Intracranial Self-stimulation Test Research Articles

Effects of α‐pyrrolidino‐phenone cathinone stimulants on brain reward function in female rats

Synthetic cathinones, commonly known as “bath salts”, are potent reinforcers and produce stimulant-like effects. In these studies, the intracranial self-stimulation (ICSS) procedure was used to investigate the facilitation of brain reward functioning, as indexed by reduction in reward thresholds, in female rats following exposure to α-PPP, α-PVP or α-PHP. Female Wistar rats were prepared with unilateral electrodes aimed at the medial forebrain bundle (coordinates: AP -0.5mm, ML ±1.7mm, DV skull -9.5mm). Rats were trained in a procedure adapted from the discrete-trial current-threshold procedure, with thresholds being defined as the mean of four alternating descending-ascending series. Prior to ICSS testing, rats were administered saline vehicle, α-PPP (0-2.0 mg/kg, i.p.), α-PVP (0-2.0 mg/kg, i.p.), α-PHP (0-2.0 mg/kg, i.p.) or methamphetamine (0.56 mg/kg, s.c) with a 15 minute pretreatment interval. Active drug days were conducted a maximum of twice per week, separated by at least one nondrug session. Brain reward thresholds were significantly decreased (p<0.05) in rats exposed to α-PPP or α-PHP, with similar efficacy and lesser potency compared with methamphetamine. Exposure to α-PVP resulted in modest decrease in ICSS threshold. These data are the first to confirm the effects of cathinone stimulants on ICSS reward function in female rats. Reduced reward thresholds in the ICSS procedure were consistent with pro-reward effects shown for other psychomotor stimulants such as methamphetamine.

Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice

Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/-) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/- on innate and MA-modulated reward sensitivity are not known. We examined innate reward sensitivity and facilitation by MA in H1+/- mice via intracranial self-stimulation (ICSS). We used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5-4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. H1+/- mice displayed reduced normalized maximum response rates in response to MA. H1+/- females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. H1+/- mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/- females (lower normalized M50 values).

Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.

BackgroundNew treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development.MethodsWe screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964).ResultsIn the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay.ConclusionsThese results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

Effects and Side Effects of Cannabinoid/Opioid Combination in a Chronic Pain Model in Rats

Chronic pain is considered a growing healthcare problem becoming a major cause of global burden. Prolonged use of the currently used analgesics such opioids is associated with adverse effects; urging the need for safer alternatives. Cannabinoids are a group of compounds structurally related to Δ9‐tetrahydrocannabinol (Δ9‐THC). Both cannabinoids and opioids produce antinociception in different chronic pain animal models. However, therapeutic doses of these drugs may be accompanied by undesirable side effects, such as abuse liability and decrease locomotion in animals. The aim of this study was to assess the outcomes of combining range of doses of opioids and cannabinoids that are sufficient to produce antinociception without producing unwanted side effects. Inflammatory pain was induced by intra‐plantar injection of Complete Freund's Adjuvant (CFA) into the left hindpaw of adult male Sprague Dawley rats. Von Frey filaments were applied to the mid‐plantar aspect of the left hind paw using the “up‐down” method to determine the CFA‐induced mechanical allodynia. Antinociceptive effect of morphine (0.32, 1 and 3.2 mg/kg; i.p), the synthetic cannabinoid CP55940 (0.032, 0.1 and 0.32 mg/kg; s.c.), their combinations, or their vehicles was evaluated 3–9 day post‐CFA administration. Intracranial self‐stimulation (ICSS) test was utilized to evaluate the abuse liability of these drugs or their combinations. Morphine produced significant antinociceptive effects at 1 and 3.2 mg/kg, but not at the lowest dose of 0.32 mg/kg with minimal changes in ICSS. CP55940 showed significant antinociceptive effects only at the highest administered dose (0.32 mg/kg), while producing depression in ICSS at 0.1 and 0.32 mg/kg. The sub‐theraputic dose of morphine (0.32 mg/kg) was co‐administered with the different doses of CP55940 (0.032, 0.1 and 0.32 mg/kg). 0.32 mg/kg morphine enhanced the antinocicpetive effects of CP55940, such that CP55940 produced antinociception at lower dose (0.1 mg/kg) compared to vehicle. However, in ICSS test, the aforementioned combinations did not change CP55940‐induced depression of ICSS. In conclusion morphine and CP55940 produce analgesic effects at lower doses if combined together with no additional risk of abuse liability side effects, which may be useful in clinical practice.Support or Funding InformationScientific Research Support Fund (MPH/1/29/2016)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pituitary Adenylate Cyclase–Activating Polypeptide Disrupts Motivation, Social Interaction, and Attention in Male Sprague Dawley Rats

BackgroundSevere or prolonged stress can trigger psychiatric illnesses including mood and anxiety disorders. Recent work indicates that pituitary adenylate cyclase–activating polypeptide (PACAP) plays an important role in regulating stress effects. In rodents, exogenous PACAP administration can produce persistent elevations in the acoustic startle response, which may reflect anxiety-like signs including hypervigilance. We investigated whether PACAP causes acute or persistent alterations in behaviors that reflect other core features of mood and anxiety disorders (motivation, social interaction, and attention). MethodsUsing male Sprague Dawley rats, we examined if PACAP (.25–1.0 µg, intracerebroventricular infusion) affects motivation as measured in the intracranial self-stimulation test. We also examined if PACAP alters interactions with a conspecific in the social interaction test. Finally, we examined if PACAP affects performance in the 5-choice serial reaction time task, which quantifies attention and error processing. ResultsDose-dependent disruptions in motivation, social interaction, and attention were produced by PACAP, as reflected by increases in reward thresholds, decreases in social behaviors, and decreases in correct responses and alterations in posterror accuracy. Behavior normalized quickly in the intracranial self-stimulation and 5-choice serial reaction time task tests but remained dysregulated in the social interaction test. Effects on attention were attenuated by the corticotropin-releasing factor receptor-1 antagonist antalarmin but not the κ opioid receptor antagonist JDTic. ConclusionsOur findings suggest that PACAP affects numerous domains often dysregulated in mood and anxiety disorders, but that individual signs depend on brain substrates that are at least partially independent. This work may help to devise therapeutics that mitigate specific signs of these disorders.

Effects of Striatal ΔFosB Overexpression and Ketamine on Social Defeat Stress–Induced Anhedonia in Mice

Chronic social defeat stress (CSDS) produces persistent behavioral adaptations in mice. In many behavioral assays, it can be difficult to determine if these adaptations reflect core signs of depression. We designed studies to characterize the effects of CSDS on sensitivity to reward because anhedonia (reduced sensitivity to reward) is a defining characteristic of depressive disorders in humans. We also examined the effects of striatal ΔFosB overexpression and the N-methyl-D-aspartate receptor antagonist ketamine, both of which promote resilience, on CSDS-induced alterations in reward function and social interaction. Intracranial self-stimulation (ICSS) was used to quantify CSDS-induced changes in reward function. Mice were implanted with lateral hypothalamic electrodes, and ICSS thresholds were measured after each of 10 daily CSDS sessions and during a 5-day recovery period. We also examined if acute intraperitoneal administration of ketamine (2.5-20 mg/kg) reverses CSDS-induced effects on reward or, in separate mice, social interaction. ICSS thresholds were increased by CSDS, indicating decreases in the rewarding impact of lateral hypothalamic stimulation (anhedonia). This effect was attenuated in mice overexpressing ∆FosB in striatum, consistent with pro-resilient actions of this transcription factor. High, but not low, doses of ketamine administered after completion of the CSDS regimen attenuated social avoidance in defeated mice, although this effect was transient. Ketamine did not block CSDS-induced anhedonia in the ICSS test. This study found that CSDS triggers persistent anhedonia and confirms that ΔFosB overexpression produces stress resilience. The findings of this study also indicate that acute administration of ketamine fails to attenuate CSDS-induced anhedonia despite reducing other depression-related behavioral abnormalities.

Effects of the anticonvulsant lacosamide compared to valproate and lamotrigine on cocaine-enhanced reward in rats

Some drugs developed as anticonvulsants (notably, valproate and lamotrigine) have therapeutic effects in bipolar and related disorders. Lacosamide, a recently approved anticonvulsant, has unique effects on sodium channels that may play a role in producing the mood-stabilizing effects of anticonvulsant drugs. We tested whether lacosamide would have effects similar to or different from valproate and lamotrigine in a model of reward and elevated mood. The intracranial self-stimulation (ICSS) test is sensitive to the function of brain reward systems. Changes in ICSS may model aspects of disorders characterized by abnormalities of reward and motivation. Cocaine elevates mood, and reduction of cocaine-induced facilitation of ICSS has been used to predict antimanic-like or mood stabilizing effects of drugs. We tested lacosamide, lamotrigine, and valproate in the rat ICSS test alone or in the presence of cocaine. A high dose of lacosamide (30mg/kg) significantly elevated ICSS thresholds, indicating that it reduced the rewarding impact of medial forebrain bundle stimulation. Lower doses (3–10mg/kg) did not alter ICSS, but blocked the cocaine-induced lowering of ICSS thresholds. The highest doses of valproate (300mg/kg) and lamotrigine (30mg/kg) also elevated ICSS thresholds, and only these high doses significantly lowered cocaine-induced effects. Of the drugs tested, only lacosamide significantly attenuated the reward-facilitating effects of cocaine at doses that had no effects on ICSS response in the absence of cocaine. Abnormalities of mood and reward are common in psychiatric disorders, and these results suggest that lacosamide deserves further study in models of these disorders.

Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats

Drug dependence is characterized by dysregulation of brain reward systems and increased sensitivity to stress. Chronic exposure to drugs of abuse is associated with increased expression of the neuropeptide dynorphin, the endogenous ligand for kappa opioid receptors (KORs). Activation of KORs causes depressive- and aversive-like responses in rodents, raising the possibility that drug-induced upregulation of dynorphin plays a role independence-associated negative states. Here we used “binge” exposure to cocaine (3 daily intraperitoneal injections of 15 mg/kg for 14 days) to examine the development of dependence-like behavior in the intracranial self-stimulation (ICSS) test and the forced swim test (FST). When rats were tested 1 h before their first scheduled injection of each day—a period of drug withdrawal corresponding to 20 h after their last injection on the previous day—there were exposure-dependent increases in ICSS thresholds (a putative indicator of anhedonia) and decreases in latencies to immobility in the FST (a putative indicator of behavioral despair). Administration of the long-lasting KOR antagonist norBNI (20 μg, intracerebroventricular) before the beginning of the binge regimen attenuated the development of cocaine withdrawal-induced anhedonia in the ICSS test. In contrast, administration of norBNI in the midst of the binge regimen had no effect on expression of cocaine withdrawal-induced anhedonia in the ICSS test, although it did attenuate despair-like behavior in the FST. These data suggest that blockade of KORs before exposure to a stressor (in this case, cocaine withdrawal or forced swimming) can attenuate the development of stress-induced behavioral adaptations.This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Schizophrenia-Like Attentional Deficits Following Blockade of Prefrontal Cortex GABAA Receptors

Attentional deficits are a core symptom of schizophrenia. Post-mortem analyses of the brains of schizophrenics reveal consistent abnormalities in γ-aminobutyric acid (GABA) interneurons indicative of reduced cortical GABA transmission, raising the possibility that this pathology contributes to attentional deficits. We examined whether blockade of prefrontal cortex (PFC) GABA(A) receptors with bicuculline (BMI) impairs attention in rats using the 5-choice serial reaction time task (5CSRTT). For comparison, we also examined whether administration of the GABA(A) receptor agonist muscimol (MUS) would improve attention. In parallel, we examined the effects of both manipulations on activity in an open field and on motivation using the intracranial self-stimulation (ICSS) test. BMI increased PFC neuronal activity, as reflected by increased Fos immunolabeling, and impaired attention, as reflected by decreased accuracy and increased omissions. Although increased omissions also may reflect reductions in locomotor activity or motivation, the overall pattern of effects does not support either of these interpretations: BMI did not affect locomotor activity, and it enhanced motivation in the ICSS test. MUS did not affect attention, although it increased impulsive behavior at a dose that suppressed PFC neuronal activity, as reflected by decreased Fos immunolabeling. These impulsivity effects are not due to altered locomotor activity (which was decreased) or motivation (which was not affected). Our data support the hypothesis that cortical GABA neurons have an important role in regulating attention and may have direct implications for the treatment of schizophrenia.

Both GABA B receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats

Nicotine dependence is maintained by the aversive, depression-like effects of nicotine withdrawal and the rewarding effects of acute nicotine. GABA B receptor antagonists exhibit antidepressant-like effects in rodents, whereas GABA B receptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABA B receptor positive modulators showed that these compounds represent potentially improved medications for the treatment of nicotine dependence because of fewer side-effects than GABA B receptor agonists. Thus, GABA B receptor agonists and antagonists, and GABA B receptor positive modulators may have efficacy as smoking cessation aids by targeting different aspects of nicotine dependence and withdrawal. The present study assessed the effects of the GABA B receptor agonist CGP44532, the GABA B receptor antagonist CGP56433A, and the GABA B receptor positive modulator BHF177 on the anhedonic aspects of nicotine withdrawal. Rats were prepared with stimulating electrodes in the posterior lateral hypothalamus. After establishing stable intracranial self-stimulation (ICSS) thresholds, rats were prepared with subcutaneous osmotic minipumps delivering either nicotine or saline for 7 or 14 days. ICSS thresholds were assessed 6 h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and BHF177 were administered 30 min prior to ICSS testing. Both GABA B receptor activation (CGP44532 and BHF177) and blockade (CGP56433A) elevated ICSS thresholds in all groups, resulting in exacerbated effects of nicotine withdrawal in the nicotine-treated groups. These similar effects of GABA B receptor activation and blockade on the anhedonic depression-like aspects of nicotine withdrawal were surprising and perhaps reflect differential efficacy of these compounds at presynaptic hetero- and autoreceptors, as well as postsynaptic, GABA B receptors.

Lack of evidence for appetitive effects of Δ9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference procedures in rodents

Data on the ability of Delta 9-tetrahydrocannabinol (THC) to modify reward processes in experimental animals are inconsistent. This study examined the effects of Delta 9-THC on brain reward function using the rate-frequency curve shift paradigm of intracranial self-stimulation (ICSS) and the conditioned place preference (CPP) paradigm. In ICSS tests, rats were implanted with electrodes into the medial forebrain bundle. After brain stimulation reward thresholds stabilized, rats received intraperitoneal injections of Delta 9-THC (0, 0.5, 1 and 2 mg/kg) or the CB1 receptor antagonist SR141716A (0, 0.02 mg/kg) and Delta 9-THC (0, 2 mg/kg). The two highest doses of Delta 9-THC significantly increased the threshold ICSS frequency. SR141716A reversed the action of Delta 9-THC (2 mg/kg), without affecting reward thresholds by itself. In the CPP test, mice received intraperitoneal injections of Delta 9-THC (0, 1 or 3 mg/kg). Delta 9-THC showed neither statistically significant preference nor aversion in either of the doses tested. These findings indicate that Delta 9-THC, in contrast to other drugs of abuse, does not facilitate ICSS or support CPP under the present experimental conditions, but rather has a dose-dependent inhibitory influence on ICSS.

Depressive-Like Effects of the κ-Opioid Receptor Agonist Salvinorin A on Behavior and Neurochemistry in Rats

Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of kappa-opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressive-like behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective kappa-opioid agonist, would produce depressive-like effects in the forced swim test (FST) and intracranial self-stimulation (ICSS) test, which are behavioral models often used to study depression in rats. We extracted, isolated, and purified SalvA from Salvia divinorum plant leaves and examined its effects on behavior in the FST and ICSS test across a range of doses (0.125-2.0 mg/kg) after systemic (intraperitoneal) administration. SalvA dose dependently increased immobility in the FST, an effect opposite to that of standard antidepressant drugs. Doses of SalvA that produced these effects in the FST did not affect locomotor activity in an open field. Furthermore, SalvA dose dependently elevated ICSS thresholds, an effect similar to that produced by treatments that cause depressive symptoms in humans. At a dose that caused the depressive-like effects in both the FST and ICSS assays, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain kappa-opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.

Effects of scopolamine on the rewarding and seizure-inducing properties of amygdaloid stimulation

The relationship between amygdaloid brain-stimulation reward and the evolution of seizure activity was evaluated in this study. Current levels that maintained optimal intracranial self-stimulation (ICSS) rates were found to be lower than the minimal current intensity required to elicit an afterdischarge (AD) from the central nucleus of the amygdala. After the ICSS session, AD thresholds (ADTs) were reduced to the same levels of current used to support ICSS. Assessment of seizure stage development during ICSS testing revealed that the emergence of early-stage epileptiform events following repeated amygdaloid stimulation suppressed ICSS performance. While administration of the antimuscarinic scopolamine did not prevent the stimulation-elicited reduction in AD thresholds, it was observed to inhibit seizure progression and increase ICSS rates. These results are consistent with the excitatory function of acetylcholine in epileptogenesis and were related to the possibility that different mechanisms underlie the rewarding and seizure-inducing properties of amygdaloid stimulation.

Sensitization of mesolimbic brain stimulation reward after electrical kindling of the amygdala

The effects of partial kindling of the central amygdaloid nucleus on brain stimulation reward were evaluated. Intracranial self-stimulation (ICSS) rate intensity functions were determined using a two-hole nose-poke discrimination paradigm in rats implanted with electrodes in the A10 dopamine (DA) neuronal region of the ventral tegmental area (VTA), and in the medial forebrain bundle (MFB) at the level of the lateral hypothalamus. The kindling process did not influence ICSS baseline rates from either site. However, following stage 4 kindling, a low dose amphetamine challenge increased ICSS, resulted in a significant shift to the left of the rate intensity functions, and decreased reward thresholds. Analysis of the error scores which consisted of nonreinforced responses made during ICSS testing revealed that the interaction between kindling and amphetamine on ICSS was specific to changes in central reward processes, and could not be attributed to the influence of rate-enhancing performance variables. The kindling-elicited Sensitization of mesolimbic DA reward functioning seen after amphetamine challenge was discussed in relation to the role of the central amygdala in the integration of stimulus-reward associations, and in the conditioning of affective emotional states.

Postcocaine depression and sensitization of brain-stimulation reward: Analysis of reinforcement and performance effects

The effects of acute and chronic cocaine administration on intracranial self-stimulation (ICSS) were evaluated in a two-hole nose-poke discrimination paradigm. Analysis of ICSS rates as a function of current intensity revealed that cocaine increased rates of responding in a dose-dependent manner (5.0–20.0 mg/kg), resulted in a shift to the left of the rate-intensity function, and decreased thresholds for half-maximal responding. Brain-stimulation reward was modified by chronic exposure to cocaine, however, the direction of change was dependent on the schedule of drug administration. Repeated daily administration of cocaine (40.0 mg/kg) and ICSS testing 24 hr postinjection decreased rates and increased reward thresholds. A response depression was also observed when time-dependent variations in ICSS performance were evaluated after repeated cocaine administration. Using a different chronic cocaine/test schedule (30.0 mg/kg, twice daily), a sensitization of ICSS and decreased reward thresholds developed when rate-intensity functions were determined after 5-day drug intervals. These findings were discussed in terms of the role of dopamine in modulating central reward processes. It was suggested that depressed reward-system functioning might reflect reduced dopamine synthesis following cocaine withdrawal, and the ICSS sensitization was related to long-term compensatory changes in dopamine neurotransmission possibly involving presynaptic mechanisms.

Effects of chronic electrode implantation on dopaminergic neurons in vivo

The present study evaluated the effects of chronic electrode implantation on stimulus-dependent increases of the dopamine (DA) metabolite dihydroxyphenylacetic acid (DOPAC) in relationship to a well characterized in vivo model which used electrical stimulation from acute electrode placements in the nigro-striatal pathway. Five days after bipolar electrodes were implanted into the nigro-striatal pathway, non-contingent electrical stimulation (100 μA, 25 Hz, 1.5 msec duration, 20 min session) did not change DA or DOPAC concentrations in the caudate nucleus, nucleus accumbens, or olfactory tubercles, whereas the same stimulation from acute electrode placements causes significant ipsilateral increases in caudate DOPAC. Although DOPAC concentrations did not change when these chronically implanted electrodes were stimulated, similar chronic electrode placement supported intracranial self-stimulation (ICSS). In order to examine the effects of self-stimulation on DOPAC concentrations, five ICSS test groups were established for comparison: implanted only, trained only, minimum response rate, 50% maximum response rate and maximum response rrate. Following a 50 min test session, a comparison of either DA, or DOPAC concentrations across the different ICSS conditions revealed no change for the caudate nucleus, nucleus accumbens or olfactory tubercles. Likewise, there was no change between the stimulated and unstimulated sides within each ICSS group. When a comparison was made between implanted only and maximal ICSS response rate groups for changes in DA or DOPAC concentrations in the frontal cortex, no differences were found. Apparently, chronic electrode implantation abolished the ability to electrically stimulate nigro-striatal dopaminergic neurons under non-contingent conditions, and the relationship between dopaminergic neurons and ICSS appears to be indirect in nature.

Effects of lateral hypothalamic stimulation on acquisition, reversal and extinction of a visual discriminative learning task

The present experiment was carried out to investigate the effects of lateral hypothalamic (LH) stimulation on a negatively reinforced complex learning task including acquisition, reversal and extinction of a visual discrimination in an Y-maze. Male swiss mice were stimulated 45 sec after each training session during 60 sec (group ST). The stimulation intensity administrated in post-session was that which produced a rate of 50 responses by min during intracranial self-stimulation (ICSS) testing carried out prior to the learning experiment. Three control groups were constituted by animals either submitted to ICSS testing but not stimulated after training session (group NST). The post-session stimulated (group I) or non-implanted (group NI). The post-session stimulation improved the learning performance of the animals, but this effect was significant only during reversal learning of the task. ICSS testing carried out before learning, as well as electrode implantation, had no effect by themselves on the acquisition of the visual discrimination task. Moreover, no sign of extinction was observed in any group tested. These results suggest that facilitating effects induced by LH stimulation may depend on the complexity of the task and that cues of the learning situation have to reach a minimum of salience in order for LH stimulation to be effective.

Personality, amphetamine and intracranial self-stimulation in rats

The relationship between open-field ambulation and intracranial self-stimulation (ICSS) at the lateral hypothalamic area was studied in rats. A treatment with i.p. saline of d-amphetamine was also applied to the animals prior to ICSS tests. High-ambulatory rats (comparable to human extraverts) showed an equally higher susceptibility to ICSS reward than low-ambulatory rats (comparable to human introverts) with both saline and amphetamine. These findings were interpreted comsidering the ICSS as a strong stimulation which would tend to produce ‘unconditioned inhibition’ much earlier in low-ambulatory rats than high-ambulatory rats thus leading to a better conditioning among the high-ambulatory Ss.

Locus coeruleus and intracranial self-stimulation: A cautionary note

In an effort to confirm the presence of intracranial self-stimulation (ICSS) within the locus coeruleus, an ICSS testing procedure typically employed in our laboratory was used. Eighty male albino rats were implanted with bipolar electrodes made with either 78.7-μm or 254-μm nichrome wire. ICSS was not observed with electrodes in or adjacent to the locus coeruleus. Examination of the histological material revealed that some of the small-diameter electrodes were embedded within the locus coeruleus and yet no ICSS could be demonstrated in such cases. These results contrast with ICSS that we have observed previously in frontal cortex, both medial and sulcal, septohippocampal area, lateral hypothalamus, ventral midbrain tegmentum, and dorsal tegmentum in the region of the decussation of the superior cerebellar peduncle.