Search

Genome-wide association studies in humans have suggested that variants of the cadherin-13 (CDH13) gene are associated with substance use disorder, subjective response to amphetamine, and attention deficit hyperactivity disorder. To examine the role of the Cdh13 and its peptide ligand adiponectin (AdipoQ) in addiction-related behaviors, we assessed Cdh13 knock-out rats and AdipoQ knock-out mice using intravenous cocaine self-administration and conditioned place preference paradigms. During intravenous cocaine self-administration, male Cdh13 heterozygous (+/−) and knock-out (−/−) rats showed increased cue-induced reinstatement compared to wild-type rats when presented with a cocaine-paired stimulus, whereas female Cdh13 rats showed no differences across genotype. Cdh13 −/− rats showed higher responding for a saccharin reinforcer and learned the choice reaction time task more slowly than wild-types. However, we found no differences between Cdh13 −/− and +/+ rats in responding for sensory reinforcement, number of premature responses in the reaction time task, tendency to approach a Pavlovian food cue, conditioned place preference and locomotor activation to cocaine (10 or 20 mg/kg). In AdipoQ −/− mice there was a significant increase in conditioned place preference to methamphetamine (1 mg/kg) but not to a range of d-amphetamine doses (0.5, 1, 2 and 4 mg/kg). Taken together, these data suggest that Cdh13 and AdipoQ regulate sensitivity to psychomotor stimulants and palatable rewards without producing major changes in other behaviors. In humans, these two genes may regulate sensitivity to natural and drug rewards, thus influencing susceptibility to the conditioned drug effects and relapse.

The stimulant, methylphenidate (MPH), is commonly used to treat attention deficit hyperactivity disorder (ADHD) and has been increasingly prescribed for school age children and adolescents. Concerns regarding its long-term effects on later substance use disorders (SUDs) have been raised. Previous animal studies have produced contradictory results regarding whether early exposure to MPH increases or protects against SUD in adulthood. The goal of our study was to determine if clinically relevant doses of MPH during adolescence alter cocaine responsiveness in adulthood in a rat model of ADHD, the spontaneous hypertensive rat (SHR). We pretreated SHRs with saline or MPH (2.5 mg/kg once or twice day) via oral gavage during their dark cycle from postnatal day 35 (p35) to p44. Adult rats (p80) were assessed in an eight-session cocaine-conditioned place preference test (CPP). Four doses of cocaine were administered via intraperitoneal injection (i.p.) during the conditioning sessions: 1, 5, 10 and 20 mg/kg. Once per day MPH treatment had a small sensitizing effect on baseline general locomotor activity in a novel environment at p80 as well as a limited suppressive effect on reward-specific locomotor activity as measured by the decreased preference to enter the cocaine-paired chamber. This treatment did not have any effect on the amount of time that rats chose to spend in the cocaine-paired chamber. Twice per day MPH treatment had no effect on locomotion or drug-preference. Our results suggest that MPH treatment of ADHD rats during adolescence does not alter preference for cocaine in adulthood.

Stimulant drugs such as nicotine (NIC) and methylphenidate (MPH) are hypothesized to increase the reinforcing value of sensory stimuli, thus increasing the effectiveness of such reinforcers as alternatives to sucrose reinforcers. Inbred Fischer-344 rats (n = 30) were assigned to three groups: saline (SAL; n = 10), nicotine (NIC; n = 10), or methylphenidate (MPH; n = 10). Testing was done in three phases: sucrose only, (SUC), sucrose and drug (SUC/DRUG), and sucrose, drug, and social reinforcement (SUC/DRUG/SOC). During the SUC phase, rats were trained on a progressive ratio 5 (PR5) reinforcement schedule for sucrose (20% solution). In the SUC/DRUG phase, animals were treated with SAL, NIC (0.4 mg/kg, n = 10 SC), or MPH (2.0 mg/kg, n = 10 IP) 30 min prior to testing. In the SUC/DRUG/SOC phase, animals continued receiving drug treatment, and social reinforcement was introduced concurrently with the sucrose reinforcer. The progressive ratio for each reinforcer ran independently of the others. Reinforcing value was measured as break point (BP), the highest number of responses resulting in a reinforcer. SAL-treated animals showed no significant change in sucrose BP. MPH-treated animals showed decreased sucrose BP in the SUC/DRUG phase, with a further reduction in the SUC/DRUG/SOC phase. NIC-treated animals decreased sucrose BP only when a social alternative was offered. Both NIC and MPH reduce the sucrose BP in the presence of a social alternative. The decrease in sucrose responding, coupled with increased social responding, suggests that the social alternative acted as an effective alternative reinforcer to sucrose. From a translational perspective, these results suggest that stimulant drugs such as NIC and MPH may increase the effectiveness of treatments that use alternative social reinforcers to decrease eating.

© 2016, Springer-Verlag Berlin Heidelberg. Rationale: Disorders of behavioral regulation, including attention deficit hyperactivity disorder (ADHD) and drug addiction, are in part due to poor inhibitory control, attentional deficits, and hyper-responsivity to reward-associated cues. Objectives: To determine whether these traits are related, we tested genetically variable male and female heterogeneous stock rats in the choice reaction time (CRT) task and Pavlovian conditioned approach (PavCA). Sex differences in the response to methylphenidate during the CRT were also assessed. Methods: In the CRT task, rats were required to withhold responding until one of two lights indicated whether responses into a left or right port would be reinforced with water. Reaction time on correct trials and premature responses were the operational definitions of attention and response inhibition, respectively. Rats were also pretreated with oral methylphenidate (0, 2, 4 mg/kg) during the CRT task to determine whether this drug would improve performance. Subsequently, during PavCA, presentation of an illuminated lever predicted the delivery of a food pellet into a food-cup. Lever-directed approach (sign-tracking) and food-cup approach (goal-tracking) were the primary measures, and rats were categorized as “sign-trackers” and “goal-trackers” using an index based on these measures. Results: Sign-trackers made more premature responses than goal-trackers but showed no differences in reaction time. There were sex differences in both tasks, with females having higher sign-tracking, completing more CRT trials, and making more premature responses after methylphenidate administration. Conclusions: These results indicate that response inhibition is related to reward-cue responsivity, suggesting that these traits are influenced by common genetic factors.

Recent research has suggested that intra-individual variability in reaction time (RT) distributions of children with ADHD is characterized by a particularly large rightward skew that may reflect lapses in attention. The purpose of the study was to provide the first randomized, placebo-controlled test of the effects of the stimulant methylphenidate (MPH) on this tail and other RT distribution characteristics. Participants were 49 9- to 12-year-old children with ADHD. Children participated in a 3-day double-blind, placebo-controlled medication assessment during which they received long-acting MPH (Concerta®), with the nearest equivalents of 0.3 and 0.6 mg/kg t.i.d. immediate-release MPH. Children completed a simple two-choice speeded discrimination task on and off of medication. Mode RT and deviation from the mode were used to examine the peak and skew, respectively, of RT distributions. MPH significantly reduced the peak and skew of RT distributions. Importantly, the two medication effects were uncorrelated suggesting that MPH works to improve both the speed and variability in responding. The improvement in variability with stimulant treatment is interpreted as a reduction in lapses in attention. This, in turn, may reflect stimulant enhancement of self-regulatory processes theorized to be at the core of ADHD.

Rationale Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT2A receptors, with serotonergic receptors of the 5-HT1A and 5-HT2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT2A receptor density is decreased and, at a functional level, the head-twitch response following the administration of DOI, an index of activation of 5-HT2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter. Objective Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice. Methods SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle. Results The visual stimulus exerted control in both genotypes. LSD-induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital-induced stimulus control in 80% of WT mice and 54% of knockout mice. Conclusions Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT1A and/or 5-HT2A receptors underlies the absence of stimulus control by LSD.

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.

Behavioral and neuronal abnormalities observed in mice exhibiting a reduced expression of the dopamine transporter model important aspects of schizophrenia, addiction, and attentional disorders. As the consequences of a chronic hyperdopaminergic tone for striatal output regulation have remained poorly understood, the present experiments were designed to determine the status of striatal interneuronal cholinergic neurotransmission in dopamine transporter knockdown animals. The high-affinity choline transporter represents the rate-limiting step of acetylcholine synthesis and release. Compared with wild type mice, striatal high-affinity choline transporter expression in dopamine transporter knockdown mice was significantly decreased. As in vivo basal striatal acetylcholine release did not differ between the strains, reduced high-affinity choline transporter expression in dopamine transporter knockdown mice was not due to reduced basal cholinergic activity. Furthermore, the proportion of high-affinity choline transporters expressed in plasma membrane-enriched versus vesicular membrane-enriched fractions did not differ from wild type animals, suggesting that changes in intracellular high-affinity choline transporter trafficking were not associated with lower overall levels of striatal high-affinity choline transporters. Synaptosomal choline uptake assays indicated a reduced capacity of striatal high-affinity choline transporters in dopamine transporter knockdown mice, and thus the functional significance of the reduced level of high-affinity choline transporter expression. Likewise, in vivo measures of the capacity of striatal high-affinity choline transporters to clear increases in extracellular choline concentrations, using choline-sensitive microelectrodes, revealed a 37-41% reduction in hemicholinium-sensitive clearance of exogenous choline in dopamine transporter knockdown mice. Furthermore, clearance of potassium-evoked choline signals was reduced in dopamine transporter knockdown mice (1.63+/-0.15 microM/s) compared with wild type animals (2.29+/-0.21 microM/s). Dysregulated striatal cholinergic neurotransmission is hypothesized to disrupt the integration of thalamic and cortical information at spiny projection neurons and thus to contribute to abnormal striatal information processing in dopamine transporter knockdown mice.

Rationale Drug-induced stimulus control has proven to be a powerful tool for the assessment of a wide range of psychoactive drugs. Although a variety of species has been employed, the majority of studies have been in the rat. However, with the development of techniques which permit the genetic modification of mice, the latter species has taken on new importance. Lysergic acid diethylamide [LSD], the prototypic indoleamine hallucinogen, has not previously been trained as a discriminative stimulus in mice. Objective To demonstrate the feasibility of LSD-induced stimulus control in the mouse and to provide a preliminary characterization of the stimulus properties of LSD in that species. Methods Male C57BL/6 mice were trained using a left or right nose-poke operant on a fixed ratio 10, water reinforced task following the injection of lysergic acid diethylamide [LSD, 0.17 or 0.30 mg/kg, SC; 15 min pretreatment] or vehicle. Results Stimulus control was established in 6 of 16 mice at a dose of LSD of 0.17 mg/kg after 39 sessions. An increase in dose to 0.30 mg/kg for the remaining mice resulted in stimulus control in an additional 5 subjects. In the low dose group, subsequent experiments demonstrated an orderly dose–effect relationship for LSD and a rapid offset of drug action with an absence of LSD effects 60 min after injection. When LSD [0.17 mg/kg] was administered in combination with the selective 5-HT2A antagonist, M100907, LSD-appropriate responding was significantly but incompletely reduced to approximately 50%; concurrently, response rates declined significantly. In mice trained with a dose of LSD of 0.30 mg/kg, full generalization to the phenethylamine hallucinogen, [−]-2,5-dimethoxy-4-methylamphetamine [DOM] was observed. Conclusions The present data demonstrate the feasibility of LSD-induced stimulus control in the mouse. The general features of stimulus control by LSD in the mouse closely resemble those observed in the rat but the present data suggest that there may be significant differences as well.

Crack cocaine use is more associated with impulsivity and a propensity to take risks than heroin use, yet no studies have examined this relationship in the absence of acute drug effects. The current study examined impulsivity (using the Delay Discounting Task) and risk-taking propensity (using the Balloon Analogue Risk Task) across independent groups of primary crack cocaine users with minimal heroin use (n = 16) and primary heroin users with minimal crack cocaine use (n = 11) in residential treatment, with all participants drug abstinent during participation. Crack cocaine users evidenced greater levels of impulsivity and risk-taking propensity, with only the difference in impulsivity persisting after controlling for age and gender. These data hold potential theoretical importance in understanding differences between crack cocaine and heroin users, as the findings cannot be attributed solely to acute pharmacological drug effects.

This study examined the effects of low, therapeutic doses of diazepam on several measures of impulsive behavior in healthy volunteers. Volunteers (N=35) participated in a three-session double-blind randomized design in which they received diazepam (5 or 10 mg) or placebo. The volunteers were classified as high and low impulsive based on the Barratt Impulsiveness Scale-11 (BIS-11). One hour after ingesting the capsule on each session, participants completed mood questionnaires and five impulsivity tasks: go/no-go task, delay discounting task, time estimation task, stop task, and the balloon analogue risk task (BART). Diazepam (5 and 10 mg) produced its prototypic sedative-like mood effects. However, the drug did not affect performance on any of the measures of impulsive behavior in either the high or low BIS participants. These results suggest that low doses of diazepam, including doses that are used therapeutically, do not increase impulsive behavior. Whether higher doses would increase impulsivity remains to be determined.

It has been reported that human opiate addicts discount delayed rewards more than non-addicts, indicating that they are more impulsive. However, it is not clear whether this difference reflects pre-existing traits, or the effects of exposure to the opiates. This study was designed to investigate the effects of an opioid agonist and antagonist on delay discounting in rats. The study had three objectives: to determine (1) the acute effects of the opioid agonist morphine (MOR) on delay discounting, (2) the acute effects of the opioid antagonist naltrexone (NAL) on delay discounting, and (3) whether NAL reverses the effects of MOR on delay discounting. An adjusting amount procedure (AdjAmt) was used to determine how much animals discounted the value of delayed rewards. Acute doses of MOR (0.3, 1.0, and 1.8 mg/kg SC), NAL (0.01, 0.1, 1.0, and 10 mg/kg SC) and NAL (0.1 mg/kg SC) prior to MOR (1.8 mg/kg SC) were tested in 15 rats. MOR dose dependently increased the rate of delay discounting (i.e., made the animals more impulsive). NAL alone had no effect on the value of delayed rewards, but NAL blocked the effects of MOR. These results suggested that the direct effects of MOR may contribute to the high level of impulsive behavior seen among opiate users.

Rationale: Moderate doses of d-amphetamine (given both acutely and chronically) have been shown to decrease impulsivity in children with attention deficit hyperactivity disorder (ADHD) and to improve attention and learning in normal adults. In contrast, chronic doses of methamphetamine (METH) in drug abusers have been associated with increased impulsivity, and impairments in learning and attention. Objectives: We report the effects of METH on an animal model of impulsive behavior. Methods: Rats were tested using the adjusting amount (AdjAmt) procedure in which the animals choose between a delayed fixed (large) amount of water and an immediate adjusting (small) amount of water. In the acute METH study, rats were given a single dose of 0.5, 1.0, 2.0, and 4.0 mg/kg METH or saline 30 min before testing. In the chronic METH study, we determined the effects of the 4.0 mg/kg dose of METH injected chronically 1 h after behavioral testing for 14 days. Thus the rats were tested using the AdjAmt procedure 22 h after injections of METH or saline. Results: After 0.5, 1.0 and 2.0 mg/kg METH, the rats valued the delayed large rewards more than after saline, indicating that the METH decreased impulsiveness. At the 4.0 mg/kg dose, the rats failed to respond. Rats treated repeatedly with the post-session large behaviorally disruptive dose of METH valued the delayed large rewards less than the saline-treated rats, indicating that this dosing regimen of METH increased impulsiveness. Conclusions: In these experiments, the rats became less impulsive after acute non-disruptive doses of pre-session METH, whereas they became more impulsive after receiving repeated post-session injections of a dose that was behaviorally disruptive when administered acutely.

Background: The functioning of the brain serotonin system has been implicated in the action of antidepressant drugs. The behavior of rats performing the Differential Reinforcement of Low Rate–72 sec (DRL 72s) has been used as a screen for drugs with antidepressant activity. Many antidepressant drugs alter serotonergic function. Hence, experiments were designed to investigate the role of the brain serotonin system in the performance of DRL 72s behavior. Methods: Rats were trained to perform a DRL 72s, and then depleted (LESION) of brain serotonin (5-HT) using intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT). Control rats (SHAM) were injected with the 5,7-DHT vehicle. Results: The 5,7-DHT-treated rats showed a higher response rate, a decrease in the number of reinforcements, and a shift in the interresponse time (IRT) distribution toward shorter IRTs when compared to SHAM and prelesion performance. The behavioral deficit in the 5,7-DHT rats persisted for 17 weeks. Postmortem assays indicated extensive depletion of 5-HT in all the assayed brain regions of the LESION rats. The effects of the serotonergic agonists 8-hydroxy-2-di-N-propylaminotetralin (8-OH-DPAT), 5-methoxy-dimethyltryptamine (5-MeODMT), buspirone, and 5-hydroxytryptophan (5-HTP) were assessed. 5-MeODMT and 8-OH-DPAT resulted in greater improvement of DRL 72s performance in the LESION rats than in the SHAM rats. Buspirone failed to ameliorate the behavioral deficit in the LESION rats and produced a behavioral deficit in the SHAM rats. 5-HTP improved performance in the SHAM rats and in the LESION rats. Conclusions: These results support the contention that the brain 5-HT system is involved in the mediation of antidepressant drug effects.

BIMT 17, the only compound reported to be a full 5-HT1A agonist and a 5-HT2A antagonist at the frontal cortex, was assessed in three animal paradigms sensitive to antidepressants in rats: olfactory bulbectomy (OB), differential-reinforcement-of-low rate 72-s (DRL 72-s) and learned helplessness (LH). In the OB rats, BIMT 17, given once daily for 14 consecutive days at an i.p. dose of 10 mg/kg, but not of 20 mg/kg, reduced the increase in ambulation of OB rats, 24 h after the last administration. In the DRL 72-s test, BIMT 17 had a different profile than imipramine. A single i.p. injection of 5, 10, 15 or 20 mg/kg BIMT 17, in contrast to the same doses of imipramine, did not affect response and reinforcement rate in DRL 72-s 1 h after the administration. On the other hand, BIMT 17 slightly shifted the peak of the interresponse time (IRT) distribution towards shorter IRT duration, while imipramine shifted the peak of the IRT distribution towards longer IRT duration. In the LH test, acute oral doses (36, 48 or 60 mg/kg) of BIMT 17, given 30 min before testing, reduced the number of escape failures in LH without altering the intertrial crossings. This effect was also induced by a repeated, but not single, administration with 8 or 16 mg/kg imipramine. The plasma levels following i.p. 10 or oral 48 mg/kg BIMT 17 were in the same range. These results indicate that BIMT 17 does not behave like imipramine in all the tests, and suggest that BIMT 17 acts through different mechanisms of action than imipramine. Only clinical trials will tell whether these mechanisms will be relevant, but if so, BIMT 17 might induce a faster onset of therapeutic activity.

Background Light onset can be both a sensory reinforcer (SR) with intrinsic reinforcing properties, and a conditioned reinforcer (CR) which predicts a biologically important reinforcer. Stimulant drugs, such as methamphetamine (METH), may increase the reinforcing effectiveness of CRs by enhancing the predictive properties of the CR. In contrast, METH-induced increases in the reinforcing effectiveness of SRs, are mediated by the immediate sensory consequences of the light. Methods The effects of novelty (on SRs) and METH (on both CRs and SRs) were tested. Experiment 1: rats were pre-exposed to 5 s light and water pairings presented according to a variable-time (VT) 2 min schedule or unpaired water and light presented according to independent, concurrent VT 2 min schedules. Experiment 2: rats were pre-exposed to 5 s light presented according to a VT 2 min schedule, or no stimuli. In both experiments, the pre-exposure phase was followed by a test phase in which 5 s light onset was made response-contingent on a variable-interval (VI) 2 min schedule and the effects of METH (0.5 mg/kg) were determined. Results Novel light onset was a more effective reinforcer than familiar light onset. METH increased the absolute rate of responding without increasing the relative frequency of responding for both CRs and SRs. Conclusion Novelty plays a role in determining the reinforcing effectiveness of SRs. The results are consistent with the interpretation that METH-induced increases in reinforcer effectiveness of CRs and SRs may be mediated by immediate sensory consequences, rather than prediction.

The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5-HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT1A compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT1A compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT1A receptor.

Rats were treated with a high-dose methamphetamine (METH) regimen (50 mg/kg 3 times at 8-h intervals). Three weeks after treatment, they were trained on a reaction-time task. METH-treated rats failed to improve over a 3-month test period, while controls demonstrated a gradual increase in reaction-time speed over the same test period. METH treatment resulted in a significant dopamine depletions in the caudate/putamen and nucleus accumbens/olfactory tubercle; significant serotonin depletions in caudate/putamen, nucleus accumbens/olfactory tubercle, somatosensory cortex, amygdala and hippocampus. In contrast to the decreases observed in other brain regions, serotonin levels were significantly greater than controls in the hypothalamus. It is suggested that the behavioral impairment in the METH-treated animals is due to (a) serotonin and/or dopamine depletions or (b) abnormal or hyper-innervation of serotonin to the hypothalamus.

The beta adrenergic (beta) agonist salbutamol increased reinforcement rates and decreased response rates on a differential-reinforcement-of-low-rate (DRL) 72-S schedule. These changes in DRL 72-S schedule performance are also produced by most clinically used antidepressants. The effects of salbutamol on a DRL 72-S schedule were dose-dependently antagonized by the beta antagonist metoprolol, but not changed by the 5HT antagonist methysergide. Additionally, neither salbutamol nor the antagonism of salbutamol by metoprolol caused disruption of DRL 72-S schedule performance. These results indicate that stimulation of beta receptors, and not of 5HT receptors, mediates salbutamol antidepressant-like effects on a DRL 72-S schedule.

Rats with hippocampal dialysis probes were treated with DL-fenfluramine (FEN), fluoxetine, or FEN with fluoxetine pre-treatment. FEN (12.5 mg/kg) increased extracellular serotonin (5-HT) from 0.4 +/- 0.04 to 25.2 +/- 4.16 pg/10 microliters. Fluoxetine (10.0 mg/kg) increased extracellular 5-HT levels from 0.4 +/- 0.05 to 2.4 +/- 0.33 pg/10 microliters. FEN-induced increases in extracellular 5-HT were attenuated by 66% with fluoxetine pre-treatment. This result supports the view that the 5-HT releasing properties of FEN are mediated by the 5-HT uptake transporter.

Rats were administered 8 injections of 12.5 mg/kg fenfluramine over a 4-day period. Extracellular hippocampal serotonin levels were monitored in vivo during the 4-day treatment period. Predrug baseline serotonin levels were 0.6 +/- 0.17 pg/5 microliters; 60 min after the first fenfluramine injection extracellular serotonin levels were increased to 28.06 +/- 5.2 pg/5 microliters. Fenfluramine-induced increases in serotonin were substantially reduced on the 2nd through 4th days of the regimen. Baseline serotonin levels were increased on days 2 through 4 of the treatment regimen. In a separate group of animals post-mortem tissue concentrations of serotonin were measured 2 weeks after 1,2,4, or 8 injections of 12.5 mg/kg fenfluramine. There were decreases in serotonin tissue concentrations which were related to the number of fenfluramine injections administered. The in vivo dialysis and post-mortem tissue assay results are consistent with the view that fenfluramine is neurotoxic.

We describe an interresponse-time analysis of performance on a differential-reinforcement-of-low-rate 72-s schedule. This analysis compares the obtained interresponse-time distribution of individual rats to a corresponding random interresponse-time distribution. The random interresponse-time distribution is a negative exponential probability function; it predicts the relative distribution of interresponse times if the rat emitted the same number of responses randomly (i.e., with a constant probability) with respect to time. The analysis provides quantitative measures of peak location and dispersion of the interresponse times toward random performance. In Experiment 1, an unexpected outcome of this analysis was that the rats would have obtained more reinforcers had they responded at the same rate but randomly. Based on the interresponse-time analysis in Experiment 1, it was shown that rats trained on the differential-reinforcement-of-low-rate 72-s schedule could increase the number of reinforcers obtained in two ways: first, by a coherent shift of the interresponse-time distribution toward longer durations and, second, by dispersal of the interresponse times toward a random interresponse-time distribution. Experiment 2 applied the analysis described in Experiment 1 to the effects of desipramine and gepirone. Both drugs decreased response rate and increased reinforcement rate, but their effects on the distribution of interresponse times were different. The increase in reinforcement rate observed with desipramine was accompanied by a coherent shift of the reinforcement rate observed with gepirone was accompanied by dispersal of the interresponse-time distribution toward the random negative exponential prediction.

Rats were trained to rotate for a water reward using a procedure which required each rat to turn in both the left and right directions. The rats were then lesioned with unilateral injections of 6-hydroxydopamine in the nigrostriatal bundle to produce unilateral dopamine depletion. Rats which had greater than 95% depletion had significant deficits in turning both ipsilateral and contralateral to the depleted side. Circling contralateral to the lesion was more impaired than circling ipsilateral to the lesion. All animals showed deficits in both the initiation of movement and in speed of turning. In addition, the rats displayed a chronic turning bias in the ipsilateral direction 16 weeks postlesion. These results indicate that unilateral dopamine depletion causes a variety of impairments in trained circling behavior. Although contralateral circling is most impaired, there is a significant decrease in ipsilateral performance. We conclude that normal conditioned circling behavior requires bilateral dopamine innervation.

In vivo dialysis was used to measure extracellular fluid concentrations of dopamine and dihydroxyphenylacetic acid (DOPAC) in rats which were trained to run on a circular disk treadmill for water reinforcement. Turning resulted in bilateral increases in DOPAC in lateral striatum as well as nucleus accumbens/medial striatum. Dopamine release showed small but not significant increases at both sides. Changes in DOPAC release were not lateralized. Free drinking without circling also resulted in significant increases in DOPAC in these two brain areas. During free drinking, dopamine release was significantly increased in lateral striatum but not in nucleus accumbens/medial striatum. These experiments indicate that dopamine metabolism is increased in rat striatum and nucleus accumbens in animals running on circular treadmills as well as by free drinking.

There are reports that diazepam can increase, decrease, or have no effect on measures of impulsive behavior, which may be related, in part, to differences among the tasks used to measure impulsivity. This study examined the effects of a relatively high dose of diazepam (20 mg) on 5 measures of impulsive behavior in healthy adult men and women. Volunteers (N = 18) participated in a 2-session double-blind randomized design in which they received 20 mg diazepam or placebo. One hour after ingesting the capsule, participants completed mood questionnaires and several impulsivity tasks to measure subtypes of impulsive behavior, including behavioral inhibition, delay and probability discounting, and risk taking. Diazepam impaired behavioral inhibition but had no effect on measures of discounting or risk taking. These results are discussed in the context of other recent findings suggesting that different behavioral indices of impulsivity are dissociable and governed by separate underlying mechanisms.

This study investigated the acute behavioral effects of d-amphetamine on several behavioral indices of impulsivity. Impulsivity has been defined, variously, as difficulty in inhibiting inappropriate behaviors, inability to wait, insensitivity to delayed consequences or an alteration in the perception of time; standardized procedures have been developed to measure these behavioral dimensions. However, it is not known how drugs affect these measures, and few studies have examined more than one measure in a single study. In this study, 36 healthy men and women participated in three sessions, in which they received placebo, 10 mg, or 20 mg d-amphetamine in randomized order. On each session they performed the following five tasks: the Stop Task, which measures behavioral inhibition, a delay discounting task, which measures the relative value of immediate vs. delayed rewards, a delay of gratification task, a Go/No-Go task, and a time estimation task. Subjects also completed mood questionnaires. Amphetamine produced its expected subjective, mood-altering effects, including increases in POMS Friendliness and Elation scales, and ARCI Euphoria and Stimulant scales. On the measures of impulsivity, amphetamine decreased impulsive responding on three of the tasks: on the Stop Task it decreased Stop reaction times without affecting Go reaction time, on the Go/No-Go task, it decreased the number of false alarms, and on the delay discounting measure, amphetamine (20 mg) decreased k values indicating less discounting of delayed reward. Other measures of impulsive behavior were unaffected. These results suggest that acute doses of amphetamine decrease several forms of impulsive behavior. These findings extend and confirm previous findings in humans and laboratory animals.

This study was designed to develop a version of the stop task, a putative measure of behavioral inhibition, for use in rats and to assess the effects of d-amphetamine (AMP) and alcohol (ALC). The stop task provides a quantitative index of the ability to inhibit a response that has been initiated. Rats (N = 11) were tested after intraperitoneal injections of AMP (0.125, 0.25, 0.5, 1.0 mg/kg) and ALC (250, 500, 750 mg/kg). AMP improved the ability to inhibit responses only in rats with relatively poor inhibitory performance at baseline. ALC impaired inhibition at doses that did not affect simple reaction time. The results support the sensitivity, reliability, and validity of the procedure as a measure of behavioral inhibition in rats and are highly concordant with a parallel study conducted with humans.

Rationale: Impulsive individuals exhibit an exaggerated preference for immediate rewards over delayed but larger rewards, perhaps because they value the delayed rewards less. Dopamine (DA) has been postulated to mediate the incentive value of rewards, thus it may also mediate the exaggerated preference for immediate rewards in impulsive individuals. In this paper, we investigate the effects of DA agonists and antagonists on the value of delayed versus immediate rewards. Objectives: The study had three main objectives: (1) to determine the effects of D1 and D2 type DA antagonists on the value of delayed rewards, (2) to determine the effect of the indirect DA agonist d-amphetamine on the value of delayed rewards, (3) to determine the sensitivity of the adjusting amount (AdjAmt) procedure to acute one-day changes in delay to reward, amount of reward, deprivation level and starting amount. Methods: In the AdjAmt procedure, rats choose between an adjusting amount of water given immediately (adjusting alternative) and a constant 150 µl water delayed by 4 s (standard alternative). The immediate amount of water is adjusted across trials until the rat chooses both alternatives with equal frequency (indifference point). The final adjusted amount is an indicator of the subjective value of the standard alternative. Results: The D1/D2 antagonist flupenthixol (25, 50, and 100 μg/kg) and the D2 antagonist raclopride (40, 80, and 120 μg/kg), decreased the indifference points, whereas the D1 antagonist SCH 23390 (5, 10, and 20 μg/kg) did not affect the indifference point. All three DA antagonists slowed responding. The indirect DA agonist amphetamine (0.5, and 1.0 mg/kg) had effects opposite to those of the DA antagonists, it decreased choice latency, increased the number of trials completed and increased the indifference point. Decreasing the water deprivation level (6, 24, and 48 h) had no effect on the indifference points but slowed responding. Increasing the delay to reward (2, 4, and 8 s) and decreasing the amount of water available for choosing the standard alternative (300, 150, 75 µl) decreased the indifference point. Conclusions: The results indicate that amphetamine increased the value of delayed rewards (decreased impulsivity) and that D2 but not D1 receptor antagonists decreased the value of delayed rewards (increased impulsivity). The procedure was sensitive to acute 1-day changes in delay and magnitude of reward.

Amphetamine and related compounds have previously been shown to differentially release dopamine (DA) and serotonin (5HT) in vivo and in vitro. The purpose of this report is directly to compare five amphetamine analogs on differential reinforcement of low rate 36-s (DRL 36-s) schedule performance, and to determine whether the reported increases in dopamine and/or serotonin release induced by these drugs can be related to observed behavioral differences. Amphetamine (AMPH) and methamphetamine (METH) induced large increases in response rate, methylene-dioxymethamphetamine (MDMA) and para-chloroamphetamine (PCA) caused small increases in response rate, while fenfluramine (FEN) had no effect on response rate. AMPH, METH, PCA and MDMA caused a dose-dependent decrease in reinforcement rate, and FEN had no effect on reinforcement rate. AMPH, METH, and PCA but not FEN, shifted the peak of the inter-response time (IRT) distribution toward shorter intervals, MDMA decreased peak location only at the highest dose. All five drugs caused a dose-dependent decrease in peak area, indicating a loss of schedule control on the DRL 36-s schedule. Consistent with in vitro and in vivo release studies, the differential results of these five drugs on DRL 36-s schedule performance suggest a predominant dopamine role for AMPH and METH, a predominant serotonin role for FEN, and different degrees of combined dopaminergic and serotonergic roles for MDMA and PCA in the mediation of the task.

Rats were trained to turn for water reinforcement and then were given unilateral 6- hydroxydopamine lesions. After lesion, rats showed deficits in trained turning both contraand ipsilateral to the side of the lesion, with contralateral turning more severely impaired. The lesioned rats were then transplanted with fetal mesencephalic dopamine tissue into striatum. A control group of lesioned rats were sham transplanted. Four weeks after transplant, 1.5 mg/kg D-amphetamine challenge injections were used to test the functioning of the transplants. In the control rats, D-amphetamine induced ipsilateral turning; in transplanted rats, D-amphetamine slowed the rate of ipsilateral turning or reversed the direction of amphetamine-induced rotation. Only rats which reversed their, amphetamine-induced turn direction after transplant were used for the rest of the experiment. Trained turning was assessed at 4, 8, 12 and 16 weeks post transplant. Transplants did not improve learned performance at any time post transplant. When D-amphetamine was administered in conjunction with the trained turning sessions, a low dose (0.12 mg/kg) enhanced contralateral trained turn rates, without affecting ipsilateral turn rates. Higher doses of amphetamine reduced ipsilateral turn rate in the transplanted animals. The results of this study suggest that transplants alone do not reinstate performance of conditioned rotation.

The non-competitiveN-methyl- d -aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain. dl -Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.

Transplantation of fetal dopamine neurons has been performed in rats for 10 years (Bjorklund and Stenevi, 1979; Perlow et al., 1979) and these experiments have established several basic principles likely to be of value for transplantation efforts in other species including man. First is an appropriate experimental model. The unilaterally lesioned rat which circles in response to amphetamine or apomorphine as described by Anden et al. (1966) and Ungerstedt (1969) has been useful for studying transplant effects. Ventral mesencephalon from fetal embryonic day 13 to 15 is transplanted to dopamine denervated striatum. After 3 to 6 weeks of growth, the transplants produce changes in circling behavior (Bjorklund and Stenevi, 1979; Perlow et al., 1979; Dunnett et al., 1984). With amphetamine treatment, animals which formerly circled ipsilateral to the side of the dopamine denervation lesion may reverse their circling direction to circle contralateral to the initial lesion. Successful transplants are demonstrated by showing survival of dopamine cells along the transplant track as well as by replacement of dopamine content on the side of transplant from values of near total depletion to about 10% of intrinsic dopamine concentration (Schmidt et al., 1984).

Nearly 10 years have elapsed since the first reports in rats that transplantation of fetal dopamine neurons have an influence on motor behavior in animals with a unilateral lesion of the nigrostriatal tract (Bjorklund and Stenevi, 1979; Perlow et al., 1979). These experiments were important in establishing several basic principles for brain transplantation. First it is a good experimental model. The unilaterally lesioned rat which circles in response to amphetamine or apomorphine as described by Anden et al. (1966) and Ungerstedt (1969) has been useful for studying transplant effects. Second was the discovery that only fetal tissue of a narrow developmental range was useful for transplant. Only the dopamine cells from ventral mesencephalon of fetal rat embryonic day 13 to 15 could successfully reinnervate dopamine denervated striatum. In this animal model, the transplants produced changes in circling behavior within three to six weeks of transplant (Bjorklund and Stenevi, 1979; Perlow et al., 1979; Dunnett et al, 1984). With amphetamine treatment, animals which formerly circled ipsilateral to the side of the dopamine denervation lesion may show a reversal in their circling direction to circle contralateral to the initial lesion. Successful transplants have dopamine cells which survive along the transplant track. In addition, dopamine concentration increases from near total depletion to about 10% of the normal intrinsic dopamine concentration (Schmidt et al., 1984).