The effects of pimozide on the consumption of a palatable saccharin-glucose solution in the rat

Two experiments investigated the role of dopamine in reward mechanisms by examining the effects of the specific dopamine receptor blocker pimozide on drinking behavior in the rat. In Experiment 1, the effects of pimozide on the consumption of a palatable saccharin-glucose solution were compared to the effects of quinine adulteration of the same solution. Pimozide and quinine both reduced 30 min/day consumption, decreased lick rate early in the drinking session and reduced lick efficiency in a dose related manner. In Experiment 2, the effects of pimozide on the consumption of a saccharin-glucose solution and water were compared in thirsty and nonthirsty rats. Pimozide suppressed the consumption of both water and the saccharin-glucose solution in a dose related manner. However, saccharin-glucose solution intake was suppressed more than water intake, and this effect was independent of thirst drive. The drug also decreased lick rate early in the drinking session and lick efficiency. The results are discussed in terms of the reward and sensory-motor deficits produced by dopamine receptor blocking agents.     

Unimpaired quinine metabolism in rats with ventromedial hypothalamic lesions

Rats with lesions of the ventromedial hypothalamus (VMH) show a greater decrease in food intake than normal rats if fed diets adulterated with quinine. To determine if this hyperresponsivity is due to impaired quinine metabolism, in vitro rates of drug metabolism of female hooded rats with VMH lesions were measured. Determinations were made both under basal conditions and under conditions known to cause induction of drug metabolizing enzymes. VMH rats showed rates of drug metabolism virtually identical to controls under all conditions tested. These data suggest that VMH lesioned rats are not more sensitive to quinine dietary adulteration because of impaired quinine metabolism.     

Pituitary-adrenal axis and oral morphine consumption in rats.

Removal of the pituitary gland in rats leads to suppression of oral morphine and quinine intake behavior. Experiments measuring oral intake of solutions containing graded concentrations of morphine or quinine, revealed that the detection acuity for bitter taste is changed in hypophysectomized (hypox) animals. Treatment of these rats with ACTH 1--24 restored oral morphine intake towards that on intact rats. Morphine consumption in hypox rats was not affected by administration of ACTH 4--10 or ACTH 11--24, but was normalized by treatment with corticosterone. Adrenalectomy also diminished oral morphine intake. It is concluded that hypophysectomized animals refuse a morphine solution because their threshold for bitter taste quality is altered, presumably due to a diminished release of corticosteroids.     

Similar effect of raclopride and reduced sucrose concentration on the microstructure of sucrose sham feeding

Raclopride, a dopamine D2 antagonist, decreases the intake of sucrose solutions during sham feeding tests and of water during sham drinking tests in rats. To determine whether the reduced intake of sucrose by raclopride was due to a decrease in the positive reinforcing effect of sucrose or to an impairment in licking movements, we compared the rate, efficiency and pattern of licking after two procedures each of which decreased sucrose sham intake about 50%; these were (a) pretreatment with raclopride (ID50), and (b) dilution of the sucrose concentration sham fed from 10 to 5%. Microstructural analysis failed to reveal significant differences in the rate, efficiency (licks/ml) or patterns of licking between these two procedures. When raclopride inhibited the sham drinking of water, the rate and efficiency of licking were normal, but the patterns of licking were qualitatively different from those observed when raclopride inhibited the sham feeding of sucrose. We conclude that raclopride decreases intake of 10% sucrose during sham feeding and intake of water during sham drinking by decreasing the positive reinforcing potency of the orosensory effect(s) of the two liquids on licking rather than by decreasing the ability to lick. These results provide strong evidence that interaction of dopamine at D2 receptors is necessary for the normal sensory and/or hedonic processing of the orosensory stimuli produced by sucrose during sham feeding and by water during sham drinking.     

Extinction and dopamine receptor blockade after intermittent reinforcement training: Failure to observe functional equivalence

Response decrements in an operant task produced by either extinction or by the dopamine receptor blocker pimozide were examined in three experiments which employed intermittent reinforcement schedules. In contrast to the congruency between these treatments previously observed following continuous reinforcement training, treatment with pimozide was markedly more effective than extinction in decreasing performance after training with variable interval, fixed interval, and fixed ratio reinforcement. The two treatments also produced substantially different patterns of responding. A shift from extinction to pimozide did not alter the progressive decline in response rate over days, but a shift from pimozide to extinction caused a pronounced increase of performance. These results indicate that the pimozide and extinction treatment did not produce functionally equivalent effects, and that the role of dopamine on reward processes should not be inferred from comparisons between pimozide and extinction.     

TRH and its analog (DN-1417). Effects on central dopaminergic system-dependent behaviors in rats and mice

Effects of TRH and its analog, gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide citrate (DN-1417), on circling, stereotyped or climbing behavior were investigated in rats and mice. High doses of TRH (100 mg/kg, i.p.) and DN-1417 (20-50 mg/kg, i.p.) produced a significant ipsilateral circling behavior in rats with the lesions of the unilateral dopamine (DA) pathway by 6-hydroxydopamine. In intact mice, stereotyped sniffing accompanying hyperactivity was caused at low doses of TRH or DN-1417 (1-20 mg/kg, i.p.), and stereotyped licking behavior was observed at high doses of TRH or DN-1417 (20-200 mg/kg, i.p.). Furthermore, TRH, DN-1417 or methamphetamine caused a dose-related climbing behavior in mice pretreated with L-DOPA and Ro 4-4602. Circling behavior, stereotyped sniffing or licking behavior induced by TRH or DN-1417 was markedly suppressed by pretreatment with pimozide or alpha-methyltyrosine. However, atropine and scopolamine potentiated the circling inducing action of TRH or DN-1417, in contrast with suppression of the licking behavior. These results suggest that TRH and DN-1417 produce circling, sniffing, licking and climbing behaviors via activation of the central DA system, and that cholinergic mechanisms may be also involved in licking behavior induced by TRH or DN-1417.     

Effects of ovariectomy and estradiol injections on food intake and body weight in rats with ventromedial hypothalamic lesions

Female rats with lesions of the ventromedial hypothalamus (VMH) were ovariectomized during the static obese stage efter body weight levels had stabilized. Following ovariectomy, rats with VMH lesions showed smaller increases in food intake and less body weight gain than non-lesioned controls ovariectomized at the same time. Subsequently, the effects of peripheral injections of estradiol benzoate (EB) on feeding and body weight were examined. Ovariectomized rats with VMH lesions were also less responsive to exogenous EB treatment; they lost significantly less weight in response to estrogen than controls. EB caused a somewhat smaller reduction in food intake by the VMH group but this difference was not significant. Considered together the available data on changes in responsiveness to endogenous and exogenous estrogen following VMH lesions suggests a role for VMH estrogen receptors in the regulation of body weight, but these estrogen receptors may not modulate weight by directly altering food intake as previously suggested.     

Disulfiram-induced hypothermia in the normal rat; its attenuation by pimozide

Intraperitoneal injection of disulfiram, a dopamine-β-hydroxylase inhibitor (DβHI), in normal rats produced a dose-dependent hypothermia which was significantly reduced by pimozide, a selective blocker of dopamine receptors. Intraperitoneal injection of another DßHI, methimazole, in normal rats also produced hypothermia which was significantly reduced by pimozide. These experiments demonstrate that disulfiram is capable of producing hypothermia in the normal rat when it is given systemically. The fact that pimozide significantly reduced the hypothermia induced by disulfiram or methimazole, indicates that this hypothermie response might involve activation of dopamine receptors.     

Some effects of pimozide and of shifts in sucrose concentration on lick rate, duration, and interlick interval

Multiple dependent measures were employed to characterize the licking behavior of rats exposed to shifts in reward magnitude or injected with pimozide (PIM). Nondeprived rats licked either a 32% (n = 14) or 4% (n = 15) sucrose solution in daily 10 min sessions. Rats in the 32% condition were then down-shifted to either a 16% (n = 7) 4% (n = 7) sucrose solution. Rats in the 4% condition were up-shifted to either 16% (n = 7) or 32% (n = 8) sucrose solution. The response profiles generated by those rats shifted to a lower reward magnitude were contrasted with either rats shifted from a 32% sucrose solution to a no-reward (plain tap water) condition, or with rats maintained on a 32% sucrose solution and administered the neuroleptic PIM (0.5 mg/kg or 1.0 mg/kg). Rats down-shifted from a 32% to 4% sucrose solution generated response profiles more similar to rats shifted to plain tap water than rats maintained on a 32% sucrose solution and administered PIM. These results suggested that PIM treatment is not functionally equivalent to either a shift to no-reward or to a shift to reduced reward conditions.     

Glucose homeostasis in rats treated acutely and chronically with quinine

Glucose homeostasis in normal rats was studied after chronic or acute administration of quinine. Male rats received a daily dose of 10-30 mg/kg of quinine in the drinking water for 20 weeks. The high dose caused a slight decrease in food intake and weight gain. Though basal plasma insulin levels were increased in treated rats, their plasma glucose levels were only slightly and not consistently decreased. After oral or intravenous administration of glucose, the plasma insulin levels were higher and the disappearance rate of glucose was greater in rats receiving quinine than in the controls. The insulin content of the pancreas was not affected by quinine treatment. Intraperitoneal injection of a high dose of quinine (30 mg/kg) transiently increased plasma glucose and insulin levels. The insulin response was increased during a subsequent administration of glucose but the glucose levels were not modified. This study shows that chronic administration of quinine increases plasma insulin levels, accelerates disposal of oral or intravenous glucose but does not cause hypoglycaemia in normal rats.     

Dopamine D2 receptors and ingestive behavior: brainstem mediates inhibition of intraoral intake and accumbens mediates aversive taste behavior in male rats

RATIONALE: One of the factors that terminate the ingestion of an intraorally infused solution of sucrose may be an increase in the perceived aversiveness of its taste. OBJECTIVES: We tested the hypothesis that dopamine D(2), as opposed to D(1), receptors in the brainstem or nucleus accumbens inhibit intraoral intake by enhancing the aversiveness of the taste of the infused solution. METHODS: Male rats were infused intraorally with a 2 M sucrose solution (1 ml/min) and intake and the display of gapes and chin rubs, i.e. taste-related aversive behavior, was measured. Gapes and chin rubs were also measured in rats during and 40 s after brief intraoral infusion (1 ml/min during 20 s) of a 0.3 mM solution of quinine HCl. The full D(1) receptor agonist dihydrexidine (0.1-3.0 mg/kg) and antagonist SCH-23390 (0.03-0.1 mg/kg), the D(2) receptor agonist quinpirole (0.3 mg/kg) and antagonist raclopride (1.7 mg/kg) were injected IP. Quinpirole (14-55 microg) and raclopride (5 microg) were also infused into the fourth brain ventricle. In addition, quinpirole (2 or 10 microg) was infused into the shell region of the nucleus accumbens. RESULTS: IP dihydrexidine and quinpirole inhibited the intraoral intake of sucrose and pretreatment with raclopride, but (in the case of dihydrexidine) not SCH-23390, attenuated this effect. Injection of quinpirole into the fourth ventricle produced raclopride-reversible inhibition of intraoral intake but did not stimulate the display of gapes and chin rubs. Infusion of quinpirole into the shell region of the nucleus accumbens had the opposite effects. The intake of sucrose was suppressed by the addition of quinine HCl but this suppression was unaffected by dopamine agonist or antagonist treatment. CONCLUSIONS: It is suggested that brainstem dopamine D(2) receptors mediate suppression of consummatory ingestive behavior and that D(2) receptors in the shell region of the nucleus accumbens mediate the display of gapes and chin rubs, but that neither of these D(2) receptor populations mediate the hedonic evaluation of taste.     

Time-response effects of pimozide on operant behavior and schedule-induced polydipsia

Previous research has indicated that the administration of specific doses of pimozide results in the suppression of the acquisition of schedule-induced polydipsia in rats while not affecting operant behavior. The purpose of this study was to determine if these results were due to a specific action of pimozide on schedule-induced polydipsia or if they were due to an insufficient presession time of drug administration. Pimozide at 1.0 mg/kg was administered to three groups of rats at either 30, 60 or 120 minutes presession with control subjects receiving administration of the drug vehicle also at these times. The results of the study were that both operant behavior and the acquisition of schedule-induced polydipsia were affected in a nondifferential and time-dependent manner by pimozide. It was also found that pimozide caused an alteration in the temporal pattern of both schedule-induced polydipsia and operant responding. This latter result appears to have been caused by a disruption in sensorimotor integration due to the dopamine blocking properties of pimozide.     

Pimozide prevents the response-reinstating effects of water reinforcement in rats

Thirsty animals were trained to traverse a straight runway once each day for a reward consisting of 100 licks from a water-filled drinking tube. Once running speeds had stabilized, single daily extinction trials were initiated during which no water reinforcement was provided in the goal box. Extinction trials continued until running had slowed to levels approximately half of that observed during reinforced trials. A single treatment trial was then conducted in which some animals found water in the goal box and others continued to find an empty water bottle. Those subjects that were reinforced on treatment day subsequently demonstrated a reinstatement of their operant running response on the very next trial (i.e., 24 hr later). However, pretreatment with 1.0 mg/kg (but not 0.5 mg/kg) of the dopamine antagonist drug, pimozide, attenuated this response-reinstating effect of water-reinforcement. This action of pimozide was not likely a consequence of some residual sedative or motor incapacitation since a) the test day was conducted 24 hr after the treatment day by which time the pharmacological actions of the drug had greatly subsided; b) a Motor Control group administered pimozide after the reinforced trial exhibited normal response-reinstatement 24 hr later on Test Day; and c) on treatment day, pimozide did not reliably attenuate running times, latency to initiate drinking, nor the rate of licking behavior. Together, these data suggest that dopamine receptor antagonism can produce an attenuation in the reinforcing efficacy of water.     

Potentiation of licking in rats by stimulation of both D-1 and D-2 dopamine receptors

Apomorphine-induced licking in rats was assessed by recording the total number of licks by direct observation. Apomorphine induced licking dose dependently. The maximum response was obtained by 0.5 mg/kg of the drug and 30 min after drug administration. Pre-treatment with dopamine antagonists, sulpiride and SCH 23390 decreased the apomorphine effect. Pre-treatment of animals with reserpine+α-methyl-p-tyrosine (AMPT) increased apomorphine-induced licking. In normal rats the D-2 agonist quinpirole and the D-1 agonist SKF 38393 also induced significant licking. The effect of quinpirole or SKF 38393 was decreased by reserpine+AMPT pre-treatment. Combined treatment with SKF 38393 and quinpirole induced more intense licking in both reserpinized and non-reserpinized animals. It is therefore concluded that the apomorphine-induced licking is mediated through both D-1 and D-2 receptors, and that pre-treatment with reserpine hypersensitizes these receptors to the drug effect. However, for either SKF 38393- or quinpirole-induced licking, the presence of endogenous dopamine seems essential.     

Effect of mazindol on insulin and glucagon secretion in ventromedial hypothalamic obese rats

The effect of mazindol on insulin and glucagon secretion was studied in ventromedial hypothalamic lesioned (VMH) obese rats with hyperinsulinemia and VMH sham rats. Three weeks after the VMH or sham operation, VMH and sham rats were divided into two groups: one was fed diet containing mazindol (50 mg/kg) and the other was fed diet without mazindol. They were housed three more weeks before the experiment. Mazindol reduced significantly body weight increase and calorie intake in VMH rats, but not in sham rats. In addition, the fasting plasma insulin level and the arginine-induced insulin secretion in VMH rats treated with mazindol were significantly lower than those in the VMH rats without treatment of mazindol. On the other hand, in both in vivo and in vitro experiments, mazindol produced no significant change in the insulin secretion of sham-operated rats. These results suggest that mazindol suppresses hypersecretion of insulin in VMH rats probably through an anorectic effect and/or suppression of vagal hyperactivity.     

Effects of a diazoxide inhibition of insulin release on food intake of normal and hyperphagic hypothalamic rats.

In order to clarify the role of endogenous insulin in generating normal and pathological feeding behaviors, the effect of an anti-insulin drug, Diazoxide, on the meal pattern has been investigated in both normal and VMH rats. A dose-dependent reduction of food intake under Diazoxide treatment was found in normal rats. The same percentage reduction was obtained at night with a higher dose than required in the daytime. Conversely, hyperphagic VMH rats exhibited a dose-dependent reduction which was identical in the two portions of the diurnal cycle. The dose effective in entirely suppressing eating in VMH rats was twice that required for normal rats in the daytime period and identical at night. The results are discussed in relation to earlier findings concerning the diurnal insulino-secretory pattern in normal and VMH rats.     

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.     

Some effects of pimozide on nondeprived rats licking sucrose solutions in an anhedonia paradigm

The present work examines the generalizability of the anhedonia phenomenon (extinction-like responding with repeated neuroleptic treatment) by examining rats' licking behavior, a response heretofore untested, in the anhedonia paradigm. Nondeprived rats learned to lick a sucrose solution (32%) and were then tested for eight consecutive days in either a no-reward condition (N = 8) or two pimozide (PIM) with reward conditions (N = 8 at each of these two doses: 0.5 and 1.0 mg/kg). PIM treated animals did not exhibit rates or patterns of responding equivalent to animals in the extinction condition. Instead of an across session decline in rate, PIM treated animals showed a trend towards recovery on the rate measure. Within session patterns of responding of PIM treated animals more closely resembled animals in a normally rewarded condition responding at a generally lower rate, than animals in an extinction condition. The experimental procedure included the the use of home cage control animals, replication of the intermittent dosing procedure, and tests for transfer effects; all of these failed to produce patterns of responding typically obtained in the anhedonia paradigm when the response is lever pressing. Median lick duration and median interlick interval (ILI) were both lengthened with PIM treatment relative to injection control and extinction conditions, suggesting that pimozide treatment creates a motoric deficit. Taken together these results emphasize the importance of neuroleptics' motor vis a vis anhedonic effects.     

Effects of dopamine receptor blockade on alimentary behaviors: Home cage food consumption,magazine training,operant acquisition,and performance

Administration of the dopamine receptor blocker pimozide (1.0 mg/kg) disrupted the initiation, but not the maintenance, of home cage food consumption. Likewise, the number of pellets consumed during magazine training was decreased among pimozide-treated rats during the first, but not the second day of training. The acquisition of a bar-press response for food reinforcement (using a retractable bar) was severely retarded by pimozide. However, such an impairment was not evident if animals initially received 2 training days in the absence of the drug. Further, among rats trained to bar press to asymptote using a nonretractable bar, pimozide reduced the within and between days bar-press rate such that performance was indistinguishable from that of animals placed on extinction in the absence of the drug treatment. When transferred from the pimozide treatment to extinction in the absence of drug, the response rate increased to the level observed during the first session of either extinction or pimozide in the continuous reinforcement condition. The results are discussed in terms of sensory-motor and reinforcement consequences of dopamine receptor blockade.     

The effects of cadmium on the self-administration of ethanol and an isocaloric/isohedonic equivalent

During a period of baseline fluid intake recording, adult male rats were presented with a three-bottle, two-fluid choice test that offered either a 10% ethanol solution (v/v) and tap water as alternatives, or a sucrose/quinine solution and tap water as alternatives. The sucrose/quinine solution was equivalent to the ethanol solution both in terms of calories and palatability. After intakes stabilized, half of the animals from each test condition were placed on a diet containing 100 ppm cadmium and the remaining half of the animals were placed on a standard laboratory diet. After 60 days of exposure to their respective diets, all animals were presented their earlier test solutions, both in a nonchoice and choice format. The results from the choice test indicated that although cadmium treatment did not produce a clear preference for ethanol over water, cadmium exposure was associated with a significant increase in ethanol consumption. Moreover, the self-administration of the isocaloric/isohedonic equivalent (sucrose/quinine solution) was unaffected by cadmium contamination. These data are discussed in terms of their implications for both nutritional and sensory-impairment accounts of metal-related changes in the volitional intake of ethanol.