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Cocaine inhibits the 5-HT2-mediated (+/-)-DOI-induced head-twitch response (HTR) in mice in a dose-dependent manner. In order to investigate the possible inhibitory mechanism(s) of cocaine on 5-HT2 receptor function, we studied the effects of the selective adrenergic alpha 2 receptor antagonist yohimbine and the beta-adrenergic/5-HT1 receptor antagonist alprenolol, and the 5-HT3 antagonist ICS 205-930 on the inhibitory action of cocaine on the (+/-)-DOI-induced HTR. Neither yohimbine (0.1 and 0.5 mg/kg) nor alprenolol (10 mg/kg) pretreatment had any significant effect on the (+/-)-DOI-induced HTR. However, both antagonists prevented the inhibitory effects of cocaine on the (+/-)-DOI-induced HTR. The 5-HT3 antagonist ICS 205-930 neither produced HTR nor decreased the (+/-)-DOI-induced HTR frequency. The present results suggest that cocaine inhibits 5-HT2 receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and thus indirectly stimulating the respective inhibitory adrenergic alpha 2 and serotonergic 5-HT1A receptors. Furthermore, cocaine's 5-HT3 antagonist properties appear not to play a role in the inhibition of head-twitch behavior.

In order to establish a functional role for the various populations of serotonin (5-HT) receptors, behavioral studies have been conducted over the past decade with serotonergic agonists and antagonists. And, although there is reason to believe that certain behavioral effects may be mediated via particular populations of 5-HT receptors, evidence now suggests that some serotonin-mediated behaviors may be modulated by the interaction of serotonergic agents at multiple subtypes of 5-HT receptors. The generality of these effects, and the exact mechanism(s) by which they occur, have yet to be elucidated. Nevertheless, over the past year, results from several different laboratories provide a growing recognition of this novel phenomenon.

Computer competition analysis of 3H-DHA (3H-dihydroalprenolol, a nonselective beta-adrenergic radioligand) binding in the presence of unlabeled metoprolol (a beta 1-selective antagonist) indicates the existence of both beta 1- and beta 2-adrenergic receptor subtypes in the rat placenta and confirms previous reports that both beta-adrenoceptors are present in adult rat cortex. In the fetal brain (20th day of gestation), however, only beta 1-receptors were detected. Pregnant rats were chronically exposed to methadone from day 7 to day 20 of gestation via implanted osmotic minipumps (6.3-9.0 mg/kg/day). This treatment schedule did not induce a change in the affinity and density of either beta-receptor subtype in the placental, fetal and maternal brain homogenates. The results are discussed in terms of the reported monoaminergic and opiate receptor functional interactions.

Mice were injected once daily for 13 days with (+/-)-DOI ((+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and the induced head-twitch response (HTR) was scored. On days 2-5 HTR was reduced to less than 50% of day 1, and then returned to control levels by day 13. Challenge doses of (+/-)-DOI administered on days 15, 17 or 19 elicited significantly exaggerated responses. Thus, chronic treatment with (+/-)-DOI may cause an initial down-regulation followed by an up-regulation of 5-HT2 receptor function after cessation of such treatment.

(+/-) 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)-DOI], a phenylisopropylamine hallucinogen, is a 5-HT2-receptor agonist. The drug induced a dose-dependent increase in ear-scratch response (ESR) in mice, and the R(-)-isomer was more than 6 times as potent as its S(+)-enantiomer. The induced behavior was potently inhibited by selective 5-HT2-receptor antagonists such as ketanserin and spiperone. The (+/-)-DOI-induced ESR is also inhibited by stimulation of 5-HT1-receptors and the inhibition seems to be through a 5-HT1B-receptor mechanism. Thus, taken together, the present investigation indicates that ESR is due to selective stimulation of 5-HT2-receptors and that simultaneous costimulation of 5-HT1B-receptors inhibits the induced behavior. The study further suggests that the inability of the indolealkylamine hallucinogens to induce ESR is due to simultaneous excitation of 5-HT1B-receptors which are inhibitory to induction of ESR. Moreover, the data suggest possible inhibitory control mechanisms through 5-HT1-receptor subtypes to provide a damping mechanism to reduce excessive 5-HT2-receptor excitation due to exogenous drug stimulation or pathological conditions.

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 inhibitory effects of aminobeclamide (N-(p-aminobenzyl)-beta-chloropropionamide) on socially offensive behaviour has been studied and compared with those of the parent drug beclamide (N-benzyl-beta-chloropropionamide). Following oral administration in mice which had been individually housed for a 28 day period then paired with normal group-housed opponents, aminobeclamide and beclamide both produced significant and dose-related inhibition of socially offensive behaviour. Aminobeclamide (20-150 mg kg-1 p.o.) and beclamide (50-250 mg kg-1 p.o.) gave increased offense onset latency whilst at the same time they reduced the incidence of offense encounters/animal and decreased the group percentage of animals displaying offense behaviour. It is likely that both drugs have similar monoamine modifying effects though this animal study suggests that aminobeclamide is 1.5 to 2.7 times more potent than beclamide against socially offensive behaviour.

The purpose of the present study was to investigate the effects of acute and chronic cocaine administration on aggressive behaviour in mice. The animals were made more aggressive by individual housing for a period of 6 weeks. Group-housed anosmic conspecifics which were not aggressive were used as intruder controls. In acute studies, cocaine induced no significant change in aggressive behaviour at low doses (0.5-5 mg/kg) but significantly decreased aggressive behaviour after doses of 10 and 20 mg/kg. Cocaine increased the isolation-induced aggressive behaviour in mice when they were injected twice daily for a week with low doses of 0.5 or 1 mg/kg. In particular, the latency to first attack was significantly decreased by the drug and the frequency of attack towards the non-aggressive intruder was dramatically increased. Higher cocaine doses (10 or 20 mg/kg) under the described treatment regimen decreased these agonistic repertories. Tolerance did not develop to the anti-aggressive effects of high doses of cocaine on continued treatment.

Adenosine, theophylline and enprofylline induced concentration-dependent relaxations of guinea-pig isolated tracheal spirals whether they had intrinsic tone or were precontracted with carbachol or histamine. The potency order was enprofylline greater than theophylline greater than adenosine and the maximum relaxation in absolute terms was generally less for adenosine. The maximum relaxation (measured in absolute terms of change in tension) induced by the three spasmolytics in preparations with intrinsic tone was generally less than in precontracted tissues. This was attributed to the higher resting tone of precontracted tissues than the intrinsic tone. The adenosine transport inhibitor dipyridamole potentiated adenosine but not theophylline or enprofylline so that the potency order became adenosine greater than enprofylline greater than theophylline. Without dipyridamole, theophylline in a concentration producing 10-30% relaxation of the trachea, failed to antagonize adenosine. However, in the presence of dipyridamole, adenosine was antagonized, indicating that the relaxation by adenosine was mediated via an extracellular P1 receptor. Enprofylline, in a concentration producing equivalent direct effects, failed to antagonize adenosine. It is concluded that the tracheal relaxation by xanthines is independent of adenosine antagonism.

Following subchronic (5-day) dosing with B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo(4,5-d)azepine (1 mg kg-1 day-1 i.p.) in rats there was a significant increase in both apomorphine-induced motor activity and stereotypy. On continued B-HT 920 treatment, however, the enhancement of apomorphine motor activity faded into insignificance but the increase in stereotypy persisted beyond 15 days. The results are discussed in terms of dopamine autoreceptor tolerance, postsynaptic D2 supersensitivity and possible differential effects in different brain loci on the above two receptor sub-classes.

The anti-aggressive effects of orally administered beclamide (N-Benzyl-beta-chloropropionamide) have been studied in male albino mice which were individually isolated for a 28-day period. Beclamide (50-250 mg kg-1 p.o.) caused an overall dose-dependent increase in the attack onset latency, a reduction in the percentage of animals attacking and the mean number of attacks/animal for this model of aggression. In addition, the highest dose of beclamide (250 mg kg-1 p.o.) did not significantly modify locomotor activity in mice. It was concluded that beclamide induced anti-aggressive effects at non-sedative doses. This anti-aggressive action was thought be at least partially mediated, through a beclamide-induced release of 5-HT from presynaptic sites.