Differential effects of drug treatments on nose-poke and bar-press self-stimulation

To assess the possibility of dissociating drug-induced gross performance deficits from effects on brain stimulation reward, the nose-poke and bar-press operants were systematically compared. Pentobarbital and methocarbamol (a muscle relaxant) reduced bar-pressing more strongly than nose-poking. In contrast, clonidine and haloperidol, which disrupt noradrenergic and dopaminergic neurotransmission respectively, had no differential effect on these operants. The nose-poke operant appears less vulnerable to drug-induced gross motor impairment and may be more suitable for pharmacological studies of self-stimulation.     

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.     

Self-stimulation response decrement patterns differentiate clonidine,baclofen and dopamine antagonists from drugs causing performance deficit

Fouriezos and co-workers have reported that rats treated with the neuroleptics, pimozide or d-butaclamol, barpress at baseline rates at the start of an intracranial self-stimulation (ICSS) session, but cease responding within afew minutes. They suggested that this response decrement pattern (RDP) resembles natural extinction, indicating attenuation of reward by neuroleptic treatment. In the present experiments, the RDPs produced by several different drug classes were systematically compared. Two dopamine receptor antagonists, haloperidol and metoclopramide, produced an extinction-like RDP. In contrast, the alpha-1 adrenoceptor blocker, prazosin, and the muscle relaxant, methocarbamol, caused uniformly low response rates that did not decrease further as the session progressed. Clonidine, an alpha-2 adrenoceptor agonist, and baclofen, a novel GABA_B receptor agonist, were associated with RDPs that resembled those of the dopamine antagonists tested. Analysis of drug-induced RDPs is characterized as a valuable tool for exploring the nature of drug effects on ICSS responding.     

Effects of dopamine supersensitivity on lateral hypothalamic self-stimulation in rats

Dopamine (DA) receptor supersensitivity was demonstrated by potentiated d-amphetamine stereotypy after a three-day treatment regimen in which the DA receptor blocker pimozide (4.0 mg/kg) was administered twice daily. Similarly-induced DA supersensitivity produced a significant increase in the rate of lever-pressing for lateral hypothalamic (LH) intracranial self-stimulation (ICSS) and a significant decrease in ICSS thresholds. No change from pretreatment baselines was observed in vehicle-treated control animals. Following three-day treatment with the noradrenaline-(NA) and DA-receptor blocker, haloperidol (4.0 mg/kg twice daily), a single injection of the alpha-adrenergic agonist clonidine (0.15 mg/kg) caused increased running behavior. In contrast clonidine decreased running in rats pretreated with chronic pimozide or vehicle. These results indicate an increase in the sensitivity of central NA receptors following chronic haloperidol but not chronic pimozide. Taken together, these findings were interpreted as a potentiation in the reinforcing properties of LH-ICSS after chronic pimozide treatments due to increases in the sensitivity of DA and not NA receptors.     

Effects of catecholamine manipulations on three different self-stimulation behaviors

Rats with self-stimulation electrodes in the medial part of lateral hypothalamus (LH) or in the lateral part of LH were trained to bar press, to run in a continuous, square-shaped runway, and to move their tails from side to side while otherwise restrained, all using LH stimulation on an FI 2 sec schedule as the reinforcement. At low doses of pimozide (a dopaminergic blocker) or of FLA-57 (a dopamine betahydroxylase inhibitor) different effects on rates of responding were observed on each of the 3 tasks at the 2 electrode placements, indicating that the rate reductions were not the results of specific performance effects of the drugs. The patterns of rate changes suggested that the effects of LH stimulation on behavior in the runway were primarily, but not exclusively mediated by a dopaminergic system; that the effects of LH stimulation on tail movement were primarily, but not exclusively mediated by a noradrenergic system; and that the effect of LH stimulation on bar pressing was mediated by both, or either of these substrates. These results suggest that the reinforcement of behavior by LH stimulation is flexibly mediated by at least 2 different neural system.     

A comparison of atropine,benztropine and diphenhydramine on the reversal of haloperidol induced suppression of self-stimulation

Acute haloperidol administration (0.25, 0.5 mg/kg) produced a severe reduction in locomotor activity and operant responding for intracranial self-stimulation in rats. If the rats were also given 10 mg/kg of either diphenhydramine or benztropine, this behavioral inhibition was substantially reversed. Atropine (10 mg/kg), however, did not significantly alter the haloperidol inhibition. In a second study, the rats were tested 30 and 120 minutes after the haloperidol treatment (0.25 mg/kg). Again, diphenhydramine and benztropine but not atropine substantially reversed the haloperidol suppression after 30 minutes. When retested after 120 minutes, however, atropine and benztropine but not diphenhydramine partially reversed the haloperidol suppression. Thus, the present study provides support that diphenhydramine can be effective in reversing haloperidol induced suppression of self-stimulation but for a shorter duration than benztropine.     

Amphetamine,chlorpromazine and clonidine effects on self-stimulation in caudate or hypothalamus of the squirrel monkey

In 2 separate groups of squirrel monkeys and within 3 animals low rates of intracranial self-stimulation (ICSS) elicited from caudate or lateral hypothalamic brain sites were increased by as much as 200% above control levels by amphetamine (0.5 mg/kg). Thresholds for responding were decreased by 50%. Increasing the drug dose from 2 to 10mg/kg produced response inhibition at both brain sites. The duration of inhibitory action of amphetamine (2.0 mg/kg) on ICSS from the medial forebrain bundle (MFB) area of the lateral hypothalamus was 6 hr. At caudate sites ICSS did not occur until 48 hr had elapsed. A 10 mg/kg dose of amphetamine produced a duration of action of 36 hr in the MFB and 84 hr in the caudate. Chlorpromazine (CPZ) doses of 0.5 and 1.0 mg/kg decreased caudate ICSS significantly more than lateral hypothalamic ICSS. At 1.0 mg/kg the duration of action of CPZ was 6 hr at lateral hypothalamic brain sites and 24 hr at caudate sites. At a 2.0 mg/kg CPZ dose the duration of action was 12 hr in the MFB and 36 hr in the caudate. A dose of 0.10 mg/kg of clonidine blocked high rates of MFB ICSS while within the same animal caudate ICSS was much less affected. Higher doses (0.25 mg/kg) sedated the animal and ICSS was equally inhibited at both sites. These findings, using ICSS as a behavioral measure, suggest that the effects of amphetamine and CPZ involve not only hypothalamic structures but more anterior telencephalic sites as well. The prolonged actions of amphetamine and CPZ on caudate ICSS suggest that drugs acting, in part, on dopamine containing neurons will interfere with certain caudate mediated behavior. Further, since hypothalamic but not caudate ICSS sites are more dose sensitive to drugs that selectively act on NE containing neurons, other amines in addition to NE may play a role in the support of ICSS.     

Suppression of play fighting by amphetamine: effects of catecholamine antagonists, agonists and synthesis inhibitors

Moderate doses of amphetamine and methylphenidate profoundly depress play fighting in juvenile rats. To test the idea that this behavioral effect was dependent on the release of catecholamines (CAs) we administered haloperidol (0.05-0.8 mg/kg), chlorpromazine (0.5-5 mg/kg), phenoxybenzamine (0.5-20 mg/kg) or propranolol (0.5-20 mg/kg) alone or in combination with 0.5 or 1 mg/kg d-amphetamine sulfate. None of these CA antagonists reversed the suppression of play fighting (indexed by pinning) caused by amphetamine, but at higher doses haloperidol, chlorpromazine and phenoxybenzamine depressed both pinning and rearing. The presynaptic NE agonist clonidine (0.05-0.2 mg/kg) also failed to block the effects of amphetamine on play; instead it too depressed both pinning and rearing. Finally the CA synthesis inhibitor, alpha-methyltyrosine (total dose: 100 mg/kg) did not attenuate the suppression of play by amphetamine. Ephedrine (10-80 mg/kg) mimicked the effects of amphetamine on pinning, but apomorphine did not. At doses from 0.125-0.5 mg/kg apomorphine stimulated pinning while 1 mg/kg had no effect. The present findings confirm earlier reports that amphetamine suppresses play fighting but the mechanism of action remains obscure.     

Actions and interactions of amphetamine on self-stimulation in rats.

The dose-response relationship for d-amphetamine (0.125-2 mg/kg, IP) and its l-isomer (0.125-3 mg/kg, IP) was studied in self-stimulation behavior of rats each with an electrode at posterior hypothalamus (PH, mainly monoaminergic) or area ventralis tegmentum (A10, dopaminergic). The drug effects increased with the dose reaching a peak (at 0.5 mg/kg with d-amphetamine and at 1.0 mg/kg with 1-amphetamine) and then decreased. The d-isomer was approximately twice as potent as the l-isomer in enhancing intracranial self-stimulation (ICSS) rate with electrodes at either site. Azaperone (mainly an alpha-adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) used in small doses (0.05 and 0.008 mg/kg respectively) which did not affect the baseline responding, blocked amphetamine-induced enhancement of ICSS in both groups of rats. Thus, amphetamine-induced facilitation of ICSS at both PH and A10 areas and its blockade by an alpha-adrenergic blocker as well as an antidopaminergic neuroleptic show the involvement of both noradrenergic and dopaminergic mechanisms in self-stimulation behavior.     

Effects of chronic amphetamine or reserpine on self-stimulation responding: Animal model of depression?

The acute effects of 5 neuroleptic drugs were tested in rats implanted with stimulating electrodes in the medial forebrain bundle and trained in a brain selfstimulation threshold procedure. Haloperidol (0.01–0.10 mg/kg) and loxapine (0.03–0.56 mg/kg) produced increases in reinforcement thresholds accompanied by reductions in response rates. Chlorpromazine (0.10–3.0 mg/kg) did not significantly alter reinforcement thresholds, but did produce dose-dependent reductions in response rates. Pimozide (0.1–1.75 mg/kg) was similar to chlorpromazine and significantly increased the reinforcement threshold only at the highest dose, although a graded decrease in response rates occurred over a wide dose-range. Clozapine (0.1–1.75 mg/kg) increased reinforcement thresholds without producing any significant changes in response rates, but when 3.0 mg/kg was administered, a marked disruption of behavior occurred. The results suggested that a distinction can be made between the effects of neuroleptics on motor behavior and on central reinforcement thresholds, and this may help in the interpretation of the relation between the chemical and clinical potency of antipsychotic drugs.     

Effects of clozapine,olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat

Rationale. Antipsychotic drugs, particularly the newer atypical compounds, have been associated with rapid weight gain in a clinical setting. However, there are few reported animal models producing reliable hyperphagia correlating with the human weight gain liability of these drugs. Objective. To compare the effects of the classic neuroleptic haloperidol with the atypical antipsychotics clozapine and olanzapine on the microstructure of ingestive behaviour in rats. Methods. Male hooded Lister rats drank a palatable high-calorie fat emulsion (10% Intralipid) during 30-min test sessions and microstructural analyses were made following administration of each drug over a range of doses. Results. Clozapine (0.3 mg/kg) and olanzapine (0.1, 0.3, 1 mg/kg) significantly increased intake, whilst haloperidol (0.05, 0.1, 0.2 mg/kg) significantly decreased drinking. No significant changes in the latency to the first lick were observed following any of the drugs tested. Median interlick intervals showed small, dose-related increases after clozapine (3.0 mg/kg), olanzapine (0.3, 1.0 mg/kg) and haloperidol (0.1, 0.2 mg/kg). Olanzapine (1.0 mg/kg) significantly elevated the number of clusters of licking (bouts of licking separated by pauses greater than 500 ms), whilst clozapine and haloperidol did not. Mean cluster size (licks per cluster) was not affected by clozapine or olanzapine, but haloperidol (0.025, 0.05, 0.1, 0.2 mg/kg) produced marked, significant decreases in cluster size. Conclusions. Clozapine and olanzapine increased fat intake whereas haloperidol did not, and this resembles the greater weight gain liability of atypical antipsychotics in humans. A delay or reduction of the post-ingestive satiety signal combined with preserved palatability appears to be the mechanism responsible for fat hyperphagia in rats treated with clozapine and olanzapine. Conversely, haloperidol leaves satiety unaffected but reduces the palatability of the fat emulsion resulting in reduced intake. Electronic Publication     

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.     

Effects of the antipsychotics haloperidol,clozapine, and aripiprazole on the dendritic spine

Three types of antipsychotics, typical (e.g. haloperidol), atypical (e.g. clozapine), and dopamine partial agonist (e.g. aripiprazole), are administered for treatment of schizophrenia. These antipsychotics have different efficacy and side-effect profiles. We investigated whether aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine through the AKT-GSK-3 beta cascade. Dissociated cortical neurons from Sprague-Dawley rats were prepared and cultured for 28 days. Aripiprazole, clozapine, or haloperidol was administered to the rat cortical neurons. The levels of PSD95 protein and AKT-GSK-3 beta cascade-related proteins were investigated by Western blot. The number of spines and PSD95 puncta were investigated by immunofluorescence cell staining. Aripiprazole (1?µM or 10?µM) and clozapine (1?µM) increased the levels of PSD95 protein, the number of spines, phosphorylated Akt Thr308 and Ser473, and phosphorylated GSK-3 beta Ser9. On the other hand, haloperidol (1?µM or 10?µM) or an inappropriate concentration of clozapine (10?µM) decreased them. A GSK inhibitor also increased the levels of PSD-95 protein and caused the same morphology. Aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine, and this effect may occur through the AKT-GSK-3 beta cascade. Selection and appropriate dose of these antipsychotics may be important for the protection of dendritic spines in patients with schizophrenia.     

Effects of parenteral morphine and oral methadone on self-stimulation in the rat

Facilitation of self-stimulation has been reported following the administration of various opiates. Methadone, a synthetic narcotic used in the treatment of narcotic addiction, has recently been demonstrated to facilitate self-stimulation when administered parenterally. The present study examined the effects of orally administered methadone (20 and 30 mg/kg), the route of administration used clinically, on MFB-LH self-stimulation at 2.5, 5, 8, 12, 17, and 24 hours post-administration. reliable facilitation was observed at 2.5 hours post-administration. However, the effect of methadone was less pronounced than that observed with a dose of parenteral morphine which was approximately equivalent in terms of analgesic potency.     

The actions of dopaminergic and noradrenergic antagonists on conditioned avoidance responses in intact and 6-hydroxydopamine-treated rats

The actions of various doses of haloperidol, pimozide, clozapine, and phenoxybenzamine were assessed on a conditioned-avoidance response (CAR) in control and 6-hydroxydopamine-treated rats, using a pole-climbing device. Haloperidol proved to be the most potent in disrupting the CAR. Pimozide was about 1.6 times less potent, and clozapine and phenoxybenzamine were approximately 52 and 155 times less potent than haloperidol, respectively. Prior treatment with 6-hydroxydopamine slightly enhanced the sensitivity to some of the doses of the DA and NE antagonists. Significantly lower levels of responding, however, were observed only after the highest dose of pimozide.Clonidine was not only ineffective in reverting avoidance decrements, but also induced a further decline of the CAR. Apomorphine produced a partial, but significant, reversal of the haloperidol and pimozide-induced depression of conditioned responses. Regarding the clozapine-pretreated animals, a significant antagonism was observed only with the smaller dose of apomorphine. The highest dose induced a further decline of the CAR. The DA agonist was also ineffective in the phenoxybenzamine-injected rats. Amphetamine was effective in antagonizing the avoidance decrements produced by all the CA antagonists.Our results support the suggestion that CAR depends on both DA and NE mechanisms. DA seems to be more significant that NE, however, since the CAR was more depressed when receptors depending on the former neurotransmitter were blocked.     

Alpha-noradrenergic modulation of hypothalamic self-stimulation: studies employing clonidine, 1-phenylephrine and alpha-methyl-p-tyrosine.

An alpha-noradrenergic substrate of rewarding intracranial stimulation (ICS) has been hypothesized based on the observation that the alpha-antagonist phentolamine produced an inhibition of self-stimulation. The present experiment investigated the effects on hypothalamic self-stimulation of the alpha agonist clonidine in normal and in catecholamine-depleted rats. Using a shuttle-box technique that provides a rate-independent index of the rewarding and aversive components of ICS, it was demonstrated that clonidine produces a dose-dependent inhibition of reward that is clearly dissociable from any non-specific effects of the drug. The ineffectiveness of the peripheral alpha-agonist 1-phenylephrine indicates that the inhibition of reward produced by clonidine is mediated centrally. Clonidine and the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine act together in a synergistic manner to greatly increase the magnitude and prolong the duration of the inhibition of reward while leaving the aversive component unaffected. These data are interpreted as supporting an alpha-noradrenergic basis of ICS reward while indicating that the aversive component of ICS is essentially independent of noradrenergic transmission.     

Effects of clozapine, chlorpromazine and haloperidol on schedule-controlled behavior

The effects of clozapine, chlorpromazine, and haloperidol were determined in mice and pigeons responding under a multiple fixed-ratio 30, fixed-interval 600 sec schedule of food presentation. In both species, low doses were without effect and moderate to high doses of all three antipsychotics decreased responding. In contrast to other behavioral tests used to predict antipsychotic activity, clozapine was equipotent or more potent than chlorpromazine in decreasing responding under the multiple fixed-ratio 30, fixed-interval 600 sec schedule. The order of potency observed in the mouse was: haloperidol greater than chlorpromazine greater than or equal to clozapine. The order of potency in the pigeon was: haloperidol greater than clozapine greater than chlorpromazine. In mice and pigeons, the rate of responding under the fixed-ratio component was decreased at lower than, or the same doses of clozapine as that required to decrease fixed-interval responding. However, in both species, chlorpromazine and haloperidol decreased fixed-interval responding at lower doses or the same dose as that required to decrease fixed-ratio responding.     

Intracranial self-stimulation under a progressive-ratio schedule in rats: effects of strength of stimulation, d-amphetamine, 7-OH-DPAT and haloperidol

Progressive-ratio (PR) schedules, which have been widely used to study the reinforcing efficacy of various reinforcers (in particular IV psychostimulants), have been very seldom applied to the study of positively reinforcing electrical brain stimulation (EBS). In the present study, rats were required to emit a progressively increasing number of lever-presses (3,4,6,7,9,11,14,16, etc.) for access to successive reinforcers (periods of VTA self-stimulation). Each period of self-stimulation consisted of ten trains of square pulses of EBS; each train was available under a continuous reinforcement schedule. The number of periods of EBS earned during a session was deemed the breaking point (BP). After acquisition and stabilization of self-stimulation, a study was carried out to verify that changes in the strength of the EBS (i.e. changes in the frequency, the intensity or the pulse duration, one parameter at a time) induced changes in the BP. The effects of IP pretreatments with d-amphetamine, the dopamine D₃/D₂ receptor agonist 7-OH-DPAT and haloperidol were then assessed. Decreases in the strength of EBS decreased the BP. However, increasing the strength above training values resulted in minimal increases in the BP. d-Amphetamine (0.25–1 mg/kg) dose-dependently increased the BP; additionally, when the reinforcer was withheld (i.e. in conditions of extinction, with the stimulator turned off) d-amphetamine was also found to augment the BP. This might indicate that d-amphetamine preferentially potentiated the motivational (non-rewarded presses) aspects of VTA self-stimulation under this type of PR schedule. 7-OH-DPAT had biphasic effects: at low doses (0.01 and 0.03 mg/kg), it tended to decrease the BP while higher doses (1 and 3 mg/kg) robustly increased the BP. Under conditions of extinction, 7-OH-DPAT (1 mg/kg) had a tendency to increase the BP, but this effect was not statistically significant and did not approach the magnitude of effects observed with d-amphetamine. Haloperidol (0.08–0.48 mg/kg IP) dose-dependently reduced the BP, suggestive of a decrease in the reinforcing efficacy of the EBS. These results show that rats can be trained to self-administer EBS of the VTA under a PR schedule of reinforcement and that this behaviour is sensitive to disruption or potentiation of dopaminergic neurotransmission. Received: 12 January 1998/Final version 5 August 1998     

Actions and interactions of cocaine on self-stimulation behavior in rats

The effect of cocaine, over a dose range of 2–60 mg/kg, i.p., on self-stimulation (SS) behavior was studied in rats with electrodes either in the posterior hypothalamus (PH, monoaminergic) or the area ventralis tegmentum (A10, dopaminergic). The drug increased SS behavior with peak effects at 30 mg/kg in PH rats and 20 mg/kg in A10 rats. Azaperone (an -adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) given at doses that did not affect baseline SS responses reduced cocaine-induced enhancement of SS in both PH and A10 rats, showing the involvement of both noradrenergic and dopaminergic mechanisms in SS behavior. A scopolamine dose that itself facilitated SS responding enhanced the effect of cocaine on this behavior, thus suggesting an additional involvement of cholinergic mechanism in cocaine effect.     

Effects of morphine and naloxone on thresholds of ventral tegmental electrical self-stimulation

Summary The involvement of opioid systems in self-stimulation reward was investigated by studying the effects of the opioid antagonist naloxone (10 mg/kg s.c.) and graded doses of morphine (0.3–5.0 mg/kg s.c.) on intracranial electrical self-stimulation (ICSS) in rats with electrodes in the ventral tegmental area. Lever pressing for ICSS was analyzed using three different procedures: (1) determination of response rate i.e. the number of responses to high and threshold currents, (2) measuring threshold current when response rate was kept low and relatively constant, (3) determination of behavioural threshold using a two-lever procedure in which a response on one lever resulted in a reset of the decreasing current to a high current contingent on a response to the other lever. It was found that low doses of morphine increased the response rate of ICSS behaviour and decreased the threshold whereas the higher doses decreased the response rate but also decreased the threshold current when measured with a rate insensitive procedure. Naloxone raised the threshold for ICSS and caused a corresponding decrease of response rate.In a second series of experiments in which the behaviour of rats which had been tested in one procedure was analysed using one of the other methods, it was observed that naloxone caused smaller changes, while the effects of morphine were at least comparable to those observed in the first series of experiments.The present data suggest that response rate insensitive procedures to analyse ICSS should be preferred to response rate sensitive ones, especially when the interaction of depressant drugs such as morphine with reward mechanisms is investigated. It is concluded that opioid systems are involved in ICSS elicited by electrical stimulation in the ventral tegmental area, and that the synergistic action of electrical stimulation and the pharmacological activation of ICSS reward circuits due to morphine may be related to the addictive properties of this drug.