Chlorpromazine and brain-stimulation reward: Potentiation of effects by naloxone

Chlorpromazine (0.25–2.0 mg/kg IP) raised the threshold for brain stimulation reward in a dose-dependent manner in rats. Naloxone (4.0 mg/kg IP) administered alone was without effect on this behavior. However, this dose of naloxone administered concurrently with chlorpromazine produced substantial potentiation of the threshold increases. These resultsstrongly suggest a catecholaminergic-enkephalinergic involvement in the regulation of central reward processes.     

The effects of amfonelic acid alone and in combination with naloxone on brain-stimulation reward

Thresholds for rewarding brain stimulation delivered to the medial forebrain bundle-lateral hypothalamus were determined by means of a rate-free psychophysical method. Amfonelic acid (AFA), an indirect dopamine agonist, alone caused a significant dose-dependent lowering of the rewarding threshold. Although naloxone treatment by itself did not significantly alter the reward threshold, it blocked AFA's threshold lowering effect in every animal at one or more of the dose combinations of the two drugs tested. Naloxone was found to be more effective in blocking the threshold lowering actions of a higher (1 mg/kg) dose as opposed to a lower (0.25 mg/kg) dose of AFA. Since a lowering of threshold for rewarding intracranial stimulation is a model for drug-induced euphoria, the findings presented here indicate that AFA may have abuse potential. Furthermore, these results suggest that endogenous opioid systems may begin to modulate the effects of AFA on the reward system only when a certain level of activation of dopaminergic systems is reached.     

Effects of d-amphetamine and naloxone on brain stimulation reward

Self-stimulation thresholds were determined in rats by means of a modification of the psychophysical method of limits. Reinforcement values were determined after the administration of d-amphetamine alone, naloxone alone, and naloxone administered concurrently with d-amphetamine. d-Amphetamine yielded dose-related decreases in the threshold (0.25–2.00 mg/kg IP), while naloxone alone (2.0–16 mg/kg IP) caused no consistent changes. For each animal, a dose of d-amphetamine that substantially lowered the threshold was then selected to be administered with varying doses of naloxone. The threshold-lowering effect of d-amphetamine was blocked by naloxone at doses as low as 2.0 or 4.0 mg/kg. This finding suggests the possible involvement of an opiate receptor in the mediation of the enhancement by d-amphetamine of brain stimulation reward.     

Asymmetrical effects of morphine and naloxone on reward mechanisms

Rats with bilaterally implanted lateral hypothalamic electrodes were tested daily for self-stimulation to each side of the brain, and rotation (circling behavior) was recorded concomitantly. All rats rotated in a preferred direction regardless of the side of the brain stimulated and all rats had asymmetries in self-stimulation sensitivity related to the direction of rotation. Morphine increased rotation and lowered self-stimulation thresholds at low doses (e.g., 2.5 mg/kg) and decreased rotation and raised self-stimulation thresholds at high doses (e.g., 20.0 mg/kg). The changes in self-stimulation thresholds preferentially occurred on opposite sides of the brain, i.e., the low-dose decrease in thresholds was greater in the normally less sensitive side of the brain whereas the high-dose increase in thresholds was greater in the normally more sensitive side of the brain. Naloxone produced no changes in rates of rotation but did elicit small changes in self-stimulation that varied with the side of the brain, i.e., dose-related decreases in thresholds occurred in the normally more sensitive side of the brain whereas dose-related increases in thresholds occurred in the normally less sensitive side of the brain. Subsequently rats were tested in a choice procedure providing concurrent access to rewarding stimulation of either side of the brain; currents were titrated such that, under baseline conditions, rats continually alternated between self-stimulating one side of the brain or the other. Morphine induced a preference for the less sensitive side of the brain that was comparable in magnitude at all doses and independent of its biphasic effects on rates of responding. Naloxone induced a dose-related preference for the more sensitive side of the brain while not altering rates of responding. Naloxone (1.0 mg/kg) also completely antagonized the effects of all doses of morphine. The results are discussed in terms of lateralized actions mediating the discriminable effects of reinforcing drugs.     

The threshold lowering effects of MDMA (ecstasy) on brain-stimulation reward

3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive phenylisopropylamine which is structurally similar to both amphetamine-related sympathomimetics and the hallucinogen, mescaline. MDMA produces pleasurable effects which include euphoria, and recent reports continue to demonstrate its widespread recreational use. The aim of the present study was to assess the effects of racemic MDMA on the threshold for rewarding intracranial self-stimulation, an animal model used to assess a drug's abuse liability in man. Rewarding electrical stimulation was delivered via electrodes stereotaxically implanted in the medial forebrain bundle-lateral hypothalamic area of the rat brain. Thresholds were determined by means of a rate-independent psychophysical method. MDMA produced a dose-related lowering of the reward threshold in all four animals tested. Given that increased sensitivity for rewarding brain stimulation, measured as a lowering of the reward threshold, is an animal model of drug-induced euphoria these results suggest a similar mode of action for its reinforcing effects as other abused substances.     

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 presynpatic mechanisms.     

Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects

The effects of chronic treatment with clozapine (20 mg/kg per day), ritanserin (0.5 mg/kg per day), haloperidol (0.5 mg/kg per day), or the combination of haloperidol and ritanserin, on dopamine (DA) and serotonin (5-HT) metabolism were studied. Chronic haloperidol treatment decreased DA metabolism in nucleus caudatus. Chronic ritanserin treatment failed to alter striatal or mesolimbic DA metabolism but decreased the concentrations of 5-HT and 5-hydroxyindoleacetic acid in the nucleus raphe dorsalis. The effects of chronic haloperidol were not altered by concomitant ritanserin administration. In comparison, chronic clozapine treatment affected neither DA nor 5-HT metabolism. These results show that the biochemical effects of chronic haloperidol treatment on the major ascending DA neurons cannot be modulated by concomitant 5-HT₂ receptor blockade.     

Interactions of naloxone and haloperidol with phencyclidine: effects on milk intake

Phencyclidine (PCP), naloxone and haloperidol were administered alone and in combination to rats trained to drink sweetened-condensed milk during a 20 min daily session. PCP (1.0-16.0 mg/kg) produced a dose-dependent decrease in milk intake. All doses of naloxone (0.1-16.0 mg/kg) produced approximately a 30% decrease in milk intake. Haloperidol (0.125 mg/kg) had virtually no effect on milk intake. When a dose of naloxone which reduced milk intake by approximately 30% (8.0 mg/kg) was administered as a pretreatment to the PCP, the PCP curve was shifted to the left (lowered) to that degree. When haloperidol (0.125 mg/kg) was administered as a pretreatment to the PCP, the PCP dose-response curve was shifted 1.5 fold to the right. These interactions are similar to those observed in other behavioral paradigms and are discussed in reference to PCP's actions as an indirect dopaminergic agonist.     

Effects of concomitant pentazocine and tripelennamine on brain-stimulation reward

Reinforcing thresholds for self-stimulation behavior to the medial forebrain bundle were determined in rats by means of a rate-free psychophysical method. The acute administration of either pentazocine or tripelennamine caused a small but significant lowering of the reward threshold. Combined administration of an ineffective dose of tripelennamine with various doses of pentazocine resulted in a potentiation of this lowering effect. These results suggest that the widespread abuse of the combination of pentazocine and tripelennamine may be due to a pharmacologic potentiation rather than just a summation of their two effects.     

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats

It was recently reported that levo-tetrahydropalmatine (l-THP), a dopamine (DA) D1 and D2 receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THP's effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THP's effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10 mg/kg) increased, while a high dose (20 mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaine's rewarding effects, because the same low doses of l-THP dose-dependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10 mg/kg, but not 1-3 mg/kg, of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THP's actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction.     

Dopaminergic neurons in the nitro-striatal and mesolimbic pathways: Mediation of specific effects of d-amphetamine

The administration of d-amphetamine (15 mg/kg, i.p.) to rats causes stereotypy, hypothermia among animals placed in a cold environment, and paradoxical behavioral thermoregulation (i.e., animals in a cold environment choose not to place themselves under the beam emitted by a heat lamp). These effects are blocked in animals lesioned unilaterally in the mesolimbic dopaminergic projections to the olfactory tubercule and nucleus accumbens. In contrast, a unilateral lesion destroying the nigro-striatal projections within the caudate nucleus blocks none of these responses, and actually potentiates the induction of stereotypy by d-amphetamine. Both lesions cause the animal to exhibit rotational behavior in response to the subsequent administration of d-amphetamine. These observations suggest that the mesolimbic dopaminergic projections mediate some of the behavioral and visceral effects of d-amphetamine.     

Cannabinoid CB1 receptor antagonists attenuate cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats.

Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1-10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30-70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1-3 mg/kg) also significantly and dose-dependently inhibited (by 25-90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications.     

Effect of haloperidol and d-amphetamine on cerebral tyramine and octopamine levels.

The administration of d-amphetamine or haloperidol produced a marked reduction in the rat striatum concentration of p-tyramine, an effect that was not observed in the mesolimbic system. However, the administration of d-amphetamine to haloperidol-pretreated animals produced in both brain areas a marked reduction in p-tyramine levels. Furthermore, this latter treatment produced a marked increase in the m-tyramine levels in both brain regions. Hypothalamic p-octopamine levels were reduced by d-amphetamine, but not by haloperidol or haloperidol in the presence of d-amphetamine.     

The combined effects of morphine and d-amphetamine on the threshold for brain stimulation reward

The effect of morphine and d-amphetamine co-administration on the threshold for rewarding intracranial electrical stimulation was studied in rats with electrodes stereotaxically implanted in the medial forebrain bundle-lateral hypothalamic or ventral tegmental area of the brain. Thresholds were determined by means of a rate-independent psychophysical method. Individually, morphine and d-amphetamine both caused a dose-related lowering of the reward threshold. Low doses of morphine or d-amphetamine which were ineffective or minimally effective in lowering the reward threshold were then tested with various doses of either d-amphetamine or morphine, respectively. In both cases, the combined administration of morphine and d-amphetamine resulted in a lowering of the reward threshold that was greater than for the corresponding doses of morphine and d-amphetamine when given alone. Given that increased sensitivity for rewarding brain stimulation has been suggested to be an animal model of drug-induced euphoria, this effect is congruent with the reported increase in the degree of euphoria produced when amphetamine is used in conjunction with opiate drugs.     

Effects of morphine on brain-stimulation reward thresholds in young and aged rats

Mesolimbic opioid systems are altered with aging; however, the effects of these changes on the rewarding actions of opioids have not been examined. The present experiment assessed differences in the responsiveness of brain reward pathways in young and aged rats to the effects of morphine using the brain-stimulation reward (BSR) model. Aged (24 months) and young (5 months) male F344/BNF1 rats were stereotaxically implanted with a bipolar stainless steel electrode into the lateral hypothalamic (LH) region of the medial forebrain bundle. Thresholds were determined using the rate-independent psychophysical method. Each animal was tested after the administration of saline or morphine at 0.5, 1, 2.5, 5 and 10 mg/kg doses. A significant difference in the mean baseline threshold between aged (99.8+/-6 microA) and young rats (149.1+/-14 microA) was observed. Although in both groups morphine lowered the BSR threshold, there were no significant differences between the groups except at the 10-mg/kg dose, the difference did approach significance. This study indicates that there are baseline differences in the rewarding threshold in the two groups, that morphine lowers the threshold in young and aged animals and that the hedonic effects produced by morphine, for the most, part remain preserved in aged animals.     

Failure of naloxone to modify the effects of chlorpromazine and d-amphetamine on avoidance behavior in the squirrel monkey

Lever-pressing by squirrel monkeys was maintained under a continuous avoidance schedule in which each response postponed for 30 s the delivery of an electric shock to the tail. Dose-response curves were determined for chlorpromazine (0.03–0.3 mg/kg) and d-amphetamine (0.03–1.0 mg/kg) administered alone and administered concomitantly with 1.0 or 10 mg/kg of aaloxone. The dose-response curves for chlorpromazine and d-amphetamine were similar to those previously reported for monkeys under other schedules of shock-maintained behavior: Chlorpromazine decreased responding in a dose-related manner while d-amphetamine increased responding at low doses and disrupted behavior at the highest dose. Naloxone did not modify the effects of chlorpromazine, and d-amphetamine. These results suggest that interactions observed previously between naloxone and nonopiate drugs on behavior in pigeons and rodents are not general phenomena in all animal species.     

Differential antagonism by naloxone of inhibitory effects of haloperidol and morphine on brain self-stimulation

Haloperidol (0.16 mg/kg) or morphine sulfate (40 mg/kg), injected subcutaneously, completely suppressed bar-pressing for brain self-stimulation in rats implanted with electrodes in the lateral hypothalamus. Haloperidol also caused catalepsy and ptosis while morphine produced catatonia with exophthalmia. Naloxone in a dose (5 mg/kg) which was ineffective when given alone, differentially reversed the morphine-effects but was without any reversing influence on the actions of haloperidol.Visiting pharmacologist from Department of Pharmacology and Psychology, University of Rhode Island, Kingston, R. I., U.S.A.     

Some behavioural effects of risperidone in rats: comparison with haloperidol.

Risperidone is a dopaminergic as well as a 5-HT2 antagonist. The drug was found to exert beneficial effects on both positive and negative symptoms of schizophrenia. Since recently, schizophrenia is regarded as a composite of not only positive and negative but also affective and cognitive symptoms, in this study the effects of risperidone compared with typical neuroleptic haloperidol, on affective and cognitive functions were investigated in rats (anxiolytic, antidepressive and memory tests). We found, that in contrast to haloperidol, risperidone had antidepressive, anxiolytic and memory enhancing effects. The results obtained correspond with favourable effects of risperidone on mood disturbances and cognitive functions of schizophrenic patients observed under clinical conditions.     

The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.

It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, olanzapine or sham for a 17-27 month period. The resulting plasma drug levels were comparable to those seen in subjects with schizophrenia treated with these medications. After the exposure, we observed an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in both drug-treated groups compared to sham animals. The differences were observed across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in the frontal and parietal regions. Stereological analysis of the parietal region using Cavalieri's principle revealed similar volume reductions in both gray and white matter. In addition, we assessed the subsequent tissue shrinkage due to standard histological processing and found no evidence of differential shrinkage due to drug exposure. However, we observed a pronounced general shrinkage effect of approximately 20% and a highly significant variation in shrinkage across brain regions. In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume. Antipsychotic medication may confound post-mortem studies and longitudinal imaging studies of subjects with schizophrenia that depend upon volumetric measures.