Effects of peripheral and central dopamine blockade on lateral hypothalamic self-stimulation: Evidence for both reward and motor deficits

The effects of dopamine receptor antagonists on lateral hypothalamic self-stimulation were analyzed using a reward summation function (RSF) technique. This paradigm relates running speed in a runway to the number of stimulation pulses received as a reward, and it is able to separately characterize changes in reward pulse effectiveness and motor performance. Pimozide, administered peripherally (0.125, 0.25, 0.5 mg/kg, IP), dose-dependently shifted the RSF toward higher values of number of pulses indicating reduced reward. Pimozide also reduced the asymptotic running speed of the RSF, indicating a deficit in motor performance. In a second experiment, α-flupenthixol infused directly into the nucleus accumbens (0.5 μg-0.5 μg, bilaterally) induced changes in the RSF similar to those obtained with peripheral neuroleptic treatment. These findings are discussed from the perspective that dopamine is involved both in the perception of reward value and in the performance of the response to obtain reward.     

Effects on self-stimulation behavior of drugs influencing dopaminergic neurotransmission mechanisms

Summary Drugs preferentially influencing dopaminergic neurotransmission mechanisms were administered to rats which lever-pressed to receive electrical stimulation in either the lateral hypothalamus or periaqueductal mesencephalon. The same drug effects were observed regardless of the site of electrical stimulation. Blockade of dopamine receptors by 0.35 or 0.5 mg/kg pimozide reduced self-stimulation rates. Increasing the reward value of the stimulation by doubling of self-stimulation current induced control rates of lever-pressing in animals given 0.35 mg/kg pimozide but not in those receiving 0.5 mg/kg. At doses of 0.75 and 1.5 mg/kg, apomorphine, a putative dopamine receptor stimulator, reduced self-stimulation rates at normal current. Doubling of the stimulation current produced greater than normal rates of lever-pressing at 0.75 mg/kg apomorphine, but at 1.5 mg/kg no such increase in rate was observed. l-DOPA, 75 and 150 mg/kg, also reduced self-stimulation, but doubled current restored rates to control levels at both doses. For comparison purposes, pharmacological effects on predominantly noradrenergic mechanisms were also studied. Inhibition of dopamine--hydroxylase by 150 mg/kg disulfiram reduced self-stimulation under normal current, but rates were increased to above control levels with doubled current. That self-stimulation behavior could be reinstated by doubling of current suggests that motor incapacity is not a sufficient explanation for most of the observed reductions in lever-pressing rate. These results further suggest that, in addition to noradrenaline, the integrity of central dopaminergic systems may be essential for the behavioral expression of certain motivational processes.     

Pimozide-induced extinction in rats: stimulus control of responding rules out motor deficit.

Rats stopped responding for electrical stimulation of the brain following pretreatment with the dopamine antagonist pimozide, as well as following truncation of brain stimulation trains. In either case the extinguished responding was temporarily reinstated on presentation of a light if the light had previously signalled reward but not if the light had had no such significance. These results indicate that pimozide reduces self-stimulation by abolishing the rewarding effect of brain stimulation rather than by interfering with motor ability.     

Differential effects of d-amphetamine,pipradrol and bupropion on shuttlebox self-stimulation

The shuttlebox self-stimulation test is claimed by Atrens to differentiate drug effects on brain stimulation reward from those on performance variables. Thus, for example, drug-induced enhancement of the reward value of stimulation should be reflected in a selective reduction of the latency to initiate stimulation (the ON latency), as compared with the latency to terminate stimulation (the OFF latency). The effects of the psychostimulant drugs, d-amphetamine and pipradrol, and the antidepressant, bupropion, were evaluated in this procedure as well as in a bar-pressing test of self-stimulation. Pipradrol (3 and 10 mg/kg) and bupropion (54 mg/kg) reduced ON latencies by 40% or more but failed to shorten OFF latencies, indicating that performance variables were not involved in the ON latency decrements. Although d-amphetamine (0.3 and 1.0 mg/kg) shortened ON latencies, the 1.0 mg/kg dose also reduced OFF latencies. Drug doses that reduced ON latencies also increased bar-pressing self-stimulation. The shuttlebox self-stimulation test appears to be capable of discriminating drug-induced enhancement in brain stimulation reward from performance variables.     

Intracranial self-stimulation in orbitofrontal cortex and caudate nucleus of rhesus monkey: Effects of apomorphine,pimozide, and spiroperidol

Rhesus monkeys were prepared with stimulating electrodes implanted into the orbitofrontal cortex and head of the caudate nucleus under stereotaxic control. These regions of the brain contain high levels of dopamine, and intracranial self-stimulation was readily elicited from these loci in all animals tested using licking behavior as the operant response. Self-stimulation at both sites was significantly attenuated following peripheral injections of the dopamine receptor blocker spiroperidol (0.02 mg/kg). Similarly, pimozide (0.15 and 0.20 mg/kg) significantly reduced self-stimulation in the orbitofrontal cortex, but the suppression observed at caudate placements did not reach statistical signifcance. Licking for a reward of blackcurrant juice was unaffected by either drug. Apomorphine (0.2, 0.4 mg/kg) had a differential effect on self-stimulation. This drug significantly attenuated self-stimulation in the orbitofrontal cortex, while the same treatment tended to facilitate self-stimulation in the caudate. Apomorphine did not significantly affect responding for the fruit juice reward. The parallels between the effects of dopamine agonists and antagonists on self-stimulation in the monkey and rat suggest that dopamine influences self-stimulation of some sites in both the primate and the rat.     

Dissociation of the attentional and motivational effects of pimozide on the threshold for rewarding brain stimulation

The decreased sensitivity of animals to rewarding brain stimulation caused by pimozide has been interpreted as a selective pharmacologic blockade of central reward pathways rather than a nonspecific disruption of performance. In an attempt to confirm this hypothesis, the effects of pimozide on both reward and detection thresholds for intracranial stimulation delivered to the medial forebrain bundle-lateral hypothalamic area (MFB-LH) were determined in four animals. The drug caused a systematic increase in the reward threshold of each subject but had no such effect on the detection threshold. We conclude that pimozide selectively inhibits the rewarding effects of brain stimulation, and that therefore, the D2 dopamine receptor has a major role in activating central reward pathways subserving pharmacologic and electrical reinforcement. The dual anhedonic/antipsychotic effects of neuroleptic medication are discussed as a possible paradox of central importance to the psychopathology of schizophrenia.     

Is the release of noradrenaline necessary for self-stimulation of the brain?

The hypothesis that a quantity of noradrenaline released contingently on every response made to obtain brain stimulation mediates the reward produced by the stimulation was tested. An alternative hypothesis is that reward is mediated by a different system, but that a steady activation of post-synaptic receptors by noradrenaline is necessary for normal behavior. The synthesis of noradrenaline was inhibited by disulfiram, and when lateral hypothalamic self-stimulation in the rat had ceased, α-aarenergic stimulants were injected intraventricularly (IC) or intraperitoneally (IP). The directly acting receptor stimulants oxymetazoline (0.9–250 μg IC), naphazoline (20–250 μg IC), and clonidine (0.75–3 μg IC, 0.037–3 mg/kg IP) did not restore self-stimulation, but the indirectly acting stimulants amphetamine (2 mg/kg IP), methylphenidate (3 mg/kg IP) and phenylephrine (15 μg IC) did restore self-stimulation. In Experiments 2 and 3, in which either the functional noradrenaline pool was depleted with disulfiram and amphetamine, or the reserve noradrenaline pool was depleted with reserpine, the action of phenylephrine in restoring self-stimulation was shown to be indirect, probably by mobilizing a reserve pool of noradrenaline. Because only indirectly acting noradrenergic stimulants which facilitate the release of noradrenaline restored self-stimulation, it is concluded that noradrenaline must be released contingent on every response for self-stimulation to occur. Whether this released noradrenaline mediates the reward or has some other function associated with bar-pressing behavior remains to be shown.     

Pimozide blocks reinforcement but not priming from MFB stimulation in the rat

When given non-contingent pretrial stimulation (priming stimulation) rats ran an alley for brain-stimulation reward faster than when there was no priming. This is one manifestation of the priming effet of rewarding stimulation. After treatment with the neuroleptic, pimozide, the first few trials fell in the range of normal primed performance when the rats were primed, and in the range of normal unprimed performance when they were not. In either case, an extinction-like decline in performance occurred after the first few trials. Run in a T-maze with water in one arm and a level producing brain stimulation reward in the other, thirsty rats chose the stimulation reward when primed and the water reward when unprimed. Pimozide in doses that produced extinction of Skinner box responding did not alter this effect of priming on reward preference. These results demonstrate that the priming effect is unaltered by doses of pimozide that block the reinforcing effect of the stimulation.     

alpha-Adrenergic modulation of hypothalamic self-stimulation: effects of phenoxybenzamine, yohimbine, dexamphetamine and their interactions with clonidine.

The alpha-adrenoceptor agonist clonidine (12.5--50.0 microgram/kg) produced a dose-dependent increase in the latency to initiate lateral hypothalamic stimulation. The insurmountable postsynaptic alpha-adrenoceptor antagonist phenoxybenzamine (0.2-0.8 mg/kg) had no effect on self-stimulation by itself, but potentiated the inhibitory effects of clonidine. The fact that the concurrent escape behavior to the intracranial stimulation was unchanged by either clonidine or the phenoxybenzamine-clonidine combination suggests that the inhibition is specific to the rewarding component of hypothalamic stimulation. Yohimbine (0.5--2.0 mg/kg) produced a dose-dependent increase in both response latencies. This lack of behavioral specificity may reflect yohimbine's wide range of pharmacological activity, Dexamphetamine (0.25--0.50 mg/kg) reversed clonidine's inhibition of self-stimulation reward in a specific and dose-dependent fashion. This reversal could be blocked by previous inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. These data support the concept that the alpha-adrenoceptors play a critical role in the modulation of hypothalamic self-stimulation reward. They further suggest that the inhibitory effects of clonidine on self-stimulation reward represent an agonist effect on presynaptic alpha-adrenoceptors.     

Paroxetine combined with a 5-HT1A receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats

Rationale Diminished interest or pleasure in rewarding stimuli is an affective symptom of amphetamine withdrawal and a core symptom of depression. An operational measure of this symptom is elevation of brain stimulation reward thresholds during drug withdrawal. Data indicated that increasing serotonin neurotransmission by co-administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the serotonin-1A receptor antagonist p-MPPI reversed reward deficits observed during drug withdrawal (Harrison et al. 2001).Objectives We tested the hypothesis that increased serotonergic and noradrenergic neurotransmission, using the SSRI paroxetine which also inhibits noradrenaline reuptake, would alleviate affective aspects of amphetamine withdrawal.Methods A discrete-trial, current-threshold, self-stimulation procedure was used to assess brain reward function. The effects of paroxetine and p-MPPI alone and in combination were assessed in non-drug-withdrawing animals. We assessed also the effects of paroxetine and p-MPPI alone and in combination on reward deficits associated with amphetamine withdrawal.Results Paroxetine or p-MPPI alone had no effect on thresholds, while the co-administration of p-MPPI (3 mg/kg) and paroxetine (1.25 mg/kg) elevated thresholds in non-withdrawing rats. Amphetamine withdrawal resulted in threshold elevations. The co-administration of p-MPPI and paroxetine reduced the duration of amphetamine-withdrawal-induced reward deficits.Conclusions Increased serotonergic and noradrenergic neurotransmission decreased reward function in non-withdrawing rats, while the same treatment reversed reward deficits associated with amphetamine withdrawal. Considering that paroxetine acts on both the serotonin and noradrenaline transporter, these results indicate that the affective symptoms of amphetamine withdrawal, similar to non-drug-induced depressions, may be, in part, mediated through reduced serotonergic and noradrenergic neurotransmission.     

Motivational effect of nomifensine in the intracranial self-stimulation behavior using a runway method

Intracranial self-stimulation (ICSS) behavior is an experimental methodology to study reward and motivational effects. We have established a new paradigm to evaluate enhancing motivation by drugs in the runway method using the priming stimulation of ICSS. In the present study, we investigated the effects of nomifensine on the experimental extinction process of non-reinforcing reward and pre-trial electric priming stimulations in lateral hypothalamic self-stimulation. In this study, the experimental extinction process of the non-reinforcing reward means the experimental method of excluding reward effect in ICSS behavior. The extinction process in the runway method consisted of these 15 trials. Nomifensine, an antidepressant drug, delayed the running speed of the extinction process at doses of 5 and 10 mg/kg (i.p.) compared with the vehicle alone. This result suggests that the delay in the running speed of the extinction process promotes a motivational effect in rats. Previously, priming stimulation in the runway method was found to affect motivational function of ICSS. Therefore, our findings suggest the possible application of nomifensine for improving motivation.     

Quantitative determination of the effects of catecholaminergic agonists and antagonists on the rewarding efficacy of brain stimulation

The effects of amphetamine, clonidine, molindone, pimozide and yohimbine on the rewarding efficacy of electrical stimulation of the medial forebrain bundle in the rat were determined from the effects of these drugs on the rate-frequency function, which is the plot of the rat's rate of pressing a lever against the frequency of the pulses in a rewarding train of fixed duration. These catecholaminergic agonists and antagonists produced dose-dependent alterations in the measurable rewarding efficacy, but only up to a factor of about 2, even though the method is capable of measuring 25-30-fold changes. At elevated doses, the effects on rewarding efficacy became unmeasurable, because the animals would not consistently self-stimulate at any parameters of stimulation. Amphetamine (0.5-3 mg/kg) enhanced rewarding efficacy. Clonidine (0.05-0.4 mg/kg), molindone (0.25-1 mg/kg) and pimozide (0.1-0.6 mg/kg) attenuated it. Pimozide and clonidine were equipotent despite their radically different receptor affinities. The effects of pimozide, clonidine and amphetamine were approximately additive (amphetamine cancelled the effects of pimozide and clonidine, while clonidine augmented the effect of pimozide). The alpha 2 antagonist yohimbine (0.05-10 mg/kg) had the same effect as the alpha 2 agonist clonidine (attenuation of rewarding efficacy), but these effects did not combine additively: yohimbine neither cancelled nor augmented the effect of clonidine. It is suggested that catecholaminergic agonists and antagonists do not alter the magnitude of the rewarding signal by acting on postsynaptic receptors in the reward pathway; rather, they may drive beyond functional limits a variable that is crucial to the proper recording of the magnitude of the rewarding signal.     

The effects of pimozide and of reward omission on fixed-interval behavior of rats maintained by food and electrical brain stimulation

Pimozide (0.125 to 2.0 mg/kg) was administered to rats whose behavior was maintained by a fixed-interval schedule in which the reward was either food (Experiment 1) or electrical stimulation of the brain (Experiment 2). The effects of the drug were compared with the effects of withholding reward (i.e., extinction) in both experiments. Reward omission and administration of pimozide both resulted in decreases in overall rates of responding and increases in the time taken by the subjects to complete a specified number of fixed-intervals. The typical patterning of responding during the sessions of reward omission was also characteristic of the effects of pimozide with food reward but not with brain stimulation reward. The duration of trains of brain stimulation which was under the control of the subjects in Experiment 2, was not altered by administration of pimozide. The differences between the effects of pimozide on behavior maintained by intermittent food reward or by intermittent brain stimulation reward limits a global interpretation of the effects of neuroleptics.     

Animal model for investigating the anxiogenic effects of self-administered cocaine

Male albino rats were trained to traverse a straight alley for a reward of five intravenous injections of cocaine (0.75 mg/kg/injection in a volume of 0.1 ml/injection delivered over 4 s). Animals were tested one trial per day with the following dependent measures assessed on each trial: start latency, running time, the number of retreats, and the location within the alley where each retreat occurred. While start latencies remained short and stable, running times tended to increase over days. This effect was apparently related to a concomitant increase in the number of retreats occurring in the alley (r=0.896). Retreats tended to occur in very close proximity to the goal box, suggesting that animals working for IV cocaine come to exhibit a from of conflict behavior (i.e., retreats) putatively stemming from the drug's well documented rewarding and anxiogenic properties. Consistent with this hypothesis was the demonstration that diazepam (0.5, 1.0, 2.0 mg/kg IP) pretreatment dose-dependently reduced the incidence of retreat behaviors in the alley. In addition, the rewarding efficacy of the cocaine dosing parameters was subsequently confirmed in the runway subjects by conditioned place preference. The present paradigm, therefore, provides a useful method for investigating the anxiogenic effects of self-administered cocaine in laboratory animals.     

Effect of diazepam on the runway method using priming stimulation of intracranial self stimulation behavior

Intracranial self-stimulation (ICSS) behavior is an experimental methodology to study reward and motivational effects. We have established a paradigm to evaluate enhancing motivation by drugs in the runway method using the priming stimulation of ICSS. In the present study, we investigated the effects of diazepam on the experimental extinction process of non-reinforcing reward and pre-trial electric priming stimulations in lateral hypothalamic self-stimulation. The extinction process in the runway method consisted of these 15 trials. Diazepam, an anti-anxiety drug, at doses of 0.5 and 1 mg/kg (i.p.) delayed the extinction of running behavior when priming stimulation was given. The GABAergic antagonist flumazenil at doses of 5 and 10 mg/kg (i.p.) totally prevented the effect of diazepam. These results demonstrate that diazepam delays the extinction of running behavior on ICSS in the runway method and flumazenil, a GABAergic antagonist, eliminates the delayed effect of diazepam, that is, indicating that the delayed extinction effect of diazepam may be related to facilitation of motivation, which was promoted via the GABAergic system in the ICSS behavior.     

Chronic morphine fails to enhance the reward value of prefrontal cortex self-stimulation.

Dopamine (DA) plays an important role in the rewarding effects of drugs of abuse and intracranial self-stimulation (ICSS). We previously reported that ICSS derived from the prefrontal cortex appears insensitive to the reward-enhancing effects of amphetamine, a drug that increases DA release and reward at other ICSS sites. In the present study, rats with prefrontal electrodes were tested to see if morphine (7.5 or 10.0 mg/kg, IP) given once per day for 10 days enhanced prefrontal reward as assessed with the curve-shift method. Morphine initially produced sedation; however, after 3-4 days response rates increased sharply while frequency thresholds were unaffected. These results demonstrate that morphine does not enhance prefrontal ICSS reward and provide further evidence that prefrontal brain stimulation reward does not display the same characteristics as other ICSS sites.     

A new view of the effect of dopamine receptor antagonism on operant performance for rewarding brain stimulation in the rat

Rationale

Previous studies of neuroleptic challenges to intracranial self-stimulation (ICSS) employed two-dimensional (2D) measurements (curve shifts). Results so obtained are ambiguous with regard to the stage of neural processing at which the drug produces its performance-altering effect. We substituted a three-dimensional (3D) method that measures reward-seeking as a function of both the strength and cost of reward. This method reveals whether changes in reward seeking are due to drug action prior to the output of the circuitry that performs spatiotemporal integration of the stimulation-induced neural activity.

Objectives

The aim of this study was to obtain new information about the stage of neural processing at which pimozide acts to alter pursuit of brain stimulation reward (BSR).

Methods

Following treatment with pimozide (0.1 mg/kg) or its vehicle, the proportion of trial time allocated to working for BSR was measured as a function of pulse frequency and opportunity cost. A surface defined by Shizgal's reward-mountain model was fitted to the drug and vehicle data.

Results

Pimozide lowered the cost required to decrease performance for a maximal BSR to half its maximal level but did not alter the pulse-frequency required to produce a reward of half-maximal intensity.

Conclusions

Like indirect dopamine agonists, pimozide does not alter the sensitivity of brain reward circuity but changes reward-system gain, subjective effort costs, and/or the value of activities that compete with ICSS. The 3D method is more sensitive and informative than the 2D methods employed previously.     

Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats.

The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concomitant antidepressant treatment and may provide an heuristic animal model of depression.     

Enhancement of endocannabinoid neurotransmission through CB1 cannabinoid receptors counteracts the reinforcing and psychostimulant effects of cocaine

Cannabinoids, in contrast to typical drugs of abuse, have been shown to exert complex effects on behavioural reinforcement and psychomotor function. We have shown that cannabinoid agonists lack reinforcing/rewarding properties in the intracranial self-stimulation (ICSS) paradigm and that the CB1 receptor (CB1R) agonist WIN55,212-2 attenuates the reward-facilitating actions of cocaine. We sought to determine the effects of the endocannabinoid neurotransmission enhancer AM-404 (1, 3, 10, 30 mg/kg) on the changes in ICSS threshold and locomotion elicited by cocaine and extend the study of the effects of WIN55,212-2 (0.3, 1, 3 mg/kg) on cocaine-induced hyperlocomotion. AM-404 did not exhibit reward-facilitating properties, and actually increased self-stimulation threshold at the highest dose. Cocaine significantly reduced self-stimulation threshold, without altering maximal rates of responding. AM-404 (10 mg/kg) attenuated this action of cocaine, an effect which was reversed by pretreatment with the selective CB1R antagonist SR141716A. WIN55,212-2 decreased locomotion at the two highest doses, an effect that was blocked by SR141716A; AM-404 had no effect on locomotion. Cocaine caused a significant, dose-dependent increase in locomotion, which was reduced by WIN55,212-2 and AM-404. SR141716A blocked the effects of WIN55,212-2 and AM-404 on cocaine-induced hyperlocomotion. SR141716A alone had no effect on ICSS threshold or locomotion. These results indicate that cannabinoids may interfere with brain reward systems responsible for the expression of acute reinforcing/rewarding properties of cocaine, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for the treatment of psychostimulant addiction and pathological states associated with psychomotor overexcitability.     

Motivational effects of methamphetamine as measured by the runway method using priming stimulation of intracranial self-stimulation behavior

Priming stimulation is known to promote the motivational effects of intracranial self-stimulation (ICSS) behavior. The runway method using priming stimulation can experimentally distinguish the reward and motivational effects of ICSS behavior. In this study, we examined the motivational effect of a drug as determined by the runway method using priming stimulation of ICSS behavior. Electrodes were implanted chronically into the medial forebrain bundle (MFB) of the rats. A lever for stimulation of the MFB was set on the opposite side of the start box in the apparatus. The rats were trained to obtain a reward stimulation (50-200 muA, 0.2 ms, 60 Hz) of the MFB by pressing the goal lever, and then priming stimulation of the MFB was applied. After priming stimulation, rats were placed in the start box of the runway apparatus and the time taken by the rat to press the lever was recorded. Priming stimulation frequency was significantly correlated with running speed (r=0.897, p<0.05). Methamphetamine (1, 3 mg/kg) induced an increase in running speed (F(3, 20)=16.257, p<0.01), and was further increased with increase in priming stimulation frequency. In addition, methamphetamine significantly enhanced the motivational effect. These results suggest that the runway method using priming stimulation of ICSS behavior may be an effective way to evaluate the enhancing effect of a drug on motivation.