METH-induced Stereotypy Research Articles

Psychotomimetic-like behavioral effects of memantine in the mouse

A single administration of mice with memantine (1-amino-3,5-dimethyladamantane), a glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, induced stereotyped behaviors in dose- and time-dependent manners. The predominant behavioral component of the stereotypy was a continuous, exaggerated sniffing which was accompanied by persistent locomotion. In contrast, a psychostimulant methamphetamine (METH) predominantly induced a stereotyped biting and other forms of intense stationary stereotypical behaviors. Memantine-induced stereotyped sniffing was attenuated by pretreatment with haloperidol, a dopamine D2 receptor antagonist, in a dose-dependent manner. The memantine-induced stereotyped sniffing was also attenuated by pretreatment with betahistine (2-[2-(methylamino)ethyl]pyridine), an agent which increases histamine turnover and releases histamine in the brain. These observations suggest that memantine might induce stereotypies through neuronal mechanisms that are somewhat different from those of METH, but still overlap to a certain extent, since memantine-induced stereotypies can be attenuated by the mechanisms that also suppress METH-induced stereotypy. Importantly, these data suggests that the effects of memantine may be more limited to the ventral striatum including nucleus accumbens than those of METH, which is associated with dorsal striatal stimulation at high doses. In this respect memantine may also have pharmacological properties such as compartmentation (i.e. brain distribution) and neuronal mechanisms different from those of other NMDA receptor antagonists, such as ketamine, which may have important implications for therapeutic uses of these drugs.

Methamphetamine-induced behavioral sensitization in a rodent model of posttraumatic stress disorder

BackgroundSingle prolonged stress (SPS) is a rodent model of posttraumatic stress disorder (PTSD)-like characteristics. Given that PTSD is frequently comorbid with substance abuse and dependence, including methamphetamine (METH), the current study sought to investigate the effects of SPS on METH-induced behavioral sensitization. MethodsIn experiment 1, Sprague-Dawley rats were subject to SPS or control treatment and subsequently tested across four sessions of an escalating METH dosing paradigm. METH was injected (i.p.) in escalating doses (0, 0.032, 0.1, 0.32, 1.0, and 3.2mg/kg; dissolved in saline) every 15min and ambulatory activity was recorded. In experiment 2, SPS and control treated rats were injected (i.p.) with either saline or METH (5mg/kg) for five consecutive daily sessions and tested for stereotypy as well as ambulatory activity. Two days later, all animals were injected with a challenge dose of METH (2.5mg/kg) and again tested for activity. ResultsNo differences in the acute response to METH were observed between SPS and controls. SPS enhanced METH induced ambulatory activity across sessions, compared to controls. METH-induced stereotypy increased across sessions, indicative of behavioral sensitization; however, SPS attenuated, not enhanced, this effect suggesting that SPS may prevent the development of stereotypy sensitization. ConclusionsCollectively, results show that SPS increases repeated METH-induced ambulatory activity while preventing the transition across sessions from ambulatory activity to stereotypy. These findings suggest that SPS alters drug-induced neuroplasticity associated with behavioral sensitization to METH, which may reflect an effect on the shared neurocircuitry underlying PTSD and substance dependence.

Striatal patch compartment lesions alter methamphetamine-induced behavior and immediate early gene expression in the striatum, substantia nigra and frontal cortex

Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of the striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. However, the specific contribution of the patch compartment to METH-induced stereotypy is not clear. To elucidate the involvement of the patch compartment to the development of METH-induced stereotypy, we determined if destruction of this sub-region altered METH-induced behaviors. Animals were bilaterally infused in the striatum with the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/μl) to specifically ablate the neurons of the patch compartment. Eight days later, animals were treated with METH (7.5 mg/kg), placed in activity chambers, observed for 2 h and killed. DERM-SAP pretreatment significantly reduced the number and total area of mu-labeled patches in the striatum. DERM-SAP pretreatment significantly reduced the intensity of METH-induced stereotypy and the spatial immobility typically observed with METH-induced stereotypy. In support of this observation, DERM-SAP pretreatment also significantly increased locomotor activity in METH-treated animals. In the striatum, DERM-SAP pretreatment attenuated METH-induced c-Fos expression in the patch compartment, while enhancing METH-induced c-Fos expression in the matrix compartment. DERM-SAP pretreatment followed by METH administration augmented c-Fos expression in the SNpc and reduced METH-induced c-Fos expression in the SNpr. In the medial prefrontal, but not sensorimotor cortex, c-Fos and zif/268 expression was increased following METH treatment in animals pre-treated with DERM-SAP. These data indicate that the patch compartment is necessary for the expression of repetitive behaviors and suggests that alterations in activity in the basal ganglia may contribute to this phenomenon.

Methamphetamine-induced changes in the striatal dopamine pathway in μ-opioid receptor knockout mice

BackgroundRepeated exposure to methamphetamine (METH) can cause not only neurotoxicity but also addiction. Behavioral sensitization is widely used as an animal model for the study of drug addiction. We previously reported that the μ-opioid receptor knockout mice were resistant to METH-induced behavioral sensitization but the mechanism is unknown.MethodsThe present study determined whether resistance of the μ-opioid receptor (μ-OR) knockout mice to behavioral sensitization is due to differential expression of the stimulatory G protein α subunit (Gαs) or regulators of G-protein signaling (RGS) coupled to the dopamine D1 receptor. Mice received daily intraperitoneal injections of saline or METH (10 mg/kg) for 7 consecutive days to induce sensitization. On day 11(following 4 abstinent days), mice were either given a test dose of METH (10 mg/kg) for behavioral testing or sacrificed for neurochemical assays without additional METH treatment.ResultsMETH challenge-induced stereotyped behaviors were significantly reduced in the μ-opioid receptor knockout mice when compared with those in wild-type mice. Neurochemical assays indicated that there is a decrease in dopamine D1 receptor ligand binding and an increase in the expression of RGS4 mRNA in the striatum of METH-treated μ-opioid receptor knockout mice but not of METH-treated wild-type mice. METH treatment had no effect on the expression of Gαs and RGS2 mRNA in the striatum of either strain of mice.ConclusionsThese results indicate that down-regulation of the expression of the dopamine D1 receptor and up-regulation of RGS4 mRNA expression in the striatum may contribute to the reduced response to METH-induced stereotypy behavior in μ-opioid receptor knockout mice. Our results highlight the interactions of the μ-opioid receptor system to METH-induced behavioral responses by influencing the expression of RGS of dopamine D1 receptors.

μ‐Opioid receptor knockout mice are insensitive to methamphetamine‐induced behavioral sensitization

Repeated administration of psychostimulants to rodents can lead to behavioral sensitization. Previous studies, using nonspecific opioid receptor (OR) antagonists, revealed that ORs were involved in modulation of behavioral sensitization to methamphetamine (METH). However, the contribution of OR subtypes remains unclear. In the present study, using mu-OR knockout mice, we examined the role of mu-OR in the development of METH sensitization. Mice received daily intraperitoneal injection of drug or saline for 7 consecutive days to initiate sensitization. To express sensitization, animals received one injection of drug (the same as for initiation) or saline on day 11. Animal locomotor activity and stereotypy were monitored during the periods of initiation and expression of sensitization. Also, the concentrations of METH and its active metabolite amphetamine in the blood were measured after single and repeated administrations of METH. METH promoted significant locomotor hyperactivity at low doses and stereotyped behaviors at relative high doses (2.5 mg/kg and above). Repeated administration of METH led to the initiation and expression of behavioral sensitization in wild-type mice. METH-induced behavioral responses were attenuated in the mu-OR knockout mice. Haloperidol (a dopamine receptor antagonist) showed a more potent effect in counteracting METH-induced stereotypy in the mu-OR knockout mice. Saline did not induce behavioral sensitization in either genotype. No significant difference was observed in disposition of METH and amphetamine between the two genotypes. Our study indicated that the mu-opioid system is involved in modulating the development of behavioral sensitization to METH. (c) 2010 Wiley-Liss, Inc.

Methamphetamine-induced stereotypy correlates negatively with patch-enhanced prodynorphin and arc mRNA expression in the rat caudate putamen: The role of mu opioid receptor activation

Amphetamines induce stereotypy, which correlates with patch-enhanced c-Fos expression the patch compartment of caudate putamen (CPu). Methamphetamine (METH) treatment also induces patch-enhanced expression of prodynorphin (PD), arc and zif/268 in the CPu. Whether patch-enhanced activation of any of these genes correlates with METH-induced stereotypy is unknown, and the factors that contribute to this pattern of expression are poorly understood. Activation of mu opioid receptors, which are expressed by the neurons of the patch compartment, may underlie METH-induced patch-enhanced gene expression and stereotypy. The current study examined whether striatal mu opioid receptor blockade altered METH-induced stereotypy and patch-enhanced gene expression, and if there was a correlation between the two responses. Animals were intrastriatally infused with the mu antagonist CTAP (10 μg/μl), treated with METH (7.5 mg/kg, s.c.), placed in activity chambers for 3 h, and then sacrificed. CTAP pretreatment attenuated METH-induced increases in PD, arc and zif/268 mRNA expression and significantly reduced METH-induced stereotypy. Patch-enhanced PD and arc mRNA expression in the dorsolateral CPu correlated negatively with METH-induced stereotypy. These data indicate that mu opioid receptor activation contributes to METH-induced gene expression in the CPu and stereotypy, and that patch-enhanced PD and arc expression may be a homeostatic response to METH treatment.

Striatal Mu Opioid Receptor Blockade Alters Methamphetamine‐Induced Stereotypy

Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. Mu opioid receptors are densely expressed in the patch compartment and may contribute to stereotypy. The goal of this study was to determine if mu opioid receptor blockade alters METH‐induced stereotypy. Animals were bilaterally infused in the striatum with the mu antagonist CTAP (10 μg/μl) or vehicle. Animals were then given METH (7.5 mg/kg) or saline, placed in locomotor activity chambers and observed for 3h. Stereotypy was scored on a scale from 1‐10 in four behavioral dimensions: repetitiveness, frequency, duration and spatial distribution. Horizontal and rearing activity was also monitored during the 3h period. CTAP pretreatment significantly reduced the degree of stereotypy induced by METH. METH‐induced stereotypy is accompanied by spatial immobility and CTAP significantly reduced this effect. In support of this observation, CTAP pretreatment significantly increased horizontal locomotor activity in METH‐treated animals. There was also an increase in rearing activity in CTAP‐pretreated METH‐treated animals. These data indicate that striatal mu opioid receptor activation contributes to METH‐induced stereotypy.

Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice

The effects of sigma receptor antagonists on methamphetamine (METH)-induced stereotypy have not been examined. We examined the effects of sigma antagonists on METH-induced stereotypy in mice. The administration of METH (10 mg/kg) to male ddY mice induced stereotyped behavior consisting of biting (90.1%), sniffing (4.2%), head bobbing (4.1%), and circling (1.7%) during an observation period of 1 h. Pretreatment of the mice with BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol; 1, 5, and 10 mg/kg), a non-specific sigma receptor antagonist, significantly increased METH-induced sniffing (19.2%, 30.5%, and 43.8% of total stereotypical behavior) but decreased biting (76.6%, 66.9%, and 49.3% of total stereotypical behavior) in a dose-dependent manner. This response was completely abolished by (+)-SKF 10,047 ([2S-(2alpha,6alpha,11R)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol; 4 and 10 mg/kg), a putative sigma(1) receptor agonist, and partially by PB 28 (1-cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalen-1-yl)-n-propyl]piperazine; 1 and 10 mg/kg), a putative sigma(2) receptor agonist. The BMY 14802 action on METH-induced stereotypy was mimicked by BD 1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine; 10 mg/kg), a putative sigma(1) receptor antagonist, but not by SM-21 ((+/-)-tropanyl 2-(4-chlorophenoxy)butanoate; 1 mg/kg), a putative sigma(2) receptor antagonist. The BD 1047 effect on METH-induced stereotypy was also abolished completely by (+)-SKF 10,047 and partially by PB 28. The overall frequency of METH-induced stereotypical behavior was unchanged with these sigma receptor ligands, despite the alteration in particular behavioral patterns. The BMY 14802 action on METH-induced stereotypy was unaffected by pretreatment with centrally acting histamine H(1) receptor antagonists (pyrilamine or ketotifen, 10 mg/kg), suggesting that these effects are independent of histamine H(1) receptor signaling systems. In summary, modulation of central sigma(1) receptors alters the pattern of METH-induced stereotypy, producing a shift from stereotypical biting to stereotypical sniffing, without affecting the overall frequency of stereotypical behavior.

Lack of effect of anticonvulsant topiramate on methamphetamine-induced stereotypy and rewarding property in mice

The effects of topiramate, a structurally novel anticonvulsant, on the methamphetamine (METH)-induced expression of stereotypy and conditioned place preference (CPP) in male ICR mice were investigated. After a single administration of METH (10 mg/kg, i.p.), mice showed stereotyped behaviors with a plateau level 25 min after drug challenge. Pretreatment with topiramate (1, 10, and 100 mg/kg, i.p.) 30 min prior to METH challenge had no effect on the expression frequency of stereotypy, compared with saline challenge. No differential effects of topiramate on METH-induced stereotyped behavior (that is, head-bobbing, circling, continuous sniffing, nail and/or wood-chip biting, and vigorous and compulsive grooming) were observed. In saline-challenged groups, the doses of topiramate examined did not induce any stereotyped behaviors. Although mice showed a significant CPP for METH (0.5 mg/kg, i.p.), pretreatment with subchronic topiramate did not affect the magnitude of CPP. Locomotor activity was not affected by the doses of topiramate tested. Conditioned rewarding or aversive effects of topiramate were not observed as indexed by the place preference procedure. These results suggested the lack of effect of topiramate on METH-induced stereotypy and rewarding property in mice.

Lobeline Attenuates Methamphetamine-induced Stereotypy in Adolescent Mice

In this study, we investigated the effects of lobeline, an alkaloid constituent of Indian tobacco, on methamphetamine (METH)-induced stereotypy in male ICR mice (41-50 days old), an animal model for amphetamine psychosis. After a single administration of METH (10 mg/kg, i.p.), mice showed an initial short-lasting hyperlocomotion and subsequent stereotyped behaviors with a plateau level 25 min after drug challenge. Pretreatment with lobeline (3.0-30 mg/kg, i.p.) 15 min prior to the drug challenge significantly decreased the intensity of stereotypy and increased its latency to onset in a dose-dependent manner, especially 20 min after the drug challenge. In saline challenge groups, the doses of lobeline examined did not affect spontaneous locomotion nor induced any stereotyped behaviors. High-performance liquid chromatography analysis revealed that the range of lobeline doses examined except 30 mg/kg did not affect apparent monoamine turnover in the cerebral cortex, the region of the striatum and nucleus accumbens, and the region of the thalamus and hypothalamus of the mice 20 and 60 min after the drug challenge. These results suggested that the inhibitory effect of lobeline (3.0-10 mg/kg) on METH-induced stereotypy was not attributed to the change in the apparent monoamine turnover.

Effects of Monoamine Oxidase Inhibitors on Methamphetamine-Induced Stereotypy in Mice and Rats

In male ICR mice, a single intraperitoneal administration of methamphetamine (METH) (10 mg/kg) induced stereotyped behavior such as continuous sniffing, circling, and nail biting, reaching a plateau level 20 min after the injection. Subcutaneous pretreatment with clorgyline, a monoamine oxidase (MAO)-A inhibitor, at a dose of 0.1 mg/kg 2 h prior to the drug challenge significantly decreased the initial (first 20 min) intensity of stereotypies and increased the latency to onset. The effect was not observed with either higher doses of clorgyline (1 and 10 mg/kg) or l-deprenyl, a MAO-B inhibitor, at doses of 0.1-10 mg/kg. In male Wistar rats, the inhibitory effect of clorgyline on METH-induced stereotypy was not observed. Pretreatment of the mice with clorgyline (0.1 mg/kg) had no effect on apparent serotonin and dopamine turnover in the striatum, although the higher doses of clorgyline (1 and 10 mg/kg) significantly decreased the turnover. These results suggest that a low dose of clorgyline tends to increase the latency and decrease the intensity of stereotypies induced by METH in a dopamine metabolism-independent manner in mice.

Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats.

The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative antiaddictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.