Pharmacologic control of pemoline induced self-injurious behavior in rats

Administration of oral Pemoline produces long lasting amphetamine-type stereotyped behavior and persistent self-biting behavior in rats. The effects of haloperidol, pimozide, diazepam, and serotonin depletion by pretreatment with p-chlorophenylalanine (PCPA) or chronic pretreatment with p-chloroamphetamine (PCA) on abnormal behavior produced by pemoline were studied. Diazepam consistently increased the duration of stereotyped behavior. It also reduced licking/biting and self-biting but the latter effects were not consistent. Pretreatment with PCA had negligible effects on stereotyped behavior. Pretreatment with PCPA dramatically increased locomotion and rearing without affecting the other components of stereotypy--stereotyped head movements, licking/biting, and self-biting. Haloperidol (0.2 and 0.3 mg/kg) produced a dose related normalization of pemoline induced behaviors, including elimination of self-biting. Pimozide (0.5, 0.8 and 1.3 mg/kg) had little or no effect on behaviors such as locomotions, rears, licking/biting, or stereotyped head movements but eliminated self-biting at 1.3 mg/kg. These data suggest that pemoline, like amphetamine, produces stereotyped behavior through central dopaminergic mechanisms. Dopaminergic mechanisms also appear to be involved in pemoline induced self-biting. pemoline is apparently pharmacologically and behaviorally very similar to amphetamine. Pemoline may provide a useful animal model for syndromes characterized by self-injurious behavior and other repetitive behaviors.     

Dissociation of d-amphetamine-induced locomotor activity and stereotyped behaviour by lesions of the superior colliculus

To investigate the role of the nigrotectal pathway in the expression of the behavioral effects of increased dopamine transmission, the behavior of rats with lesions of the superior colliculus was studied in open-field and hole-board after systemic administration of d-amphetamine. The rats with collicular lesions had higher locomotor activity scores than controls after saline injections, and after all doses of amphetamine studied (0.5–24 mg/kg): the difference was particularly marked at the highest doses used (16 and 24 mg/kg). Stereotyped behavior, on the other hand, was less pronounced in the rats with collicular lesions, who unlike controls rarely showed stereotyped sniffing, head waving, or forepaw padding while moving about in either apparatus, and never licked or gnawed in the hole-board. This evidence suggests that the nigrotectal pathway may play a role in the expression of some of the stereotyped behaviors observed after the administration of dopamine agonists, but that it is not necessary for the increased locomotor activity produced by such drugs.     

Effects of histamine agents on methamphetamine-induced stereotyped behavior and behavioral sensitization in rats

In this study, effects of histamine (HA) agents on methamphetamine (METH)-induced stereotyped behavior and behavioral sensitization were examined in rats. Pretreatment with a precursor of HA, L-histidine (750 mg/kg), significantly inhibited the METH (3 mg/kg)-induced stereotyped behavior, whereas pretreatment with an inhibitor of HA synthesis, α-fluoromethylhistidine (FMH) (100 mg/kg), an H₁ antagonist pyrilamine (5 mg/kg) or an H₂ antagonist zolantidine (5 mg/kg) enhanced it. The inhibitory effect of L-histidine on METH-induced stereotyped behavior was significantly blocked by coadministration of pyrilamine and zolantidine, indicating that the effect is mediated through H₁ and H₂ receptors. Moreover, chronic treatment with METH (3 mg/kg) significantly enhanced stereotyped behavior at the rechallenge with METH (1 mg/kg). Chronic treatment with L-histidine (750 mg/kg) plus METH inhibited the METH-induced argumentation of stereotyped behavior, while that with FMH (100 mg/kg), pyrilamine (5 mg/kg) or zolantidine (5 mg/kg) potentiated it. These findings suggest that the HA neuron system has an inhibitory role in METH-induced stereotyped behavior and behavioral sensitization. Received: 1 July 1996/Final version: 26 November 1996     

Acute and long-term effects of thyrotropin releasing hormone on behavior mediated by dopaminergic and cholinergic activities in mice

Acute and long-term (3 weeks) effects of thyrotropin releasing hormone (TRH) on behavior were investigated in mice. A single injection of TRH produced Straub tail, tremor and salivation, as well as stereotyped responses, such as head bobbing, jaw movement, digging and sniffing. Dose- and time-dependency for the effects of TRH were different depending on each response. A single injection of TRH at a low dose of 2.5 mg/kg SC did not produce stereotypy but this behavior was induced when this dose of TRH was administered in combination with atropine (3 mg/kg IP). In addition, a single low dose of TRH elicited tremor and salivation which were potentiated by physostigmine (0.1 mg/kg IP). A single high dose (20 mg/kg IP) produced marked tremor and salivation which were conversely blocked by atropine. Following daily administration of TRH at a low dose of 2.5 mg/kg SC for 21 days, stereotyped behavior was progressively increased whereas tremor and salivation were decreased. This increase in stereotyped behavior was inhibited by haloperidol (1 mg/kg IP) or physostigmine (0.1 mg/kg IP). When saline was administered instead of TRH for 3 days after long-term administration of TRH, stereotyped behavior was maintained for 2 days but thereafter decreased to some extent. When TRH (1.25 mg/kg SC) was again administered at this stage, there was a marked increase in stereotyped response. These results suggest that TRH induces dopaminergic activation, accompanied by both cholinergic inhibition and cholinergic activation, and that the former is potentiated while the latter is reduced after daily administration of TRH.     

The effect of a single administration of phencyclidine on behavior in the rat over a 21-day period

The effects of phencyclidine (PCP) (7.0, 11.7, 19.5, 32.6, and 54.4 mg/kg) on locomotor activity, stereotyped behavior (circling, backing up, and weaving frequency), and rotarod performance were evaluated. In addition, the frequency of other PCP-induced abnormal behaviors (head in corner, arched back, and cataleptic freeze) was determined. All doses of PCP produced a significant increase in locomotor activity and stereotyped behavior as well as an impairment of rotarod performance. Both the duration and the time to peak effects (with the exception of rotarod performance) of these PCP-induced behavioral changes appeared to be dose dependent. The delay in attaining peak effects for locomotor activity and stereotypy was attributed to PCP-induced gross motor ataxia, which became more severe and long lasting with increasing dose. Although the longest period of time that significant changes were seen in locomotor activity, stereotyped behavior, and rotarod performance was 12 hr, sporadic recurrences of stereotypy and a significant increase in cataleptic freeze were observed in the high-dose groups (19.5, 32.6, and 54.4 mg/kg) up to 21 days postadministration. These persistent behaviors (stereotypy and cataleptic freeze) are not unlike certain of the prolonged behaviors seen in man with PCP overdose (catatonic stupor along with repetitive orofacial and limb movements).     

d-Amphetamine in squirrel monkeys of different social status: Effects on social and agonistic behavior,locomotion, and stereotypies

The influences of social status on amphetamine-induced behavioral effects in squirrel monkeys were investigated. Social status was determined by constructing a sociogram. d-Amphetamine (0.3–1.0 mg/kg orally, 0.3 and 0.6 mg/kg IM) increased stereotyped head movements and reduced the time spent in the sitting posture in all monkeys (N=25) regardless of sex, age, or social status. The high levels of locomotor activity in dominant and juvenile monkeys were decreased at higher amphetamine doses (0.6 mg/kg IM, 0.6 and 1.0 mg/kg orally), whereas the same doses increased locomotion in otherwise less active subdominant and submissive animals. Low doses of amphetamine (0.1, 0.3 mg/kg) decreased the incidence of agonistic behavior initiated by dominant monkeys, and higher doses (0.6, 1.0 mg/kg) caused these monkeys to change from predominant initiators of agonistic behavior into recipients. At 2 h after amphetamine administration (0.3 mg/kg IM), the high levels of locomotor behavior had returned to baseline, the social isolation began to disappear, and the disrupted agonistic behavior of dominant monkeys returned to control levels, yet the stereotyped head movements continued to occur with high frequency. In half of the monkeys, amphetamine produced a large increase in distress-like vocalizations. Amphetamine-mediated motor stereotypies may be mediated by mechanisms different than those responsible for agonistic behavior. The selective changes in agonistic behavior by dominant monkeys when challenged with amphetamine may reflect a status-related functional alteration of catecholaminergic processes upon which the drug acts.     

Interaction between d-amphetamine and ethanol with respect to locomotion,stereotypies, ethanol sleeping time,and the kinetics of drug elimination

The interaction between d-amphetamine and ethanol with respect to locomotor activity, stereotyped behavior, and sleeping time was investigated in rats. Ethanol 0.8 g/kg i.p. enhanced and prolonged locomotor activity produced by d-amphetamine 1 mg/kg s.c. The increased motility after 5 mg/kg d-amphetamine was not influenced by alcohol 0.8 g/kg i.p. or 3.2 g/kg orally, but slightly protracted. Stereotyped head and paw movements as well as stereotyped licking, were distinctly strengthened and protracted by 3.2 g/kg ethanol orally. The modified d-amphetamine motility and stereotypies can be explained by alcohol-induced prolongation of the life of d-amphetamine. The effect is produced by alcohol's inhibition d-amphetamine p-hydroxylation in rat liver. After 3.2 g/kg ethanol i.p., the sleeping time of male rats amounted to 153 min. Simultaneous administration of 5 mg/kg d-amphetamine s.c. reduced the sleeping time to 84 min. This is obviously based on a central antagonism.     

Episodic excitation and changes in aggressive behavior induced by apomorphine in rats subjected to rem sleep deprivation

Behavioral changes induced by apomorphine in normal, pseudodeprived (control) and REM sleep-deprived AM-2/TOR inbred rats were investigated. Deprived rats exhibited aggressive behavior for nearly 30 min in the absence of administration of drug, this effect not being observed in normal or control rats. The administration of apomorphine (1, 2 and 5 $\text{mg}\text{kg}$) 5min before the test elicited short periods of aggressive behavior in normal and control rats, but decreased the total duration of aggressive behavior in deprived rats. However, the deprived rats exhibited a more intense aggressive behavior, since the frequency of real fighting events was enhanced. The administration of apomorphine to deprived rats elicited stereotyped behavior. Enhancement of stereotyped behavior by increasing the dose was correlated with a reduction in the duration of aggressive behavior. Apomorphine also induced short episodes of intense excitability, manifested by increased locomotor activity, jumping and vocalization. This behavioral response was termed “episodic excitation”. Deprived rats were significantly more sensitive to apomorphine-induced episodic excitation than normal and control rats. The episodic excitation, stereotyped and aggressive behavior displayed by deprived rats, injected with apomorphine, alternated with time. The results demonstrate increased responsiveness to apomorphine after deprivation of REM sleep. The possible mechanism for such interaction is discussed.     

Effects of the Partial M1 Muscarinic Cholinergic Receptor Agonist CDD-0102A on Stereotyped Motor Behaviors and Reversal Learning in the BTBR Mouse Model of Autism

BackgroundAutism spectrum disorders (ASD) are a set of neurodevelopmental disorders marked by a lack of social interaction, restrictive interests, and repetitive behaviors. There is a paucity of pharmacological treatments to reduce core ASD symptoms. Various lines of evidence indicate that reduced brain muscarinic cholinergic receptor activity may contribute to an ASD phenotype.MethodsThe present experiments examined whether the partial M₁ muscarinic receptor agonist, 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A), alleviates behavioral flexibility deficits and/or stereotyped motor behaviors in the BTBR mouse model of autism. Behavioral flexibility was tested using a reversal learning test. Stereotyped motor behaviors were measured by eliciting digging behavior after removal of nesting material in a home cage and by measuring repetitive grooming.ResultsCDD-0102A (0.2 and 0.6 mg/kg but not 1.2 mg/kg) injected prior to reversal learning attenuated a deficit in BTBR mice but did not affect performance in B6 mice. Acute CDD-0102A treatment (1.2 and 3 mg/kg) reduced self-grooming in BTBR mice and reduced digging behavior in B6 and BTBR mice. The M₁ muscarinic receptor antagonist VU0255035 (3 mg/kg) blocked the effect of CDD-0102A on grooming behavior. Chronic treatment with CDD-0102A (1.2 mg/kg) attenuated self-grooming and digging behavior in BTBR mice. Direct CDD-0102A infusions (1 µg) into the dorsal striatum reduced elevated digging behavior in BTBR mice. In contrast, CDD-0102A injections in the frontal cortex were not effective.ConclusionsThe results suggest that treatment with a partial M₁ muscarinic receptor agonist may reduce repetitive behaviors and restricted interests in autism in part by stimulating striatal M₁ muscarinic receptors.     

Disruption of primate social behavior by d-amphetamine and cocaine: Differential antagonism by antipsychotics

Psychostimulants lead to withdrawal from social interactions and to a decline of affective behavior in squirrel monkeys. These changes, in addition to motor stereotypies, may be related to stimulant-induced psychosis in humans. In the first of two series of experiments, 1 mg/kg d-amphetamine or 10 mg/kg cocaine, administered orally three times over 24 h to one adult male member of an established group (n=6–9), engendered stereotyped movements of the head and hands, reduced rest postures, and greatly reduced all forms of social initiatives. Chlorpromazine (0.25–1.0 mg/kg), haloperidol (0.25, 0.5 mg/kg), and physostigmine (0.04, 0.08 mg/kg), administered before the third amphetamine or cocaine injection, blocked the motor stereotypies and hyperactivity. Chlorpromazine, haloperidol, and physostigmine did not reliably antagonize the pronounced reduction in social behavior. The second series of experiments focused on agonistic behavior in the context of resident-intruder confrontations and on affiliative behavior toward group members. d-Amphetamine (3×0.5 mg/kg) and, to a lesser extent, cocaine (3×10 mg/kg) decreased affiliative and agonistic behavior. Chlorpromazine (0.5, 1.0 mg/kg) and haloperidol (0.1, 0.25 mg/kg) did not block the severe disruption of the affiliative and agonistic behavior in amphetamine-treated monkeys; physostigmine (0.06 mg/kg) reversed the decline in time spent close to the familiar monkey in amphetamine-treated monkeys. By contrast, stimulant-induced stereotypies were effectively antagonized by chlorpromazine, haloperidol, and physostigmine. These results suggest that psychostimulant-induced changes in primate social behavior may be mediated by mechanisms other than those underlying motor stereotypies.     

Modulation of the behavioral effects of amphetamine in rats by clonidine

Clonidine (0.01, 0.05, 0.5 mg/kg) dramatically reduced the locomotor response to amphetamine (2 mg/kg) in a dose related fashion. In contrast, the same doses of clonidine had no effect on locomotions produced by a higher dose of amphetamine (6 mg/kg). Clonidine also had no effect on stereotyped head movements or the duration of the behavioral response to amphetamine. The lower dose of clonidine reduced amphetamine induced licking/biting while the two higher doses potentiated amphetamine induced licking/biting. Thus the behavioral effects of clonidine vary depending upon the dose of amphetamine and the particular behavior selected for study. The known neurochemical effects of clonidine do not account for this phenomenon.     

Sensitization of apomorphine-induced stereotyped behavior in mice is context dependent

Rationale: The role of the environment in the sensitization of the stereotyped behavioral effects of apomorphine is unclear, since sensitization of this drug effect has either been difficult to demonstrate or has been shown to occur with a low but not a higher dose of apomorphine. Objectives: The present study was designed to determine whether sensitization of the stereotyped behavioral effects induced by a single dose of apomorphine is dependent on environmental context. Methods: CF-1 mice were pretreated with apomorphine or vehicle under different environmental conditions and tested for stereotyped behavior after apomorphine challenge. Animals were scored positively for stereotyped behavior if they remained stationary and exhibited repetitive head and/or fore-limb movements, and data are reported as the percentage of mice rated as positive for stereotyped behavior. Results: When mice were pretreated with 40 mg/kg apomorphine and later tested in the same environment, the dose–response curve for stereotyped behavior elicited by apomorphine was shifted threefold to the left 48 h after pretreatment, and this sensitization persisted for at least 28 days after pretreatment. Mice pretreated with apomorphine did not have higher brain levels of apomorphine after administration of the test dose of apomorphine. When the pretreatment environment was different from the test environment, mice did not exhibit sensitization to apomorphine. Conclusions: These results show that pre-exposure to a single high dose of apomorphine induces a long-lasting sensitization of apomorphine-induced stereotyped behavior that is context dependent. Since apomorphine directly activates dopamine receptors, these observations suggest that a mechanism located postsynaptic to dopamine neurons may be responsible for sensitization of stereotyped behavior. Received: 12 November 1998 / Final version: 14 April 1999     

Clozapine and prazosin slow the rhythm of head movements during focused stereotypy induced by <Emphasis Type="Italic">d</Emphasis>-amphetamine in rats

Rationale Clozapine is an efficacious, symptom-ameliorating, atypical antipsychotic drug with few extrapyramidal side effects. Clozapine has been reported either not to affect or to increase d-amphetamine-induced stereotypy, a behavior that is blocked by typical antipsychotic drugs. Objectives This work used a high-resolution measurement system to reassess clozapine’s effects on d-amphetamine-induced focused stereotypy (FS) in rats. Materials and methods A force-plate actometer permitted the quantitation of the rhythm and vigor of movements during FS. Eight rats received a sensitizing series of doses of 5.0 mg/kg d-amphetamine sulfate, and this dosing regimen induced head movements with a rhythm near 10 Hz. Thirty minutes after d-amphetamine treatment, rats received acute clozapine (2.5–10.0 mg/kg), followed by eight, daily clozapine injections (5.0 mg/kg) given with d-amphetamine on days 2, 5, and 8. Effects of acute doses of the α₁-noradrenergic antagonist prazosin (0.5–2.0 mg/kg) on the d-amphetamine response were also examined. Results Clozapine dose-dependently slowed the near 10-Hz rhythm and reduced the vigor of the d-amphetamine-induced FS. Clozapine significantly lengthened the duration of the FS phase, but the rhythm remained slowed. No evidence for tolerance to clozapine’s rhythm-slowing effects was seen in the subchronic phase. Prazosin dose-dependently reduced the near 10-Hz rhythm induced by d-amphetamine, but prazosin did not lengthen the FS phase. Conclusions The results show that clozapine diminished the rhythm and vigor of d-amphetamine-induced stereotyped head movements but, at the same time, lengthened the duration of the expression of the stereotypy. α₁ antagonism is a likely contributor to the rhythm-modulating effects of clozapine. Supported by MH43429 and HD02528     

An analysis of stereotyped behaviour in Mastomys natalensis

Summary The stereotyped behaviour was analysed in Mastomys natalensis, a species of desert rat recently introduced in laboratory practice. The components of stereotyped behaviour were similar to rat characterised by repetitive sniffing, rearing, licking, head movements and biting. Apomorphine (0.5–2.0 mg/kg), amphetamine (2.5–10 mg/kg), methylphenidate (10 – 30 mg/kg) and adamantanamine (10 – 50 mg/kg) administered intraperitoneally, induced stereotyped behaviour in dose-dependent manner. Positive response was also obtained by other drugs acting on dopamine receptors like 1-dopa, GBR 12909, piribedil, tyramine, BS 9648, BS 9641 and BS 8824. Yohimbine (2 mg/kg) failed to produce any response. Apomorphine (2 mg/kg), amphetamine (10 mg/kg), methylphenidate (30 mg/kg) and piribedil (12 mg/kg) induced stereotypy which could be blocked by dopamine receptor blockers haloperidol (1 mg/kg) or pimozide (1 mg/kg) but yohimbine (2 mg/kg) an alpha adrenoceptor blocker was ineffective. Adamantanamine, piribedil and GBR 12909 enhanced the stereotypy induced by low doses of apomorphine, amphetamine and methylphenidate. The data shows that the stereotyped behaviour in Mastomys natalensis is mediated through dopaminergic mechanisms. It appears that both excitatory and inhibitory types of dopamine receptors are involved. Send offprint requests to A. Gulati     

Blockade of dopamine receptors explains the lack of 5-HT stereotypy on treatment with the putative 5-HT1A agonist LY165163

The putative serotonin (5-HT)_1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT_1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.     

Effects of ovariectomy,castration, and chronic lithium chloride treatment on stereotyped behavior in rats

The effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior (SB) induced by apomorphine (APO) (0.3–0.6 mg/kg) were investigated in rats. Duration of stereotyped behavior (interval between APO injection and termination of SB) increased in ovariectomized rats compared to female control rats. Castration had no effect on the duration of stereotyped behavior. On the other hand, ovariectomized rats that were treated chronically with LiCl (2 mEq/kg daily) showed no difference in duration of stereotyped behavior compared to female controls chronically treated with LiCl. Neither treatment group showed a significantly altered intensity of stereotyped behavior compared with the appropriate control. These findings are consisten with the hypothesis that estrogen deficit contributes to a greater incidence of neuroleptic-induced tardive dyskinesia in postmenopausal women than in men of comparable age. Furthermore, LiCl may attenuate the symptoms associated with increased postsynaptic dopamine receptor sensitivity following ovariectomy.     

The effects of lesions produced by 5,7-dihydroxytryptamine on 5-hydroxytryptamine-mediated behaviour induced by amphetamine in large doses in the rat

The role of 5-hydroxytryptamine (5-HT)-containing terminals in the spinal cord and basal ganglia in behavioural responses induced by amphetamine in large doses have been investigated using the neurotoxin for 5-HT, 5,7-dihydroxytryptamine (5,7-DHT). The effects of pretreatment with 5,7-DHT were also examined using the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). d-Amphetamine (25 mg/kg) induced several classical 5-HT-dependent behavioural responses (head weaving, forepaw treading, hind limb abduction, “wet dog” shakes, Straub tail), together with some classical dopamine (DA)-dependent behaviour and backward locomotion which requires both transmitters. Pretreatment with 5,7-DHT, given into the striatum significantly decreased “wet dog” shakes and virtually abolished backward walking. Pretreatment with 5,7-DHT in the nucleus accumbens or substantia nigra did not significantly alter behaviour. Pretreatment with 5,7-DHT intraspinally did not significantly alter behaviour induced by amphetamine, although a decrease of Straub tail just failed to reach significance (P = 0.056). Similar pretreatment in rats given 5-MeODMT (8 mg/kg) significantly enhanced both Straub tail and tremor but did not alter the other behavioural responses induced by this drug (limb abduction, forepaw treading, head weaving). The results in general suggest that behavioural responses induced by 5-HT can be classified into 3 groups (a) those requiring striatal 5-HT (“wet dog” shakes and backward locomotion), (b) those requiring spinal 5-HT (Straub tail, tremor) and (c) those requiring neither spinal nor striatal 5-HT (hind limb abduction, head weaving and forepaw treading).     

Differential sensitivity to acute administration of Ritalin,apormorphine, SCH 23390, but not raclopride in mice selectively bred for hyperactive wheel-running behavior

Rationale. Previous studies of mice (Mus domesticus) selectively bred for high voluntary wheel running have suggested that the hyperactivity is associated with dysfunction in the dopaminergic neuromodulatory system and that high-running mice may represent a useful genetic model for attention deficit hyperactivity disorder (ADHD). Objectives. We tested the hypothesis that mice from the four replicate hyperactive lines would respond differently to methylphenidate (Ritalin), apomorphine (non-selective dopamine agonist), SCH 23390 (selective D1-like dopamine antagonist), and raclopride (selective D2-like dopamine antagonist) than individuals from the four replicate, randomly bred, control lines. Methods. After animals were habituated (3 weeks) to their cages with attached wheels, drugs were administered via intraperitoneal injections, at night, during peak wheel-running activity. Revolutions on wheels 10–70 min post-injection were used to quantify drug responses. Results. Ritalin (15 mg/kg and 30 mg/kg) increased wheel running in control lines but decreased running in selected lines. A low-dose (0.125 mg/kg) of apomorphine reduced wheel running by a similar amount in control and selected lines; however, higher doses of apomorphine (0.25 mg/kg and 0.5 mg/kg) produced greater reductions in wheel running in the control lines. SCH 23390 (0.025, 0.05, and 0.1 mg/kg) caused greater reductions in wheel running in control than in selected lines. Raclopride (0.5, 1, and 2 mg/kg) reduced wheel running by a similar amount in control and selected lines. Conclusions. These results support the interpretation that genetically determined hyperactive wheel-running behavior is associated with altered dopaminergic function in this mouse model. More specifically, results suggest that D1-like (D1 or D5), but not D2-like (D2, D3, or D4), dopamine receptors have reduced function in the high-running mice. The fact that Ritalin decreased wheel running in selected lines further supports their use as an animal model of ADHD. Electronic Publication     

Discrimination of nicotine content in electronic cigarettes

IntroductionBehavioral discrimination of nicotine has only recently been assessed in humans, administered mostly by nasal spray before the newly available Spectrum research cigarettes differing in nicotine content. Here we wanted to explore applicability of these procedures to assess discrimination of nicotine administered by e-cigarettes.MethodsIn this feasibility study, 16 adult smokers were tested on ability to discriminate e-cigarettes with nicotine concentrations of 36, 24, and 12 mg/ml, one per session (in that order), from a placebo (0 mg/ml), each identified only by letter code. Reliable discrimination was defined by accurately identifying which was which (i.e. nicotine vs placebo) on >85% of trials (i.e. ≥7 of 8; p < .05). Subjective perceptions were also assessed.ResultsDiscrimination from placebo was shown with 36 mg/ml and with 24 mg/ml nicotine in 15 of 16 subjects, but only 10 discriminated placebo from 12 mg/ml nicotine. Subjective items previously related to acute nicotine exposure (“how much nicotine”, “head rush/buzzed” on 0–100 VAS) generally showed nicotine concentration-dependent effects, as expected, but so did “throat irritation”.ConclusionsPreliminary results confirm feasibility of using our behavioral procedure to assess ability to discriminate nicotine administered via these e-cigarettes, broadening generalizability of this procedure beyond nicotine via nasal spray and smoked tobacco cigarettes. Findings also suggest its applicability with testing discrimination of nicotine via other methods of rapid dosing (e.g., hookah, novel products), including the newer e-cigarette products. Further study with larger samples may identify individual difference and other factors influencing nicotine discrimination administered via e-cigarettes and other products.     

Gonadectomy and sex differences in the behavioral responses to amphetamine and apomorphine of rats

Following treatment with 5 mg/kg d-amphetamine sulfate or 2 mg/kg apomorphine hydrochloride female rats displayed more intense and longer lasting stereotyped behavior than males. Gonadectomy did not affect the display of stereotyped behavior induced by either drug in either sex. A lower dose of amphetamine (1 mg/kg) caused greater stimulation of locomotor activity in females than in males. Castration of males had no effect, but ovariectomy blocked the stimulating effect of amphetamine on activity. By contrast, low doses of apomorphine depressed activity in a dose-dependent manner that was somewhat greater in ovariectomized females than in the other groups. These data add to the growing body of literature demonstrating that gonadal hormones modulate the activity of brain dopamine systems.