavior itself, but the physiological function of the substrate revealed by the intracranial self-stimulation (ICSS) technique. I have suggested that certain components of the brain stimulation reward system may function as a memory consolidation system. In view of the biological specificity of brain reinforcement pathways, I suggest the hypothesis that activity in the mesocortical dopaminergic brain stimulation reward pathways participates in the memory consolidation process. Consequent to activity in such anatomical systems, phosphorylation of band F in the frontal cortex is altered. Thus, intracranial self-stimulation pathways are considered to play a role in memory formation by providing a biochemical residual following learning.     

Hypothalamic self-stimulation and stimulation escape in relation to feeding and mating.

This review begins with James Olds' discovery that self-stimulation at various brain sites can be influenced by food intake or androgen treatment. It then describes our research designed to reveal the functional significance of self-stimulation. The evidence suggests that lateral hypothalamic self-stimulation is controlled by many of the same factors that control feeding. We believe this control is exerted by at least two neural mechanisms. One is the classical, medial hypothalamic satiety system. Another is an adrenergic system ascending from the midbrain to the lateral hypothalamus. Damage to either one can disinhibit self-stimulation and feeding, thus contributing to obesity. Some of our studies use rats with two electrodes, one that induces feeding and one that induces mating. There are two response levers in the test cage, one for self-stimulation and one for escape from automatic stimulation. With the feeding electrode, rats self-stimulated less and escaped more after a meal than before. The same shift occurred after an anorectic dose of insulin or the commercial appetite suppressant phenylpropanolamine. With the sex electrode the shift from reward to aversion occurred after ejaculation. The review ends with credit to James Olds for pioneering this line of research into the neuropsychology of reinforcement.     

Long-term changes in self-stimulation threshold by repeated morphine and naloxone treatment

To analyse the interaction between endogenous opioid systems and brain reward, the influence of repeated treatment for 3 weeks with morphine and the opioid antagonist naloxone was investigated in rats with self-stimulation electrodes in the ventral tegmental area. Changes in threshold of self-stimulation determined by a response rate insensitive two lever method were considered as changes in reward. Morphine induced a temporary decrease of the response rate which lasted 3 days, and decreased the threshold for self-stimulation. The effect on threshold remained present till morphine treatment was discontinued, indicating that tolerance does not develop to this effect of morphine. Repeated naloxone treatment gradually increased the threshold for self-stimulation. This effect persisted after discontinuation of naloxone treatment. It is concluded that blockade of opioid receptors induces long term changes in the setpoint of self-stimulation reward.     

The effect of different activating influences on the self stimulation reaction]

A study was made of the influence on self-stimulation of non-painful sensory stimuli of different modalities, and of intra-brain stimulations of emotionally positive and neutral points with the wiew to elucidate the specificity of certain functional relations appearing during interaction between emotionally negative and positive conditions. The data obtained attest that the influence of various excitation sites on self-stimulation reactions depends not so much on the strength of the stimuli, as on the specific neurophysiological organization of emotionally negative zones in the brain. A reciprocal enhancement of excitation of self-stimulation zones points to a certain non-specificity of positively reinforced structures.     

Reinforcing stimulation of the postero-lateral hypothalamus and mating behaviour in the rat.

Male rats implanted with chronic electrodes into the postero-lateral hypothalamic site were tested for self-stimulation behaviour. Rats exhibiting steady self-stimulation behaviour were observed during mating tests with an oestrus female. During these tests the hypothalamus of male rats was stimulated. Results show that no stimulus-bound sexual behaviour was observed. Nevertheless, correlations were found between the rewarding value of the cerebral stimulation and the specific sexual components of mating behaviour. These results are interpreted with the hypothesis of a balancing effect between the reward elicited by direct stimulation of the brain and reward acquired by the presence of an oestrus female.     

The neurochemical substrates of prefrontal cortex self-stimulation: a review and an interpretation of some recent data.

The medial and sulcal prefrontal cortex of the rat have been shown to be the only part of the frontal cortex which supports intracranial self-stimulation. The fact that these two areas of the cerebral cortex are particularly rich in dopaminergic terminals has recently led to the speculation as to the possible essential role of dopamine in self-stimulation of this part of the brain. The present paper reviews the work done on self-stimulation of the prefrontal cortex and pays special attention to a recent series of studies which seem to provide some evidence for the involvement of dopamine as the neurochemical substrate. A theoretical interpretation of the results is discussed.     

Cyclic nucleotides in the rat brain in the dynamics of hypothalamic self-stimulation

The content of cyclic nucleotides was measured in the brain structures of rats performing hypothalamic self-stimulation. Changes of the cAMP content were shown to possess a specific pattern corresponding to the features of self-stimulation. An increasing self-stimulation frequency (SSF) was followed by the maximum increase in the above index in the sensorimotor cortex; a stable SSF was accompanied by activation of the cAMP-dependent mechanisms of the septum, hypothalamus, and posterior hypophysis, while a decreasing SSF correlated with suppression of these processes in the septum, hypothalamus, and anterior hypophysis. Changes in the cAMP phosphodiesterase activity were less intensive and did not depend on the cGMP level. Changes in the cGMP content were nonspecific and unidirectional: this index increased, with the maximum at the stable self-stimulation mode. The ratio of cyclic nucleotides shifted toward cAMP when the SSF increased, and towards cGMP when the SSF decreased, while at a stable frequency their content was equal to the control level. The changes in the cyclic nucleotide contents were non-reciprocal (except an inverse correlation between their contents in the hypothalamus observed when the SSF dropped).     

Behavioral reactions to stimulation of the emotiogenic zones of the brain in the rats with different individual experience

Emotional reactions evoked by electric stimulation of the hypothalamus and amygdala were studied in white outbred rats, grown either in conditions of isolation or in community. The method of self-stimulation in shuttle box was used. The values of self-stimulation reaction were significantly lower and those of avoidance reactions were higher in animals bred in isolation. Their food-procuring behaviour disappeared faster at stimulation of the negative emotiogenic zones. The observed differences are due to plastic reorganization of the brain reinforcing systems.     

Motivation dependence of brain self-stimulation in the pigeon

Several brain sites in the pigeon were identified as maintaining electrical brain self-stimulation. Depending on the site, stimulus currents yielding maximal responding varied from 20 to 160 μA. A high proportion of the sites only yielded self-stimulation behaviour if the subjects were deprived of food; when the birds were at full weight there was only one site at which the stimulation continued to be rewarding. Some, but weak, evidence of stimulus satiation was found. Overt behaviour elicited by non-contingent stimulation did not correlate with the reinforcing or neutral nature of the sites tested. While some positive sites were associated with structures known to be involved in the control of feeding, others were not. The hypothesis that stimulation at the hunger-dependent sites might have elicited temporary satiation signals is considered.     

Relation between the dynamics of the extinction process and the initial rate of hypothalamic self-stimulation in the rabbit

In experiments on rabbits with electrodes chronically implanted in the lateral hypothalamus, dynamics was studied of extinction of self-stimulation reaction as a result of cancellation of intracerebral reinforcement. General dynamics of extinction of the unreinforced instrumental actions and behavioural manifestations of orienting-investigating reaction were revealed. It was found, that in 30% of rabbits, the orienting reaction appearing as a result of "discordance" between expected and actual afferentation is attended by a species-specific form of behaviour, expressed in the form of hind paws synergic strokes against the floor. It is suggested that these strokes may be a somatic expression of a negative emotional state of animals during self-stimulation extinction. The comparison of extinction dynamics with the level of self-stimulation background frequency showed a relative independence of the strength of drive towards getting positive emotions on motivational effects created by electric stimulation of the reinforcing brain structures.     

Preference and aversion for brain stimulations estimated by the conditioned place preference

Rats implanted with chronic electrode into the medial forebrain bundle at the level of the hypothalamus (which elicited self-stimulation behaviour) display conditioned place preference after repeated stimulations of this area; conversely rats implanted into the mesencephalic dorso-medial tegmentum (which elicited switch-off behaviour) present conditioned place aversion after such repeated stimulations. Furthermore rats implanted in these two area without exhibiting self-stimulation or switch-off behaviours also display preference or aversion for the location paired with the brain stimulations. It was thus hypothesized that the conditioned place preference procedure seemed to present a higher sensitivity than the bar pressing procedures to detect preference or aversion for brain stimulation. Moreover the activation of the medial forebrain bundle which was associated with positive affect is more effective for a long term retention of the preferred location than midbrain periventricular reticular activation which induces a negative affect.     

Similar effect of caerulein on intracranial self-stimulation in vagotomized and non-vagotomized rats

Electrical stimulation eliciting self-stimulation behavior from postero-lateral hypothalamic implanted electrode was controlled by factors that control normal feeding. In this idea, lateral hypothalamic stimulation possessed an appetite whetting property and this is experienced as rewarding. The octapeptide cholecystokinin, a gut hormone, has been experimented upon to produce the complete behavioral sequence of satiety in rats. We observed that an i.p. injection of caerulein (an analog of cholecystokinin) did decrease, in a dose-related manner, the rate for brain self-stimulation. However, a similar effect on the rate of ICSS was measured after a bilateral cut of the vagus nerve at a subdiaphragmatic level. This result suggests that the decreasing effect on ICSS after an i.p. injection of caerulein is not strictly related to feeding. We interpret the decrease of reinforcement induced by caerulein as the action of a general satiety for any object presenting a rewarding value for behavior.     

Model representation of rat motor behavior during electrical self-stimulation of the brain. I. Brief review of experimental data. Formal model]

The stimulation of the brain in self-stimulation situation activated the motor behaviour. The activity of the motor behaviour versus duration of the movements which define the motor activity is a decreasing function. The effect of stimulation versus duration or the strength of stimulation is an increasing function. The solutions of equation having made after comparing these two functions demonstrate the relations between the motor behaviour and stimulation parameters.     

Interrelations of the emotionally positive and negative areas of the brain in the edible snail

Fine wire electrodes were surgically implanted in two regions of a snail's brain (Helix aspersa). To receive electrical stimulation of the brain, the tethered snail was required to displace the end of a rod. Self-stimulation delivered to the parietal ganglion resulted in nonrepetition of the operant response, whereas self-stimulation delivered to the mesocerebrum resulted in an increase in response frequency. In neurophysiological experiments it was found that extracellular stimulation of mesocerebrum inhibits spontaneous activity of serotonergic cells modulating avoidance reactions, and decreases synaptic input of a command cell for avoidance behaviour. These findings make possible intracellular investigations of the mechanisms of positive and negative reinforcement.     

The role of biological needs in the genesis of self stimulation]

It has been found in fifteen rats with monopolar electrodes implanted in the lateral hypothalamus that after stimulation of the brain with bursts of electrical pulses of fixed duration, with definite combinations of stimulation parameters, the histograms of the duration of pedal pressing have a polymodal appearance. As the combinations of stimulation parameters change, the number, position and magnitude of the modes undergo a corresponding change. With unchanged parameters of stimulation the form of pressing duration histogram does not change significantly. A conclusion has been drawn that the modal duration of pressing in the course of self-stimulation is apparently an effector manifestation of central integration of reinforcing excitation. In a state of hunger and thirst as well as under weak nembutal anaesthesia, the previously monomodal histograms of the pressing durations produce additional modes which diminish and disappear after satiation and discontinuation of the nembutal effect. It is assumed that at least some modes of the histograms of the pressing duration of self-stimulation may reflect an activation of the systems of biological needs.     

Self stimulation against a background of action of blockers of the synthesis of proteins and oligopeptides

The experiments on rabbits have demonstrated that blockade of protein synthesis by the administration of cycloheximide and actinomycin D abolishes self-stimulation in the central nervous system. The treatment with ACTH fragment (ACTH4-10) restored the self-stimulation. Unlike ACTH, injections of pentagastrin, Met-enkephalin, Leu-enkephalin and cholecystokinin were ineffective. The present study shows that ACTH4-10 plays an important role in genetic determination of self-stimulation behaviour.     

Behavioral interactions in cocaine-treated rats

Effects of a single dose of cocaine (10 mg/kg,i.p.) were studied on spontaneous motor activity (SMA), stereotypy. self-stimulation of the posterior hypothalamus or area ventralis tegmentum (A10 area) and nonreinforced bar-pressing in rats. Interactions among these behaviors were investigated under different experimental designs. Cocaine caused an initial increase of SMA, which was later decreased significantly, as stereotypy became more prominent. Cocaine also caused facilitation of self-stimulation responding that further increased SMA. In both groups of self-stimulating rats, stereotypy disappeared completely during self-stimulation. Following cessation of self-stimulation, SMA and bar-pressing (that became nonreinforced) decreased, and stereotypy reappeared in both groups of rats.     

Naloxone blocks the excitatory effect of ethanol and chlordiazepoxide on lateral hypothalamic self-stimulation behavior

Ethanol (ETOH, 0.5 g/kg) and chlordiazepoxide (CDP, 4.0 mg/kg) enhance operant responding by rats for lateral hypothalamic (LH) self-stimulation (SS). Naloxone (NOX, 5.0 mg/kg) does not affect LH SS or blood alcohol level, but prevents the increased responding for LH SS produced by ETOH and CDP. Thus, ETOH and CDP, but not brain stimulation reward itself, may release an endogenous opioid whose action at opiate receptors results in an excitatory behavioral (euphorigenic?) effect which can be blocked by NOX.