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PubMed1981

[Addiction-like behavior with continuous self-stimulation of the mediothalamic system (author's transl)].

In a patient with postamputation pain a continuous self-stimulation of the mediothalamic system by a chronic deep brain electrode induced a change in behavior, similar to addiction. At the same time various psychological tests (HAWIE, Benton, Hooper-VOT and concentration tests) were significantly disturbed. After interruption of the deep brain stimulation all induced psychic abnormalities normalized within a few days.

Adult↗

PubMed2004

CB1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat.

RATIONALE: Addictive drugs have a number of commonalities in animal behavioral models. They lower intracranial self-stimulation (ICSS) thresholds, support self-administration, and produce conditioned place preference (CPP). However, cannabinoids appear atypical as drugs of abuse, since there are controversial data in the literature concerning their reinforcing properties. OBJECTIVES: The aim of the present study was to examine the effects of cannabinoids on brain reward using the rate-frequency curve shift paradigm of ICSS. METHODS: Male Sprague-Dawley rats were implanted with electrodes into the medial forebrain bundle (MFB). Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After brain stimulation reward thresholds stabilized rats received intraperitoneal (IP) injections of the potent CB1 receptor agonists WIN 55,212-2 (graded doses 0.1, 0.3, 1 and 3 mg/kg), CP 55,940 (graded doses 10, 30, 56 and 100 microg/kg), or HU-210 (graded doses 10, 30, 100 microg/kg). RESULTS: With the exception of the highest dose of all cannabinoid agonists tested, which significantly increased the threshold frequency required for MFB ICSS, all other doses of the tested drugs did not affect ICSS thresholds. The CB1 receptor antagonist SR141716A reversed the actions of WIN 55,212-2 and CP 55,940, but not HU-210. However, the selective CB1 cannabinoid receptor antagonist AM 251 counteracted the effect of HU-210. Both CB1 receptor antagonists, at the doses used in the present study, did not affect reward thresholds by themselves. CONCLUSIONS: The present results indicate that cannabinoid agonists do not exhibit reinforcing properties in the ICSS paradigm, but rather have an inhibitory influence on reward mechanisms. The results suggest that the anhedonic effects of cannabinoids are probably mediated by cannabinoid CB1 receptors.

Animals↗

PubMed2001

Comparison of two intracranial self-stimulation (ICSS) paradigms in C57BL/6 mice: head-dipping and place-learning.

A variety of intracranial self-stimulation (ICSS) paradigms have been utilized for investigations of reward. Among them, nose-poking and spatial-preference paradigms are known to be relatively more resistant to the effects of drug-induced motor-deficits in rat studies, although these two ICSS paradigms have not been directly compared in previous studies. In the present study, head-dipping and place-learning (forms of nose-poking and spatial-preference tasks, respectively) paradigms with lateral hypothalamus stimulation were systematically analyzed using C57BL/6 mice in the presence and absence of two motor-deficit-inducing drugs: tolperisone and harmaline. Rapid acquisition and rapid extinction patterns of ICSS responding were observed in the head-dipping and place-learning paradigms. In contrast to these pre-drug similarities in responding, dramatic differences were noted after drug administration. Tolperisone significantly reduced head-dipping but not place-learning ICSS responding. Similarly, reduction of ICSS responding after harmaline was more pronounced in the head-dipping task. Therefore, the place-learning paradigm may be superior for the assessment of reward values under motor-deficit-inducing conditions in C57BL/6 mice. The relative benefits and disadvantages of both ICSS paradigms are discussed. Combinations of complementary ICSS paradigms using mice may be useful for further investigations of the molecular bases of reward.

Animals↗

PubMed1992

Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations.

A discrete-trial current-threshold intracranial self-stimulation (ICSS) paradigm has been used extensively to examine the effects of drugs on reward thresholds. However, there is little work to date validating that this specific procedure measures reward. The purpose of the present study was to establish the construct validity of this procedure by testing the procedure's ability to measure reward effects and to discriminate these reward effects from performance effects. The discrete-trial ICSS procedure provides four measures: current thresholds, response latency, extra responses and time-out responses. The effects of a performance manipulation (variations in the force required to operate the manipulandum) and of a reward manipulation (variations in the train duration of the electrical stimulation) were evaluated on the four measures. Reward effects were reflected primarily in changes in thresholds, with no effect on any of the other three measures. Conversely, performance effects were reflected primarily in changes in response latency, extra responses and time-out responses, with only a small effect on thresholds. Finally, the paradigm's potential as a useful tool in the elucidation of the neurobiological basis of reward was demonstrated by investigating the effects of two pharmacological agents, cocaine and curare, on the four measures derived from the discrete-trial current-threshold ICSS procedure. The results suggest that the discrete-trial current-threshold procedure can readily discriminate reward from performance treatments.

Animals↗

PubMed1988

Main effects of current and pimozide on prepared and learned self-stimulation behaviors are on performance not reward.

This work examined four independent variables which influence behavior of self-stimulating rats: site of electrode placement (cingulate cortex versus lateral hypothalamus), type of operant response (lever press versus nose poke), current intensity (50, 100, 150 microA) and pimozide dosage (0.125, 0.250, 0.500 mg/kg). The dependent measures were: total responding, alternation between two identical manipulanda and mean duration per response. Naive rats made more nose pokes than lever presses, suggesting nose pokes are more "prepared." The cingulate cortex was insensitive to current and pimozide manipulations in contrast with hypothalamic sensitivity, tentatively suggesting a cingulate role in release of prepared behaviors, hypothalamic in plasticity of learned ones. Lever pressing, more prevalent with lateral hypothalamic stimulation, was more affected by current and pimozide manipulations than nose poking. More prepared nose pokes might thus be less susceptible to brain stimulation reward manipulations. Intensifying current produced more but shorter responses, increasing pimozide dosage produced fewer and nonsignificantly longer ones, suggesting a primary effect on motor performance not reward. Decrements in performance over nondrug days were tentatively attributed to long-lasting effects of pimozide.

Animals↗

PubMed1992

Schedule-controlled brain self-stimulation: has it utility for behavioral pharmacology?

We review evidence that schedule-controlled intracranial self-stimulation (ICSS) has properties in common with conventional reinforcements, such as food and water, but unlike the latter, animals will respond for ICSS for long periods of time at a near-constant rate. Schedule-controlled ICSS has proven to be more sensitive to drug-induced changes than has ICSS on a continuous reinforcement schedule, and it permits a more fine-grained analysis of the pattern of responding that results in the reinforcement. Evidence is accumulating that the schedule of ICSS itself leads to neurochemical changes in areas of the brain, such as the nucleus accumbens, in which reward processes occur. Results obtained from schedule-controlled ICSS would complement those obtained by drug self-administration studies which generally use intermittent reinforcement. A systematic examination of ICSS schedules at different brain sites would greatly facilitate our interpretation of drug effects and this would have utility for behavioral pharmacology.

Animals↗

PubMed1990

The notion of response invariance in trade-off studies of self-stimulation.

Trade-off profiles, displaying the co-variations of 2 electrical parameters required to maintain a constant magnitude of brain stimulation reward (BSR), have been used extensively in order to characterize the self-stimulation (SS) neurons. It has often been assumed that constancy in the magnitude of BSR can be achieved more accurately by holding SS at a constant proportion of the maximum rate, rather than at a constant rate. The validity of this assumption was tested in 2 experiments using rats. In Exp. 1, we first computed the function that relates SS barpressing rate to pulse frequency (RF function) for two different pulse intensities, separately. The peak SS rate was found to be lower in the low current than in the high current RF function. The rats were then placed in a 2-lever box and were allowed to select either a fixed frequency of the high current pulses or a variable frequency of the low current pulses. In Exp. 2, the RF function was first computed for 2 different lever weights, separately. The peak SS rate was found to be lower in the heavy-lever RF function than in the light-weight lever RF function. The rats were then allowed to select either a fixed pulse frequency delivered by the heavy lever or a variable pulse frequency delivered by the light-weight lever. Isopreference was noted in both experiments, for pulse frequencies which, in the single-lever box, elicited the same proportion of the maximum SS rate, not the same SS rate. The data thus validate the idea that a constant magnitude of BSR is translated into a constant proportion of the maximum SS rate, not a constant SS rate.

Animals↗

PubMed1976

The effect of 6-aminodopamine on electrical self-stimulation in rats.

The compound 6-aminodopamine is a powerful CNS catecholaminergic neurotoxin. Small dosages of 6-aminodopamine injected intraventricularly markedly depress electrical self-stimulation rates in rats. This 6-aminodopamine treatment produced whole brain lowering of norepinephrine to ca. 50% of normal while the dopamine content was unchanged. The possible use of 6-aminodopamine treatment to elucidate the relative roles of norepinephrine and dopamine pathways is discussed.

Animals↗

PubMed1983

Differential effects of amphetamine isomers on SN self-stimulation: evidence for DA neuron subtypes.

The present experiment investigated the effects of varying doses of D- and L-amphetamine on intracranial self-stimulation (ICSS) in the medial or lateral substantia nigra (SN). It was found that the effects of D- and L-amphetamine on ICSS in the SN differ in these two sites. In the medial SN, there were no significant differences between the effects of D- and L-amphetamine on ICSS at any of the doses tested. Both isomers moderately facilitated ICSS with the peak effect at 0.8 to 2.0 mg/kg. By contrast, in the lateral SN, D-amphetamine produced a strong dose-dependent facilitation of ICSS which peaked at 2 mg/kg while L-amphetamine was ineffective below 7 mg/kg. Above 7 mg/kg L-amphetamine increased ICSS rates. The present experiments suggest that the medial and lateral SN are functionally different with respect to ICSS. The possibility that the present medial-lateral SN differences are mediated by two different types of dopamine cells is discussed. In addition, the effects of D- and L-amphetamine on ICSS in the lateral hypothalamus are discussed in light of the present findings.

Amphetamine↗

PubMed1987

[Changes in the duration of pauses between self-stimulations in response to cortisol].

Intraperitoneal administration of glucocorticoid hormone cortisol (10 mg/kg) decelerated the self-stimulation (SS) frequency within 5-7 min. The maximal effect occurred within 10 to 20 min. Histograms of pauses duration between SS revealed a shift of mean values from 2.0-2.5 to 4-6 sec. A sharp increase of long pauses transformed chiefly mono- modal forms of control histograms into bimodal those under the hormonal effect. Behaviourally this was manifested by occurrence of burst type of SS responses when series of uninterrupted instrumental responses alternated with prolonged pauses between them. The data obtained are considered from the stand-point of systemic approach to analysis of organization of willed behaviour and role of cortisol in central mechanisms of positive reinforcement.

Animals↗

PubMed1988

Effect of morphine on self-stimulation in rats and its modification by chloramphenicol.

The effect of morphine was studied on self-stimulation (SS) behavior in rats implanted with bipolar electrodes in the posterior hypothalamus. A single dose (10 mg/kg) of morphine decreased SS responding within 10-20 min, reaching a minimum level between 20-40 min after which the responding gradually returned to normal. The SS responding then increased above the control level at 120-180 min postdrug, then slowly returned to normal, thus showing a rebound effect. The combination treatment with morphine (10 mg/kg) and chloramphenicol (50 mg/kg) on SS behavior produced an accentuation of the initial decrease in responding, which was prolonged before gradually returning to the control levels without showing any rebound effect. The data suggest that alterations in protein synthesis may underlie the suppressed excitatory effect of a high dose of morphine on SS behavior.

Animals↗

PubMed1977

Effect of tryptamine antagonists on self-stimulation. Interaction with amphetamine.

In order to investigate the role played by serotonergic mechanisms in self-stimulation (SS) behavior, the effects of two tryptamine antagonists, cyproheptadine and methysergide on SS were measured. Also the influence of antitryptaminic drug pre-treatment on the facilitatory effect of amphetamine, a pro-adrenergic drug, on SS was studied. Rats with brain electrodes permanently implanted at the lateral hypothalamus and trained to lever-press for response-contingent brain electric stimulus presentation were used. Stimulus current was maintained at threshold level. Both tryptamine antagonists used potentiated the enhancing effect of amphetamine on low SS rates, displacing to the left its dose-effect curve; cyproheptadine was at least three times more potent than methysergide. In addition, cyproheptadine, but not methysergide, caused dose-related increases in SS rate, when given alone. These results suggest that brain serotonergic systems play an inhibitory role in SS, opposing the facilitatory influence of adrenergic mechanisms.

Amphetamine↗

PubMedDate not supplied

Influence of social dominance on self-stimulation behavior in male golden hamsters.

The effect of a socially dominant hamster on the self-stimulation behavior of the subordinate hamster was examined. After determining social ranking, six hamsters were trained to press a lever in an operant chamber in which a dominant hamster was presented over a grid wall. The threshold of rewarding effect was evaluated by using a descending series of current intensity as electrical reward. When a dominant hamster was present, the subordinate hamster showed a shift of intensity-response function to the right (higher intensity). The presence of a subordinate hamster did not influence the response in dominant hamsters. Furthermore, beta-carboline (FG-7142) (5, 10, and 20 mg/kg, IP) caused a decrease in rewarding effect in dose-dependant manner. These results suggest that the presence of a dominant animal may have caused "a state of anxiety" somewhat similar to the anxiety caused by the benzodiazepine inverse agonist.

Animals↗

PubMed1984

Selective neonatal depletion of dopamine has no effect on medial prefrontal cortex self-stimulation in the rat.

The role of the dopaminergic input to the medial prefrontal cortex (MFC) on self-stimulation (SS) was investigated in adult rats injected neonatally with 6-hydroxydopamine (6-OHDA). Each subject on day 3 or 5 received bilateral intraventricular injection of 6-OHDA (total dose 200 micrograms, 50 micrograms/injection/2.5 microliters vehicle which contained 1 mg/ml ascorbic acid) or of the vehicle alone after pretreatment with desmethylimipramine (50 mg/kg i.p.) 30 min earlier. At 150 days of age, the animals were implanted with monopolar (100 microns) stainless steel electrodes in the MFC. One long (10 h) and 5 short (2 h) SS sessions resulted in similar percentages of responders for the brain reward in test and control subjects, and similar response rates in both groups. Biochemical assays of the levels of norepinephrine (NE) and dopamine (DA) in the frontal cortex showed depletion of DA 90% in the test animals, but no depletion of NE. Histochemical fluorescence visualization of the catecholamine input verified the biochemical results in the MFC. These results are viewed as negative evidence for the hypothesis that DA innervations in the MFC are critical neural substrates for SS, and suggest that activation of intrinsic neurons in the MFC are responsible for SS in the region.

Animals↗

PubMed1982

Plasticity of the medial prefrontal cortex: facilitated acquisition of intracranial self-stimulation by pretraining stimulation.

Prior electrical stimulation of the medial prefrontal cortex MFC facilitated the subsequent acquisition of intracranial self-stimulation (ICSS) from the same MFC electrode site. Stimulations that were spaced over a period of six days were more effective in producing this facilitation than the same number of stimulations delivered over a two day period. These data suggest that the rewarding effects of MFC stimulation may involve some process akin to the kindling phenomenon and as such may provide insights in the neuronal modifications thought to underlie learning and memory.

Animals↗

PubMed1979

Simultaneous rate-independent and rate-dependent assessment of intracranial self-stimulation: evidence for the direct involvement of dopamine in brain reinforcement mechanisms.

A two-level intracranial self-stimulation (ICSS) paradigm was developed in which both rate-independent and dependent measures of ICSS could be obtained simultaneously. Responses at the first lever resulted in stimulation which decreased in magnitude after every fifth response, while responses at the second lever reset the current available. The current at which the reset responses occurred was defined as the 'reward threshold'. In addition, the rate of responding was determined at each current for which the animals responded during this stimulate-reset sequence. Decreased reward following treatment with the neuroleptic pimozide, a specific blocker of dopamine receptors, was demonstrated by an elevated 'reward threshold'. The same effect could be obtained in control animals by making each stimulation less rewarding, i.e., by decreasing the amount of charge per stimulation. Pimozide increased 'reward threshold' without a generalized disruption of response rates. While rates were decreased at low currents they were unchanged at high currents. 'Reward threshold' was decreased following D-amphetamine treatment, and was accompanied by a dose-related decrease in response rates at high to medium current intensities. These data suggest that neuroleptic attenuation of ICSS is due to diminished reward and not to motor deficits. Further, due to the specificity of pimozide, they suggest a direct role for dopamine in the mediation of reward.

Animals↗

PubMed1987

Measurement of intracranial self-stimulation thresholds using the post-reinforcement pause.

A method for measuring the current threshold for intracranial self-stimulation (ICSS) using the post-reinforcement pause (PRP) is described. Rats trained to lever press on a fixed ratio schedule for ICSS in prefrontal cortex, medial forebrain bundle, ventral tegmental area or periaqueductal gray received stimuli of opposite polarity in an alternating fashion. Stimuli of one polarity were sufficient to maintain ICSS responding by themselves (maintaining stimuli). Stimuli of the other polarity were systematically varied in 5-10 microA steps (experimental stimuli). PRPs following both maintaining (Pm) and experimental (Pe) stimuli were measured, and the ratio Pm/Pe was calculated. The PRP threshold was defined as the lowest experimental stimulus current producing PRP ratios significantly less than the ratios produced by all lower current steps. After the PRP threshold for one polarity was determined in 5 daily sessions, the experimental and maintaining stimuli were reversed, and the PRP threshold was measured for the alternate polarity. Rates of ICSS on a continuous reinforcement schedule were subsequently measured at currents around the PRP threshold. Rates increased sharply at PRP threshold, suggesting a correlation between PRP threshold and reinforcement threshold. Similar results were obtained from all four ICSS sites indicating the broad applicability of the PRP threshold method.

Animals↗

PubMed1994

N-methyl-D-aspartic acid-induced lesions of the nucleus accumbens and/or ventral pallidum fail to attenuate lateral hypothalamic self-stimulation reward.

The role of ventral striatum in the maintenance and transmission of a hypothalamic intracranial self-stimulation (ICSS) reward signal was investigated using the rate-frequency multiple-curve shift paradigm. The excitotoxin N-methyl-D-aspartic acid (NMDA) was bilaterally administered into the nucleus accumbens (15 micrograms per side), the ventral pallidum (15 micrograms per side) or the juncture between the two structures (20 micrograms per side) creating three lesion groups. Both the nucleus accumbens (NAC) lesion group and the ventral pallidum (VP) lesion group displayed substantial NMDA-induced damage which was generally restricted to the intended limbic structure. The NMDA lesions in the third group displayed extensive damage to both the NAC and VP, as intended, but also typically diffused into adjacent medial structures. NMDA-induced lesions in all groups caused a suppression in motor/performance activity at all currents tested. Contrary to motor effects, reward efficacy was relatively unaffected for the NAC and VP groups. The lack of reward effects may be due to plasticity of neuronal systems and redundancy of circuit connections. However, this explanation is questionable given the fact that NMDA lesions which encompassed both the NAC and VP had little effect on reward efficacy. The above data suggests that the nucleus accumbens and the ventral pallidum are not critical for ICSS rewards stimulation and that hypothalamic ICSS reward signals are processed downstream from these limbic structures.

Animals↗