Pharmacological characterization of performance on a concurrent lever pressing/feeding choice procedure: effects of dopamine antagonist,cholinomimetic, sedative and stimulant drugs

This experiment was undertaken to provide a pharmacological characterization of performance on a task involving food-related instrumental and consummatory behavior. Rats were tested in an operant chamber in which there was a choice between pressing a lever to receive a preferred food (Bioserve pellets) or approaching and consuming a less-preferred food (Lab Chow). The lever pressing schedule was a fixed ratio 5 (FR5). Rats usually pressed the lever at high rates to obtain the preferred food, and typically ate little of the lab chow even though it was freely available in the chamber concurrently with the lever pressing schedule. Previous work has shown that injection of dopamine (DA) antagonists, or depletion of DA in the nucleus accumbens, caused a substantial shift in behavior such that lever pressing was reduced but chow consumption increased. In the present study it was shown that the DA antagonist haloperidol decreased lever pressing and increased chow consumption at doses of 0.1 and 0.15 mg/kg. The D1 antagonist SCH 23390 (0.05, 0.1 and 0.15 mg/kg) and the non-selective DA antagonistcis-flupenthixol (0.3 and 0.45 mg/kg) decreased lever pressing and produced substantial increases in chow consumption. The D2 antagonist sulpiride decreased lever pressing, but produced only slight increases in chow intake at the highest dose. Pentobarbital reduced lever pressing and increased chow consumption at 10.0 mg/kg. The muscarinic agonist pilocarpine produced dose-related decreases in lever pressing, but failed to increase chow consumption. Amphetamine produced dose-related decreases in both lever pressing and chow consumption. These results indicate that low/moderate doses of the DA antagonists haloperidol,cis-flupenthixol and SCH 23390 can suppress lever pressing in doses that leave the animal directed towards food acquisition and consumption.     

Effects of subchronic administration of clozapine, thioridazine and haloperidol on tests related to extrapyramidal motor function in the rat

Clozapine, thioridazine (THIO) and haloperidol were administered for 14 consecutive days, and separate groups of rats were used to study the effects of these drugs on tremulous jaw movements and lever pressing. Rats were observed on day 13 for the ability of the antipsychotic drugs to induce jaw movements. Haloperidol produced a dose-related increase in jaw movements, while clozapine and THIO failed to induce jaw movements. On day 14, rats were challenged with 5.0 mg/kg of the anticholinesterase tacrine, which induces a very high level of jaw movement activity. Clozapine significantly reduced tacrine-induced tremulous jaw movements, while haloperidol did not. Although previous work had shown that acute THIO could suppress jaw movements, repeated THIO failed to do so. In order to provide an additional behavioral test for comparisons of the relative potencies of the antipsychotic drugs, rats were tested for the effects of these drugs on fixed ratio 5 lever pressing. All three drugs significantly suppressed lever pressing. Haloperidol showed sensitization with repeated injections, while clozapine showed tolerance. Data were analyzed by taking the ratio of the ED₅₀ for suppression of tacrine-induced jaw movement over the ED₅₀ for suppression of lever pressing on day 14. Clozapine reduced tacrine-induced jaw movements in a dose range slightly lower than that required for reduction of lever pressing. In contrast, THIO and haloperidol failed to affect tacrine-induced jaw movements even at doses that were 5–18 times the ED₅₀ for suppression of lever pressing. Thus, tests of jaw movement activity and lever pressing after repeated administration may be useful for assessing atypical antipsychotic drugs. Received: 2 August 1997 / Final version: 23 December 1997     

Systemic administration of the adenosine A(2A) agonist CGS 21680 induces sedation at doses that suppress lever pressing and food intake

Adenosine A(2A) receptors are involved in the regulation of several behavioral functions. Adenosine A(2A) antagonists exert antiparkinsonian effects in animal models, and adenosine A(2A) agonists suppress locomotion and impair various aspects of motor control. The present experiments were conducted to study the effects of low doses of the adenosine A(2A) agonist CGS 21680 on lever pressing, specific parameters of food intake, and sedation. In the first experiment, the effects of CGS 21680 on fixed ratio 5 lever pressing were assessed. In the second experiment, rats were tested in 30 min feeding sessions, and also were observed for drug-induced sedation using a sedation rating scale. CGS 21680 (0.025, 0.05, 0.1 mg/kg IP) produced a dose related suppression of lever pressing, and also reduced the amount of food consumed. The feeding effect was largely dependent upon a slowing of the rate of feeding, and there was only a modest suppression of time spent feeding. Doses of CGS 21680 that suppressed lever pressing and feeding also were associated with sedation/drowsiness. In conjunction with other studies, the present results suggest that sedative effects may play an important role in some of the behavioral effects produced by systemic administration of adenosine A(2A) agonists.     

Effects of clozapine, thioridazine, risperidone and haloperidol on behavioral tests related to extrapyramidal motor function

 Evidence indicates that the antipsychotic drug clozapine has a low propensity for the induction of extrapyramidal motor symptoms, and also that clozapine has therapeutic effects in patients with idiopathic Parkinson’s disease. Because tacrine-induced tremulous jaw movements in rats have been suggested as a possible model of extrapyramidal motor dysfunctions, including parkinsonian tremor, the present work was undertaken to investigate the effects of clozapine on tremulous jaw movements. Clozapine decreased tacrine-induced tremulous jaw movements in a dose-related manner, with an ED₅₀ of approximately 3.3 mg/kg. In order to determine the relative potency of this effect compared to other behavioral effects of clozapine, suppression of lever pressing was also studied. Clozapine reduced lever pressing in a dose-related manner, with an ED₅₀ of approximately 5.4 mg/kg. This indicates that clozapine suppressed jaw movements at or below the doses required for suppression of lever pressing. In contrast, the typical antipsychotic drug haloperidol failed to suppress tacrine-induced tremulous jaw movements in doses up to 1.0 mg/kg, which is about 11-fold higher than the ED₅₀ for suppression of lever pressing with that drug. Thioridazine and risperidone also suppressed tremulous jaw movements in roughly the same dose range at which lever pressing was reduced. It is possible that the suppression of tacrine-induced tremulous jaw movements by clozapine in rats is related to the unique behavioral and motor effects of clozapine. The ratio of potencies of these effects (i.e., suppression of tremulous jaw movements versus suppression of lever pressing) could be used as a behavioral procedure for assessing clozapine-like activity in novel compounds. Received: 8 October 1996 / Final version: 3 February 1997     

Behavioral effects of sertindole,risperidone, clozapine and haloperidol inCebus monkeys

Extrapyramidal side effects (EPS) are major limitations to neuroleptic treatment of psychoses. To evaluate further the behavioral characteristics of the novel antipsychotic agents, a wide range of single intramuscular doses of sertindole (0.1–2.5 mg/kg IM), risperidone (0.01–0.25 mg/kg IM), clozapine (1.0–25.0 mg/kg IM), and haloperidol (0.01–0.25 mg/kg IM) were blindly evaluated at weekly intervals inCebus monkeys previously sensitized to neuroleptics. All drugs except clozapine produced dystonia and parkinsonian symptoms, but haloperidol and risperidone were 50–100 times more potent than sertindole in producing EPS. Sertindole, risperidone and haloperidol had no significant sedative effects, whereas clozapine produced dose related sedation. Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity. Sertindole, risperidone and clozapine had a calming effect at doses below the EPS threshold, unlike haloperidol. Sertindole has many behavioral effects in nonhuman primates that are similar to those seen with the new antipsychotics, risperidone and clozapine, which suggests a favorable antipsychotic benefit/risk ratio in the clinic, especially regarding EPS.     

Quetiapine (Seroquel) shows a pattern of behavioral effects similar to the atypical antipsychotics clozapine and olanzapine: studies with tremulous jaw movements in rats

Rationale Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing.Objective The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model.Methods The effect of acute quetiapine on the suppression of tacrine-induced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug.Results Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED₅₀ for suppression of jaw movements divided by the ED₅₀ for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1–14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing.Conclusions On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.     

Unusual interactions between the neuroleptic haloperidol, and the dopamine D2 partial agonist, terguride

Terguride is an ergoline derivative which has been reported to act as a partial agonist at central dopamine D2 receptors. Depending on the state of the receptor, terguride may resemble an agonist or an antagonist in its pharmacological effects. The present study investigated interactions of terguride with the dopamine D2 antagonist haloperidol in the rat. Terguride (0.025 mg/kg, i.p.) lowered, whereas haloperidol (0.025 mg/kg, s.c.) increased serum prolactin levels. When given together there was a tendency for prolactin to be lowered, i.e. terguride fully antagonized the action of haloperidol. Both terguride and haloperidol dose-dependently reduced locomotor activity, with terguride being at least 50 times more potent. However, in the presence of a subthreshold dose of haloperidol (0.1 mg/kg), terguride was effective in reducing locomotor activity. Terguride and haloperidol were equally potent in disrupting performance of lever pressing for food on a VI 120 sec schedule (ED(50) values 0.22 and 0.28 mg/kg, respectively). When given together, there was a statistically significant interaction; a terguride dose of 0.2 mg/kg lowered rates of lever pressing when given with vehicle or a low (0.03 mg/kg) haloperidol dose, but antagonized the effect of 0.3 mg/kg haloperidol. Terguride dose-dependently disrupted lever pressing for intracranial stimulation reward (ED(50) value approx. 0.3 mg/kg). Haloperidol (0.26 mg/kg) also disrupted lever pressing but the two drugs together showed no greater effect than haloperidol alone. These observations are discussed in the context of terguride's suggested partial agonistic properties.     

Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure

An important aspect of motivated behavior is that organisms will perform complex instrumental behaviors to gain access to stimuli such as food. In the present study, food-deprived rats were tested in an operant chamber in which the animals had a choice between pressing a lever to obtain a more-preferred food (Bioserve pellets), or free feeding on a less-preferred food (lab chow). Typically, rats pressed the lever to obtain the preferred food pellets, and ate little of the less-preferred food even though it was freely available. Pre-fed rats showed suppression of both lever pressing and feeding. Systemic administration of 0.1 mg/kg haloperidol (HP) led to a dramatic shift in the behavior of these rats, such that the number of lever presses was substantially reduced, but the amount of less-preferred food consumed showed a significant increase. This result occurred if the rats pressed a lever on either a CRF or FR5 schedule. Injection of 3.5-7.0 micrograms HP directly into the nucleus accumbens, or intra-accumbens injections of 6-hydroxy-dopamine, also decreased lever pressing for food and increased feeding on laboratory chow. Thus, interference with brain dopamine suppressed a highly active instrumental response for food, although the behavior of the animal was still directed towards food acquisition and consumption.     

Behavioral assessment of atypical antipsychotics in rats: studies of the effects of olanzapine (Zyprexa)

Rationale: Previous work has shown that clozapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. Objective: The novel atypical antipsychotic olanzapine was assessed in these behavioral tests. Methods: The effect of acute olanzapine on the suppression of tacrine-induced tremulous jaw movements was examined. In order to determine the relative potency of this effect compared with other behavioral effects of olanzapine, suppression of lever pressing also was studied. In a second series of experiments, rats received olanzapine for 14 consecutive days to study the effects of repeated injections of this drug on jaw movements and lever pressing. Results: Acute olanzapine administration decreased tacrine-induced jaw movements (ED₅₀: 0.4 mg/kg), and also reduced lever pressing (ED₅₀: 1.12 mg/kg). The ratio of the ED₅₀ for suppression of jaw movements to that for suppression of lever pressing was used as an index of liability to produce extrapyramidal side effects, and the present results demonstrate that olanzapine has a ratio similar to that previously shown for clozapine. In the repeated administration studies, rats were observed on day 13 of drug treatment for the ability of olanzapine to induce jaw movements, and olanzapine failed to induce jaw movements. On day 14, olanzapine reduced tacrine-induced tremulous jaw movements (ED₅₀: 1.12 mg/kg). In a separate experiment, olanzapine significantly suppressed lever pressing, and this effect showed sensitization with repeated administration (day 14, ED₅₀: 0.76 mg/kg). Thus, repeated injections of olanzapine reduced tacrine-induced jaw movements in a dose range similar to or slightly higher than that which suppressed lever pressing. Conclusions: On tests of jaw-movement activity and lever pressing after both acute and repeated drug administration, olanzapine demonstrated a profile somewhat similar to clozapine, and both of these drugs differ substantially from the typical antipsychotic haloperidol. Received: 14 October 1998 / Final version: 15 March 1999     

Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior

Rationale Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission. Objective To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased. Results Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05–0.2 mg/kg) or the D2 antagonist eticlopride (0.025–0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0–16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0–8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake. Conclusions These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission.     

Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol.

Selective dopamine D(2) antogonists increase meal size and decrease the rate of feeding within a meal. Three experiments investigated the extent to which the atypical antipsychotics, clozapine and olanzapine, and the prototypical antipsychotic, haloperidol, affected meal size and feeding rate. Microstructural analyses of meal patterning were made over a range of drug doses administered to free feeding male Lister hooded rats. Haloperidol and clozapine produced a short-term increase in food intake. Haloperidol (0.05-0.2 mg/kg) enhanced meal size (maximal at 0.1 mg/kg) and reduced feeding rate (monotonic decrease with increasing dose). Neither clozapine (1-10 mg/kg) nor olanzapine (0.3-3 mg/kg) enhanced meal size, although both drugs produced similar reductions in feeding rate to haloperidol. These data suggest that enhancement of meal size may be correlated with a high level of extrapyramidal side effects in an antipsychotic drug. The absence of an increase in meal size by two atypical compounds suggests that the increase in body weight associated with clinical treatment with these drugs cannot be modelled by acute stimulation of meal size in the rat.     

Effects of remoxipride,a dopamine D-2 antagonist antipsychotic,on sleep-waking patterns and EEG activity in rats and rabbits

The antipsychotic remoxipride, a selective dopamine D-2 receptor antagonist, was studied for its effects on sleep-waking patterns in the rat and electroencephalographic (EEG) activity in the rabbit. Haloperidol, which has lesser selectivity for D-2 receptors, was used for comparison. In the rat, remoxipride (1–10 mg/kg SC) did not affect either total sleep or non-rapid eye movement (non-REM) sleep. Only REM was slightly reduced by the high dose of 10 mg/kg. Haloperidol (0.1–1 mg/kg PO) enhanced duration of both total sleep and non-REM sleep. In the rabbit, remoxipride (3 and 10 mg/kg IV) induced no significant changes of the EEG power spectrum over 0.1–38.5 Hz or individual frequency bands. In both cortex and hippocampus the drug did not alter the arousal response to acoustic sensory stimuli. Plasma concentration of remoxipride 10 mg/kg IV in rabbits declined biexponentially and was 4 and 2 µmol/1 at 30 min and 1 h, respectively. Haloperidol (0.3 and 1 mg/kg) slowed down the EEG activity, enhanced the power spectrum of the cortical and hippocampal activity, and significantly reduced the duration of arousal induced by sensory stimuli. The results indicate that, unlike haloperidol, remoxipride has weak or no sedative effects. The data also provide support to the notion that D-2 receptors are not involved in the regulation of states of sleep and sedation.     

Sedation and disruption of maternal motivation underlie the disruptive effects of antipsychotic treatment on rat maternal behavior

The behavioral mechanisms underlying antipsychotic-induced maternal behavior deficits were examined in the present study. Different groups of postpartum rats were treated with haloperidol (0.1 mg/kg), clozapine (10.0 mg/kg), chlordiazepoxide (5.0 mg/kg, an anxiolytic) or vehicle (0.9% saline) on Days 4 and 6 postpartum and their maternal behaviors were tested under either pup-separation (e.g. pups were removed from their mothers for 4 h before testing) or no-pup-separation condition. Maternal behavior and drug-induced sedation were further tested for 3 days from Day 8 to 12 postpartum. Results show that pup-separation, which putatively increases maternal motivation, did significantly shorten clozapine-elongated pup approach latency, increase pup licking and nursing but fail to reverse the deficits in pup retrieval and nest building in the lactating rats treated with haloperidol and clozapine. Repeated haloperidol treatment produced a progressively enhanced disruption on pup retrieval and nest building and an attenuated sedation. In contrast, clozapine showed a progressively diminished disruption on pup retrieval and a concomitantly diminished sedative effect. Based on these findings, we suggest that antipsychotic drugs disrupt active maternal responses at least in part by suppressing maternal motivation, and drug-induced sedation also contributes to this disruptive effect, especially with clozapine.     

Failure of CCK receptor ligands to modify anxiety-related behavioural suppression in an operant conflict paradigm in rats

The effects of cholecystokinin (CCK) receptor ligands were studied in the rat safety signal withdrawal conflict procedure, an operant paradigm sensitive to both anxiolytic and anxiogenic compounds. In this procedure, behavioural suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety without the usual presentation of a conditioned signal for danger. The compounds tested were selective CCK-B antagonists [CI-988 (0.01–1 mg/kg SC), L-365,260 (0.004–2 mg/kg IP) and LY 262,691 (0.001–1 mg/kg SC)], CCK-B agonists [CCK-4 (0.01–1 mg/kg SC) and BC 264 (0.004–1 mg/kg IP)] and CCK-A antagonists [devazepide (0.001–1 mg/kg SC) and lorglumide (0.01–1 mg/kg SC)]. None of these drugs induced the expected behavioural effects, i.e. an anxiolytic-like release of the behavioural suppression with CCK-B and, possibly, CCK-A antagonists and/or a further reduction of lever pressing with CCK-B agonists, indicative of an anxiogenic-like potential. In contrast, the established anxiolytic lorazepam (0.06–0.25 mg/kg IP), as well as diazepam (2 mg/kg IP) and buspirone (0.25 mg/kg SC) used as positive control drugs, released the suppression of pressing for food during the period associated with the safety signal withdrawal, whereas picrotoxin (1 mg/kg IP), used as an anxiogenic control, further reduced responding during this conflict period. The present results contrast with a series of published data suggesting the involvement of CCK processes in anxiety-related behaviour in rodent models such as the elevated plus-maze or the light:dark two compartment test, and in panic disorders in humans. They indicate that the behavioural effects of one category of drugs might vary considerably, depending on the experimental situation. Furthermore, they allow the conclusion that anticipatory anxiety generated by withdrawal of conditioned signals for safety does not involve CCK-related processes.     

Olanzapine,an atypical antipsychotic,increases rates of punished responding in pigeons

The effects of olanzapine [LY 170053; 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2, 3b][1,5]benzodiazepine), a potential atypical antipsychotic, were determined in pigeons whose keypeck responding was punished. These effects were compared to the anxiolytic agents chlordiazepoxide and pentobarbital, and to other antipsychotic agents. Keypeck behavior was maintained under a multiple FR30 FR30 schedule, signalled by white and red stimulus lights, respectively. Each component of the schedule alternated every 3 min with a 30-s timeout. During the white keylight component, responding was maintained by food presentation. During the red keylight component, responding was maintained by food and simultaneously suppressed by electric shock presentation, with response rates being only about 5% of those during the white stimulus light. Olanzapine (0.01–1.0 mg/kg) increased punished responding at doses below those which had an effect on unpunished responding. Clozapine (0.01–1.0 mg/kg), ritanserin (0.1–3.0 mg/kg), and, to a lesser extent, risperidone (0.1–1.0 mg/kg) were also effective at increasing punished responding. Generally, the maximum effect seen with olanzapine was equal to that seen with ritanserin, and it exceeded that seen with clozapine. However, these effects were generally less than those seen with chlordiazepoxide and pentobarbital. Haloperidol (0.01–0.1 mg/kg) was completely without effect on punished responding, while it caused decreases in unpunished behavior. These results provide further evidence that olanzapine has a profile in behavioral tests unlike the typical antipsychotic haloperidol. Moreover, this profile is similar to clozapine, a clinically effective antipsychotic with an atypical profile.     

Antipsychotic drug effects on the behavior of squirrel monkeys differentially controlled by noxious stimuli

The effects of several antipsychotic compounds were examined on two types of behavioral performances of squirrel monkeys. Both behaviors occurred simultaneously and were maintained separately by different schedules using noxious stimuli. Steady rates of responding were maintained when a chain pulling response postponed electric shock delivery (avoidance schedule). Concurrently, positively accelerated rates of responding were maintained on a lever where the first response after 3 min produced electric shock (fixed-interval 3-min schedule). The effects of the different drugs depended both upon whether the behavior postponed or presented shock and on the particular drug. Chlorpromazine (0.001–0.03 mg/kg), haloperidol (0.001–0.01 mg/kg), molindone (0.001–0.03 mg/kg) and thiothixene (0.001–0.03 mg/kg) increased slightly or had no effect on responding under the shock-postponement schedule at doses that decreased responding maintained by shock presentation. The effects of clozapine, a clinically effective antipsychotic compound, differed markedly from the other antipsychotic drugs. Clozapine (0.01–1.0 mg/kg) increased responding maintained by the presentation of shock at doses that decreased responding under the shock-postponement schedule. Higher doses of these drugs decreased responding under both schedules and, with the exception of clozapine, resulted in increased frequency of shocks under the postponement schedule.     

Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine,haloperidol, loxapine and chlorpromazine

The present study has compared the abilities of clozapine, haloperidol, chlorpromazine and loxapine to induce dopamine (DA)-receptor hypersensitivity in rats, as measured by the apomorphine response after withdrawal of the antipsychotic drugs. Haloperidol, chlorpromazine and loxapine, but not clozapine, potentiated the apomorphine response during 1–2 weeks after withdrawal. Clozapine, given prior to apomorphine, reduced the responses of the haloperidol and loxapine groups to the control level. The effects of haloperidol and clozapine were quantified in rats with unilateral striatal lesions.Biochemical investigations showed that tolerance developed to the increase in striatal homovanillic acid (HVA) after chronic treatment with haloperidol, chlorpromazine and loxapine, whereas clozapine (20 mg/kg p.o.) failed to affect the HVA content, and no tolerance developed to the increase seen at 80 mg/kg. Cross-tolerance to the rise in HVA was seen with haloperidol, chlorpromazine and loxapine, but chronic pretreatment with clozapine failed to affect the rise in HVA induced by a single dose of the former compounds.On the basis of these results, it is predicted that tardive dyskinesias are unlikely to develop after this drug, and that clozapine may attenuate or abolish neuroleptic-induced tardive dyskinesias.Part of this work was presented at the IXth Congress of the C.I.N.P. in Paris, July 1974.     

Neostriatal and mesolimbic neurons: Dose-dependent effects of clozapine

To determine whether clozapine, an antipsychotic drug devoid of extrapyramidal side effects, acts preferentially on neurons in the nucleus accumbens rather than in the neostriatum, an analysis of clozapine-induced changes in spontaneous neuronal activity was performed on locally anesthetized, immobilized rats. In both brain sites, intraperitoneal administration of clozapine (10, 20 or 80 mg/kg) produced a comparable dose-dependent increase in neuronal activity. Haloperidol, at a dose (2.0mg/kg) that typically elicits extrapyramidal side effects in rats, also increased the firing rate of neurons in the neostriatum and nucleus accumbens. However, haloperidol produced a greater effect on neuronal activity in the neostriatum during the first 15 min after injection, whereas 80 mg/kg clozapine was more effective during this period in the nucleus accumbens. In contrast, the neuronal response to the lower doses of clozapine paralleled that produced by haloperidol in the neostriatum; no differential regional effects were recorded at any time after injection of 10 or 20 mg/kg clozapine. The results suggest that the lack of extrapyramidal side effects associated with clozapine cannot be simply explained by a selective action of this drug on neurons in the nucleus accumbens.     

Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task

Rationale

Effort-related motivational symptoms such as anergia and fatigue are common in patients with depression and other disorders. Research implicates pro-inflammatory cytokines in depression, and administration of cytokines can induce effort-related motivational symptoms in humans.

Objectives

The present experiments focused on the effects of the pro-inflammatory cytokine interleukin 1-beta (IL-1β) on effort-related choice behavior.

Methods

Rats were tested on a concurrent fixed ratio 5 lever pressing/chow feeding choice procedure, which assesses the tendency of rats to work for a preferred food (high carbohydrate pellets) in the presence of a concurrently available but less preferred substitute (laboratory chow).

Results

IL-1β (1.0–4.0 μg/kg IP) shifted choice behavior, significantly decreasing lever pressing and increasing intake of the freely available chow. The second experiment assessed the ability of the adenosine A_2A antagonist (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl] propyl] ester disodium salt (MSX-3) to reverse the behavioral effects of IL-1β. MSX-3 attenuated the effort-related impairments produced by IL-1β, increasing lever pressing and also decreasing chow intake. In the same dose range that shifted effort-related choice behavior, IL-1β did not alter food intake or preference in parallel free-feeding choice studies, indicating that these low doses were not generally suppressing appetite or altering preference for the high carbohydrate pellets. In addition, IL-1β did not affect core body temperature.

Conclusions

These results indicate that IL-1β can reduce the tendency to work for food, even at low doses that do not produce a general sickness, malaise, or loss of appetite. This research has implications for the involvement of cytokines in motivational symptoms such as anergia and fatigue.     

Effects of haloperidol and d-amphetamine on perceived quantity of foods and tones

The hypothesis that dopamine (DA) receptor agonists and antagonists affect hedonia associated with natural rewards was tested, using a psychophysical procedure previously shown to be sensitive to both the sweetness of food and the motivational state of rats. Rats were first trained to discriminate between two different quantities of a rewarding stimulus by pressing one of two levers. Perceived quantity was subsequently derived from generalization trials of intermediate quantities. Haloperidol (0.03–0.083 mg/kg), a DA receptor antagonist, did not influence perceived food quantity, an indirect marker of hedonic value. On the other hand, d-amphetamine (0.25–1.0 mg/kg) affected perceived food quantity in a dose-dependent fashion, and in the same direction as occurs after increasing hunger or food sweetness. Both haloperidol and amphetamine influenced the perceived quantity of a stimulus without natural reinforcing properties (a tone), but the effect of amphetamine on the perceived quantity of this initially neutral stimulus was opposite in direction to that observed with food. These results suggest that whereas amphetamine affects hedonic processes, haloperidol does not. In addition, it seems that haloperidol probably produces its actions through effects on motor mechanisms or by interfering with the response-facilitating properties of rewards.