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Serotonin (5-HT) has been implicated in the regulation of the stress response. Two experiments were conducted to investigate the possibility that the 5-HT(2A), 2C agonist DOI would reduce behavioral responsiveness to stress, and that selective blockade of one or both of these receptor subtypes would reverse this effect. Stressors employed were mild tail pinch and an illuminated open field. In Experiment 1 DOI (0.1, 0.5, 1.0 mg/kg, s.c.) was found to decrease stress-evoked oral behavior directed at food and to increase rearing behavior in a dose-dependent fashion. Neither of these effects was reversed by spiperone (5-HT(2A) antagonist) or SDZ SER-082 (5-HT(2C) antagonist). DOI also increased the frequency of head shaking. This effect was reversed by SDZ SER-082. In Experiment 2 DOI was injected singly or in combination with ketanserin (5-HT(2A). 2C antagonist). DOI decreased tail pinch-evoked oral behavior directed at food, the amount of food eaten, and increased vocalization. In the open field DOI decreased rearing, increased the number of head shakes, and increased the incidence of flat body posture. While ketanserin alone (0.5, 2.5, 5.0 mg/kg) had no effect on any behavioral measure, coadministration of ketanserin (5.0 mg/kg) with DOI (0.5 and 1.0 mg/kg) significantly blocked the effects of DOI on oral behavior directed at food, eating, rearing, head shaking, and flat body posture. It is concluded that the observed effects of DOI on behaviors evoked by stress were mediated by activation of both 5-HT(2A) and 5-HT(2C) receptors.

In earlier studies it was found that glutamatergic transmission within the nucleus accumbens septi is involved in the performance of a learned visual shape discrimination in pigeons. This study examines what effects several kinds of glutamate and dopamine antagonists have on the same task. Pigeons were trained with the relevant discrimination, bilaterally implanted with cannulas into the nucleus accumbens and tested after various transmission blockers had been administered intracerebrally. SCH-23390, a D1 dopamine antagonist, at the dose used, had no effect, and Spiperone, a D2-dopamine and 5HT2a-serotonine antagonist, significantly decreased the error repeat trials. CNQX, a non-NMDA glutamate receptor antagonist, and Cycloleucine, an antagonist of the glycine allosteric site of NMDA receptors, had no effect. CGS-19755, a selective competitive NMDA antagonist, significantly impaired performance by significantly decreasing the percent correct trials and increasing the error repeat trials. CPPG, a II/III metabotropic glutamate antagonist, remarkably improved performance. MMPG, a III/II metabotropic glutamate antagonist, at the dose used, did not have any significant effect. The preparation employed may be a useful animal model of perceptual disturbances in schizophrenia.

The effect of the serotonin1A (5-HT1A) agonist alnespirone (S-20499) on the secretion of both oxytocin and vasopressin was examined in the same conscious, unrestrained male rats. The dose-response and time-course effects on the secretion of oxytocin and vasopressin revealed that alnespirone stimulated oxytocin in a dose-dependent manner, but did not increase vasopressin secretion. Time of maximal effect following injection of alnespirone (5 mg/kg, i.p.) was as early as 15 min postinjection, with significant stimulation persisting for 30 min. Pretreatment with a low dose of the 5-HT1A/beta-adrenoceptor antagonist (-)-pindolol (0.3 mg/kg, s.c.), 30 min prior to injection of alnespirone (0, 2, 5, and 10 mg/kg, i.p.) shifted the dose-response curve to the right and inhibited the effect of alnespirone on plasma oxytocin concentration. Furthermore, pretreatment with a low or a high dose of the 5-HT1A/2A/dopamine D2 antagonist spiperone (0.01 or 3 mg/kg, s.c.) dose dependently shifted the alnespirone dose-response curve effect of alnespirone to the right. None of these drugs, alone or in combination, altered plasma vasopressin levels. These studies suggest that 5-HT1A receptor mechanisms mediate the effect of alnespirone on the secretion of oxytocin. Furthermore, these studies suggest that 5-HT1A receptor mechanisms do not participate in the serotonergic regulation of vasopressin secretion.

The effects of acute treatment with 5-HT3 receptor antagonists, ondansetron and ICS 205-930, on the stimulation of activity induced by ethanol-and cocaine were examined. Ethanol (1.8 or 2 g/kg i.p.) or cocaine (15 mg/kg i.p.) produced a significant increase in locomotor activity (LMA) in DBA/2N mice. Pretreatment with ondansetron or ICS 205-930, in doses ranging from 0.001 to 0.1 mg/kg (s.c), did not modify ethanol or cocaine induced stimulation of activity. In contrast, pretreatment with a 10 micrograms/kg dose of either SCH 23390 or spiperone, a D1 and D2 dopamine (DA) receptor antagonist respectively, completely antagonized the stimulation of LMA induced by ethanol. Similar dose of SCH23390, but not spiperone, blocked the stimulation of activity induced by cocaine. These results indicate that D1 but not D 2 DA receptors play a significant role in cocaine induced hyperactivity whereas both D1 and D2 are involved the locomotor activating effects of ethanol.

The present experiments were performed to investigate effects of (+/-)-2-(dipropylamino)-7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT) or quinpirole (LY 171555), putative dopamine (DA) D3 receptor agonists, on serum prolactin levels in male rats. Basal prolactin levels were reduced dose-dependently by SC administration of 7-OH-DPAT or quinpirole at respective doses of 10-100 micrograms/kg and 25-250 micrograms/kg. Daily treatment with estradiol, 35 micrograms/kg/day for 3 days, increased serum prolactin levels to fourfold higher levels than those of nonprimed rats. Intraperitoneal injection of alpha-methyl-p-tyrosine (alpha-MT), 300 mg/kg, also increased serum prolactin levels. 7-OH-DPAT or quinpirole at a dose of 50 micrograms/kg caused a marked reduction in serum prolactin levels in both the estradiol- and alpha-MT-induced hyperprolactinemia. The 7-OH-DPAT- and quinpirole-induced decreases in serum prolactin levels were antagonized by the administration of the DA D2 receptor antagonist, spiperone, at 0.5 mg/kg. The results indicate that 7-OH-DPAT and quinpirole decrease prolactin levels in rats by stimulation of the D2 receptor.

Mechanisms of tryptophan (a 5-HT precursor)-induced changes in body temperature were investigated in rats pretreated with pargyline, a monoamine oxidase inhibitor (MAO-I). Tryptophan (100 mg/kg, i.p.) did not affect the body temperature in rats, but it produced significant hypothermia followed by marked hyperthermia and higher mortality in the pargyline-pretreated rats. 5-HT depletion with p-chlorophenylalanine (p-CPA, 100 mg/kg/day for 3 days) significantly suppressed not only the body temperature change but also the mortality and 5-HT syndrome following tryptophan plus pargyline administration. Although propranolol (10 mg/kg, i.p.), a beta-adrenoceptor antagonist, did not alter the hypothermia caused by tryptophan in the pargyline-pretreated rats, pindolol (2 mg/kg, S.C.), a 5-HT1A receptor and beta-adrenoceptor antagonist, suppressed the hypothermia but not the hyperthermia or mortality caused by the same treatment. On the other hand, spiperone and ketanserin, 5-HT2 receptor antagonists, at doses of 3 mg/kg, potentiated the hypothermia and completely suppressed the hyperthermia and mortality caused by tryptophan in the pargyline-pretreated rats. These results suggest that tryptophan-induced hypo- and hyperthermia are mediated by 5-HT1A and 5-HT2 receptors, respectively, in the pargyline-pretreated pretreated rats.

Bilateral electrolytic lesions of the red nucleus (RN) of rat decreased apomorphine-induced stereotypy, increased haloperidol-induced catalepsy, reversed apomorphine-induced hypothermy, decreased spiroperidol-induced hypomotility, and BHT-920-induced yawning and penile erection episodes. Moreover, apomorphine antagonized haloperidol-induced catalepsy in the RN-lesioned group. The lesioned animals revealed depleted levels of dopamine and its metabolites in brain areas as well as serotonin and its metabolite. The brain areas analyzed were pyriform cortex, substantia nigra, striatum, enthorinal cortex, and cerebellum. Based on these results, it is very likely that the RN has a complex role in the behavior of rats as a consequence of dopaminergic-serotoninergic changes in the central nervous system.

This study characterizes the cue properties of quinpirole (LY 171555), a selective D2 agonist, and the blocking capabilities of spiperone, a selective D2 antagonist. After rats were trained to discriminate 0.025 mg/kg quinpirole from distilled water, a dose-response curve and time course of the quinpirole discriminative stimulus were determined. The effectiveness of three doses of spiperone in blocking the discriminative stimulus produced by 0.02 mg/kg quinpirole was then assessed. Finally, the time course of spiperone's blocking action was determined. Given the putative selective action of these drugs on D2 receptors and the parametric data presented here, it was predicted that following chronic treatment with spiperone, a rebound increase in quinpirole-appropriate responding would occur. Neither chronic treatment with spiperone nor chronic treatment with haloperidol produced the predicted changes. This result, however, may be confined to the specific dose and time parameters used.

The effects of dopamine D1 and D2 agonists and antagonists on fixed-interval (FI) self-stimulation were investigated using a reward-summation model, trading off frequency with train duration. The D1 antagonist SCH 23390 (0.005-0.02 mg/kg) decreased FI self-stimulation and the inhibition was reversed by increasing stimulation frequency. Moreover, amphetamine (0.5 mg/kg) reversed the inhibition by a low dose of SCH 23390 (0.005 mg/kg) but not after a higher dose inhibition could not be dissociated from a performance deficit. There was no significant interaction between low doses of spiperone and SCH 23390 when coadministered that could not be predicted from their effects when given individually. Self-stimulation was inhibited by the D1 agonist SKF 38393 (5 mg/kg). When coadministered with amphetamine, SKF 38393 partially blocked amphetamine's facilitation. The D2 agonist bromocriptine (10 mg/kg) produced an extraordinary enhancement of performance that was also evident after a lower dose (5 mg/kg) when it was combined with amphetamine. This enhancement of performance showed little extinction when stimulation was no longer available, suggesting it was a novel form of stereotypy. These results support the concept that D1 dopamine receptors play a critical role in modulating the reinforcing consequences of lateral hypothalamic stimulation. The involvement of D2 receptors on reinforcement processes remains contentious due to their effects on performance and insensitivity of responding to coincide with changes in reinforcement magnitude.

The ability of D1 and D2 dopamine antagonists to reduce the subjective effects of nicotine was examined in rats trained to discriminate nicotine (0.3 mg/kg, base) from saline. Each of SCH 23390 (a D1 antagonist) and spiperone (a D2 antagonist) reduced responding on the drug-appropriate lever, and produced a reduction in overall response rates. The nicotine cue was also tested for generalization to the dopamine reuptake blocker GBR 12909. Doses of GBR 12909 that produced complete responding on the drug-appropriate lever in cocaine-trained animals led to only minimal selection of the nicotine-appropriate lever in nicotine-trained animals; as with the dopamine antagonists, response rates after GBR 12909 were markedly reduced in nicotine-trained, but not in cocaine-trained, rats. These data suggest that dopaminergic mechanisms play, at best, a small role in the discriminative stimulus properties of nicotine.

In the rat, dopamine (DA) facilitates male copulatory behavior. Indirect evidence based largely on neuroanatomical data suggest that in quail DA is also implicated in the control of male reproductive behavior but there is no pharmacological evidence to support this conclusion. To test this idea, castrated testosterone (T)-treated male quail were injected with various doses of the dopaminergic agonist apomorphine (APO) in the range 1-10,000 micrograms/kg. The sexual behavior of birds was recorded starting 15 min after APO injection for a duration of 30 min. A dose-dependent inhibition of male reproductive behavior that lasted for the entire duration of the test was observed. In a second experiment, gonadectomized T-treated male Japanese quail were injected daily with APO (0, 10, or 1,000 micrograms/kg) during 8 days. Their sexual interactions with a partner were quantified either 24 h or 15 min after the last injection. No influence of the treatment on copulatory behavior was observed 24 h after the last injection, but a strong inhibition was present when the test was performed 15 min after. To research whether the inhibitory effects of APO were due to a preferential action on D2 presynaptic autoreceptors, male quail were pretreated with two different D2 antagonists (spiperone or pimozide; 0.5 or 2 mg/kg) before being injected with APO (100 micrograms or 1 mg/kg). Spiperone facilitated male sexual behavior but did not suppress the inhibitory effect of APO. No significant effect of pimozide was observed. These results support the notion that DA modulates male sexual activity in the Japanese quail. The specific role of the different dopaminergic receptor subtypes remains, however, to be elucidated.

The purpose of this investigation was to determine whether selectively blocking D1 and D2 dopamine receptors produces a differential effect on the characteristics (speed and success) of the reaction time response in rats. Animals were shaped to release a lever in response to an auditory/visual stimulus to avoid mild foot shock. The selective D1 antagonist SCH 23390 (0, 70, and 100 micrograms/kg, IP) and the selective D2 antagonists spiperone (0, 1, and 10 micrograms/kg, IP) and haloperidol (0, 10, and 100 micrograms/kg, IP) were studied for their effects on successful avoidance and response latency. SCH 23390 impaired successful avoidance and increased response latencies in a dose-dependent manner. Spiperone and haloperidol also produced dose-related decreases in successful avoidance. In contrast to the dose-related increase in response latencies produced by SCH 23990, 1 microgram/kg spiperone and 10 micrograms/kg haloperidol significantly decreased the latencies of successful responses. Spiperone (10 micrograms/kg) had little effect on response latencies, while 100 micrograms/kg haloperidol increased them. The results of these experiments demonstrate that reaction time is differentially affected by selective dopamine receptor blockade and that the speed and success of reaction time responses can be independently modulated by D1 vs. D2 receptor activity.

The effects of bilateral olfactory bulbectomy on serotonergic 5-HT2 and 5-HT1A receptor binding were studied in the frontal cortex (FC), limbic structures (LS), including the hippocampus, amygdala, olfactory tubercule, and piriform cortex, and hypothalamus (HTH) in mice. Bulbectomy resulted in the increase of Bmax for [3H]spiperone binding with 5-HT2 receptors in FC in C57Bl/6j. The receptors in LS and HTH remained unchanged. Subchronic treatment of the bulbectomized mice with antidepressant trazodone (20 mg/kg/day, IP, 14 days) induced downregulation of 5-HT2 receptors in FC and LS. The other two antidepressants used, amitriptyline (20 mg/kg/day, IP, 14 days) and imipramine (10 mg/kg/day, IP, 14 days), did not alter these receptors. [3H]8-OH-DPAT binding with 5-HT1A receptors was not altered by bulbectomy in any brain area in C57Bl/6j mice. Amitriptyline and trazodone decreased Bmax for these receptors in FC in the bulbectomized mice while imipramine was ineffective. Amitriptyline and imipramine significantly increased Bmax and decreased Kd in HTH, and trazodone displayed the same tendency. Bulbectomy did not alter 5-HT2 receptors in DBA/2j mice. Amitriptyline increased Kd in the all brain areas without changing Bmax in the bulbectomized DBA/2j mice. Trazodone significantly decreased Bmax in FC and increased Kd in FC and LS. Imipramine decreased Bmax while increasing Kd in LS. The possible involvement of the serotonin receptor subtypes in the bulbectomy-induced behavioral deficits and in the restorative action of the antidepressants is discussed.

The influence of a genotype of inbred mice on the aggressive behavior induced by clonidine and the role of dopamine D1 and D2 receptors in that behavior were studied. Clonidine in a dose of 10 mg/kg evoked a strong aggressiveness in BALB/c, DBA/1, and CC57Br mice and an intermediate response in C57BL/6J, Albino Swiss, and CBA mice, whereas DD, A/He, and C3HA/y mice did not show any aggressive behavior. Apomorphine significantly potentiated the clonidine-induced aggressiveness in C57BL/6J mice. In Albino Swiss mice, SK&F38393 as well as quinpirole augmented the aggressive behavior evoked by clonidine. The clonidine-induced aggressiveness was blocked by SCH23390 and cis-flupentixol but not by (-)-sulpiride. In aggressive mice, the binding of [3H]SCH23390 was decreased in the limbic forebrain, whereas the binding of [3H]spiperone was not changed. The obtained results indicate that the potency of the clonidine-induced aggressiveness depends upon genotype of mice; moreover, the presence of a physiological function of D1 receptors is necessary for its occurrence.

Present results show that a single treatment with dizocilpine (MK-801, 0.25 mg/kg IP) failed to modify the specific binding to D1 or D2 DA receptors. In contrast, repeated administrations for 3 weeks resulted in a statistically significant decrease of [3H]Spiroperidol binding to cortical or striatal membranes but did not change the number or the apparent affinity of [3H]MK-801 binding in well-washed cortical membranes. Consistent reduction in specific D2 receptor mediated behavior was obtained. The data suggest that the changes in DAergic function following repeated administrations with MK-801 could be suggestive of potential therapeutic uses of negative allosteric drugs in some DA related dysfunctions.

Pharmacological agents known to stimulate monoamine systems improve memory, and destruction of the dopaminergic systems or dopamine depletion lead to impairments in various learning-related tasks. These reported effects of the central dopaminergic system imply the involvement of D2 receptors. The aim of the present study was to investigate changes in [3H]spiroperidol binding in seven areas of rat brain following informal and active avoidance learning. Littermate male and female rats were reared until 3 months of age in standard colony conditions and treated as active controls or in enriched environmental conditions and exposed to pole-jump active avoidance trials. Female rats acquired avoidance behavior more rapidly than males. Among the brain regions, only the hippocampus showed significant variations in D2 receptor binding between the groups; sex differences and learning-sex interaction were observed in the corpus striatum. There was an inverse correlation between learning performance and hippocampal D2 receptor binding. Our results show that learning affects hippocampal D2 receptors in a sexually dimorphic pattern.

Enhanced oral responses have been observed in rats that are treated shortly after birth with 6-hydroxydopamine (6-OHDA). A series of studies was conducted to characterize this effect. A dose-response curve demonstrated that the dopamine D1 receptor agonist, SKF 38393, produced a maximal response in 6-OHDA-treated rats at a dose of 0.10 mg/kg (IP). With the D2 receptor antagonist, spiperone, a bell-shaped dose-response curve was seen, with a maximal effect in the 6-OHDA group occurring at 80 micrograms/kg. There were only slight increases in oral activity with different SKF 38393 or spiperone doses in the saline group, indicating that there was an overt supersensitization of D1 receptors in the 6-OHDA-treated rats. The D1 antagonist SCH 23390 (0.30 mg/kg, IP) attenuated the response to both SKF 38393 and spiperone. The oral response to the D2 agonist, quinpirole (0.10 mg/kg, IP) was not preferentially increased in the 6-OHDA group of rats. These findings indicate that the enhanced oral response in neonatal 6-OHDA-treated rats is mediated by supersensitive dopamine D1 receptors. The persistence of the enhanced oral response in 6-OHDA-treated rats at 8 months demonstrates that this sensitization of D1 receptors is a long-lived phenomenon.

Rats were trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement with a 1-min time-out period following each infusion. Cocaine was available at doses of either 0.1, 0.3 or 1.0 mg/kg/infusion. A low dose (3 microgram/kg) of the D1 antagonist SCH23390 caused an increase in cocaine self-administration which was more prominent at higher, as compared to lower, doses of cocaine. Higher doses of SCH23390 generally caused decreases in self-administration which may in part be due to the response-decreasing properties of this agent. The D2 antagonist spiperone generally caused an increase in self-administration of cocaine. These data suggest that cocaine reinforcement depends upon both D1 and D2 receptor subtypes.

The influence of central dopaminergic fibers on drug-induced oral activity in rats has not been well studied. Rats were treated 3 days after birth with bilateral intracerebroventricular 6-hydroxydopamine (6-OHDA; 134 micrograms total, base form) to destroy dopaminergic fibers in the brain. Control rats received vehicle by the same route. At about 10 weeks of age, a challenge dose of the dopamine D2 receptor antagonist, spiperone (40 micrograms/kg, IP), produced an 8-fold increase in the number of oral movements during a 60-minute observation period, vs. the control group. SKF 38393 (3.0 mg/kg, IP), a D1 agonist, produced the same number of oral movements as spiperone in the 6-OHDA group, representing a 2.4-fold increase over the controls. The Bmax and Kd for both D1 and D2 receptors was not changed in rat striatum by neonatal 6-OHDA treatment, even though dopamine content was reduced by 96%. These findings demonstrate that oral activity in rats can be greatly altered, even when there is no change in absolute numbers of D1 and D2 receptors and no change in the ratio of D1:D2 receptors.

To investigate the possible functional relationship between 5-HT1 and 5-HT2 receptors, we studied the effects of a nonselective 5-HT agonist (5-MeO DMT), a 5-HT1A-selective (8-OH-DPAT) and a 5-HT1B/5-HT1C-selective (TFMPP) agonist on the head-twitch behavior induced by the putative 5-HT2-selective receptor agonist (+/-)-DOI. In the mouse (+/-)-DOI produced the head-twitch response in a dose-dependent manner and (-)-DOI was twice as potent as the (+) isomer. Selective 5-HT2 antagonists, ketanserin and spiperone, dose-dependently inhibited the (+/-)-DOI-induced head-twitch response. The nonselective and the 5-HT1A-selective agonists also dose-dependently reduced the behavior, whereas 5-HT1B/5-HT1C-selective agonist (TFMPP) failed to affect the (+/-)-DOI-induced response. Taken together with previously published literature data, we propose a 5-HT1A inhibitory action on the 5-HT2 receptor-mediated response when induced by its selective agonist (+/-)-DOI.

The main aim of the present study was to investigate if responses to the direct dopamine agonist, apomorphine, could be modified by changes in the activity of cholinergic neurones. A novel approach was adopted in which these responses were assessed following reduction of muscarinic receptor concentration (mAChR) in the brain (assessed from [3H] QNB binding) by the alkylating derivative of oxotremorine, N-[4-(2-chloroethylmethylamino)]-2-pyrrolidone (BM 123). Stereotyped responses elicited by apomorphine were significantly reduced when QNB binding was 12% and 50% of control values. No changes in [3H] spiperone binding were found. There was significant hypothermia in the group with 12% QNB binding sites which was significantly increased by apomorphine. Body temperature returned to normal when QNB binding was 50% of control values. There was a significant decrease in activity when QNB sites were reduced to 12% of normal and vertical activity was still significantly reduced at 50% QNB binding, though horizontal activity was not then different from controls. These data are consistent with the hypothesis that changes in the function of mAChR modify responses elicited by dopamine receptor stimulation in both the striatum and other brain regions.

Animals were trained to discriminate heroin from saline in a two-lever food-reinforced paradigm. Tests with the heroin metabolites O6-monoacetylmorphine and morphine suggest that the heroin discriminative stimulus was mediated by monoacetylmorphine. The heroin discriminative stimulus was not blocked by pretreatment with low doses of the D1 dopamine antagonist SCH23390 or the D2 antagonist spiperone; higher doses of the antagonists produced decreases both in selection of the drug-appropriate lever after heroin, and in food-maintained responding. The data suggest that dopamine may mediate the heroin discriminative stimulus. When administered in the absence of opioids, the D2 antagonist spiperone did not have rate-decreasing effects, whereas SCH23390 did. Heroin partially reversed the rate-decreasing effects of SCH23390, possibly as a result of the ability of opioids to release dopamine.

The effects on feeding and drinking of various doses of droperidol, haloperidol and spiroperidol were studied in a number of paradigms. All three buryrophenones produced generally similar effects. After food deprivation, feeding was slightly increased at low doses but was decreased at the higher doses; the concomitant postprandial drinking was attenuated at all doses. Desalivate rats showed a marked attenuation of feeding (and prandial drinking) at low doses, but when wet mash was given instead of pellets and water a normal dose-response relationship was obtained. After water deprivation drinking was attenuated at all doses, and when food was also available during the drinking test the food intake was decreased in proportion to the drinking. Drinking was blocked more when food was present than in its absence. Insulin and 2-deoxyglucose induced feeding in sated rats was attenuated but not abolished by haloperidol. The findings are discussed relative to the role of activation and brain catecholamines in feeding and drinking.

The development of cholinergic influence on neuroleptic-induced catalepsy was investigated in 10-, 15- and 20-day-old rat pups. It was found that the antimuscarinic atropine was ineffective in decreasing the catalepsy produced by spiroperidol treatment at 10 and 15 days. By day 20, however, atropine attenuated cataleptic behavior in a dose-dependent manner. Atropine alone was shown paradoxically to elicit mild to moderate cataleptic responses in 10- and 15-day-olds, but not at day 20. Clozapine by itself produced the same age dependent pattern of catalepsy response as the spiroperidol and atropine combination treatment. These results suggest that cholinergic mechanisms which interact antagonistically with the dopamine systems underlying cataleptic behavior are not functionally mature until after day 15 in the rat.

Rhesus monkeys with a history of drinking methadone, but presently drug-free, were injected with low doses of methamphetamine (MA). They immediately developed oral dyskinesias resembling the symptoms of tardive dyskinesia in humans, a condition resulting from chronic blockade of striatal dopamine receptors by neuroleptics. Nine of 11 control monkeys failed to develop dyskinesias during prolonged MA administration. A stressful stimulus intensified the MA-elicited oral dyskinesias, an effect analogous to exacerbation of tardive dyskinesias by emotional stress. Control monkeys were then injected with methadone, chlorpromazine, haloperidol, or saline for 45 days. Ten days following this chronic treatment, MA immediately elicted oral dyskinesias in the methadone and chlorpromazine monkeys. Acute administration of the dopaminergic blocking agents chlorpromazine, spiroperidol, and clozapine eliminated MA-elicited dyskinesias, whereas the alpha-adrenergic blocker phentolamine was ineffective. Physostigmine blocked the dyskinesias in 1 of 2 cases. Sedative doses of phenobarbital and diazepam had no effect on oral dyskinesias. These data indicate that chronic treatment with methadone or other dopamine receptor blocking agents leads to receptor supersensitivity to the actions of MA.

Different behavioral and biochemical data suggest that ethanol has different effects on central dopaminergic transmission in rat and mouse. We found that ethanol induces an increase of striatal dopamine turnover which does not persist after chronic drinking. Following chronic ethanol treatment, we observed the development of supersensitivity of the striatal dopamine (DA) recognition sites, in terms of an enhanced affinity. We investigated various experimental models to clarify the existence of an enkephalinergic modulation of ethanol effects on the dopaminergic system. We found that in the rat, a pretreatment with naloxone abolishes the striatal DA turnover increase observed after ethanol. DBA 2J mice, which differ from C57 BL/6J and Swiss Albino, by genetically lacking enkephalinergic modulation on dopaminergic activity in the striatum, do not show any change of DA metabolism after acute ethanol. In the rat retina, where we hypothesized a less operant regulation of dopaminergic activity by enkephalins, tolerance does not develop after chronic drinking to the increase in DA turnover as it did in striatum. Our results confirm the importance of the endogenous opioid system in the regulation of the ethanol induced neurochemical and behavioral effects.

Bmax and Kd for the serotonin receptors (5-HT-1) as well as the ratios of 5-HT-1A and 5-HT-1B receptors were assessed at 3-hour intervals over a 24-hour period in the cortex of rats that were housed under a 12-hour lighting cycle, with the light turned on at 18:00. The circadian rhythm of the Bmax for the high- and low-affinity sites in 5-HT-1 receptor became evident. The peak of the Bmax for the high- and low-affinity sites occurred between 21:00 and 00:00. No circadian rhythm was observed for Kd at each site for the 5-HT-1 receptors. The ratios of Bmax for the high- and low-affinity sites of the 5-HT-1 receptors were constant at 8.6 +/- 1.4% and 91.4 +/- 1.4% respectively over the test period. The ratios of 5-HT-1A and 5-HT-1B receptors were constant at 36.8 +/- 1.3% and 63.2 +/- 1.2% respectively over the test period. No circadian rhythm was observed for Kd. These results suggest that the Bmax for the 5-HT-1 receptors may have the same circadian rhythm as high- and low-affinity sites and the Bmax for the 5-HT-1A and 5-HT-1B receptors may also have circadian rhythm.

The influence of cyproheptadine on the neuroleptic-catalepsy in rats was studied. Cyproheptadine antagonized dose-dependently the catalepsy induced by spiroperidol, pimozide, fluphenazine and reserpine. The anticataleptic effect of two antiparkinsonian drugs, L-DOPA or amantadine was potentiated by cyproheptadine.

In a dose-response experiment it was shown that intraperitoneal injections of 0.062 mg/kg, and 0.1 mg/kg of the dopamine-receptor blocking agent and neuroleptic spiroperidol severely attenuate self-stimulation in the orbitofrontal cortex, hypothalamus, and in the region of the locus coeruleus, in the rhesus monkey and in the squirrel monkey. In the rhesus monkey intracranial injections of 6 mug of spiroperidol bilaterally into the nucleus accumbens or the hypothalamus attenuated self-stimulation of the amygdala, and injections into the orbitofrontal cortex attenuated self-stimulation of the amygdala and lateral hypothalamus. Self-stimulation at other sites tested (including the region of the locus coeruleus) was much less affected by the injections, and injections into the region of the locus coeruleus were ineffective. These results together with other control experiments suggest that spiroperidol can attenuate self-stimulation in the monkey independently of any motor impairment or sedation produced, and that dopamine receptors in particular brain regions are involved in self-stimulation of particular brain sites.

Prolintane (1-[alpha-propylphenethyl]-pyrrolidine) but not l-(alpha-methylphenethyl)-pyrrolidine markedly enhanced the increase in 3,4-dihydroxyphenylacetic acid concentration in the brains of rats treated with spiperone, a neuroleptic drug. This action and other properties of prolintane described in the literature place it in a group of stimulant drugs that includes methylphenidate, cocaine and amfonelic acid with properties that differ from those of amphetamine.

Apomorphine (5.0 mg/kg) accelerated the disappearance of 5-HIAA from the brain of pargylinepretreated rats as well as depletion of brain 5-HT caused by inhibition of its synthesis. The latter effect has been abolished by spiroperidol. The results obtained suggest that apomorphine increases the 5-HT turnover rate, secondary to the stimulation of central dopamine receptors.

The potency of structurally rigid analogues of dopamine (DA) at striatal dopamine receptors was evaluated in rats using three types of assessments: (a) effectiveness in producing rotational and sniffing behaviors by intrastriatal injections (b) inhibition of [3H]-spiroperidol binding and (c) stimulation of adenylate cyclase activity. The compounds included apomorphine (APO) and its analogues, (R)-2,10,11-trihydroxyaporphine (R-THA) and (R)-2-hydroxy-10,11-methylenedioxyaporphine (MDO-APO), 2-amino-6,7-dihydroxyaminotetraline (ADTN) and its analogue, exo-2-amino-6,7-dihydroxybenzonorbornene (exo-amine). (R)-THA produced no stereotypy yet it was a potent inhibitor of [3H]-spiroperidol binding and adenylate cyclase activity. MDO-APO was quite active in inducing stereotypy and stimulating cyclase activity, but it showed low potency in displacing [3H]-spiroperidol. The exo-amine and ADTN were equally potent in enhancing rotation and sniffing intensity, however, the former was completely inactive in biochemical assessments. Except for (R)-THA, all DA analogues studied elicited dopaminomimetic behavioral activities of circling and sniffing. Relationships between the actions of these drugs in the behavioral and biochemical assessments are discussed.

The fetal alcohol syndrome is characterized by a number of abnormalities consisting of a pre- and post-natal growth deficiency, microcephaly, areas of abnormal nerve cell migration in the brain, mental and psychomotor retardation in children of alcoholic women. These findings may be referred as a teratogenic effect of ethanol on the central nervous system. In order to investigate the above ethanol-neurotoxic effect the striatal dopaminergic transmission was studied. The dopaminergic turnover was measured by 3,4-dihyroxyphenilacetic acid content and 3H-Spiperone binding has been carried out to determine dopaminergic receptor alterations induced by chronic ethanol consumption during pregnancy. Our work demonstrates long-lasting modifications of dopaminergic neuronal function after exposure of the experimental animal to ethanol during fetal life. In particular, a decreased receptor function has been observed in rats exposed to ethanol only during the perinatal period. In the same group of rats, diminished receptor activity leads to an enhancement in DOPAC content still detectable after a long period from cessation of ethanol treatment. Neurochemical data are reinforced by behavioral observations. In fact, a significant decrease of spontaneous locomotor activity in the rats chronically treated with ethanol during fetal life was observed. In addition, the altered response of locomotor activity after drug administration may be ascribed to the modified dopaminergic function. With this experimental approach we assume that the action of ethanol on the central nervous system may be a marker of its teratogenic effect.

Rats showing reliable decrements in conditioned avoidance behavior after the intraventricular administration of 6-hydroxdopamine (6-HD) with pargyline pretreatment were given various dopaminergic and noradrenergic agonists. Intraventricular injections of DA or L-NE or intraperitoneal injections of apomorphine or L-DOPA reversed the avoidance decrements, often restoring performance to pre-6-HD-treatment levels. Furthermore, these agonists all produced behavior characteristic of activity in dopaminergic neurons. Clonidine, a noradrenergic agonist, also reversed avoidance decrements, but did not produce behavior characteristic of stimulation of dopaminergic neurons in the brain. Pretreatment with spiroperidol, a dopaminergic receptor blocker, prevented the recovery induced by all agonists, although clonidine-induced recovery was affected least. The results are discussed in terms of possible separate roles for dopaminergic and noradrenergic neurons in the brain in avoidance behavior.

We have previously confirmed in mice that apomorphine (APO) induces dopamine specific stereotypic cage climbing. Apparent changes in dopamine receptor sensitivity induced by chronic drug administration appear to be measurable by this technique. In the present experiments, murine stereotypic cage climbing was evauated as a model system for assessing the dopamine receptor supersensitivity induced by chronic administration of the potent butyrophenone neuroleptic spiroperidol. Spiroperidol induced a significantly enhanced response induced by APO (about a 7-fold increase) manifest by 48 hr (but not 24 hr) following cessation of the last chronic injection. Time-response analyses demonstrated that the action of test doses of APO (1.0 or 4.5 mg/kg, IP) was significantly prolonged in the chronic-spiroperidol animals relative to controls. The supersensitivity in the spiroperidol-treated animals lasted more than three weeks for each dose of the neuroleptic and the APO dose-response curve was shifted to the left in spiroperidol-treated animals. Results are discussed in terms of the utility of the model for establishing dose-response, time-course, and duration of effect data within the same group of animals.

The possible participation of D1 versus D2 dopamine receptors in mediating dopaminergic neurotransmission of self-stimulation (SS) in the medial prefrontal cortex (MPC) of the rat was studied neuropharmacologically. Intracerebral as well as intraperitoneal injections of agonists and antagonists of dopamine receptors were used in this study. In all experiments performed with systemic injections, spontaneous motor activity (SM) was measured parallel to self-stimulation behavior as control for non specific effects of the drugs. Intracranial injections were done unilaterally serving SS of the contralateral side (not injected or injected with 0.9% NaCl) as control in the same animals. Spiroperidol and pimozide were used as D1-D2 dopamine antagonists, while sulpiride was used as a specific D2 antagonist. Apomorphine was used as D1-D2 agonist, while bromocriptine and lergotrile were used at doses in which these ergot drugs are considered predominantly D2 agonists. Sulpiride, intraperitoneally or intracerebrally injected at the same locus at which the stimulating electrode was located produced no effect on SS. On the contrary, the D1-D2 antagonists, spiroperidol and pimozide intraperitoneally or intracerebrally injected produced a dose-dependent decrease on SS. On the basis of these data it is suggested, that the dopamine neurotransmission involved in SS of the MPC is mediated via D1 dopamine receptors. This suggestion is further emphasized by the results obtained with the agonists, apomorphine, bromocriptine and lergotrile. Apomorphine produced a dose-related decrease on SS and a decrease at lower doses and an increase at higher doses on SM. Bromocriptine and lergotrile had, on the contrary, no effect on SS and a dose-related decrease on SM.

Metoclopramide is a widely used anti-emetic drug with potent dopamine-blocking effects on brain structures involved in emesis and prolactin secretion but it is apparently devoid of therapeutic effect in schizophrenia, thus calling into question the supposed role of dopamine blockade in the action of antischizophrenic drugs. This investigation compared the depression of hypothalamic self-stimulation produced by metoclopramide and by a 'typical' neuroleptic, spiroperidol (spiperone), when injected by different routes. Metoclopramide was found to9 be nearly 30 times more potent when administered directly into the brain via the cerebral ventricles than when injected intraperitoneally; on the other hand the potency of spiroperidol was virtually unaffected by the route of administration. The blood-brain barrier is known to be absent from brain sites controlling emesis and prolactin secretion; thus the potency of metoclopramide as an anti-emetic and in releasing prolactin, and its relative ineffectiveness as an antipsychotic can be accounted for by a failure to enter the brain freely except at privileged sites. Thus its anomalous properties are not necessarily inconsistent with the dopamine theory of schizophrenia.

Bilateral lesions of the locus coeruleus (LC) markedly increased susceptibility to the cateleptogenic effects of neuroleptics. The apomorphine-induced stereotypy was enhanced in rats with lesioned LC whilst amphetamine stereotypy was only slightly increased. No changes in locomotor activity have been observed in LC-lesioned rats treated with apomorphine and amphetamine. This data indicates that lesions of the LC produce decreased activity of dopaminergic brain neurons as well as supersensitivity of dopaminergic receptors.

Administration of L-5-hydroxytryptophan (25 mg/kg body weight, SC) to female rats resulted in copious drinking. The dipsogenic response to administration of L-5-hydroxytryptophan (5-HTP) was blocked by propranolol (6 mg/kg body weight, IP), a beta-adrenergic antagonist, and captopril (35 mg/kg body weight, IP), an angiotensin converting enzyme inhibitor. In addition, clonidine (12.5 and 25 microgram/kg body weight, IP), a central alpha-adrenergic agonist known to inhibit renin release, attenuated drinking during 1, 2 and 3 hours after 5-HTP was administered. These results suggest that 5-HTP-induced drinking is mediated by way of the renin-angiotensin system. Haloperidol (150 microgram/kg body weight, IP), a dopaminergic antagonist, also attenuated the dipsogenic response to administration of 5-HTP. In addition, incremental reductions in 5-HTP-induced drinking with increasing doses of spiperone (37.5 to 150 microgram/kg body weight, IP), a more potent dopaminergic antagonist, were demonstrated. Thus, the dipsogenic response to administration of 5-HTP to rats is dependent on both the renin-angiotensin system and an intact dopaminergic pathway.

The peripheral administration of the serotonin type 2 receptor (5-HT2) antagonist pirenperone inhibited sexual receptivity in ovariectomized female rats primed either chronically with estradiol benzoate (EB), or acutely with EB plus varying doses of progesterone. An inhibition occurred at 50, 100 and 150 but not 25 micrograms/kg pirenperone. Increasing the dose of progesterone did not attenuate the inhibitory effect of pirenperone. Two other 5-HT2 antagonists, ketanserin (2.5 mg/kg) and spiperone (250 micrograms/kg), also inhibited receptivity in females primed with EB and progesterone. The inhibitory effect of pirenperone on receptivity was attenuated by the 5-HT agonist quipazine (3 mg/kg), though quipazine alone had no effect on receptivity. Whereas the 5-HT antagonist methysergide (3 mg/kg) failed to have an effect on receptivity in EB-primed females, methysergide co-administered with quipazine facilitated receptivity. Pirenperone also inhibited proceptivity in females primed with EB and progesterone. Although quipazine did not attenuate the pirenperone-induced inhibition of proceptivity, quipazine alone increased proceptivity. Moreover, quipazine facilitated proceptivity in EB-primed rats whether progesterone was present or absent. The results suggest that 5-HT may serve both a facilitatory and inhibitory role in female sexual behavior, perhaps reflecting 5-HT2 and 5-HT1 receptor activity, respectively.

The range of central dopaminergic mechanisms involved in both d-amphetamine- and pilocarpine-induced head-shaking was studied in 7--9 days old rats by means of two DA antagonists: pimozide and spiroperidol. Both blocking agents exert their effects on H--S following dose-response curves which are similar, whatever the drug used to evoke head-shaking. A complete blocking effect on H--S is reached with pimozide at a dose of 2 mg kg-1; with spiroperidol at 0.1 mg kg-1 (for pilocarpine-induced H--S) and at 0.2 mg kg-1 (for H--S evoked by d-amphetamine). These results, together with those previously reported, suggest that dopaminergic and cholinergic facilitatory influences on H--S seem to be organized in series.