Diethylpropion-induced psychosis reprecipitated by an MAO inhibitor: case report.

A case of diethylpropion-induced psychosis in a 26-year-old woman is reported. The patient's psychosis recurred while she was receiving phenelzine. It is postulated that chronic stimulant use leads to increased sensitivity to the psychosis-inducing effects of monoamine oxidase inhibitors.

An assessment of the spontaneous activity of rats administered morphine, phencyclidine, or nicotine using automated and observational methods.

The effects of morphine, phencyclidine, and nicotine on motor activity in rats were characterized using both observational and automated methods. Activity was scored observationally using a time-sampling method that tabulates discrete response categories (still, locomotion, rearing, sniffing, licking, gnawing, head down, swaying, grooming, falling). Behavior was assessed automatically using an activity monitor that records both the time and activity counts spent in large and small (less than 3 cm) movements, rearing, and resting. The following results using male Sprague-Dawley rats represent significant differences from saline-treated controls. Morphine (1-4 mg/kg SC) increased the incidence of locomotion, sniffing, swaying, and grooming depending on the time after drug injection. These changes corresponded to an increase in large and small movement counts and time as measured by the activity monitor. Phencyclidine (1.25-5 mg/kg SC) caused dose-related increases in the incidence of locomotion, sniffing, swaying, and falling, and induced greater large and small activity movement counts and time especially after the 5 mg/kg dose. Nicotine (0.033-0.33 mg/kg SC) decreased the incidence of rearing and increased the frequency of sniffing and grooming. These changes corresponded to a decrease of rearing activity and to a slight increase in small activity. The present data indicate that morphine, phencyclidine, and nicotine exert dose-related and time-related appearances of various categories of behavior in the rat, and that the data from the automated method complement the findings of the direct observational method.

Nicotine conditions place preferences after intracerebral administration in rats.

A single-trial place conditioning procedure, one treatment and one non-treatment during two daily conditioning sessions followed by a single test session on the 3rd day, was used to examine the place conditioning effects of intracerebrally administered nicotine. In the first series of experiments, Sprague-Dawley male rats were implanted unilaterally with guide cannulas aimed at the lateral ventricle. After 1 week, rats received either "treatment" (nicotine in 2 microliters phosphate buffer or 2 microliters of buffer alone) or "no treatment" (no injections) before being placed in the black or white compartment of a three-compartment place-conditioning apparatus for 20 min. The next day the rats received the opposite treatment before being conditioned in the opposite compartment. On day 3, animals had free access to the entire apparatus for 15 min and the time spent in each compartment was recorded automatically. Even though the rats exhibited a baseline bias for the black compartment, intracerebroventricular nicotine induced positive place preferences relative to buffer control, i.e. if treatments were paired with the black compartment, nicotine enhanced the preference for the black compartment, and if the treatments were paired with the white compartment, nicotine induced a preference for the white compartment. In addition, the nicotine-induced preference response was antagonized by the co-intraventricular administration of mecamylamine. In a second series of experiments, animals were implanted unilaterally with guide cannulas aimed at the pendunculopontine tegmental nucleus of the mesopontine tegmentum. Nicotine microinjection, 1.2-18.5 nmol in 0.5 microliter buffer, induced a dose-dependent positive place preference response.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the pharmacologic effects of N-allylnormetazocine and phencyclidine: sensitization, cross-sensitization, and opioid antagonist activity.

The effects of phencyclidine (PCP) on locomotor activity were compared to those of the stereoisomers of N-allylnormetazocine (NAN) after acute administration to rats. PCP produced swaying and falling movements, increased sniffing behavior, and enhanced horizontal locomotor activity. d-NAN also induced swaying, falling, sniffing behavior and locomotion, and decreased rearing behavior. l-NAN decreased rearing activity, depressed locomotion, antagonized morphine antinociception and precipitated the morphine-withdrawal syndrome. Sensitization to drug-induced sniffing, rearing and locomotion developed after four daily injections of PCP, d-NAN or l-NAN in rats. Rats which were sensitized to PCP-induced locomotion, sniffing, and rearing were also cross-sensitized to both d-NAN and l-NAN. Animals sensitized to the effects of either d- or l-NAN exhibited cross-sensitization to PCP. There was little evidence that the cross-sensitization between the three agents was stereoselective. These data indicate that the acute effects of PCP are similar to those of d-NAN, but differ from l-NAN, the only agent of the three with opioid antagonist properties. The data further indicate that as sensitization to the motor effects develops during repeated administration of PCP, d-NAN or l-NAN, the differences among the three agents become less apparent.

Actions of nicotine on the acquisition of an autoshaped lever-touch response in rats.

Experimentally naive male, Sprague-Dawley rats maintained at 85% of their original body weight were trained to touch a retractable lever that was presented on a random interval 48-s schedule. The lever retracted when touched or after 15 s had elapsed, and one 45 mg food pellet was delivered simultaneously with lever retraction or after an 8-s delay. Rats received ten daily sessions each consisting of ten lever presentations. Nicotine (0.25-0.8 mg/kg SC) administration, either 15 min prior to (pre-session) or immediately after (post-session) the daily autoshaping sessions, caused a significant dose-related impairment of acquisition with the post-session injections having the greater effect. Low doses of nicotine (0.025-0.1 mg/kg SC) had little effect on acquisition when injected pre-session or post-session. Injections of 0.45 mg/kg nicotine either immediately (t = 0) or at +5 min after the daily sessions impaired acquisition of the lever-touch response. Nicotine injected at +15, +30, +60, or +120 min had no effect on acquisition. A single intraventricular injection of the ganglionic blocker chlorisondamine (5 micrograms) 2 weeks prior to autoshaping blocked the impairment produced by 0.45 mg/kg nicotine. Post-session injections of nicotine did not alter the lever-touch behavior of well-trained animals, but suppressed responding in animals that were partially trained. Thus, nicotine-induced impairment of the autoshaped lever-touch response is dose dependent, centrally mediated, occurs within 5 min of a SC injection, and may interfere with post-training consolidation processes.

Conditioned aversion after delay place conditioning with nicotine.

Rats received subcutaneous injections of either nicotine (NIC; 0.05-0.8 mg/kg) or vehicle [VEH (phosphate buffer); 1 ml/kg] immediately after conditioning sessions in a place-conditioning paradigm (delay conditioning). NIC was paired for three delay-conditioning sessions with one environment of a three-compartment place-conditioning apparatus; VEH was paired with another environment. The subjects were then tested for place preference or aversion by determining the proportion of time spent in each compartment during a 15-min test session. Delay conditioning with NIC only produced a dose-related place aversion (greater time was spent in the VEH-paired chamber on test day). Place aversion was evident when NIC, 0.8 mg/kg, was administered either immediately or 5 min after conditioning sessions but not when given 15 min after conditioning. Chlorisondamine (5 micrograms, lateral ventricle), but not saline, administered 2 weeks prior to delay conditioning with 0.8 mg/kg NIC completely blocked the NIC-induced place aversion. These data suggest that delay conditioning with NIC produces place aversion by a central mechanism. Since standard conditioning (NIC injection immediately before the place-conditioning sessions) with NIC only produced dose-related place preferences (Fudala et al. 1985; Fudala and Iwamoto 1986), the time of administration of the unconditioned stimulus is a strong determinant of the place-conditioning effects of NIC.

Circling behavior in rats with 6-hydroxydopamine or electrolytic nigral lesions,.

Unilateral destruction of dopaminergic cell bodies in the substantia nigra zona compacta (SNC) was performed in rats using either electrocoagulation or chemical lesioning (6-hydroxydopamine, 6-OHDA). Neostriatal dopamine concentration ipsilateral to an electrolytic lesion was 34% of the contralateral side 2-3 weeks after operation; serotonin and noradrenaline brain levels were not altered. In contrast, dopamine and noradrenaline forebrain concentrations ipsilateral to a 6-OHDA lesion were 20 and 31%, respectively, of the contralateral side. After 6-OHDA, dopamine concentrations in the ipsilateral neostriatum were reduced to levels below the sensitivity of the fluorometric assay; cortical, brainstem and neostriatal serotonin levels, on the other hand, were not altered after 6-OHDA. Ipsilateral circling behavior was elicited by d-amphetamine after electrolytic and chemical lesioning. In contrast, the direction of circling produced after apomorphine differed between the two lesion models: contralateral circling behavior was exhibited by 6-OHDA-lesioned rats, whereas ipsilateral circling was produced in animals with electrolytic lesions. Contralateral circling was induced in both lesion-type models by haloperidol or pimozide. S.c. atropine administration induced ipsilateral circling in rats with 6-OHDA lesions, whereas contralateral circling was observed after arecoline. Animals with electrolytic SNC lesions turn ipsilaterally after s.c. administrations of either arecoline or atropine. The data indicate that the electrolytic and 6-OHDA circling behavior models represent two different neuropharmacological states and it is, therefore, suggested that comparisons of data obtained from models using different methods of lesioning be made with caution.

Dopaminergic-cholinergic interactions in naloxone-induced circling in morphine-dependent rats with nigral lesions.

3-4 weeks after placement of a unilateral, electrolytic lesion of the substantia nigra zona compacta, rats were highly dependent on morphine by the s.c. morphine pellet implantation technique. Following challenge with a supramaximal naloxone dose of 20 mg/kg i.p., both continuous contralateral circling behavior and severe withdrawal signs in morphine-dependent, lesioned rats were elicited. After various drug pretreatments, the contralaeral circling behavior precipitated by naloxone was: (a) reversed to ipsilateral circling by i.p. apomorphine or d-amphetamine, (b) unaltered by i.p. haloperidol or intraneostriatal arecoline administered into the intact neostriatum, and (c) reversed to ipsilateral circling by the administration of atropine into the intact neostriatum. Atropine, apomorphine and amphetamine all interfered with the manifestation of naloxone-precipitated abstinence. These data suggest that a diminution of dopaminergic or an enhancement of cholinergic activities, or both, occur at the level of the neostriatum during naloxone-precipitated withdrawal in morphine-dependent rats.

Effect of pargyline on morphine tolerance and physical dependence development in mice.

The effects of single and repeated pargyline administration on morphine antinociception in both naive and morphine-tolerant mice and on naloxone-precipitated withdrawal in morphine tolerant-dependent animals were investigated. Adult, male Swiss-Webster mice were rendered tolerant to and dependent on morphine by the s.c. pellet implantion technique. Morphine analgesia, as assessed by the tail-flick antinociceptive test, was potentiated in tolerant animals by acute adminstration of pargyline but antagonized by repeated pargyline administration; pargyline produced similar effects in non-tolerant mice and to the same relative degree. Repeated pargyline treatment during morphine pellet implantation enhanced the withdrawal jumping response precipitated by naloxone in dependent mice. Pargyline also, after a single injection, exacerbated jumping in mice undergoing abrupt withdrawal. Neither acute nor chronic pargyline administration altered the brain distribution of injected morphine in non-tolerant mice. It was concluded that pargyline may modify acute morphine actions and withdrawal without materially altering the process(es) involved in the development of tolerance and physical dependence.

Dynorphin A [1-17] induces "reward" in rats in the place conditioning paradigm.

Intracerebroventricular (i.c.v.) administration of dynorphin A [1-17] induced significant place preference conditioning in male, Sprague-Dawley rats. Place preferences were induced by 2.3 and 3.5 nmole, but not 1.2 nmole of dynorphin A. Co-administration of naloxone, 27.5 nmole but not 5.5 nmole, antagonized the reward response induced by 2.3 nmole of dynorphin A. Leu-enkephalin, 5 or 25 nmole, and dynorphin A [2-17], 2.3 or 3.5 nmole, had no effect in the place conditioning paradigm.

Evidence for a model of activation of central sigma systems.

Evidence for a drug-induced activation of central sigma systems is presented. The model is the locomotor activation initiated by a subcutaneous (SC) challenge of 1.6 mg/kg of (+)-butaclamol, (+)-BUT, given 30 min before 10 mg/kg SC of (-)-N-allylnormetazocine, (-)-NAN, in Sprague-Dawley male rats which have been pretreated with four daily injections of 10 mg/kg SC of (-)-NAN. The locomotor activation is characterized by an initial 20 min period of retropulsion and sideways-circling followed by 90 to 100 min of forward locomotion. The locomotor syndrome is antagonized by 10 mg/kg of (+/-)-BMY 14802, 20 mg/kg of rimcazole, and 0.2 mg/kg of haloperidol, but not by 0.04 mg/kg of R(+)SCH23390, 100 mg/kg of S(-)sulpiride, 10 mg/kg of naltrexone, or 2.5 mg/kg of MR2266. The data suggest that the manifestation of the (+)-BUT/(-)-NAN-induced syndrome depends upon intact transmission at central sigma sites.

Methionine oxidation enhances opioid activity of an enkephalin analog.

D-ala2-met-sulfoxide5-enkephalinamide, DALA(0), was synthesized by oxidizing the 5-methionine residue of D-ala2-met5-enkephalinamide (DALA). Antinociception was assessed on the hot-plate and catalepsy estimated using an immobility test in rats administered DALA, DALA(0) and morphine intraventricularly. By comparing areas under time-effect curves, DALA(0) was 30 times more antinociceptive and up to 40 times more cataleptogenic than DALA. For comparison, morphine induced one-tenth the antinociception and one-fortieth the immobility caused by DALA(0). These results demonstrate that the opiate activity of DALA is clearly enhanced by oxidation of its terminal methionine.

Leu-enkephalin provokes naloxone-insensitive pulmonary vasoconstriction.

Leu-enkephalin evoked dose-dependent pulmonary vasoconstriction in isolated perfused rat lungs. The pressor responses were not attenuated by either naloxone or naltrexone nor were they mimicked by morphine. Blockade of histamine receptors with pyrilamine or blockade of serotonin receptors with methysergide also failed to antagonize leu-enkephalin-induced pulmonary vasoconstrictor responses. These results suggest that neither opiate, histamine, nor serotonin receptors are involved with the pressor effects of leu-enkephalin on the pulmonary circulation. We propose that leu-enkephalin may have direct vasoconstrictor effects on the pulmonary circulation of isolated perfused rat lungs that may not be mediated by conventional opiate receptors.

Nicotine impairs acquisition of radial maze performance in rats.

The effects of nicotine (NIC) and scopolamine (SCOP) on radial maze acquisition were examined using an 8-arm radial maze. In Experiment 1, food-deprived Sprague-Dawley rats were trained to eat food pellets located at the ends of each arm of the radial maze without repeating arm choices. Both NIC (0.45 mg/kg, SC) and SCOP (0.25 mg/kg, IP) impaired acquisition when they were administered before, but not after the daily training sessions. Experiment 2 examined the effect of nicotine on working and reference memory in rats trained to a criterion of 3 correct choices out of the first 4 choices with only 4 of the 8 arms baited. NIC (0.1-0.45 mg/kg) had no effect on working memory (reentry into baited arms) or reference memory (entry into unbaited arms) errors. It is concluded that NIC impairs processes involved in the acquisition but not maintenance of radial maze performance. Neither NIC nor SCOP affects post-training consolidation processes.

Studies on desglycinamide arginine vasopressin and scopolamine in a modified/lever-touch autoshaping model of learning/memory in rats.

Vasopressin administration has been reported to improve acquisition and retard extinction of both conditioned avoidance and food-reinforced behavioral tasks. In the present experiment the effects of a vasopressin analog (DGAVP) and scopolamine (SCOP) were tested in an autoshaped lever-touch model of learning and memory. Rats were food-deprived to 80% of original body weights and tested in modular cages which contained a retractable lever that was presented on a random interval 48 sec schedule. The lever retracted after 15 sec or when it was touched, at which time one 45 mg food pellet was delivered. Subcutaneous injection of 10 micrograms/kg DGAVP 1 hr prior to acquisition and extinction sessions did not alter responding compared to saline controls. DGAVP at doses of 10, 20, and 30 micrograms/kg also failed to affect responding in a more difficult task which included an 8 sec delay between lever retraction and reinforcement. Homozygous Brattleboro rats, which are deficient in vasopressin, did not differ from normal heterozygous littermates in the acquisition of the lever-touch response. Intraperitoneal injection of SCOP (0.1-0.8 mg/kg) 30 min prior to testing caused a dose-related impairment of acquisition compared to saline controls, but did not alter responding in animals which had previously acquired the lever-touch response. These data suggest that manipulations of vasopressin do not affect, while SCOP impairs, the acquisition of a positively reinforced lever-touch response in rats.

Nicotine-induced taste aversion: characterization and preexposure effects in rats.

Rats were trained to drink their 24 hr water intake during a single daily 30 min period. After stabilization, rats were presented with 0.1% (w/v) of sodium saccharin for 30 min. Immediately after removal of the saccharin solution, the animals were injected with saline, mecamylamine hydrochloride or hexamethonium hydrobromide; thirty minutes later, saline or nicotine, 0.05, 0.16, or 0.50 mg/kg were administered. Twenty-four hr later, rats were allowed access to both water and saccharin. Nicotine caused a dose-related decrease in the proportion of fluid consumed as saccharin solution during the 30 min testing situation. Neither mecamylamine nor hexamethonium alone decreased saccharin preference; however, 3 mg/kg of mecamylamine blocked the decrease of saccharin preference induced by nicotine. Preexposure of drug-naive rats to 0.5 mg/kg of nicotine for 2 or 4 days abolished the nicotine-induced taste aversions to saccharin when tested one day, or one week, after conditioning.

Further studies on nicotine-induced conditioned place preference in the rat.

Rats received subcutaneous (SC) injections of either nicotine (NIC, 0.001 to 2.0 mg/kg) or saline (SAL, 1 ml/kg) immediately prior to conditioning sessions in a conditioned place preference (CPP) paradigm. NIC was paired for 3 conditioning sessions with one environment of a 3 compartment CPP apparatus; SAL was paired with another environment. The animals were then tested for place preference by determining the proportion of time spent in each compartment during a 15 min test session. A dose-response curve was obtained for the place conditioning effect of nicotine as measured by its ability to alter baseline preferences calculated from control rats. NIC's place preference, but not place aversion, effect was linearly correlated with respect to dosage within the range of 0.1 to 0.8 mg/kg. NIC, 0.8 mg/kg, induced a place preference when it was administered immediately prior to conditioning sessions, but not when administered 20, 60 or 120 min prior to the sessions. Three repeated conditioning and testing cycles, or the daily administration of NIC for 2 weeks between conditioning and testing cycles had little or no effect on NIC place conditioning. Lobeline (2, 10 and 20 mg/kg) or cotinine (1 to 50 mg/kg) failed to condition a place preference. NIC, 0.1 or 1.2 mg/kg SC, administered to rat pups on postnatal days 5 through 8, did not alter subsequent place preference (induced by 0.8 mg/kg of NIC) measured at approximately 40 and 70 days of age. Periodic measurements of spontaneous motor activity, forelimb grip strength and negative geotaxis were unaltered by the perinatal exposure to nicotine.

Conditioned aversion after delay place conditioning with amphetamine.

Male, Sprague-Dawley rats received subcutaneous injections of either dextroamphetamine sulfate (AMP; 3.0 mg/kg) or vehicle [VEH (phosphate buffer); 1 ml/kg] immediately before (standard conditioning) or after (delay conditioning) conditioning sessions in a place-conditioning paradigm. AMP was paired for 4 conditioning sessions with one compartment of a three-compartment place-conditioning apparatus; VEH was paired for 4 conditioning sessions with another compartment. Animals were then tested for place preference or aversion by determining the proportion of time spent in each compartment during a 15-minute test session. Standard conditioning with AMP produced a place preference while delay conditioning produced a place aversion. Similar findings had earlier been reported from studies involving conditioned place-preferences and aversions with nicotine. These studies demonstrated that the time of drug administration can be as strong a determinant of place-conditioning effects as the drug itself.

An improved drug infusion pump for injecting nanoliter volumes subcortically in awake rats.

A new drug infusion pump capable of injecting nanoliter volumes of drug solution into the brains of awake rats has been constructed which incorporates a new "turntable" commutator and a compact tubing compressor mechanism requiring no gears. Injector cannulas inserted into guide cannulas permanently mounted in the rat's skull are connected to the drug pump by spring-protected, PE 10 tubing. Drug solutions are delivered when the pump rollers compress the drug-filled PE 10 tubing. An additional animal-activated switch and motorized mechanism rotates the drug pump in response to the animal's movements so that the PE 10 drug reservoir is not twisted. Testing the drug pump's performance in vivo with injections of 14C-nicotine into the caudate nucleus shows that drug delivery is both reliable and reproducible.

Pharmacologic characterization of nicotine-induced conditioned place preference.

Rats received subcutaneous injections of either nicotine (0.1 to 1.2 mg/kg) or saline (1.0 ml/kg) immediately prior to conditioning sessions in a conditioned place preference (CPP) paradigm. The drug was paired for 3 conditioning sessions with the non-preferred environment of a 3 compartment place preference apparatus; saline was paired with the preferred environment. The animals were then tested for place preference by determining the proportion of time spent in the preferred and non-preferred compartments during a 15 min test session. Using a statistical method developed for the CPP paradigm, dose-response curves were obtained for the rewarding and aversive effects of nicotine as measured by its ability to alter previously determined baseline preferences obtained from the control animals. Nicotine's rewarding and aversive effects were linearly correlated with respect to dosage within the range of 0.1-0.8 mg/kg (reward increased and aversion decreased). A decrease in reward and an increase in aversion was measured at the 1.2 mg/kg treatment level. Mecamylamine hydrochloride and hexamethonium bromide (at 1.0 mg/kg of the base or ion, respectively) were also tested using the CPP paradigm. While neither compound produced place preferences when administered alone, mecamylamine did block the rewarding effects of 0.8 mg/kg of nicotine when administered 30 minutes prior to the nicotine conditioning sessions. Hexamethonium did not alter nicotine-induced reinforcement. The data suggest that nicotine and its rewarding effects as measured by CPP are primarily mediated by central rather than peripheral events.