Interaction of morphine and naltrexone on oral ethanol self-administration in rhesus monkeys.

Opioid antagonists, such as naltrexone (NTX), reduce ethanol consumption and opioid agonists increase or decrease ethanol consumption in rats depending upon the dose. If the opioid antagonist and agonist effects on ethanol consumption are mediated by mu-opioid receptors, then NTX doses that reduce ethanol consumption should be similar to the doses necessary to antagonize the effects of opioid agonists on ethanol consumption. The purpose of these experiments was: (1) to determine whether morphine increases ethanol consumption in rhesus monkeys as it does in rodents; (2) to determine if the mu-receptor mediates the effects of morphine on ethanol consumption by conducting a pK(B) analysis using NTX; and (3) to determine if the mu-receptor also mediates the NTX-induced decreases in ethanol consumption by making comparisons between the NTX doses that affect ethanol consumption and the NTX doses that block the effects of morphine on ethanol consumption. Three male rhesus monkeys responded for 2% ethanol and water for 2 h/day on a fixed-ratio 4 schedule of reinforcement. Morphine doses as low as 0.0032mg/kg failed to increase ethanol fluid deliveries, whereas higher doses produced a dose-related decrease in ethanol fluid deliveries. Although 0.01 mg/kg NTX alone had no effect on ethanol fluid deliveries, it reduced the suppressant effects of morphine with a mu-receptor pK(B) of 8.21 (8.08-8.34). When given alone, 0.1 mg/kg NTX decreased ethanol fluid deliveries but failed to reverse the suppression caused by 1 mg/kg morphine. Therefore, monkeys may differ from rats in their response to morphine when ethanol consumption is the dependent variable. Furthermore, because the NTX dose that reduced the effects of morphine on responding for ethanol was smaller than the NTX doses that suppressed ethanol-reinforced responding when given alone, NTX may exert these two effects through different mechanisms.     

Smoked heroin self-administration in rhesus monkeys

The purpose of the present study was to evaluate behavioral and pharmacological determinants of smoked heroin self-administration. Eight rhesus monkeys were trained to self-administer smoked heroin under a chained fixed-ratio (FR, 64-1024) for lever presses, FR 5 for inhalations schedule during daily experimental sessions. Demand for heroin was determined by plotting consumption (smoke deliveries) as a function of price which was varied by increasing the FR lever press requirement from 64 to 1024. The heroin demand curve was compared to that obtained with smoked cocaine base. Dose-effect determinations were obtained by varying the unit dose of heroin from 0.025 to 1.6 mg/kg per delivery. Pretreatment with naloxone (0.01–1.0 mg/kg IM, 10 min presession) and substitution tests with the peripherally acting opioid loperamide (0.1 mg/kg per delivery) were also conducted. Deliveries of smoked heroin decreased, but lever responding per delivery increased as the FR increased. Demand for heroin was elastic and comparable to demand for smoked cocaine base. Varying the dose of heroin available for self-administration resulted in an asymptotic dose-effect curve. Naloxone pretreatment produced dose-dependent decreases in heroin self-administration. Substitution of loperamide for heroin produced extinction-like responding within one or two sessions, with the total smoke deliveries decreasing by 80% of heroin levels within 8–15 days. Reinstatement of heroin resulted in a rapid return to baseline levels of self-administration. These data suggest that rhesus monkeys will readily and reliably self-administer heroin via the inhalation route, and behavioral and pharmacological manipulations indicate that smoked heroin functioned as a positive reinforcer.     

Naltrexone pretreatment decreases the reinforcing effectiveness of ethanol and saccharin but not PCP or food under concurrent progressive-ratio schedules in rhesus monkeys

 The purpose of this experiment was to determine whether attenuation of ethanol consumption by naltrexone is the result of selective changes in the reinforcing effectiveness of drug and non-drug reinforcers. A range of naltrexone doses (0.1–1.0 mg/kg) was administered for 5 days, and the effects on the reinforcing effects of orally delivered 8% (w/v) ethanol, 0.25 mg/ml phencyclidine (PCP), 0.03% (w/v) saccharin and food were studied in eight rhesus monkeys. Food and liquids were available under independent and concurrent progressive-ratio (PR) schedules (ratio range 8–4096) during daily 3-h sessions. Ethanol-maintained responding was attenuated by 0.3 and 1.0 mg/kg doses of naltrexone, while saccharin-maintained responding was decreased at the 1.0 mg/kg dose. Furthermore, there was a significant linear trend that consumption of available ethanol and saccharin was attenuated dose-dependently by naltrexone. Following 5 days of naltrexone pretreatment, ethanol- and saccharin-maintained responding immediately returned to or exceeded baseline levels. Food- and PCP-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. The decreased break point (BP) values for ethanol and saccharin suggest that their reinforcing effects are mediated through opioid reinforcement mechanisms. The lack of naltrexone attenuation of PCP- and food-maintained responding suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability. Received: 13 May 1998 / Final version: 28 July 1998     

Naltrexone reduces ethanol- and sucrose-reinforced responding in rhesus monkeys

 These experiments evaluated the ability of naltrexone (NTX) to reduce selectively oral and IV ethanol-reinforced responding, and examined the ethanol-NTX interaction in terms of the competitive opioid antagonist property of NTX. Five rhesus monkeys self-administered ethanol or sucrose and concurrently available water. Ethanol concentration was varied from 0.25% to 8% (w/v). Naltrexone (0.032–0.32 mg/kg) or saline was given IM 30 min prior to some drinking sessions. NTX (0.32 mg/kg) reduced ethanol-reinforced responding at the concentration that maintained the most responding (1% or 2%). NTX (0.1 mg/kg) reduced ethanol-reinforced responding, both at a low ethanol concentration (0.25%) that produced little ethanol intake (g/kg), and at a higher concentration (4%) with an appreciable intake. Thus, NTX (0.1 mg/kg) shifted the ethanol concentration-consumption curve down, in an insurmountable manner. NTX (0.1 and 0.32 mg/kg) also reduced reinforced responding for sucrose 100 g/l. In another experiment, three rhesus monkeys were given opportunities to self-administer ethanol IV. NTX (0.1 mg/kg) reduced the number of ethanol injections obtained by the monkeys at all ethanol doses tested (0.01, 0.032, and 0.1 g/kg per injection).The dose-effect curve was also shifted down. These results showed that NTX reduced behavior maintained by either ethanol or sucrose non-selectively. Furthermore, the ability of NTX to suppress ethanol-reinforced responding did not depend on the route of ethanol administration and was not overcome by increasing the concentration or dose per injection of ethanol. Received: 11 November 1997 / Final version: 19 March 1998     

Oral self-administration of ethanol, phencyclidine, methadone, pentobarbital and quinine in rhesus monkeys

Rationale: Simultaneous and sequential drug use among clinical populations is the norm, whereas the pattern of self-administration of multiple drugs among non-human primate populations has not been thoroughly explored. Objectives: To determine the relationship between the preferences and intakes of a large group of rhesus monkeys exposed to various orally available solutions. Methods: Thirteen male and eleven female young adult rhesus monkeys (Macaca mulatta) were exposed to orally available drug solutions using a concurrent choice (drug and water) procedure, where fluid delivery was made contingent upon single spout contacts (fixed ratio one). Results: Ethanol (0.25–16% w:v) produced biphasic effects on the number of fluid deliveries obtained, with peak ethanol preferences over water demonstrated at the 1–2% w:v concentrations. No preferences for the N-methyl-d-aspartate receptor antagonist phencyclidine or water were demonstrated at lower concentrations (0.0078125–0.125 mg/ml) and, at higher concentrations (0.25, 0.5 mg/ml), a preference for water was demonstrated. The μ opioid receptor agonist methadone (0.001–0.3 mg/ml) and the prototypic bitter substance quinine (0.001–0.3 mg/ml) failed to produce preferences for drug or water. A large preference for water over the barbiturate pentobarbital (0.01–3 mg/ml) was also demonstrated. After rank-ordering the subjects based on their drug preferences or intakes, modest to no correlations across drugs were demonstrated. Conclusions: These results reveal that a robust ethanol preference is not predictive of a preference for drugs of abuse from other classes and suggests that fluid intakes were correlated, irrespective of the presence or absence of drug in the solution. Received: 6 October 1998 / Final version: 27 May 1999     

Naltrexone effects on food- and codeine-maintained responding in rhesus monkeys

The delivery of food or the i.v. injection of codeine maintained lever pressing in rhesus monkeys during alternating periods of daily experimental sessions. Responding was maintained by food or codeine under a chain differential reinforcement of other behavior 30 sec (DRO 30), fixed-ratio 30 response (FR 30) schedule of reinforcement. Maximum FR rates of codeine-reinforced responding were maintained by 25–47 μg/kg per injection codeine. Both lower (8 μg/kg per injection) and higher (80–800 μg/kg per injection) doses of codeine maintained lower FR response rates. FR rates of food-maintained responding only decreased as a function of codeine dose. Response rates during the DRO component of the schedule, when either food or codeine maintained responding, were extremely low (<0.01 responses/sec) and these rates were generally unaffected by the codeine dose. Naltrexone (0.003–0.32 mg/kg i.m.), administered before experimental sessions, produced a dose-related shift to the right in the rate-decreasing effects of codeine on FR responding maintained by food. In contrast, the dose-effect curve relating the FR rate of codeine-maintained responding to codeine dose was shifted consistently to the right only by the lowest dose of naltrexone (0.003 mg/kg). Although a 10-fold higher dose of naltrexone, 0.03 mg/kg, initially shifted the codeine self-injection curve to the right in one monkey, these higher naltrexone doses (0.03–0.32 mg/kg) generally resulted in response rates as low as or lower than those maintained by saline,e across a wide range of codeine doses (25–800 μg/kg per injection). These data suggest that naltrexone may decrease codeine-reinforced responding by mechanisms other than, or in addition to, a competitive antagonism of codeine's reinforcing effects.     

Evaluation of nefazodone self-administration in rhesus monkeys.

Intravenous self-administration of nefazodone, a potential new antidepressant medication, was evaluated using a substitution procedure in rhesus monkeys. Subjects had established stable rates of responding for cocaine (0.033 mg/kg per infusion) under a fixed-ratio 10 schedule during 60-min sessions each day. Various does of nefazodone hydrochloride (0.03-0.3 mg/kg per infusion) were substituted for cocaine for four consecutive daily self-administration sessions. Compared to rates of responding obtained during saline substitutions, nefazodone failed to function as a reinforcer when substituted for cocaine. In only one monkey, at one dose, did the rate of responding exceed the range of saline responding; an effect not observed in two subsequent replications in that subject. In all three monkeys, the total number of infusions tended to decrease during the 4-day nefazodone substitution and the majority of nefazodone infusions occurred during the first quarter of each session, with few infusions occurring in the latter three-quarters. Overall intake of nefazodone increased as a function of dose per infusion. Such a result is expected when response rates do not vary with dose, which is more likely to occur when a test drug is not a reinforcer. In summary, the present results provide no evidence of reinforcing effects with nefazodone and suggest that it would possess little or no abuse liability.     

Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys.

The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n=7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose-related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self-administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n=3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.     

Desipramine effects on cocaine self-administration by rhesus monkeys

The effects of desipramine treatment (0.56-10.0 mg/kg per day) on cocaine self-administration were compared to saline treatment in five rhesus monkeys. Cocaine (0.050 or 0.100 mg/kg per inj) and food (1 g banana pellets) self-administration were maintained on an FR 4 (VR 16:S) reinforcement schedule. Desipramine (or an equal volume saline control solution) was infused over 1 h each day through the second lumen of an intravenous catheter. After 5 days of baseline saline treatment, seven doses of desipramine each were administered for 5 days in an ascending order. Cocaine self-administration increased (P less than 0.01) or remained equivalent to base-line levels in 4 of 5 subjects during the first 15 days of desipramine treatment (0.56 to 1.78 mg/kg per day). Three monkeys continued to self-administer cocaine equivalent to or significantly above base-line levels (P less than 0.01) during days 16-30 of desipramine treatment (3.2-7.86 mg/kg per day). The highest desipramine dose (10 mg/kg per day) significantly suppressed cocaine self-administration in only one of these three monkeys (P less than 0.01). Desipramine treatment (3.2-10.0 mg/kg per day) suppressed cocaine self-administration (P less than 0.01) without a concomitant suppression of food-maintained responding in one of five subjects. A generalized suppression of both cocaine and food-maintained responding (P less than 0.01) during desipramine treatment occurred in one monkey that took the highest base-line levels of cocaine (6.3 +/- 1.03 mg/kg per day). Food-maintained responding remained equivalent to or significantly above (P less than 0.01) base-line levels in four of five monkeys during desipramine treatment. A transient decrease in food self-administration at desipramine doses of 1.78-5.62 mg/kg per day occurred in one monkey (P less than 0.01). Thirty days of desipramine treatment at the highest doses (5.62, 7.86 and 10.0 mg/kg per day for 10 days each) also did not suppress cocaine self-administration in a monkey that took an average of 4 mg/kg per day of cocaine during saline base-line treatment. These primate data are concordant with the extant clinical literature on the inconsistent effects of desipramine treatment; i.e., both stimulation of cocaine use and inconsistent or incomplete attenuation of cocaine abuse during desipramine maintenance have been reported.     

Adrenal steroid hormones and ethanol self-administration in male rhesus macaques

Rationale

Hypothalamic-pituitary-adrenal (HPA) axis hormones have neuroactive metabolites with receptor activity similar to ethanol.

Objectives

The present study related HPA hormones in naïve monkeys to ethanol self-administration.

Methods

Morning plasma adrenocorticotropic hormone (ACTH), cortisol, deoxycorticosterone (DOC), aldosterone, and dehydroepiandrosterone-sulfate (DHEA-S) were measured longitudinally in male rhesus macaques (Macaca mulatta) induced to drink ethanol followed by access to ethanol (4 %?w/v, in water) and water 22 h/day for 12 months.

Results

During ethanol access, DOC increased among non-heavy (average intake over 12 months ≤3.0 g/kg/day, n?=?23) but not among heavy drinkers (>3.0 g/kg/day, n?=?9); aldosterone was greater among heavy drinkers after 6 months. The ratio of DOC/aldosterone decreased only among heavy drinkers after 6 or12 months of ethanol self-administration. ACTH only correlated significantly with DHEA-S, the ratio of cortisol/DHEA-S and DOC after the onset of ethanol access, the former two just in heavy drinkers. Baseline hormones did not predict subsequent ethanol intake over 12 months, but baseline DOC correlated with average blood-ethanol concentrations (BECs), among all monkeys and heavy drinkers as a group. During ethanol access, aldosterone and DOC correlated and tended to correlate, respectively, with 12-month average ethanol intake.

Conclusions

Ethanol self-administration lowered ACTH and selectively altered its adrenocortical regulation. Mineralocorticoids may compensate for adrenocortical adaptation among heavy drinkers and balance fluid homeostasis. As DOC was uniquely predictive of future BEC and not water intake, to the exclusion of aldosterone, GABAergic neuroactive metabolites of DOC may be risk factors for binge drinking to intoxication.     

Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam

The ability of three benzodiazepines to maintain self-administration behavior was studied in rhesus monkeys using a substitution procedure. Lever-press responding was maintained in six monkeys under a fixed-ratio schedule of IV pentobarbital delivery in daily sessions of 3 hr duration. Each of several doses of flurazepam, lorazepam and estazolam as well as saline and vehicle was periodically substituted for 4-13 consecutive sessions. Between dose or vehicle substitutions, responding was maintained by pentobarbital. All six monkeys self-administered flurazepam above vehicle or saline levels. In addition four of five monkeys tested with lorazepam and four of six tested with estazolam self-administered at least one dose of drug above control levels. These results indicate that self-administration performance can be reliably maintained in rhesus monkeys by certain benzodiazepines under appropriate experimental conditions.     

Cholinergic influence on intravenous cocaine self-administration by rhesus monkeys

The effects of intramuscular administration of atropine, methylatropine and physostigmine on intravenous cocaine self-administration in the rhesus monkey were ascertained. Atropine (0.5–2.0 mg/kg) increased cocaine intake, whereas methylatropine, over the same dosage range, produced no change in this behavior. Physostigmine (0.1–0.5 mg/kg) significantly depressed this behavior. The effect of atropine was interpreted as being the results of its central anti-cholinergic action and that of physostigmine, since it was opposite to that of atropine, was attributed to its central cholinergic action. Furthermore it was hypothesized that the effect of these cholinergic interactions on cocaine self-administration resulted from a modulation of the factors which may control self-administration i.e. drug-induced aversiveness or nonspecific behavioral disruption rather than any specific interaction with the neurochemical mechanisms of cocaine mediated reinforcement. The drug effects support the concept of a central cholinergic behavioral inhibitory system which when blocked, e.g., with atropine, results in behavioral activation.     

Second-order schedules of intravenous drug self-administration in rhesus monkeys.

Lever-pressing behavior was generated and maintained in 3 rhesus monkeys by intravenous infusions of morphine or cocaine under a second-order schedule of reinforcement. Under this schedule, every tenth lever-press response (FR 10) during a fixed interval of time produced a 2 sec stimulus light. The first FR 10 completed after a 60 min interval had elapsed produced the stimulus light and an intravenous infusion of morphine or cocaine. The stimulus light remained on for the duration of the drug infusion (50-60 sec). Sessions of morphine or cocaine presentation, each with distinct stimulus light conditions, alternated on a daily basis. Under this schedule, single doses of morphine from 0.125 to 1.0 mg/kg maintained high overall response rates (maximum of 40 Rs/min) in the pattern characteristic of fixed interval (FI) schedules of reinforcement. There was no functional relationship between the response-rates and the doses of morphine tested. The simultaneous infusion of naloxone (0.125 mg/kg/) with morphine (0.25 mg/kg) markedly decreased response rates. However, the infusion of the same dose of naloxone five min after the presentation of morphine failed to suppress self-administration behavior. Naloxone had no effects on cocaine-reinforced responding.     

Naltrexone effects on pituitary and gonadal hormones in male and female rhesus monkeys

The long-acting opioid antagonist, naltrexone, stimulates LH and FSH in women during the early follicular phase of the menstrual cycle and is a new provocative test of hypothalamic-pituitary function (42,63). The acute effects of naltrexone (0.25, 0.50 and 1.0 mg/kg IV) on anterior pituitary (LH, FSH, PRL) and gonadal steroid (T or E2) hormones were studied in 7 female and 4 male rhesus monkeys (Macaca mulatta). Integrated plasma samples were collected at 20 min intervals for 60 min before and for 300 min after intravenous infusion of naltrexone over 10 min. In females studied during the early follicular phase (cycle days 1-3), naltrexone did not stimulate LH and significantly suppressed E2 (p less than 0.0003-0.0001) and FSH (p less than 0.006-0.0001). Naltrexone (0.50 and 1.0 mg/kg) also did not stimulate LH release in late follicular phase females (cycle days 10-12) when estradiol levels were in the peri-ovulatory range. FSH and E2 were significantly suppressed (p less than 0.01-0.05) after 1.0 mg/kg naltrexone, but not after 0.5 mg/kg naltrexone. However, in males all doses of naltrexone significantly stimulated LH (p less than 0.003-0.0001) and T (p less than 0.001-0.0001) but not FSH. LH increased significantly above baseline within 20 to 40 min and T increased significantly within 60 min. These gender differences in naltrexone's effects on pituitary gonadotropins and gonadal steroid hormones were unanticipated. These data are not concordant with clinical studies which report significant naltrexone stimulation of LH in men and in women during the early follicular phase.(ABSTRACT TRUNCATED AT 250 WORDS)     

The intravenous self-administration of antihistamines by rhesus monkeys.

Rhesus monkeys were trained to lever press for infusions of cocaine during daily, 1-h experimental sessions. Following stabilization of the cocaine-maintained baselines, various antihistamines were substituted for cocaine to determine whether they would be self-administered. The results indicated that all monkeys tested self-administered tripelennamine and chlorpheniramine. One monkey out of the four self-administered pyrilamine, but only at a single (300 microgram/kg) high dose. Phenyltoloxamine, cimetidine and hydroxyzine were not self-administered. These results further illuminate differences amongst H1 antagonists in their potential for self-administration and, when examined in context with other reports, suggest that stimulant-like properties may help mediate their reinforcing effects when present.     

Effects of buspirone and gepirone on IV cocaine self-administration in rhesus monkeys

Buspirone and gepirone were evaluated as potential pharmacotherapies for cocaine abuse by studying the effects of acute and repeated treatment on IV cocaine self-administration in rhesus monkeys. Chlorpromazine was also evaluated as a positive control. Effects of IV drug pretreatments were tested during daily 60-min sessions with lever-pressing reinforced under a fixed-ratio 10 schedule of 0.02 or 0.05 mg/kg cocaine infusions. Acute pretreatment with buspirone (0.1 and 0.3 mg/kg, IV) increased rates of cocaine self-administration without disrupting food pellet consumption. Some doses of buspirone also produced changes in rates of cocaine self-administration without altering the within-session pattern of responding. In contrast, acute doses of gepirone had little effect on rates of cocaine self-administration, while disruptions in food consumption and changes in the within-session pattern of cocaine self-administration were obtained at the highest dose of gepirone tested (1.0 mg/kg). When either buspirone (0.1 and 0.3 mg/kg, IV) or gepirone (0.1 mg/kg, IV) were administered daily for 10 days, consistent effects on cocaine self-administration were not observed. Thus, the effects of acute buspirone administration on cocaine-maintained behavior were similar to the effects produced by chlorpromazine and other dopaminergic antagonists, whereas, gepirone was ineffective. These results provide some support for further evaluation of buspirone as a potential pharmacotherapy for cocaine abuse, although its lack of efficacy with repeated treatment is not encouraging. The negative results with gepirone provide less rationale for continued investigations with this drug, possibly because of its lesser involvement than buspirone with dopaminergic neurotransmission.     

Effects of pentobarbital and d-amphetamine on oral phencyclidine self-administration in rhesus monkeys

The purpose of this study was to examine the benzodiazepine-like activity of fominoben-HCl, a compound with prominent antitussive and respiratory stimulant actions. Towards this end we examined the anticonvulsant actions of fominoben as well as its ability to displace benzodiazepine (BDZ) binding from brain membranes. Scatchard analysis of binding data demonstrated that fominoben displaced 3H-flunitrazepam binding from rat cortical membrane preparations. Furthermore when tested against 3H-ethyl-beta-carboline-3-carboxylate, the addition of GABA resulted in a mean (+/- SE) shift of the IC50 from 4.05 +/- 0.10 microM to 2.2 +/- 0.05 microM, a characteristic of benzodiazepine agonists. Seizures were induced in male, Swiss Webster mice with pentylenetetrazol (PTZ) or 3-mercaptoproprionic acid (3-MP). Fominoben (50 and 100 mg/kg) completely protected mice from seizures induced by 50 mg/kg PTZ and elevated the seizure latency against 75 mg/kg of PTZ. The anticonvulsant effects of fominoben were less pronounced against 3-MP-induced seizures. The benzodiazepine antagonist Ro 15-1788 antagonized the anticonvulsant action of fominoben against both convulsants. Taken together, these data suggest that the anticonvulsant action of fominoben may be mediated by agonistic actions at benzodiazepine binding sites.     

Effects of methamphetamine self-administration on actigraphy-based sleep parameters in rhesus monkeys

Rationale

Sleep disorders and substance abuse are highly comorbid. Although methamphetamine is a very commonly abused drug, to the best of our knowledge, no study has evaluated its effects on sleep during drug use and abstinence under well-controlled conditions in laboratory animals.

Objectives

The objective of this study was to examine the effects of methamphetamine self-administration on sleep-like measures in nonhuman primates.

Methods

Adult male rhesus monkeys (Macaca mulatta; n?=?4) self-administered methamphetamine (0.01 and 0.03 mg/kg/injection, i.v.) under a fixed-ratio 20 schedule of reinforcement (60-min sessions once a day, 5 days per week) for 5 weeks. Sleep-like measures were evaluated with Actiwatch monitors before, during, and after each period of drug self-administration.

Results

Both doses of methamphetamine reliably maintained self-administration. Methamphetamine (0.03 mg/kg) increased derived measures of latency to sleep onset and sleep fragmentation, and decreased sleep efficiency compared to abstinence, and higher methamphetamine intake predicted worse sleep quality. However, sleep normalized immediately after the discontinuation of methamphetamine self-administration.

Conclusions

Methamphetamine markedly disrupted sleep-like measures; however, methamphetamine self-administration did not disrupt sleep quality during subsequent periods of drug abstinence.     

Social stimuli enhance phencyclidine (PCP) self-administration in rhesus monkeys

Environmental factors, including social interaction, can alter the effects of drugs of abuse on behavior. The present study was conducted to examine the effects of social stimuli on oral phencyclidine (PCP) self-administration by rhesus monkeys. Ten adult rhesus monkeys (M. mulatta) were housed side by side in modular cages that could be configured to provide visual, auditory, and olfactory stimuli provided by another monkey located in the other side of a paired unit. During the first experiment, monkeys self-administered PCP (0.25 mg/ml) and water under concurrent fixed ratio (FR) 16 schedules of reinforcement with either a solid or a grid (social) partition separating each pair of monkeys. In the second experiment, a PCP concentration-response relationship was determined under concurrent progressive ratio (PR) schedules of reinforcement during both the solid and grid partition conditions. Under the concurrent FR 16 schedules, PCP and water self-administration were significantly higher during exposure to a cage mate through a grid partition than when a solid partition separated the monkeys. The relative reinforcing strength of PCP, as measured by PR break points, was greater during the grid partition condition compared to the solid partition condition indicated by an upward shift in the concentration-response curve. To determine whether the social stimuli provided by another monkey led to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which may have evoked the increase of PCP self-administration during the grid partition condition, a third experiment was conducted to examine cortisol levels under the two housing conditions. A modest, but nonsignificant increase in cortisol levels was found upon switching from the solid to the grid partition condition. The results suggest that social stimulation among monkeys in adjoining cages leads to enhanced reinforcing strength of PCP.