W.J. Lang

Self administration of nicotine with and without a food delivery schedule

Abstract Rats have been shown to self administer a range of narcotic drugs using self injection procedures. However, studies of self administration of nicotine have been less successful in inducing rates of self injection comparable to that with narcotics. In this study different methods of self administration of nicotine by naive rats are evaluated. In the three series of experiments reported, rats self injected nicotine or saline through the jugular vein under normal body weight and reduced body weight conditions and also when the inhections were adjunctive to a food delivery schedule. In a fourth series of experiments, oral intake of nicotine by rats under the condition of a food delivery schedule was investigated. The ratesof self injection of nicotine by rats over a continuous 90 hr session were similar to saline injection rates. At reduced body weight the rate of self injection of nicotine was greater than saline. On a fixed interval 60 sec food delivery schedule for two hr day, the rate of self injection of nicotine was significantly greater than the rate of self injection of saline under the same conditions and also signigicantly greater than that for nicotine injections at reduced body weight without the schedule. The oral intake of nicotine under the same conditions was similar to the intake of nicotine by schedule induced injections. Schedule induced self-injections provide a paradigm for testing drug and environmental interactions.

Cardiovascular responses to injections of cholinomimetic drugs into the cerebral ventricles of unanaesthetized dogs.

1 The cardiovascular and behavioural effects of cholinomimetic drugs injected through a cannula chronically implanted into a lateral cerebral ventricle were examined in unanaesthetized dogs. 2 Acetylcholine (ACh) (10–20 μg) produced an increase in arterial pressure and heart rate, the dogs became more alert, moved their heads, licked and swallowed and then became drowsy. 3 The responses to ACh were potentiated by intraventricular physostigmine (5 μg), were abolished by intraventricular atropine (100 μg) but were unaffected by intraventricular mecamylamine (250 μg). The responses to ACh were reproducible on any one day if injections were given again after a 30 min interval but tolerance developed when ACh was injected repeatedly over periods of several days. 4 Methacholine (40 μg) produced similar behavioural and cardiovascular effects to ACh but of a longer duration. The responses to methacholine were abolished by intraventricular atropine (100 μg). 5 Nicotine (20–60 μg) produced a biphasic cardiovascular response of an initial brief pressor response and tachycardia followed by a secondary increase in arterial pressure and heart rate which was greater in magnitude and duration. The secondary cardiovascular effects were associated with restlessness and vomiting. 6 The responses to nicotine were abolished by prior injection of mecamylamine (250 μg) but were unaffected by atropine (100 μg). The responses to nicotine were not reproducible if injections were repeated on the same day but could be again produced if a few days were allowed to elapse between injections. 7 An increased heart rate occurred during the pressor response to the cholinomimetic drugs but when a comparable pressor response was produced by intravenous infusion of noradrenaline in the same unanaesthetized dogs pronounced reflex bradycardia resulted. 8 The results indicate that the activation of both muscarinic and nicotinic cholinergic mechanisms leads to cardiovascular and behavioural effects in the conscious dog although the site of action and peripheral mechanisms have not been determined.

Pharmacological and biochemical properties of isomeric yohimbine alkaloids.

The stereochemical and pharmacological properties of yohimbine and some of its isomers are briefly reviewed. Several pharmacological and physical properties of a selection of the isomers have been determined with a view to elucidating which might be important in the elaboration of the known behavioral effects produced by them. Activity is not dependent upon lipid solubility or on the ease of access to the central nervous system. The isomers are weak inhibitors of rat-brain acetylcholinesterase and weak antagonists at muscarinic cholinergic receptors. In the rat brain in vitro they do not possess significant monoamine oxidase-inhibiting properties nor do they inhibit the uptake of serotonin. They are relatively potent antagonists of 5HT on the rat isolated fundus preparation and their potency in this preparation may be related to their ability to produce behavioral and cardiovascular effects in man and dogs.

Schedule induced self injections of nicotine with recovered body weight

In a recent series of experiments we have shown that high rates of self injection of nicotine were acquired when rats are at 80% body weight on an FT-1 min food delivery schedule. This rate was significantly higher than that of rats at reduced or normal body weight without food delivery schedules or that of rats injecting saline under three parallel control conditions. In the present experiment naive rats were trained to acquire nicotine self injection at 80% body weight with an FT-1 min food delivery schedule. These rats maintained their self injection rates after they were allowed to regain free feeding body weight. The data indicate that once nicotine intake behavior is established it can be maintained with changing nutritional factors.

The effects of bradykinin and eledoisin injected into the cerebral ventricles of conscious rats

Abstract Bradykinin and eledoisin produced a pressor response and behavioural excitation when injected into the cerebral ventricles of conscious rats. The pressor responses to both peptides were prevented by pretreatment of the rats with phentolamine, but not with propranolol. Pretreatment with morphine prevented the pressor response to bradykinin but not to eledoisin.

Centrally mediated cardiovascular and EEG responses to bradykinin and eledoisin

Abstract In anaesthetized cats, the intracarotid injection of bradykinin but not of eledoisin produced EEG desynchronization and a pronounced rise in blood pressure. In anaesthetized rats, injection of bradykinin or eledoisin directly into the cerebral ventricles produced EEG desynchronization and a biphasic cardiovascular response which was abolished by hexamethonium but not affected by atropine, indicating that the responses were due to a central action and suggesting that they did not involve cholinergic nerves. The initial fall in blood pressure was abolished by phentolamine suggesting that it was due to inhibition of sympathetic tone to peripheral resistance vessels; the secondary pressor phase was blocked by propranolol, suggesting it was due to stimulation of cardiac β-adrenoreceptors. The response to bradykinin was abolished completely by propranolol plus phentolamine but the depressor component of the response to eledoisin was enhanced by propranolol alone and by propranolol plus phentolamine, suggesting it has an additional action.

Vascular dopamine receptors in the canine hindlimb.

1 Increases in femoral blood flow were produced by intra‐arterial injections of dopamine (5–50 μg) in some but not all anaesthetized dogs studied, following treatment with the α‐adrenoceptor antagonist, phentolamine. 2 The dilator effect of dopamine was not due to inhibition of adrenergic vasomotor tone as it was not affected by pharmacological procedures which completely abolished the activity of vasomotor nerves. 3 Blockade of vascular β‐adrenoceptors using propranolol reduced the flow increases produced by dopamine much less than it did those produced by isoprenaline. 4 Responses to dopamine were significantly depressed by intra‐arterial administration of ergometrine (0.5 mg). This dose of ergometrine did not reduce femoral dilator responses to acetylcholine, histamine, isoprenaline, bradykinin or 5‐hydroxytryptamine. 5 It is concluded that the femoral vascular bed in the dog contains specific vasodilator receptors for dopamine. Ergometrine appears to be a selective antagonist of dopamine at these receptors.

Ergometrine and apomorphine as selective antagonists of dopamine in the canine renal vasculature.

1 Increases in renal blood flow were produced by intra‐arterial injections of dopamine (5–50 μg) in anaesthetized dogs pretreated with α‐ and β‐adrenoceptor antagonists. 2 Intra‐arterial administration of ergometrine (0.5 mg) or apomorphine (1 mg) produced a depression of the renal dilator responses to dopamine, without affecting renal dilatations in response to intra‐arterial acetylcholine (0.1–1 μg) or histamine (2–50 μg). 3 The depression of dopamine responses lasted 10–15 min, and was greater with ergometrine than with apomorphine. 4 It is concluded that both ergometrine and apomorphine can be used as specific blocking agents at vascular dopamine receptors. Ergometrine is the preferred drug for this purpose.

Effects of changing dosage and urinary pH in rats self-administering nicotine on a food delivery schedule

Abstract The effects of different available dosage and of acidic and alkaline urinary pH have been investigated on the rates of self-administration of nicotine by rats on an FT60 food delivery schedule. Different groups of rats initially received one of 3 doses of nicotine (0.05, 0.1 and 0.25 mg/kg/infusion) contingent upon bar-pressing. The self-administration rates during an initial 6-day period of the 3 groups of rats were significantly different from each other, 26.1 ± 3.2 SEM), 15.4 ± 1.5 and 9.5 ± 0.9 at doses of 0.05, 0.1 and 0.25 mg/kg/infusion, respectively. However, once the rates of responding were established during the initial period, no significant changes occured when the doses were changed in all 3 groups after each subsequent 6-day period. These rates of self-administration decreased when saline replaced the available nicotine solution after Day 18. The urinary pH of groups of rats was maintained alkaline (pH9.0), acidic (pH 5.9) or normal (pH 6.7) by allowing them to drink sodium bicarbonate solution, ammonium chloride solution or water, respectively. The self-administration rates during the initial periods of these 3 groups of rats were also significantly different from each other 4.7 ± 0.66, 17.0 ± 0.76 and 9.4 ± 1.11, respectively). In contrast, however, when the rates of responding were established at normal urinary pH during the initial period when water was available, no significant changes occurred when urinary pH was subsequently changed in either an acidic or alkaline direction. The results suggest that the bar-pressing rates are dependent on the amount of nicotine available or present in plasma during the acquisition phase. Nevertheless, once the rate of bar-pressing is established on a food delivery schedule, it seems that the schedule exerts too powerful an effect on behavior for subsequent changes in nicotine levels to modify responding over the period of these experiments.

Changes occurring in self administration of nicotine by rats over a 28-day period

After rats at reduced body weight had established responding by lever pressing for nicotine injections under a food delivery schedule (FT60 sec) for 1 hr daily sessions for 14 days, the rate of responding was maintained over a second 14-day period even after removal of the schedule. However, the rate was not maintained by rats lever pressing for normal saline without the schedule over the second 14-day period after self administration had been established for nicotine under the schedule. Other rats maintained at reduced body weight were allowed to lever press for nicotine over a 28-day period without the food delivery schedule. Their rate of self administration increased from initially low levels until at the end of the 28-day period the rate had reached that of rats self administering nicotine adjunctive to the food delivery schedule throughout the same period. Without the schedule, rats at reduced body weight self administering normal saline or rats at normal body weight self administering nicotine, continued to lever press only at very low rates throughout the 280-day period. It is suggested that rats maintain self administration of nicotine if the behavior can be established for a critical intake of nicotine over a critical period of time. The food delivery schedule appears only to hasten the establishment of the behavior but is not essential for self administration of nicotine by rats.