Showing papers in "Pharmacology, Biochemistry and Behavior in 1973"

Criteria for an animal model of alcoholism.

Abstract: A correspondence between the various components of human alcoholism and their animal analogue has not yet been achieved; in some part, this failure resides with experimental attempts which obtain which obtain only surface equivalencies and which lack an underlying motivational structure. Seven criteria for an animal model are proposed including the oral ingestion of alcohol without food deprivation, substantial ingestion of alcohol with competing fluids available, drinking directed to the intoxicating effect of alcohol, the performance of work to obtain alcohol, the maintenance of intoxication over a long period and, finally, the production of physical dependence and, on withdrawal, the abstinence syndrome.

A review of methods to induce alcohol addiction in animals.

Abstract: Since alcoholism has been shown to be a form of addiction, there has been increasing attention to the development of an animal model of alcoholism. Within the past five years, several techniques have been developed to produce physical dependence upon alcohol in a number of species. This review presents a summary and evaluation of the various approaches used and a discussion of the relative merits of the behavioral (self-administration) and pharmacological (forced administration) models. Several questions are raised concerning the relationship between physical dependence and subsequent self-administration of alcohol. It is concluded that although it has been possible to produce physical dependence upon alcohol in animals, the critical determinants of the addictive process are still unknown.

Conditioned drug effects and absence of tolerance to d-amphetamine induced motor activity

Abstract: Tolerance development to d-amphetamine induced motor motor activity was studied under various experimental conditions. Following seven daily habituation sessions, female, albino rats were subjected to 7 daily sessions in which NaCl was injected IP 30 min before placement into activity cages (NaCl controls). In the next 9 days, the rats underwent 3 drug sessions, each separated by 2 NaCl controls, in which d-amphetamine (0.5, 10. or 1.7 mg/kg) was likewise injected before placement. A course of repeated drug administration followed for the next 14 days. One group of rats was injected with the drug 30 min before placement into the activity cage, a second group received the drug 30 min after each session as a control for conditioned activity effects, while a third group received NaCl. On the fifteenth day, all rats recieved d-aphetamine 30 min before placement as a test for tolerance development. This session was followed the next day by a test for conditioned motor effects in which NaCl was injected IP 30 min before the session. Dose related increases in motor activity were observed during the drug control sessions. The magnitude of the drug effect did not decrease following any of the conditions during the course of repeated drug administration. Animals repeatedly injected with the drug 30 min after or with NaCl 30 min before each session were affected by d-amphetamine approximately the same as they were before repeated injections. Rats administered d-amphetamine 30 min before sessions during the course of repeated injections showed an enhanced response to d-amphetamine during the test for tolerance. The magnitude of the change was related to the magnitude of the conditioned motor activity response. These experiments emphasize the importance of learned or conditioned variables that may result from repeated drug administration in conjunction with behavioral tests.

A comparison of d-aphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys

Abstract: Rhesus monkeys were trained to self-administer cocaine on a fixed-ratio 10 schedule of reinforcement during a daily 3 hr session. d-amphetamine, l-amphetamine, and methamphetamine, at various dosages, were substituted for the cocaine for six consecutive sessions. The animals were returned to cocaine baseline between each test series. All three drugs were self-administered at rates higher than saline control levels. d-Amphetamine and metamphetamine were equipotent in maintaining self-administration behavior and both were approximately 4 times more potent than l-amphetamine.

Neurochemical mediation of reward: a significant role for dopamine?

Abstract: Intraventricular injection of 6-hydroxydopamine resulted in only a temporary decrement of self-stimulation. Treatment with the alpha-adrenergic receptor blocking agent, phentolamine, had virtually no effect on self-stimulation in either 6-hydroxydopamine treated or normal rats; whereas haloperidol, a dopamine receptor blocking agent, markedly reduced self-stimulation in normal rats. Treatment with FLA-63, a potent inhibitor of dopamine-beta-hydroxylase, had no effect on self-stimulation but very significantly reduced eating. These results imply that dopamine may be importantly involved in the mediation of positive reinforcement and/or that the role of norepinephrine may be a minor one.

The pharmacology of seizures induced by sensitization with low intensity brain stimulation.

Abstract: Daily low-intensity electrical stimulation of selected brain sites causes seizures to gradually develop. Because the limbic area is particularly susceptible to both the sensitization phenomenon and psychotropic drugs, we evaluated several classes of centrally-active agents for activity against these seizures. For comparative purposes, seizures elicited from the amygdala and a nonlimbic site, the sensorimotor cortex, were tested. Rats with chronically-implanted electrodes were stimulated for one min each day with a 50-μA, 60-Hz current. Initially, no overt effects occurred; but eventually seizures wereestablished. Once the seizures stabilized, drug effects on seizure duration were measured. Antidepressive drugs were more potent in suppressing amygdaloid-elicited seizures than cortically-evoked seizures. Both antianxiety and antiepileptic drugs exerted nonselective blockade but the antianxiety agents were extremely potent in comparison to the antiepileptics. Representative neuroleptic drugs failed to block the seizures, even at doses completely debilitating the animals. Stimulants prolonged the seizures but the activity was weak. Thus, the low-intensity brain stimulation (LIBS) procedure has proved to be not only an interesting phenomenon, but one that responds differentially to various classes of CNS drugs.

Attenuated habituation due to parachlorophenylalanine

Abstract: The effect of parachlorophenylalanine (PCPA), and the presumed depletion of serotonin due to it, was studied for its effect on the habituation of a startle response in rats. Parachlorophenylalanine was found to increase overall levels of startle amplitude. Detailed examination of the data from individual animals indicated that this effect was entirely due to an attenuation of the rate of habituation.

Muricide after serotonin depleting lesions of midbrain raphé nuclei.

Abstract: Thirty days after dorsal and median raphe lesions, when the forebrain content of serotonin (5-HT) was approximately 70 per cent below normal values, lesioned rats showed increased frequency and decreased latency for lethal attacks on mice Additional observations of muricide on Days 2, 5, 8, and 30 after lesions revealed that frequency and latency of killing increased and decreased, respectively, over time Since the time-course of this muricide paralleled a progressive reduction of forebrain 5-HT, these data suggest that this neurohumor normally participates in mechanisms exerting inhibitory control over mouse killing

Aminergic influences on intravenous cocaine self-administration by Rhesus monkeys.

Abstract: Earlier observations have demonstrated that when allowed limited daily access to cocaine, monkeys self-administer approximately the same amount of cocaine daily. Treatment with neuroleptic agents increases the frequency of this behavior which could be interpreted as resulting from an antagonism of the reinforcing actions of cocaine. The present paper demonstrates that agents known to alter central aminergic systems affect cocaine self-administration. Acute treatment with pargyline (50 and 100 mg/kg) decreased the behavior; DL alpha-methylparatyrosine (50 mg/kg) increased the behavior. Treatment with the peripheral alpha adrenergic blocking agents phentolamine and phenoxybenzamine (0.5 – 8.0 mg/kg) did not significantly alter the behavior. Chronic treatment (5–10 days) with reserpine (0.1 – 1.0 mg/kg) produced an initial increase in self-administration to which tolerance developed. Upon discontinuation of reserpine treatment, cocaine self-administration was decreased below baseline levels. Results tend to implicate either dopamine or norepinephrine as mediators of either cocaine-based reinforcement or of the other effects of cocaine which may regulate the frequency of its administration. Results were discussed in relation to those obtained from clinical studies in which drug effects on amphetamine-induced euphoria were ascertained.

Effects of para-chlorophenylalanine and 5-hydroxytryptophan on alcohol intake in the rat

Abstract: Para-chlorophenylalanine, the tryptophan hydroxylase inhibitor that depletes serotonin selectively, increased alcohol intake in rats. 5-Hydroxytryptophan, the serotonin percursor, reduced alcohol intake. These findings suggest that alcohol preference in the rat may be related to the brain tryptaminirgic system.

Effects of scopolamine, amphetamine and benzodiazepines on conditioned suppression☆

Abstract: Conditioned suppression of operant behavior was produced by preshock stimuli (i.e., stimuli that precede the noncontigent presentation of electric shock), or prereward stimuli (i.e., stimuli that precede the noncontingent presentation of food) in rats and squirrel monkeys responding on a variable interval schedule of food reinforcement. Benzodiazepine derivatives and amphetamine differentially affect conditioned reactions which are elicited by preshock and prereward stimuli. Conditioned suppression to prereward stimuli were unaffected by chlordiazepoxide, diazepam, scopolamine hydrobromide and scopolamine methyl nitrate but clearly reduced by amphetamine. On the other hand, chlordiazepoxide attenuated the conditioned suppression to preshock stimuli whereas amphetamine, scopolamine hydrobromide and scopolamine methyl nitrate had no significant effects in this paradigm. The results suggest that the effects of drugs on conditioned suppression cannot be interpreted, a priori , in terms of selective effects on mechanisms related to emotional behavior or inhibition.

Alterations in consummatory behavior following intracisternal injection of 6-hydroxydopamine.

Abstract: Intracisternal administration of two doses of 6-hydroxydopamine, one with pargyline pretreatment and one without, caused an initial disruption of consummatory behavior. In spite of measures to enhance recovery from these acute effects, 6-hydroxydopamine treated rats were found to maintain body weight at a lower level than control rats. Similar to controls, treated animals were found to drink water in the absence of food and to enhance water consumption in response to the administration of a hypertonic saline solution. However, unlike control rats, animals treated with 6-hydroxydopamine failed to increase food intake following insulin administration. Desoxycorticosterone acetate (DOCA) treatment enhanced saline preference in 6-hydroxydopamine treated rats, but the maximum volume of saline consumed was markedly less than the intake of control rats following DOCA treatment. While control rats drank a large volume of either a sucrose or a saline solution when substituted for water, 6-hydroxydopamine treated animals showed little increase in their intake of these solutions. Preferential deplition of norepinephine in brain did not alter consumption of a sucrose solution; however, depletion of dopamine produced a significant reduction in sucrose intake. These latter findings suggest that this deficit observed in the 6-hydroxydopamine treated rat involves interruption of dopaminergic pathways.

Alcohol withdrawal syndrome in rats: neural and behavioral correlates.

Abstract: Rats were chronically implanted with electrodes in the ventral hippocampus, amygdala and anterior cortex and maintained on liquid diets as their only source of calories and fluid for 15 days. The diet consisted of 35–40% of the calories in the form of ethanol while a control group was pair-fed identical diets with sucrose isocalorically substituted for ethanol. On the sixteenth day the diets were removed and electrographic activity and behavior were simulataneously observed for 8–10 hr. Withdrawal symptoms were observed beginning 2–4 hr following alcohol abstinence and included tail-stiffening, tremors, severe ataxia and auditory-induced convulsions. EEG epileptiform activity was observed and initially consisted of transient spike events, which usually became progressively organized into brief spike burst sor sustained paroxysmal activity. The results suggested that cortical bioelecric activity may not play a primary role in the genesis of behavioral hyperexcitability during alcohol withdrawal. The utility of the method of combined observations of neural bioelectric activity and behavior for the delineation of the neural substrates of alcohol withdrawal symptoms was discussed.

Performance influence on the development of tolerance to amphetamine.

Abstract: This experiment was performed to determine whether performance of a behavior in the drug state was necessary for behavioral tolerance to the effects of that drug to occur. Eight rats trained on a DRL 17.5-sec schedule received daily injections of 1.5 mg/kg d-amphetamine sulfate; four received amphetamine 30 min presession, and four received amphetamine 30 min postsession. Amphetamine given presession initially resulted in a disruption of timing behavior, an increase in response rate, an increase in short IRTs and a decrease in the number of reinforcements received. With continued administration of presession amphetamine the rats developed a partial tolerance to these disruptive effects. Postsession amphetamine had no effect on performance. When tolerance developed in rats receiving presession amphetamine, they were switched to postsession amphetamine; rats receiving postsession amphetamine were switched to presession amphetamine. Amphetamine produced the same disruption of performance in the rats switched to presession amphetamine as was observed in the initial pressession amphetamine group, indicating that tolerance did not develop to amphetamine given postsession. In addition changes in the pattern of responding were observed when amphetamine was initially administered presession.

Effects of angiotensin II on central neurons

Abstract: Effects of angiotensin II administered intravenously and by means of electrophoresis through multibarrel micropipette electrodes on the frequency of extracellularly recorded action potentials of brain cells were determined. A total of 293 neurons in seven different parts of the brains of male and female hooded rats anesthetized with urethan or a mixture of urethan and chloralose were tested. Results indicate that angiotensin affects many different cells within the lateral hypothalmus, zona incerta, ventromedial and dorsomedial hypothalamic nuclei, dentate gyrus and thalamus. The cells of the LH and zona incerta are the most sensitive to angiotensin and two types of lateral hypothalamic neurons were found which were affected differently by angiotensin and stimulation of the basolateral amygdaloid nucleus. Some of the Na sensitive neurons, all of which were sensitive to angiotensin, displayed a very pronounced potentiation of discharge frequency when angiotensin and Na were administered simultaneously. Angiotensin II might therefore influence drinking because of a relatively low threshold effect on hypothalamic neurons.

Evidence for ascending noradrenergic mediation of hypothalamic hyperphagia.

Abstract: Rats sustaining unilateral ablation of the ventral ascending noradrenergic bundle, in combination with a contralateral parasagittal knife cut rostrolateral to the ventromedial nucleus of the hypothalamus (VMN), became obese. Ablation of the ventral noradrenergic (NA) bundle was effective at both mammillary and midbrain levels. The weight gains produced by this asymmetrical technique were comparable to those obtained following bilateral parasagittal knife cuts. Rats with unilateral mammillary lesions that spared the ventral NA bundle or unilateral midbrain lesions which only partially destroyed the ventral NA bundle, in combination with the contralateral parasagittal knife cut, did not become obese. The neural substrate damaged in the production of hypothalamic hyperphagia thus appears to be that part of the ascending ventral NA bundle which projects medially through the effective parasagittal knife cut locus rostrolateral to the VMN.

Induction of rage in rats by central injection of 6-hydroxydopamine

Abstract: Intracisternal injection of 300 μg of 6-hydroxydopamine in male rats elicited a syndrome of hyperreactivity or hyperemotionality, i.e., rage, similar to that previously reported after septal or ventromedial hypothalamic (VMH) lesions. Specifically, rats showed increased resistance to capture as well as increased number and magnitude of startle responses compared to vehicle injected or normal controls. As with septal but not VMH lesions, this rage subsided with repeated testings (handling). These findings are discussed with regard to the possible importance of brain neurotransmitters in the expression of behaviors.

Phencyclidine self-administration in the rhesus monkey

Abstract: Two experiments were performed in which rhesus monkeys self-administered phencyclidine through indwelling venous catheters. In the first experiment, monkeys trained to lever press for cocaine injections, maintained higher response rates as compared to saline control rates when phencyclidine at unit doses from1.5−25.0 μg/kg were substituted for the cocaine baseline. In the second experiment, experimentally naive monkeys spontaneously initiated lever-pressing for injections of 50 μg/kg/inj phencyclidine. In both studies the animals self-administered enough drug to produce behavioral effects resembling general anesthesia.

Alkali metal cations: Effects on aggression and adrenal enzymes

Abstract: Alkali metal cations (lithium, sodium, potassium, rubidium and cesium) were given to rats on a chronic large dose schedule. Lithium depressed shock induced fighting, while potassium and rubidium facilitated this aggression. After chronic high doses of the alkali cations, all groups except the sodium treated group showed an elevation of the adrenal enzymes, tyrosine hydroxylase and phenylethanolamine-N-methyl transferase (PNMT).

Learning deficits in lead-injected rats☆

Abstract: Weanling and adult rats injected with one of three concentrations of lead acetate for 37 days failed to demonstrate any learning impairments as measured by a Hebb-Williams maze series relative to water injected controls. Rats at the highest dose level showed clear symptoms of lead poisoning. Pregnant females injected during pregnancy with an asymptomatic dose of lead acetate showed a 100% abortion rate, while 75% of water injected controls delivered litters. Rats whose mothers were injected with asymptomatic doses of lead acetate throughout nursing developed more slowly, weighed less, and demonstrated learning deficits relative to controls. The behavioral and physiological effects of lead may be greatest during the earliest developmental stages.

Long-term aversion to a saccharin solution induced by repeated amphetamine injections.

Abstract: In rats repeated 2 mg/kg injections of d -amphetamine given 30 min after imbibition of a 0.1% saccharin solution proved to be as effective in reducing saccharin intake as 2 mg/kg injections of d -amphetamine given 30 min before presentation of this saccharin solution. Treatment with alpha-methyl-para-tyrosine blocked the effect on saccharin intake of amphetamine given before, but not amphetamine given after presentation of the saccharin. After amphetamine injections were terminated, subsequent saccharin vs. water preference testing showed that the amphetamine injections given after but not the injections given before resulted in a long-term aversion to the saccharin solution. In a second experiment, the 2 mg/kg dose of amphetamine was shown to facilitate intracranial self-stimulation as well as to induce an aversion to saccharin.

Memory access pathway: role of adrenergic versus cholinergic neurons.

Abstract: A temporary depletion of brain norepinephrine in rats produced by injection of a dopamine beta-hydroxylase inhibitor, diethyldithiocarbamate (DDC), 30 min prior to testing, prevented performance of a trained passive avoidance response 1, 3, 5 or 7 days after training. Subsequent recovery in performance indicated that the memory itself was not destroyed, but rather that the process of memory retrieval was affected. Anticholinesterase treatment produced a similar retrieval amnesia, but the effect was dependent upon the age of the memory at the time of drug injection [11]. In both cases, when the animals were presented a recall trial prior to injection, the normally observed amnesia was blocked. Animals treated with DDC up to 3 hr before training were capable of learning the passive avoidance task and of avoidance performance for a few minutes after training. However, these animals failed to produce a long-term memory of the trained response. Anticholinesterase treatment had no effect on memory formation. These results suggest different roles for adrenergic and cholinergic neurons in a pathway associated with memory storage and retrieval.

Age dependent effects of 5-hydroxytryptamine upon memory consolidation and cerebral protein synthesis

Abstract: In four experiments consideration was given to the effect of intracranially administered 5-Hydroxytryptamine (5-HT) upon several age dependent cerebral processes. These included (1) the tissue uptake of exogenously administered intracranial 5-HT, which in 17-day old CF-IS strain mice did not lead to increases in forebrain 5-HT level; (2) when administered in close temporal proximity with a single trial passive avoidance training trial, intracranial 5-HT produced a significant degree of retrograde amnesia in 15, 20, and 30-day-old mice, with a temporal gradient for this amnesic effect measured out to eight min. No significant retrograde amnesic effect for such passive avoidance behavior was produced in 17-day old animals. The amnesic effect appeared to be specific to 5-HT, in that (3) other amines or 5-HT analogs administered intracranially in equimolar concentration, had no amnesic effect. The relationship between age and the effect of intracranially administered 5-HT was considered with regard to regional cerebral protein synthesis. The incorporation of radioactive leucine into proteins of several regions of the brain, including cerebral cortex, basal ganglia and diencephalon, midbrain, and cerebellum, was significantly inhibited within 20 min following 5-HT administration. No significant inhibition of cerebral protein synthesis was observed in 17-day old mice of the same strain given identical treatment. The data from the series of experiments generally supported the view that inhibition of protein synthesis may be effected by increases in the regional concentration of 5-HT, and under circumstances wherein such increases are precluded either because of endogenous metabolic circumstances or tissue uptake properties, protein synthesis inhibition may not occur. Such was the case for the 17-day old CF-1S strain mouse wherein protein synthesis inhibition was attenuated and the retrograde amnesic effect of intracranial 5-HT was antagonized.

Inhibition of catecholamine synthesis and conditioned avoidance acquisition.

Abstract: The effects of α -methyl- p -tyrosine methylester hydrochloride (α-MT) (200 mg/kg s.c.) and bis-(4-methyl-l-homopiperazinylthiocarbonyl) disulfide (FLA-63) (20 mg/kg s.c.) on the acquisition of a conditioned avoidance response (CAR) were studied. Both α-MT and FLA-63 reduced brain noradrenaline about 50 per cent, 6 and 1hr respectively, after the injections. α-MT also reduced brain dopamine about 40%. Neither treatment with α-MT nor FLA-63 prevented the learning of a CAR. The acquisition of the CAR was followed over 3 test sessions and the experiment was designed to control for state-dependent effects of the drugs. The injection of FLA-63, but not α-MT was found to result in state-dependent learning. The performance of the CAR was affected by α-MT- but not FLA-63-treatment. It is concluded that the reduction of brain catecholamines obtained by α-MT or FLA-63 does not interfere with the final acquisition of a CAR.

Effects of prenatal Δ9-tetrahydrocannabinol on the development of rat offspring

Abstract: Pregnant rats were injected SC with 10 mg/kg Δ9-tetrahydrocannabinol (Δ9-THC) or vehicle solution on Days 10–12 of gestation. The course of pregnancy and parturition was unaffected by this drug treatment. The litter size, sex ratio, average birth weight and external appearance of the progeny did not differ from normal. Twenty-four male pups were selected from each of 6 Δ9-THC litters and 7 control litters for observations of physical maturation and for testing of reflexive and exploratory behavior development from birth to weaning. Cross fostered controls were employed. Offspring of Δ9-THC treated females showed delayed incisor eruption and retarded development of cliff avoidance and visual placing reflexes. Delta9-THC progeny were significantly hyperactive in an open field arena at 9 days of age. Decrements in rearing and grooming behavior were found at 13 and 17 days of age. Differences in open field exploration had disappeared by weaning age. Although no differences in body weight were present at birth, Δ9-THC exposed pups showed retarded growth from the fourth day through weaning. The failure of cross fostering procedures to reduce any of these effects indicates a direct, prenatal drug action on the developing fetus.

Effects of d-amphetamine on schedule induced polydipsia☆

Abstract: Two female Sprague-Dawley albino rats were selected in terms of the amount of schedule induced polydipsia which developed on an FI-1 min food reinforcement schedule at 80% of their initial body weights. The effecs of six different doses of d -amphetamine administered intraperitoneally, 0.05, 0.25, 0.50, 1.00, 1.50, and 2.00 mg/kg on bar presses and schedule induced licking and water consumption were determined and compared to results obtained during baseline and following placebo injections. In the animal which displayed less schedule induced polydipsia during preinjection baseline, results indicate that amphetamine in low doses tended to enhance adjunctive licking and water consumption whereas higher doses decreased the same behavior. There was no obvious enhancement in the other animal, which displayed more adjunctive licking during baseline, and drinking as well as licking decreased with increasing dose. Both animals displayed a similar dose related increase in bar presses with a maximum at 1.50 mg/kg.

6-OHDA lesions of the hypothalamus: Interaction of aphagia, food palatability, set-point for weight regulation, and recovery of feeding☆

Abstract: 6-Hydroxydopamine (6-OHDA) exerted a marked effect on normal eating behavior when injected bilaterally into certain regions of the brainstem of the rat. The drug was administered in a volume ranging from 0.5 to 1.5 μl at sites in the hypothalamus and mesencephalon extending from AP 7.0 to 2.2. In 41 of 42 rats, 6-OHDA did not elicit an ingestive response following its injection in doses of 5, 8, 15, or 30μg per site. Rather, the immediate effect of the drug was a profound aphagia and adipsia which was either short-lived, chronic, or lethal depending on the anatomical locus of injection and the concentration of the drug given. The crucial factor in the reversal of anorexia and the reinstatement of a normal feeding pattern was the nature of the diet itself. Recovery from a 6-OHDA syndrome was enhanced or attenuated in 28 of 42 rats simply by altering the esculent property of the diet. In a test of the Powley-Keesey hypothesis for weight regulation, 4 of 5 of those rats reduced by food deprivation to 75% of their normal body weight recovered from the highest dose (30 μg) of 6-OHDA, whereas all but one rat died in another high dose group in which body weight had not been previously reduced. However, when 6-OHDA was injected in lower doses into the hypothalamus, the level of body weight did not necessarily determine the time course of recovery nor the extent to which drinking and feeding resumed. At 50 of 57 sites in which 6-OHDA had been injected, 5 μg of norepinephrine failed to elicit any eating response. Neither eating nor drinking was evoked by the micro-injection of acetylcholine-eserine, angiotensin, or dopamine at many of these sites or by calcium (Ca ++ ) injected into the cerebral ventricle. Although these findings give experimental support to the supposition that a catecholaminergic mechanism may be involved in food and water intake, it is clear that the metabolic weight regulation system, gustatory, motor and other factors required for ingestive behavior are all affected to a differential degree by the chemical lesion produced by 6-OHDA.

Tolerance to the effects of daily nicotine on rat bar pressing behavior for water reinforcement.

Abstract: The effects of daily nicotine tartrate given IP in a dose of 0.25 mg/kg twice a day for 15 days was studied on bar pressing behavior for water reinforcement in the rat. A modified FR 1 5 schedule was used. Nicotine injections caused an initial disruption of bar pressing behavior with rapid tolerance development. Antidiuretic hormone (5–10 units/kg, SC) administration also suppressed water drinking behavior after an initial latency in contrast to the effects of nicotine. It is concluded that tolerance occurs to daily nicotine administration.

Drinking in the monkey evoked by nicotine or angiotensin II microinjected in hypothalamic and mesencephalic sites

Abstract: In 7 unanesthetized rhesus monkeys (Macaca mulatta), spontaneous drinking was measured following a 1 μl injection of nicotine at 153 sites in the hypothalamus and mesencephalon. Nicotine in doses of 5 and 10 μg evoked the intake of water in volumes ranging from 35–365 ml within 30 min following the microinjection. A lower dose produced less drinking or had no effect. An anatomical mapping of this response revealed that nicotine exerted its dipsogenic effect at only 18 of the 153 sites at which the alkaloid was injected. These sensitive loci were clustered in and around the mammillary complex. When 1 μl of angiotensin II solution was microinjected in a dose of 1 μg at homologous sites in the hypothalamus and mesencephalon, volumes of water from 30–320 ml were consumed within 30 min after the injection. The anatomical distribution of the loci sensitive to angiotensin correspond identically to the nicotine drinking sites, i.e., the region surrounding the mammillary bodies and extending caudally into the mesencephalon. It was hypothesized that a cholinergic pathway mediated by nicotine receptors may subserve a drinking circuit in the brain stem of the primate. Further, because of the anatomical concordance of the dipsogenic substances, it was proposed that topically applied angiotensin may act to release acetylcholine within this region.

Influence of tetrahydrocannabinols (delta8-THC and delta9-THC) on body weight, food, and water intake in rats

Abstract: Female Wistar rats, six to a group, were injected daily for a 23-day period with Δ 8 -THC (5.0 mg/kg), Δ 9 -THC (2.5 mg/kg) or vehicle. Body weight, food and water intake were recorded every second day. It was found that Δ 8 -THC caused a decrease of body weight, to a level maintained throughout the injection period, with only slight signs of recovery. Both drugs caused a marked decrease of water intake. Food intake was not significantly affected by the drugs. Factors in relation to the effects of THC on body weight, food and water intake are discussed.