Assessment of the abuse potential of methamnetamine in rodents: a behavioral pharmacology study.

RATIONALE: Methamnetamine (MNA; PAL-1046) is a new psychoactive substance that acts as a full biogenic amine transporter (BAT) substrate. BAT substrates promote neurotransmitter release from the nerve terminal and can be abused as stimulants. However, scientific information on the abuse potential of methamnetamine is lacking. OBJECTIVE: We evaluated the abuse liability of methamnetamine. METHODS: The effective dose range of methamnetamine was determined using a climbing behavior test. The rewarding effect and reinforcing effect of the test compound were evaluated in mice by conditioned place preference (CPP) testing and self-administration (SA) testing at the selected doses. Dopamine level changes were analyzed using synaptosomes and in vivo microdialysis to investigate the effects of methamnetamine on the central nervous system. Drug discrimination experiments were used to examine the potential similarity of the interoceptive effects of methamnetamine and cocaine. RESULTS: A significant response was observed in the climbing behavior test with 10 and 40 mg/kg intraperitoneally administered methamnetamine. In the CPP test, mice intraperitoneally administered methamnetamine (10 and 20 mg/kg) showed a significant preference for the drug-paired compartment. In the SA test, mice that intravenously received 1 mg/kg/infusion showed significant active-lever responses. Dopamine was significantly increased in synaptosomes and in in vivo microdialysis tests. Furthermore, methamnetamine showed cross-generalization with cocaine in a dose-dependent manner. CONCLUSIONS: Methamnetamine exhibits interceptive stimulus properties similar to those of cocaine and induces rewarding and reinforcing effects, suggesting its dependence liability potential.

An assessment of the functional effects of amphetamine-induced dendritic changes in the nucleus accumbens, medial prefrontal cortex, and hippocampus on different types of learning and memory function.

The present experiments investigated the effects of repeated amphetamine exposure on neural networks mediating different forms of learning and memory. Different components of these networks were assessed using various functional assays. The hypothesis was that abnormal dendritic changes in nucleus accumbens, medial prefrontal cortex, and hippocampus mediated by repeated amphetamine exposure would produce impairments on forms of learning and memory dependent on neural circuits relying on these brain systems, and have little or no effect on other forms of learning not dependent on these networks. Surprisingly, the results showed that many of the dendritic changes normally found in the nucleus accumbens, prefrontal cortex, and hippocampus following repeated amphetamine exposure were reversed back to control levels following extensive multi-domain cognitive training. Learning and memory functions associated with different neural networks also appeared normal except in one case. A neural network that includes, but is not limited to, the basolateral amygdala and nucleus accumbens was dysfunctional in rats repeatedly exposed to amphetamine despite the reversal of the majority of dendritic changes in the nucleus accumbens following cognitive training. Importantly, an increase in spine density that normally occurs in these brain regions following repeated amphetamine exposure remained following extensive cognitive training, particularly in the nucleus accumbens.

Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement.

While preclinical work has aimed to outline the neural mechanisms of drug addiction, it has overwhelmingly focused on male subjects. There has been a push in recent years to incorporate females into existing addiction models; however, males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction. Traditional self-administration models often include light or tone cues that serve as discriminative stimuli and/or consequent stimuli, making it nearly impossible to disentangle the effects of cue learning, the cues themselves, and acute effects of psychostimulant drugs. To disentangle the interaction between drug-associated cues and the consummatory and appetitive responding driven by cocaine, we have developed a new behavioral procedure that combines Pavlovian-instrumental transfer with behavioral economic analysis. This task can be completed within a single session, allowing for studies looking at estrous cycle stage-dependent effects in intact cycling females, something that has been difficult in the past. In this study, we found no differences in self-administration across the estrous cycle in the absence of cues; however, when cues were introduced, the cues that acquired value during estrus-but not during diestrus or in males-increased motivation. Cues paired during estrus also increased c-fos expression to a greater extent in striatal regions, an effect that may underlie the observed increases in seeking induced by these cues, even weeks later. Together, these data suggest that fundamental differences in the motivational properties of psychostimulant drugs between males and females are complex and are driven primarily by the interaction between drug-associated stimuli and drug effects.

Rapid assessment of the dose-response relationship of methamphetamine using the progressive-dosing procedure.

This paper describes a new method to rapidly obtain dose-response curves for a drug with rewarding properties using the conditioned place preference protocol. In the usual single-dosing procedure, different animals receive single, varying doses. Thus, a large number of animals are required to generate a curve. A new procedure, known as progressive dosing, alternates increasing drug doses with saline. In this way, the same animal can receive multiple tests. The dose-response curves of the rewarding effect of methamphetamine in mice were obtained using both single-dosing and progressive-dosing procedures. Although the progressive-dosing curves were not identical to the single-dosing curves, they showed a similar pattern. The progressive-dosing procedure was replicated with a new set of mice to confirm the reliability of the method and a dose-response curve similar to the previous one was obtained. This new method can reduce the number of animals required and shorten the duration of the experiment.

Neurobehavioral assessment of mice following repeated oral exposures to domoic acid during prenatal development.

Domoic acid (DA) is an algal toxin which has been associated with significant neurotoxicity in humans, non-human primates, rodents, and marine mammals. Developmental exposure to DA is believed to result in neurotoxicity that may persist into adulthood. DA is produced by harmful algal blooms of Pseudo-nitzschia, raising concerns about the consumption of contaminated seafood. We evaluated oral exposures to DA during pregnancy in mice. Doses of 0 (vehicle), 1 or 3mg/kg/d of DA were administered by gavage to C57BL/6J mice on gestational days 10 to 17. The offspring were tested for persistent neurobehavioral consequences during early development, adolescence and adulthood. Neurobehavioral tests revealed both dose- and gender-related differences in several neurobehavioral measures, including motor coordination in the rotarod test, behavior in the elevated plus maze, circadian patterns of activity in Phenotyper cages, gait as assessed in the Catwalk, and exploratory activity in the Morris water maze. This study demonstrated significant gender-specific and persistent neurobehavioral effects of repeated prenatal oral exposures to DA at low-dose levels that did not induce toxicity in dams.

An assessment of MDPV-induced place preference in adult Sprague-Dawley rats.

OBJECTIVE: Most drugs of abuse have both aversive and rewarding effects, and the use and abuse potential of such drugs is thought to be a function of a balance of these affective properties. Characterizing these effects and their relative balance may provide insight into abuse vulnerability. One drug that has received recent attention is methylenedioxypyrovalerone (MDPV), a monoamine transport inhibitor similar to, but significantly more potent than, cocaine. MDPV is self-administered and has been shown to produce aversive and rewarding effects in adult rats. The present study extended this characterization of the affective properties of MDPV by examining its ability to support place conditioning at a range of doses known to produce taste avoidance. METHODS: Male Sprague-Dawley rats were injected with MDPV (1, 1.8 or 3.2mg/kg) or saline and placed on the non-preferred side of a place conditioning apparatus for 30 min. On the next day, they were given an injection of saline and placed on the preferred side. This was repeated three times for a total of four conditioning cycles, and side preference was assessed on a final test. RESULTS: All doses of MDPV produced significant increases in time spent in the drug-paired chamber, an effect not seen in vehicle-treated animals. CONCLUSIONS: That the same doses of MDPV induced both taste avoidance and place preference allows assessments of how other factors might impact these effects and how they may, in turn, contribute to its abuse liability.

Pavlovian conditioning of morphine hyperthermia: assessment of interstimulus interval and CS-US overlap.

The present study examined the effect of interstimulus interval on acquisition of conditioned thermal responses produced by trials in which a light/noise stimulus (CS) was repeatedly paired with infusion of morphine sulphate (US). Rats were implanted with a chronic intravenous catheter for drug delivery and a biotelemetry device for remote monitoring of core body temperature. In experiment 1, different groups received morphine either 0.5 (group P0.5) or 15 min (group P15) after onset of the 15-min CS. A third group was exposed to an identical number of CS and US presentations but in an explicitly unpaired manner (group UP). After repeated exposure to morphine, all groups showed a more rapid rise in body temperature in response to drug infusion. Test presentations of CS alone revealed conditioned hyperthermic responses to CS in groups P0.5 and P15. However, the response of the P15 group was smaller than that of the P0.5 group, suggesting weaker conditioning at the longer interstimulus interval. The contribution of CS-US overlap to the diminished associative strength observed in the P15 group was assessed in experiment 2. Groups P0.5/15 and P0.5/30 received infusions of morphine 0.5 min after onset of a 15- or 30-min CS, respectively. Group P15/30 received morphine 15 min after onset of a 30 min CS, whereas group UP/30 received explicitly unpaired presentations of the US and a 30-min CS. Enhancement of the hyperthermic effect of morphine was observed in all groups after ten conditioning trials. Test presentations of the CS without drug revealed that all paired groups had acquired conditioned hyperthermic responses. These results support the conclusion that drug-induced conditioning can occur at relatively long interstimulus intervals when there is sufficient temporal overlap between the CS and unconditioned response evoked by the drug US.

Opponent-process theory and drug conditioning: an assessment for conditioned stimulant-induced movement.

Opponent-process theory occupies an important place in drug conditioning because it accounts for conditioned drug effects which are opposite to those induced by the drug itself. It has not been established, however, whether there is an opponent-process component to stimulant drug induced conditioned effects. In the present study the unilateral 6-hydroxydopamine (6-OHDA) rat model was used to examine this issue. Two groups of Sprague-Dawley rats with equivalent 6-OHDA lesions were administered five apomorphine treatments (0.05 mg/kg s.c.) either paired or unpaired to a 10-min test chamber placement. Apomorphine induced vigorous contralateral rotation and suppressed all ipsilateral rotation. While the apomorphine-induced contralateral rotation response can be conditioned to the test environment cues, the critical test of opponent-process theory in the present study was whether the opposite response of ipsilateral rotation would also become conditioned as a latent opponent-process response to the exteroceptive test environment cues associated with the apomorphine drug state. The postacquisition saline test for conditioning showed that the paired group exhibited higher rates of contralateral and ipsilateral rotation compared to the unpaired group. In addition, when the animals were subsequently tested with the dopaminergic receptor antagonist, haloperidol (0.5 mg/kg), unexpectedly, contralateral rotation was enhanced in the paired group, whereas, ipsilateral rotation was suppressed in both groups. While these findings are, in part, compatible with an opponent-process mechanism, the data supported a simpler explanation; namely, the mechanism of differential habituation in the two groups due to a blocking effect of apomorphine on habituation selectively in the paired group.(ABSTRACT TRUNCATED AT 250 WORDS)

Conditioned taste aversions as a behavioral baseline for drug discrimination learning: an assessment with phencyclidine.

When PCP was given prior to the pairing of saccharin with LiCl (and the PCP vehicle prior to a nonpoisoned exposure to the same saccharin solution), rats rapidly acquired the discrimination, avoiding saccharin consumption following PCP and consuming saccharin following the vehicle after only three conditioning trials. Conversely, when the PCP vehicle was given prior to the saccharin-LiCl pairing and PCP prior to a nonpoisoned exposure to saccharin, other subjects avoided saccharin consumption following the vehicle injection and readily consumed saccharin after an injection of PCP. During dose substitution sessions, animals displayed greater drug-appropriate responding as the dose of PCP increased. When a range of doses of ketamine was given in place of PCP prior to saccharin access, subjects displayed dose-dependent PCP-appropriate responding. When a range of doses of d-amphetamine was substituted for PCP, subjects displayed vehicle-appropriate responding at all doses. The relative efficacy of the taste aversion procedure as a baseline for drug discrimination learning is discussed.

Behavioral assessment of the toxicity of aspartame.

Six experiments with rats assessed the toxicity of aspartame with behavioral measures. The first three experiments used a conditioned taste aversion procedure since taste aversions are typically observed after a taste is followed by a toxin. Thirty min after thirsty rats drank a sweet solution they were intraperitoneally injected (Experiment 1) or intragastrically intubated (Experiment 2) with saline or 176, 352, or 704 mg/kg of aspartame. Relative to rats given saline, rats injected with 704 and 352 mg/kg aspartame showed strong and mild aversions, respectively. Rats injected with 176 mg/kg of aspartame or intubated with any dose of aspartame did not show taste aversions. In Experiment 3, rats voluntarily consumed an aspartame solution sweetened with saccharin for 7 hr each day. Consumption of the taste paired with aspartame was not reduced. When 352 mg/kg aspartame was injected (Experiment 4), but not when intubated (Experiment 5), 5 min prior to access to a running wheel, running was reduced. Wheel running was not affected by the voluntary consumption of aspartame (Experiment 6). The route of administration effect (intraperitoneal vs. intragastric) on behavior corresponded with the amino acid levels in blood plasma (Experiment 7). Aspartate, phenylalanine, tyrosine and glutamate levels increased more after the injection, than the intubation, of aspartame (176 mg/kg). Overall, the results suggest that aspartame may have adverse effects when intraperitoneally injected but not when the route of administration is oral.

Behavioral toxicological assessment of oral pralidoxime methanesulfonate in the rat.

The behavioral toxicity of pralidoxime methanesulfonate (P2S) was examined in the rat by comparing standard measures such as conditioned taste aversion (CTA), drinking behavior and acute oral toxicity. P2S produced a weak CTA at doses of 0.4 and 0.8 g/kg (PO) and a profound CTA at the highest dose (1.6 g/kg) using a single sucrose-flavored conditioning trial with a one bottle test. The CTA produced by the highest dose of P2S was blocked by a specific, and exclusively peripheral, histamine-H2blocker, cimetidine (30 mg/kg, IP), which also has a cytoprotecting effect on gastric mucosal lesions. These data suggest that the H2 receptors may be involved in inducing the aversive effects of P2S through the inherent local irritating property of P2S on the rat gastric mucosa. There was no disruption of water drinking in thirsty rats with P2S at doses ranging from 0.2 to 1.6 g/kg. The survival time after an acute oral lethal dose of P2S (8-15 g/kg) was prolonged in non-fasted rats (16.5-38.5 min) compared to fasted ones (3.5-14.5 min), however the LD50's were identical (8.7 +/- 1.0 and 7.5 +/- 0.5 g/kg; respectively); indicating that P2S taken with food delays the lethal effects, but does not affect its lethal potency.

[Des-1-tyrosine-gamma-endorphin: an assessment of its neuroleptic properties and effect on dopamine synthesis]. / Dez-1-tirozin-gamma-éndorfin: otsenka neirolepticheskikh svoistv i vliianie na sintez dofamina.

The neuropeptide des-1-tyrosine-gamma-endorphine (DTGE) has been shown to facilitate, similarly to neuroleptics, the extinction of pole-jumping avoidance behavior, to enhance the grasping reflex, and to produce catalepsy. In in vitro experiments, DTGE (10(-4) M) did not change the activity of solubilized rat brain striatal tyrosine hydroxylase. However at the concentration of 10(-4) M and 10(-6) M DTGE has been found to accelerate tyrosine hydroxylation in the striatal synaptosomes. It is suggested that the effect of DTGE on the brain dopamine biosynthesis might be involved in the development of the neuropeptide neuroleptic effect.