Key pecking of 4 pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixed-ratio schedule of food presentation. Only one schedule was in effect during an experimental session, and each was correlated with a different keylight stimulus and location (left vs. right). The different schedule components alternated across days or weeks. Cerebrospinal fluid was collected from chronically implanted intracerebroventricular cannulae following sessions with the different schedules, as well as following sessions in which reinforcement was withheld (extinction), when response-independent food was delivered, and when the experimental chamber was dark and there were no scheduled events. Metabolites of the neurotransmitters serotonin, norepinephrine, and dopamine were assayed in cerebrospinal fluid using high-performance liquid chromatography with electrochemical detection. Compared to the fixed-ratio condition, responding maintained under the fixed-interval schedule resulted in consistently higher levels of the serotonin metabolite 5-hydroxyindoleacetic acid and of the dopamine metabolite homovanillic acid in all pigeons. Levels of 3-methoxy-4-hydroxyphenylethylene glycol, a metabolite of norepinephrine, and dihydroxyphenylacetic acid, another dopamine metabolite, were also higher in 3 of the 4 pigeons following exposure to the fixed-interval schedules when compared to levels of these metabolites after exposure to the fixed-ratio schedule. Extinction of fixed-ratio responding resulted in large increases in 5-hydroxyindoleacetic acid compared to levels of this metabolite under the fixed-ratio schedule, whereas this serotonin metabolite decreased during extinction of responding under the fixed-interval schedule. Control procedures suggested that the neurochemical changes were not related to the rate of responding but were a function of the specific experimental conditions. Distinctive neurochemical changes that accompany schedule-controlled responding show the sensitivity of the neurochemical environment to behavioral contingencies and demonstrate further the profound impact that such contingencies have on biobehavioral processes.

The effects of three amphetamine analogs were assessed in pigeons key pecking under a multiple 3-min fixed-interval (FI), 30 response fixed-ratio (FR) schedule of food presentation. At doses between 0.1 and 10.0 mg/kg, (±) 3,4-methylenedioxyamphetamine (MDA), (±) 3,4-methylenedioxymethamphetamine (MDMA), and (±)-N-ethyl-3,4-methylenedioxyamphetamine (MDE) either had no effect or decreased response rates in both components of the multiple schedule in a dose-dependent manner. MDA was at least 1 log unit more potent than the other two compounds. Metergoline (0.1–1.0 mg/kg), a serotonin (5-HT) antagonist with comparable affinity for the 5-HT1 and 5-HT2 receptor subtypes, blocked the rate-decreasing effects of 3.0 mg/kg MDA in both components of the multiple schedule, but did not affect the MDMA dose-response curve. The 5-HT2 receptor antagonist ketanserin (0.1–3.0 mg/kg) also restored FI and FR responding that was decreased by 3.0 mg/kg MDA, but had no effect on responding suppressed by MDMA. The noradrenergic alpha-1 antagonist prazosin (0.3–3.0 mg/kg) blocked the behavioral effects of 3.0 mg/kg MDMA at doses that did not attenuate MDA's rate-decreasing effects. These results indicate that although MDA and MDMA are structurally similar and have similar behavioral effects, their actions appear to be mediated through different neurotransmitter systems.

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock (“conflict” procedure). Under the multiple schedule, spiroxatrine (0.3–1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01–1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.

The new phenylpiperazine derivative flesinoxan, a potent and selective serotonin(1A) (5-HT(1A)) agonist, was examined under a procedure that has proved to be a reliable and sensitive method for detecting novel anxiolytic drugs believed to produce their effects at the 5-HT( 1A) receptor subtype. Key pecking by pigeons was maintained by the presentation of food following every 30th response in the presence of a white keylight; during an alternate component, correlated with a red keylight, every 30th response produced food and electric shock which suppressed responding (punishment). Flesinoxan doses from 0.001 to 0.3 mg/ kg, intramuscularly, produced significant increases in punished responding at doses that did not affect unpunished responding. Doses of flesinoxan between 1.0 and 3.0 mg/kg also increased punished responding but produced decreases in responding that was not punished. In a second study flesinoxan substituted for the 5-HT(1A) anxiolytic buspirone under a drug discrimination procedure, providing further evidence that the behavioural effects offlesinoxan are mediated by 5-HT(1A) mechanisms. Based on these findings, it would appear that flesinoxan should be a useful compound in the clinical management of anxiety.

Behavioral and neurochemical effects of several drugs that increase punished responding were studied in pigeons. Key pecking was established under a schedule of reinforcement in which periods of food-maintained responding alternated with periods in which behavior also was suppressed by the presentation of electric shock. Buspirone (0.1-10.0 mg/kg), gepirone (0.1-1.0 mg/kg), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1-3.0 mg/kg), chlordiazepoxide (3.0-30.0 mg/kg) and to a lesser extent clozapine (0.1-1.0 mg/kg) all produced increases in punished responding at doses having little effect on or decreasing the rate of unpunished responding. Neurochemical analyses on samples of cerebrospinal fluid after administration of several doses of each compound were performed for the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), the noradrenergic metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). Gepirone, 8-OH-DPAT and the novel anxiolytic buspirone produced decreases in 5-HIAA at doses that increased punished responding in the behavioral studies. Buspirone increased levels of HVA and DOPAC, whereas its structural analog gepirone and the 5-hydroxytryptamine1A agonist 8-OH-DPAT had little effect on or decreased levels of these metabolites. Chlordiazepoxide, a prototypic benzodiazepine anxiolytic, produced only modest decreases in each of the metabolites studied. Clozapine, an atypical antipsychotic drug, produced increases in each of the metabolites studied, although only the 5-HIAA effect occurred at doses that were not behaviorally disruptive. Haloperidol (0.03-1.0 mg/kg) produced only decreases in punished and unpunished responding, whereas eliciting increases in the appearance of MHPG, DOPAC and HVA; levels of 5-HIAA were relatively unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)