Punishing and cardiovascular effects of intravenous histamine in rats: pharmacological selectivity

Although drugs may serve as reinforcers or punishers of operant behavior, the punishing function has received much less experimental attention than the reinforcing function. A sensitive method for studying drug-induced punishment is to assess choice for a punished response over an unpunished response. In these experiments, rats chose between pressing one lever and receiving a sucrose pellet or pressing another lever and receiving a sucrose pellet plus an intravenous injection of histamine. When sucrose was delivered equally frequently for either the punished or the unpunished response, rats selected the unpunished lever consistently, but decreases in the punished response did not differ as a function of intravenous histamine dose (0.1-1 mg/kg/inj). Changing the procedure so that sucrose was delivered on the unpunished lever with p = .5 increased the rats' responding on the punished lever with saline injections. In addition, the same range of histamine doses produced a much larger range of responses on the punished lever that was dose dependent. Using these procedures to assess the receptors mediating histamine's effects, the histamine H1 -receptor antagonists, pyrilamine and ketotifen, antagonized the punishing effect of histamine, but the histamine H2 -receptor antagonist ranitidine did not. However, ranitidine pretreatments reduced histamine-induced heart-rate increases to a greater extent than did the histamine H1 -receptor antagonists when administered at the same doses examined under conditions of histamine punishment. Overall, the present findings extend the general hypothesis that activation of histamine H1 -receptors mediates the punishing effects of histamine. They also introduce methods for rapidly assessing pharmacological mechanisms underlying drug-induced punishment.