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Earlier observations have shown that septal lesions released operant responding punished by foot-shock, but did not change behavior punished by electrical stimulation of the dorsal periaqueductal gray (DPAG) substance of the rat brain. In contrast, chlordiazepoxide facilitated both kinds of punished responding. In order to further study the mechanism of brain stimulation punishment, dose-response curves of two minor tranquilizers, chlordiazepoxide and pentobarbital, of two tryptamine antagonists, methysergide and cyproheptadine as well as of amphetamine on lever-pressing behavior of rats maintained by water reinforcement and punished by DPAG stimulation were determined. A multiple schedule with a variable-interval 2 min (VI 2) non-punished component and a continuous reinforcement (CRF) component in which every response was both rewarded and punished was used. Chlordiazepoxide and pentobarbital caused dose-dependent increases in punished responding. Unpunished VI response rates were also moderately increased by the minor tranquilizers. In contrast, neither methysergide nor cyproheptadine increased punished or unpunished responding at doses that have been previously shown to markedly release behavior punished by foot-shock, in the rat. Conversely, amphetamine, a drug that usually does not release responding punished by peripheral noxious stimulation, caused dose-dependent increases in responding suppressed by DPAG punishment without affecting VI response rate. These and previous results with septal lesions suggest that neither the septo-hippocampal system nor its serotonergic input from the mesencephalon mediate response suppression by DPAG electrical stimulation, in contrast to their active role in peripheral punishment. This difference may also explain the marked facilitatory effect of amphetamine on responding punished by brain stimulation shown by the present results.

In order to investigate the role played by serotonergic mechanisms in self-stimulation (SS) behavior, the effects of two tryptamine antagonists, cyproheptadine and methysergide on SS were measured. Also the influence of antitryptaminic drug pre-treatment on the facilitatory effect of amphetamine, a pro-adrenergic drug, on SS was studied. Rats with brain electrodes permanently implanted at the lateral hypothalamus and trained to lever-press for response-contingent brain electric stimulus presentation were used. Stimulus current was maintained at threshold level. Both tryptamine antagonists used potentiated the enhancing effect of amphetamine on low SS rates, displacing to the left its dose-effect curve; cyproheptadine was at least three times more potent than methysergide. In addition, cyproheptadine, but not methysergide, caused dose-related increases in SS rate, when given alone. These results suggest that brain serotonergic systems play an inhibitory role in SS, opposing the facilitatory influence of adrenergic mechanisms.

1. A method for preparing the encéphale isolé preparation in young fowls is described. Certain important differences were found between electrocortical activity of chicken and mammalian encéphale isolé preparations. Electrocortical effects of excitant sympathomimetic amines and their antagonism were readily quantified because of stable electrocortical activity of the chick encéphale isolé preparation.2. Amphetamine-like excitant amines ((+)- and (-)-amphetamine, alpha-methyltryptamine, tryptamine, beta-phenethylamine, cyclopentamine, beta-tetrahydronaphthylamine and tuaminoheptane) evoked electrocortical desynchronization in chick encéphale isolé preparations, confirming the central origin of these effects. Behavioural changes were also observed.3. The electrocortical response to these amines was antagonized by methysergide, a selective tryptamine antagonist and by a catecholamine, alpha-methylnoradrenaline. Behavioural changes were also antagonized.4. Electrocortical desynchronization to dexamphetamine was prevented by an anterior transection of the brain which separated the telencephalon from the diencephalon. More posterior transections reduced the duration of the electrocortical response to dexamphetamine; intensity of response was either increased or decreased.