Effect of isradipine,a dihydropyridine-calcium antagonist on I.V. self-administration of morphine in rats

The effect of dihydropyridine calcium channel antagonist isradipine (PN 200-110) on morphine reinforcement has been investigated using i.v. self-administration test in rats. Rats were given the opportunity to self-administer a solution of morphine (1 mg/Ml, i.v.) in a 1 hr limited access paradigm (FR = 1). Within 5–7 days rats had learned to self-administer approximately 1 mg of morphine in 1 hr as evidenced by a plateau of responding. The administration of isradipine (1.2, 2.5 and 5.0 mg/kg s.c.) 90 min before the morphine self-administration session, induced dose-dependent increase in the number of morphine self-infusions with respect to basal values. This response pattern was very similar to the one observed when morphine solution was substituted by saline in trained rats not treated with isradipine. The results indicate that isradipine inhibits partially the reinforcing properties of morphine in self-administration test.     

Central cholinergic influence on self-administration of morphine and amphetamine

Atropine and methylatropine were tested in rats for an ability to alter the reinforcing action of intravenous morphine sulfate and d-amphetamine sulfate (60 μg/kg/injection). Atropine blocked the self-administration of morphine, but methylatropine did not. Similarly, atropine but not methylatropine prevented the establishment of a conditioned reinforcer based on passive intravenous infusions of morphine. Self-administration of d-amphetamine was enhanced by atropine but not by methylatropine. The results indicate that a central cholinergic system exerts an influence on the brain mechanisms which are affected by morphine or d-amphetamine to produce positive reinforcement.     

Probability analysis of elements of rat behavior after sudden and signalled interruption of food reinforcement

Probability analysis was carried out of the appearance of single elements of rats behaviour in the process of extinction of a conditioned alimentary motor reflex. The dynamics of effector behavioural components at a sudden cessation of reinforcement (usual schedule of extinction) was compared with cessation of reinforcement signalled by a previously differentiated signal and with reinforcement cessation preceded by a stimulus initially unknown to the animal. If the reinforcement cessation is signalled by a previously differentiated (negative) stimulus, in response to its action the animals "loose the aim", what is revealed in a rapid complete reduction of all elements of the goal-directed alimentary behaviour. Obviously differentiation signal actualises the memory trace of "nonreinforcement" which was formed in the previous negative experience of the animal; this is revealed in accelerated inhibition of the alimentary motor reflex under extinction.     

The choice of reinforcement quality depending on the delay time of the instrumental reaction in cats]

In experiments on seven cats instrumental delayed reflexes with different quality reinforcement were elaborated by method of "active choice", where the time of delay of the motor reaction served as a signal of quality of the reinforcement. Five cats used a strategy with long delay high-quality reinforcement (meat), and two cats preferred short delay and low-quality reinforcement (bread-meat mixture). In special experiments with the change of alimentary motivation (24-hour alimentary deprivation and saturation of animals) it was established that the level of alimentary motivation within the studied limits did not change the strategy of behaviour preferred by the given animal. Individually varying ability to choice of reaction determining more valuable reinforcement it is possible to consider as an experimental analogue of the mechanisms of will. The question is discussed about the role of typological properties of cats in choice of behaviour strategy.     

Patterns in the transition from normal to neurosis in dogs with different typological traits in food and defensive situations

At comparison of the formation of neurosis in dogs with different typological characteristics in conditions with alimentary and pain reinforcement, a resemblance was revealed of transition from norm to the initial stage of pathology. In strong animals a development was seen of compensatory tachycardia at circular changes of conditioned activity. Weak type dogs are characterized by a lowering or full disappearance of reflexes in combination with bradycardia. The method of differentiation, allowing in situations with alimentary reinforcement to classify the tested animals according to the type of higher nervous activity and differentiate the states of "norm" and "initial stage of neurosis", proved to be effective for the analogous aims also in studies with defensive reinforcement.     

Impact of pubertal and adult estradiol treatments on cocaine self-administration

Estradiol is thought to play a critical role in the increased vulnerability to psychostimulant abuse in women. Sex differences in the ability of estradiol to influence cocaine self-administration in adult rats have been hypothesized to depend upon pubertal estradiol exposure. The current study investigated whether the presence of gonadal hormones during puberty affected cocaine self-administration behavior and its sensitivity to adult estradiol treatment in male and female Sprague–Dawley rats. Subjects were gonadectomized or SHAM-operated at postnatal day (PD) 22, and received either OIL or estradiol benzoate (EB) during the approximate time of puberty (PD27 to PD37). Adult rats were subsequently treated with either EB or OIL 30 min before cocaine self-administration (0.3 mg/kg/inf) in order to examine the effects of pubertal manipulations on the estradiol sensitivity of acquisition on a fixed ratio (FR) 1 schedule, total intake on a FR5 schedule and motivation on a progressive ratio schedule. Adult EB treatment only affected cocaine self-administration in females, which is consistent with previous research. Adult EB treatment enhanced acquisition in all females irrespective of puberty manipulations. All females, except those treated with EB during puberty, displayed increased cocaine intake following adult EB treatment. Adult EB treatment only enhanced motivation in females that were intact during puberty, whereas those treated with EB during puberty showed reduced motivation. Therefore, the sensitivities of different self-administration behaviors to adult estradiol treatment are organized independently in females, with pubertal estradiol exerting a greater influence over motivational processes, and negligible effects on learning/acquisition.     

Individual typological features of the dog behavior during the choice between food and avoidance of electrocutaneous stimulation

Two conditioned reflexes (CR) on flash were elaborated in five dogs in three experimental series. In one of them pressing on pedal were constantly reinforced with two pieces of liver, in other--escape or avoidance of skin stimulation with lifting of leg. In a third series, series of reinforcement choice, in front of animal with electrodes, fasting on leg, put the pedal. During of choice series defensive reactions were dominated in two dogs, alimentary reactions--three of them. For restoration alimentary behaviour in dog with great dominating of defensive reactions were many times reinforced with--food "passive" pressing legs on pedal during conditional stimuli, dog with less dominating of these reactions for restoration were enough a few coupling of conditional stimuli with food. With intensification electrocutaneus stimulation of legs or decreasing alimentary reinforcement we a success of diminishing of degree of alimentary reaction domination in one dog and in other ones temporarily changed of these domination on prevalence of defensive reactions. The results were compared with data, obtained in these dogs with technique of choice between probability and value of alimentary reinforcement. This comparison were permitted us of ranging dogs on scale "carefulness-riskiness", revealed of individual typological features of these animals.     

Cyclazocine revisited

Recently synthesized compounds which have long-term mu antagonist activity and short-term kappa agonist effects prevent self-administration of cocaine and morphine in rats. Cyclazocine, a compound synthesized in 1962 and studied in animals and man in the 1960's and in the early 1970's is a mu antagonist in rats and man and is a potent kappa agonist in both species. It also prevents self-administration of cocaine and morphine in rats. Although it produces unpleasant side effects in man, subjects become tolerant to these side effects but not to the antagonistic actions of the drug after prolonged administration. Deceased Special issue dedicated to Dr. Eric J. Simon.     

Evidence of possible opiate dependence during the behavioral depressant action of a single dose of morphine

Rats were trained to lever press for food pellets under a 20 response fixed ratio (FR 20) schedule of reinforcement. A single injection of 15 mg morphine SO₄/kg suppressed operant behavior for $\text{1}\text{1}\text{2}\text{–3}\text{1}\text{2}\text{hrs}$, after which time responding resumed at a reduced rate. When 0.25 mg naloxone HCl/kg was given during the recovery phase, the behavioral depressant effect of the narcotic was immediately reversed and operant performance returned to predrug rates. In contrast, when 0.5 mg naloxone/kg was given at this time, operant behavior was abolished for at least 1 hr. Naloxone, at these doses, did not affect responding in drug-naive subjects. These results suggest that a single, relatively low dose of morphine can induce transient dependence which is detectable for several hrs after drug administration, at a time when the acute pharmacological actions of morphine are still apparent.     

The dependence of hippocampal electrical activity on the probability of the reinforcement of a conditioned food stimulus

In three dogs the dynamics was studied of changes in the number of instrumental motor reactions, the heart rate and the hippocampus theta rhythm was studied at the change of constant reinforcement to various regimes of probable reinforcement of alimentary conditioned stimulus. At 70 and 50% levels of the reinforcement the instrumental reflex appeared in response to all presentations of the signal stimulus. The greatest decrease in the number of reactions took place at 5% probability. The heart rate both in the intersignal period and at getting of empty feeder depended on the used probability of reinforcement and individual characteristics of animals. The frequency of the theta rhythm in all dogs was the highest at the 30% level and the lowest values were found at the 5% level of reinforcement. The obtained facts testify once more to complex genesis of emotional excitation, the value of which depends both on informational (uncertainty) and motivational (significance of reinforcement) factors.     

Habituation and the reinforcing effectiveness of visual stimuli

The term "sensory reinforcer" has been used to refer to sensory stimuli (e.g. light onset) that are primary reinforcers in order to differentiate them from other more biologically important primary reinforcers (e.g. food and water). Acquisition of snout poke responding for a visual stimulus (5s light onset) with fixed ratio 1 (FR 1), variable-interval 1min (VI 1min), or variable-interval 6min (VI 6min) schedules of reinforcement was tested in three groups of rats (n=8/group). The VI 6min schedule of reinforcement produced a higher response rate than the FR 1 or VI 1min schedules of visual stimulus reinforcement. One explanation for greater responding on the VI 6min schedule relative to the FR 1 and VI 1min schedules is that the reinforcing effectiveness of light onset habituated more rapidly in the FR 1 and VI 1min groups as compared to the VI 6min group. The inverse relationship between response rate and the rate of visual stimulus reinforcement is opposite to results from studies with biologically important reinforcers which indicate a positive relationship between response and reinforcement rate. Rapid habituation of reinforcing effectiveness may be a fundamental characteristic of sensory reinforcers that differentiates them from biologically important reinforcers, which are required to maintain homeostatic balance.     

Stimulus properties of clonidine in chronically morphine treated rats trained to a morphine-saline discrimination

In an operant behavior procedure of lever pressing on an FR 10 schedule of food reinforcement, morphine dependent and nondependent rats were trained to respond on a lever on one side of the food tray after a morphine (10 mg/kg i.p.) injection and to respond on a lever on the alternate side after a saline injection. Following discrimination training, in both dependent and nondependent rats saline was generalized to various doses of clonidine (10, 30 and 50 micrograms/kg i.p.). A response inhibition of about 65% was obtained with the highest dose. It was concluded that, even if clonidine can suppress signs of narcotic withdrawal, the internal state induced by morphine in an abstinent rat does differ from the one induced by clonidine in the same animal.     

Increased response to morphine in mice lacking protein kinase C epsilon

The protein kinase C (PKC) family of serine-threonine kinases has been implicated in behavioral responses to opiates, but little is known about the individual PKC isozymes involved. Here, we show that mice lacking PKCepsilon have increased sensitivity to the rewarding effects of morphine, revealed as the expression of place preference and intravenous self-administration at very low doses of morphine that do not evoke place preference or self-administration in wild-type mice. The PKCepsilon null mice also show prolonged maintenance of morphine place preference in response to repeated testing when compared with wild-type mice. The supraspinal analgesic effects of morphine are enhanced in PKCepsilon null mice, and the development of tolerance to the spinal analgesic effects of morphine is delayed. The density of mu-opioid receptors and their coupling to G-proteins are normal. These studies identify PKCepsilon as a key regulator of opiate sensitivity in mice.     

Effect of tuftsin and its analog on learning, memory and exploratory behavior in rats

On Wistar male rats the influence of tetrapeptide tuftsin and its analogue TP-1 (300 mkg/kg, i/p) on animals behaviour was studied. It is shown that administration of peptides increases the rat's exploratory activity. Activating influence of TP-1 was continued for 6 h. Daily multiple administration of tuftsin or TP-1, 15 min prior to the beginning of experiments facilitates the learning and stability of conditioned reaction with food reinforcement. Experimental animals react significantly weaker than the control ones to emotionally negative influence, produced by a sharp reduction of the amount of alimentary reinforcement control.     

Capsaicin does not attenuate bombesin-induced suppression of operant responding for food reward.

Systemic treatment with capsaicin, a neurotoxin which damages unmyelinated peptide-containing sensory neurons, has been shown to attenuate bombesin (BBS)-induced suppression of food intake. To determine whether capsaicin-sensitive fibers mediate the effect of BBS on appetitive motivation, we examined BBS-induced suppression of operant responding in rats pretreated neonatally with capsaicin (50 mg/kg; SC) or control vehicle. At 8-10 weeks of age, rats were trained to bar press for food. After achieving a stable level of performance, the animals were injected with BBS (10 micrograms/kg), normal saline, or prefed with 20 Noyes 45-mg pellets. Animals were then tested in an operant chamber on an FR 5 schedule of reinforcement for one hour. The results indicated that BBS suppressed bar pressing, regardless of whether animals were pretreated with capsaicin or control vehicle. These findings are inconsistent with the hypothesis that BBS induces satiety via capsaicin-sensitive neurons. The results suggest the possibility that more than one mechanism may mediate the effects of BBS: a neural mechanism involved in consummatory responses and a humoral mechanism involved in the operant response.     

The role of context in risky choice

Human choice behavior was assessed in a concurrent-chain schedule, where two equal initial links (IL) each led to a distinct terminal-link (TL). One TL was associated with a fixed ratio schedule of reinforcement, while the other was associated with a bi-valued mixed ratio schedule of reinforcement, whose arithmetic mean equaled the Fixed TL schedule. The fixed component (FR50; FR25; FR5) was arranged to be equal to the alternative mixed component in each condition (FR1/99; FR1/49; FR1/9), and choice behavior was measured by proportion of responses to each IL. In addition, the IL duration varied across conditions (VI 30 s; VI 15 s; FI 1 s). Preference for the mixed option was observed with longer durations (e.g., when IL = VI 30 s and TL = FR1/99). Participants were relatively indifferent in other conditions, though the results suggested a monotonic increase in preference as either durations or programmed efforts increased. It is concluded that both choice and the conditioned reinforcement value of the mixed option is contextually based, so that the value of a stimulus correlated with an immediate reward (i.e., FR 1) is enhanced the greater the temporal context in which the FR1 is embedded.     

The influence of neuropeptides related to pro-opiomelanocortin on acquisition of heroin self-administration of rats

The influence of different neuropeptides related to pro-opiomelanocortin were tested on acquisition of heroin self-administration in rats. The animals were allowed to self-administer heroin intravenously on a continuous reinforcement schedule during 6 h daily sessions on 5 consecutive days. Treatment was performed subcutaneously 1 h before each daily session. It was found that the opioid peptides alpha-, gamma- and beta-endorphin hardly influenced acquisition of heroin self-administration, while the non-opioid fragments of alpha- and gamma- endorphin modulated this behavioral response. In fact, beta-endorphin (beta E) 2-9 tended to facilitate the rate of acquisition, while the gamma-type endorphins, des-Tyr1-gamma-endorphin (beta E 2-17) and des-enkephalin-gamma-endorphin (beta E 6-17), decreased heroin intake. Concerning the ACTH/MSH related peptides, a decreasing effect of heroin intake was found following treatment with (D-Phe7)-ACTH 4-10, with a high dose of the ACTH 4-9 analog Org 2766 and with gamma 2-MSH, while ACTH 1-24, ACTH 4-10 and a low dose of Org 2766 did not significantly influence self-injecting behavior. It is concluded that pro-opiomelanocortin serves as a precursor molecule for peptide fragments, which modulate the acquisition of heroin self-administration in rats.     

Conditioned suppression as a method of detecting taste thresholds in the rat

Taste thresholds of seven male Sprague—Dawley rats (meanage 10 weeks, mean weight 250 g) were determined for four basictaste qualities: sweet, sour, salty and bitter. The method ofconditioned suppression was employed. An apparatus capable ofpresenting any one of eight separate drinking tubes during atesting session was designed. Animals were reduced to 80–85%ad lib. body weight. They were then trained to lick a sippertube through a slot in the back of an experimental chamber forpellet reinforcements. Animals progressed through a series ofreinforcement schedules starting with a fixed ratio (FR) scheduleof five licks for each reinforcement. They advanced to a variableratio (VR) schedule of reinforcement and finally a variableinterval (VI) schedule with a mean of 17.5 s was used. Whileon the VI schedule animals were trained to suppress lickingwhen any tastant other than water was presented. The first lickon any tastant was followed 10 s later by a mild electric shockif a rat made more than 20 licks on the tube in the 10-s period.Less than 20 licks on a tastant tube resulted in no shock anda 5-s time out before proceeding to the next tube. Thresholdwas determined using a suppression ratio formula. Thresholdwas defined as the 0.33 suppression ratio. Results from thisexperiment reveal mean thresholds for the seven animals as:sucrose = 2.3 mM, NaCl = 0.63 mM, quinine HCl = 0.005 mM andcitric acid = 0.085 mM.