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PubMed1999

Satiety threshold: a quantitative model of maintained cocaine self-administration.

The intervals between self-injections of cocaine by rats are defined by an equation that contains only three parameters: the dose of cocaine administered, the elimination half-life of cocaine, and an amount of cocaine in the body, which we have termed the cocaine satiety threshold. This latter parameter is defined as the maximal level of cocaine at which the probability of self-administration approximates one and above which the probability of self-administration is low. The mathematical model generated mean values for the satiety threshold and the functional elimination half-life of cocaine of approximately 1.7 mg/kg (i.v.) and 8.2 min, respectively. Therefore, the simple equations presented here permit the measurement of the pharmacokinetics and pharmacodynamics of cocaine using self-administration behavior as a bioassay. Our satiety model predicts that when cocaine levels are maintained above the satiety threshold, rats would not self-administer cocaine. The elimination rate of cocaine at the satiety threshold was calculated to be approximately 2 microg kg(-1) s(-1). Therefore, an infusion of cocaine at this rate should maintain cocaine levels fractionally above the satiety threshold. A continuous infusion of cocaine at this rate prevented cocaine self-administration for the duration of the infusion, thereby confirming the validity of the satiety model. These equations provide a quantitative description of cocaine self-administration and contain no subjective terms, implying that concepts such as "craving", drug "wanting" and "liking" and "reinforcement", used in psychologically oriented models, are not necessary for descriptions of this behavior in rats.

Animals↗

PubMed2005

How to achieve chronic intravenous drug self-administration in mice.

INTRODUCTION: Self-administration, the best animal model of drug addiction, requires implantation of indwelling jugular catheters. Surgical procedures in mice, the most common species for transgenic modeling, are difficult owing to size and scale. The goal of this paper was to describe how to achieve successful intravenous drug self-administration in mice. METHOD: The surgical and self-administration training procedures developed for rats and other species have been adopted for mice and described in a step-by-step manner with reference to sources for equipment, materials, and parts. RESULTS: The method can be used for studying self-administration behavior in freely moving mice up to 4 weeks. The relatively quick loss of catheter patency was due to growth of neointima tissue. DISCUSSION: Drug self-administration is achievable in mice, and the model is limited only by eventual loss of catheter patency, a process probably triggered by mechanical damage of the endothelium, by the effect of drug injections, or a combination of these factors.

Animals↗

PubMed2000

Reduction of zif268 messenger RNA expression during prolonged withdrawal following "binge" cocaine self-administration in rats.

Cocaine self-administration increases dopamine efflux and neuronal activity in the mesocorticolimbic dopamine system compared with experimenter-administered cocaine. Following a prolonged cocaine self-administration binge, dopamine efflux in the nucleus accumbens is attenuated and behaviors emerge that are indicative of anhedonia and anxiety. The neuronal correlates of these behavioral and neurochemical effects of a cocaine binge were assessed using in situ hybridization histochemistry to detect changes in zif268 messenger RNA expression. Rats were fitted with intravenous catheters; one group was trained to self-administer cocaine (0.5mg/injection), then allowed continuous access to cocaine during a 16h binge, while yoked animals received either saline or cocaine according to the same schedule. Measurement of tactile startle responses and ultrasonic distress calls either immediately after termination of cocaine access or one or 14 days later confirmed peak withdrawal at 24h after the binge. The level of zif268 messenger RNA was lower upon termination of cocaine self-administration than in both yoked treatment groups in the ventral tegmental area and hippocampus. In contrast, zif268 messenger RNA expression increased in the periaqueductal gray matter one day after termination of passive cocaine treatment, coincident with enhanced expression of ultrasonic vocalizations. Zif268 messenger RNA expression decreased over time in the nucleus accumbens core and infralimbic cortex, with reduced expression observed in the nucleus accumbens core, caudatoputamen, hippocampus and amygdala 14 days after termination of cocaine self-administration. The results suggest that withdrawal following a cocaine self-administration binge produces a long-lasting reduction of constitutive zif268 messenger RNA expression in mesocorticolimbic brain regions related to the nucleus accumbens. The relatively greater effect in animals that self-administered cocaine implies a relationship of certain regional responses to behavioral conditioning.

Animals↗

PubMed1979

Destruction of dopaminergic nerve terminals in nucleus accumbens: effect on d-amphetamine self-administration.

Control rats initiate self-administration of d-amphetamine and achieve stable injection rates within 7-10 days. Rats in which dopamine nerve terminals in nucleus accumbens were destroyed by bilateral microinjections of 6-hydroxydopamine (6-OHDA) did not initiate self-administration of d-amphetamine when tested for as long as 19 days. In rats previously trained to self-administer d-amphetamine, 6-OHDA injections into nucleus accumbens abolished d-amphetamine self-administration. These results suggest that dopaminergic nerve terminals in nucleus accumbens are necessary for both the acquisition and maintenance of d-amphetamine self-administration.

Animals↗

PubMed1991

Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration.

Rats trained to self-administer cocaine (0.75 mg/kg/infusion) on an FR-5 schedule were treated with selective D1 or D2 antagonists. A69045, a D1 antagonist with no appreciable affinity for 5-HT receptors increased cocaine self-administration to 147, 172 and 167% of baseline at doses of 2.5, 5.0 or 10.0 mumol/kg, SC respectively. SCH-23390 (0.007, 0.015 and 0.030 mumol/kg, SC) increased self-administration to 116, 147 and 165% of baseline, respectively. Both D1 antagonists decreased responding in some animals at the highest dose tested. The D2 antagonist YM-09151-2 showed a similar profile, increasing cocaine self-administration at 0.01 and 0.016 mumol/kg, SC and suppressing responding by most animals at the dose of 0.03 mumol/kg, SC. These data give further support to the hypothesis that both D1 and D2 receptors are involved in maintaining cocaine self-administration.

Animals↗

PubMed2002

Effects of chronic administration of the D1 receptor partial agonist SKF 77434 on cocaine self-administration in rhesus monkeys.

RATIONALE: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. OBJECTIVE: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. METHODS: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. RESULTS: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. CONCLUSIONS: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1991

Opiate antagonists reduce cocaine but not nicotine self-administration.

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.

Animals↗

PubMed2002

Role of the endocannabinoid system in MDMA intracerebral self-administration in rats.

I.c.v. self-administration of MDMA (0.01-2 micro g per infusion), alone and in combination with CP 55,940 (0.4 micro g infusion(-1)), was studied on an operant responding procedure. On the basis of individual preference for one of two levers, developed during training, rats were allowed to self-administer vehicle from the preferred lever and MDMA from the other. Pressings on the MDMA associated-lever, except for the maximal unit dose, progressively increased. The combination of CP 55,940 with MDMA (1 micro g infusion(-1)) reduced the number of drug-associated lever pressings compared to the single drugs. Pre-treatment with SR 141716A (0.5 mg kg(-1) i.p.), 15 min before each daily session, significantly increased MDMA self-administration. These findings suggest that MDMA self-administration is under endogenous tonic control by the endocannabinoid system.

Animals↗

PubMed1980

Self-administration of D-Ala2-Met-enkephalinamide at hypothalamic self-stimulation sites.

The relationship between the action of enkephalin and the reinforcing action of electrical stimulation in the posterior lateral hypothalamus of the rat was studied with the self-administration approach. Adult male albino rats implanted with a combination cannula and stimulation electrode in hypothalamus were pretested for the reinforcing effects of electrical stimulation. Only subjects that self-stimulated at moderate to high rates were given self-administration tests. The chamber for the self-administration tests was fitted with one lever at each end of a rectangular plexiglass box. In a session, one lever was 'active', the other not. The active lever, if depressed, yielded 20 nl of CSF (artificial cerebrospinal fluid), or CSF in which one of the test substances was dissolved. Each subject was tested repeatedly for the reinforcing effects first of a control solution (CSF), then of D-Ala2-Met-enkephalin (DALA), a long-acting synthetic analogue of enkephalin, then of morphine, and then of opioids mixed with naltrexone or naloxone. Following these tests, the subjects were once again given self-stimulation tests to ascertain the functional integrity of the 'reward' system after the repeated self-administration tests. The results demonstrate that when the test solution was DALA instead of CSF the subjects pressed the active lever at a higher rate than for CSF, and they exhausted the supply more rapidly than for CSF. The rate on the active lever was also significantly higher than on the inactive lever. DALA at 1 and 5 microgram/microliter concentrations proved more reinforcing than at 0.1 microgram/microliter. Naltrexone did not block the reinforcing effect of DALA, whereas naloxone blocked DALA-induced reinforcement. These data extend the report of ventricular methionine-enkephalin positive reinforcement to DALA injected directly into the lateral hypothalamus.

Animals↗

PubMed1978

Intravenous self-administration of drugs in rats.

A standardized self-administration procedure in rats was used to determine the intravenous self-administration liability of graded doses of various drugs. Self-administration was reliably established with the tested addictive drugs (morphine, heroin, fentanyl and d-amphetamine), but not with the nonaddictive drugs (chlorpromazine and nalorphine). However, 1 out of 14 animals on nalorphine clearly demonstrated self-administering behavior. Self-administration was observed with delta1-tetrahydrocannabinol, but the percentage of animals (40% on the highest dose) that initiated this behavior and the amount of drug intake were low in comparison with amphetamine and narcotics. Concerning the narcotic drugs, approximate ED50 values for self-administration under the described conditions were calculated (morphine: 0.65; heroin: 0.05; fentanyl: 0.0025 mg/kg/injection). Total daily drug intake was related to the unit dose delivered per injection in that a higher drug dosage led to more drug intake. In experiments with heroin, this relationship was not caused by prior forced injections. The approximate ED50 value for amphetamine appeared to be 0.145 mg/kg/injection. Narcotic drug administration resulted in a disturbance of the patterns of food and water intake. Shortly after drug administration food intake was stimulated, followed by an increased consumption of water. The patterns of food and water intake remained disturbed in animals showing self-injecting behavior. With amphetamine both the quantity of food and the frequency of eating were reduced. These effects were observed only temporarily in animals tested without prior forced injections. The present results indicate that measuring the reinforcing efficacy of drugs under strictly defined experimental conditions provides quantitative criteria for intravenous self-administration of drugs in rats.

Animals↗

PubMed2002

Both the shell of the nucleus accumbens and the central nucleus of the amygdala support amphetamine self-administration in rats.

Intracranial self-administration of drugs offers the opportunity to localize the neuronal substrates mediating the rewarding effects of drugs. The purpose of the present study was to explore whether the nucleus accumbens shell and the central nucleus of the amygdala, two components of the "extended amygdala," would support self-administration of the psychostimulant amphetamine. Male Wistar rats were trained to lever press under a Fixed Ratio 1 schedule of reinforcement for D-amphetamine injections (0, 1.0, 1.5, 2.0 and 3.0 microg/microl/inj) into either the nucleus accumbens shell or the central nucleus of the amygdala. An ascending limb dose-response function with peak responding at the 2.0 microg/microl/inj dose was obtained for self-administration at both brain sites. These results indicate that monoaminergic transmission in both the nucleus accumbens shell and the central nucleus of the amygdala mediates the rewarding effects of amphetamine. Further, the present study provides additional evidence about the functional homogeneity of the forebrain continuum called the "extended amygdala."

Amphetamine↗

PubMed1989

Self-administration of phenylpropanolamine (PPA) by rats previously trained to self-administer amphetamine.

Central nervous system stimulation, similar to that observed for amphetamine, has been attributed to phenylpropanolamine (PPA). However, formal tests, using evaluation of locomotion or of self-administration, fail to reveal that PPA is a stimulant. Self-administration studies have trained rats to self-administer cocaine and then have attempted to switch rats to PPA with no success of transfer. The present study further examined the reinforcing properties of PPA (0.08, 0.16, and 0.32 mg/infusion, IV) in rats that were initially trained to self-administer d-amphetamine (0.005-0.08 mg/infusion) in a two-lever paradigm. Self-administration of amphetamine was a function of dose with 0.01 mg/infusion producing reliably high responding on the active lever. The proportion of active/inactive lever presses remained constant (0.60-0.80) across the amphetamine dose range. PPA was dose-dependently self-administered during the first hour of each session with rats responding at approximately 70% on the active lever. In contrast, responding on the active lever dropped off to approximately 48% when saline was substituted for amphetamine. These data document that rats with prior exposure to amphetamine will self-administer PPA during the initial portion of a three-hour test.

Amphetamine↗

PubMed1987

Diazepam self-administration and resistance to extinction.

Self-administration behavior was maintained by a unit dose of 0.03 mg/kg diazepam in 4 of 5 monkeys trained to respond on a lever by successive approximation using diazepam or saline. A dose-response function was determined using diazepam doses ranging between 0.01 and 0.3 mg/kg/infusion. Peak rates of responding occurred at doses of 0.01 or 0.03 mg/kg/infusion and drug intake was directly related to dose. When saline was substituted for diazepam either before or again after the dose-response function was determined, levels of responding remained unexpectedly high, even after as many as 16 consecutive sessions. The rates of responding maintained under extinction conditions appeared to be directly related to the amount of diazepam previously self-administered. For instance, monkeys which did not initially have high rates of responding for saline showed increases in responding after additional exposure to diazepam. Furthermore, the one monkey with low diazepam self-administration rates also had low rates of responding for saline. However, following a period of cocaine self-administration, responding declined in all monkeys when saline was substituted for cocaine. The data suggest that diazepam self-administration affects responding under extinction conditions, an effect which makes the interpretation of diazepam's reinforcing properties difficult.

Animals↗

PubMed2004

Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure.

BACKGROUND: Ethanol self-administering rats exhibit enhanced responding during withdrawal from continuous exposure to ethanol vapor. This study compared self-administration of ethanol during withdrawal from continuous versus intermittent ethanol vapor. METHODS: Experiment 1 examined self-administration of ethanol in rats trained to self-administer ethanol after continuous, intermittent (14 hr on and 10 hr off), or no (i.e., controls) ethanol vapor exposure. Exposure time was equalized such that the intermittent group received 4 weeks of exposure and the continuous group received 2 weeks of exposure. Four self-administration tests were conducted 2 hr after removal from vapor, and each test was separated by 3 to 4 days of ethanol vapor. Experiment 2 examined self-administration of ethanol after 2 weeks of intermittent vapor either 2 or 8 hr after removal from vapor. Experiment 3 addressed the specificity of the increased responding for ethanol by examining saccharin self-administration after 2 weeks of intermittent vapor. RESULTS: Four weeks of intermittent exposure produced an increase in ethanol self-administration during the first withdrawal relative to controls and relative to animals receiving 2 weeks of continuous exposure. The continuous group was indistinguishable from controls on the first test and gradually increased their responding across tests. Two weeks of intermittent exposure also increased ethanol self-administration, and there was no difference in this effect 2 or 8 hr after removal from vapor. There was no difference in saccharin self-administration in control rats and those given 2 weeks of intermittent exposure. CONCLUSIONS: The finding that intermittent exposure produces more rapid increases in self-administration of ethanol relative to continuous exposure suggests that intermittent exposure may be associated with a more rapid escalation of the allostatic processes responsible for excessive ethanol self-administration. The mechanisms that drive the increases in drinking during withdrawal are similar after 2 and 8 hr of withdrawal and seem to be specific to ethanol.

Animals↗

PubMed2006

The compulsion zone: a pharmacological theory of acquired cocaine self-administration.

In rats trained to reliably self-administer cocaine, the cumulative drug level was calculated during sessions in which cocaine was administered either contingently or non-contingently. During both types of sessions a high rate of responding was observed only when cocaine levels were above the priming threshold but below the satiety threshold. When the levels of non-contingently administered cocaine were maintained between the priming and satiety thresholds for at least 5 h rats continuously maintained high rates of responding. Although it is generally assumed that rats are responding for cocaine during self-administration sessions, the persistence of responding during non-contingent administration is consistent with responding being induced by cocaine. Therefore, in contrast to the basic assumptions underlying the operant theory of self-administration behavior, choice, contingency and reinforcement are not necessary to explain acquired cocaine self-administration. The presented data demonstrate that there is no ascending limb of the dose-response curve and that the cocaine priming and satiety thresholds delineate the lower and upper limits, respectively, of a cocaine "compulsion zone". It is concluded that the self-administration paradigm is the sum of cocaine induced responding and cocaine induced satiety and which of these cocaine-induced effects occur at any time is dependent on the cocaine level. This novel pharmacokinetic/pharmacodynamic theory provides a basis for a comprehensive understanding of the cocaine self-administration paradigm.

Animals↗

PubMedDate not supplied

Self-administration of medicines.

Self-administration of medicines by patients in hospitals and residential homes can lead to increased comprehension and compliance with treatment after discharge and thus to a reduction in readmission rates. It can also increase the self-esteem of chronically ill patients by allowing them to take responsibility for their own health.

Humans↗

PubMed2002

Brain and body hyperthermia associated with heroin self-administration in rats.

Intravenous heroin self-administration in trained rats was accompanied by robust brain hyperthermia (+2.0-2.5 degrees C); parallel changes were found in the dorsal and ventral striatum, mediodorsal thalamus, and deep temporal muscle. Temperature began to increase at variable latency after a signal of drug availability, increased reliably (approximately 0.4 degrees C) before the first lever press for heroin, increased further (approximately 1.2 degrees C) after the first heroin injection, and rose more slowly after the second and third injections to stabilize at an elevated plateau (39-40 degrees C) for the remainder of the session. Brain and body temperature declined slowly when drug self-administration was terminated; naloxone precipitated a much more rapid decrease to baseline levels. Changes in temperature were similar across repeated daily sessions, except for the increase associated with the first self-administration of each session, which had progressively shorter latency and greater acceleration. Despite consistent biphasic fluctuations in movement activity associated with heroin self-administrations (gradual increase preceding the lever press, followed by an abrupt hypodynamia after drug infusion), mean brain temperature was very stable at an elevated plateau. Only mean muscle temperature showed evidence of biphasic fluctuations (+/-0.2 degrees C) that were time locked to and correlated with lever pressing and associated movements. Drug- and behavior-related changes in brain temperature thus appear to reflect some form of neuronal activation, and, because temperature is a factor capable of affecting numerous neural functions, it may be an important variable in the control of behavior by drugs of abuse.

Animals↗

PubMed2005

Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats.

Acute administration of gamma-aminobutyric acid B (GABAB) receptor agonists decreased nicotine, cocaine, ethanol, and heroin self-administration. GABAB receptor agonists also decreased cue-induced cocaine craving or seeking in humans and animals, respectively. The present study investigated the effects of repeated subcutaneous administration of the GABAB receptor agonist CGP44532 on nicotine- and food-maintained responding under a fixed ratio 5 schedule of reinforcement. The second part of the study determined whether contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior, and whether acute subcutaneous CGP44532 administration affected cue-induced reinstatement of extinguished nicotine-seeking behavior. The results indicated that repeated administration of 0.25 mg/kg CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding during the first 7 days of treatment. Repeated administration of 0.5 mg/kg/day CGP44532 nonselectively decreased both nicotine- and food-maintained responding. Contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior. Further, acute CGP44532 administration (0.125 and 0.25 mg/kg) decreased cue-induced reinstatement of nicotine-seeking behavior. In summary, the present results indicated that 0.25 mg/kg/day CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding, and acute administration of CGP44532 (0.125 and 0.25 mg/kg) dose-dependently decreased cue-induced reinstatement of nicotine-seeking behavior.

Animals↗