Valproate modulates the expression of methylphenidate (ritalin) sensitization

Repeated administration of amphetamine, cocaine, and methylphenidate (MPD) has been reported to elicit behavioral sensitization to their locomotor and stereotypic effects in rodents. GABAergic drugs have been shown to inhibit behavioral effects of stimulants. The objective of the present study was to determine whether single or multiple administration of sodium valproate, a GABA agonist, would prevent the expression of sensitization to the locomotor effect of MPD once it has developed. Twenty-eight male Sprague-Dawley rats were randomized into three treatment groups: a control group received only 2.5 mg/kg MPD during the 14-day cycle, a group received a single 50 mg/kg valproate injection on Day 9, and a group received multiple 50 mg/kg valproate injection on Days 9-13. Rats were housed in test cages and behavioral activities were recorded for 14 consecutive days. All injections were given between 12:00 h and 14:00 h. Multiple injection of MPD elicited sensitization to its locomotor and stereotypic effects. Single administration of valproate did not block the expression of sensitization in the four locomotor indices measured. However, multiple administration of valproate prevented MPD sensitization to horizontal activity, total distance and number of stereotypic movements.     

MK-801 blocks the development of sensitization to the locomotor effects of methylphenidate

Male Sprague-Dawley rats were divided to three groups (each n = 8) and were housed in test cages where motor activity was recorded continuously for 16 days using a computerized motor activity monitoring system to determine whether repeated administration of MK-801 could block the development and/or the expression of sensitization to the locomotor effects of methylphenidate (MPD). One group of rats received six daily injections (days 4-9) of 0.30 mg/kg MK-801, followed by 5 days without injection (days 10-14) and re-challenged (day 15) with 0.30 mg/kg MK-801. The second group received a challenge dose of 2.5 mg/kg MPD (day 4) followed by 5 days of co-treatment with MK-801 (0.30 mg/kg) given 1 h prior to MPD (days 5-9). This group was then re-challenged with MPD (2.5 mg/kg) on day 15. The last group received six daily injections of 2.5 mg/kg MPD (days 4-9). They were then split into two subgroups of rats which received either no treatment (control) or five daily injections of 0.30 mg/kg MK-801 (days 10-14) before being re-challenged on day 15 with 2.5 mg/kg MPD. MK-801 sensitized to its own locomotor effects. MK-801 given after sensitization had developed (i.e., days 10-14) was able to mask the expression of a sensitized response on day 15, but the effect was only transient since the sensitized response was present 3 weeks later. Moreover, MK-801, when coadministered during the repeated treatment phase was able to block the development of a sensitized response, which suggest that NMDA receptors involved in the process of MPD sensitization.     

Gamma-vinyl GABA,an irreversible inhibitor of GABA transaminase,alters the acquisition and expression of cocaine-induced sensitization in male rats

We examined the effect of (+/-)-gamma-vinyl GABA (GVG, Vigabatrin), an irreversible inhibitor of the enzyme GABA transaminase, on the acquisition and expression of cocaine-induced sensitization in albino male Sprague-Dawley rats. Animals received a single injection of 1 ml/kg i.p. of 0.9% saline or 15 mg/kg i.p. of (-)-cocaine and locomotor activity was assessed using automated locomotor cages and stereotyped behaviors were scored using a 4-point rating scale (Day 1). Subsequently, animals were given 15 mg/kg i.p. of cocaine every 48 h in their home cage for 1 week (Days 3, 5, and 7) and then given no treatment for 1 week. A challenge injection of 15 mg/kg i.p. of cocaine, but not vehicle, produced a significant increase in locomotor activity and stereotyped behaviors on Day 15 compared to animals that received cocaine on Day 1. Administration of 75 mg/kg i.p. of GVG 2.5 h before the cocaine injections did not significantly alter the acquisition of cocaine-induced locomotor sensitization. However, 150 mg/kg i.p. of GVG significantly attenuated the acquisition of cocaine-induced locomotor sensitization. Administration of 150 mg/kg i.p. of GVG 2.5 h before the cocaine challenge injection on Day 15 significantly attenuated the expression of cocaine-induced locomotor sensitization. Acquisition and expression of cocaine-induced sensitization of stereotypy was also significantly attenuated by 150 mg/kg i.p. of GVG. Since sensitization may be one of the factors involved in relapse to drug use, the present results, in combination with previous findings that GVG blocks the rewarding and incentive motivating effects of cocaine, suggest that GVG might prove useful in the treatment of cocaine addiction.     

Valproate prevents the induction, but not the expression of morphine sensitization in mice

Repetitive exposure to opioids elicits sensitization to its locomotor stimulating effects. Several lines of evidence have shown that the central GABAergic system is involved in behavioral sensitization induced by morphine. Valproate, a clinically widely used anticonvulsant and mood stabilizer, can mainly inhibit gamma-aminobutyric acid (GABA) transaminase and activate glutamic acid decarboxylase, which result in decrease in the degradation and increase in the synthesis of GABA, and then the elevation of extracellular GABA in the central nervous system. However, the effects of valproate on behavioral sensitization to morphine have not been documented. Herein, we investigated the effects of valproate on the induction and the expression of behavioral sensitization to morphine. Mice treated daily for 7 days with 10 mg/kg morphine and challenged with the same dose after 7 days of washout showed increased locomotor activity. Co-administration of valproate (37.5, 75, 150 mg/kg, intraperitoneal (i.p.)), at doses that did not affect the spontaneous activity, 30 min prior to morphine dose-dependently inhibited the induction of morphine sensitization. However, neither single nor multiple administration (37.5, 75, 150 mg/kg x 7 injections) of valproate had any effect on the expression of morphine sensitization once it developed. Our results indicated that GABA plays an important role in the induction, but not in the expression of morphine sensitization in mice.     

Diurnal differences in sensitization to methylphenidate

Using a computerized monitoring system, we investigated the development of motor sensitization to methylphenidate (MPD) in the rat, and determined whether sensitization was dependent on the time of drug administration. Male Sprague-Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days served as baseline for each rat, and on day 3 each rat received a saline injection. The locomotor response to 0.6, 2.5, or 10 mg/kg of MPD was tested on day 4, followed by 5 days of single injections of 2.5 mg/kg MPD (days 5-9). After 5 days without injection (days 10-14) rats were re-challenged (day 15) with the same doses they received on day 4. There were three separate challenge doses and four different times of administration: 08:00, 14:00, 20:00, or 02:00 h. Horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements were recorded. Sensitization to MPD was dependent on the time of administration, the motor index studied, and the challenge dose used. It was more pronounced for forward ambulation than for rearing, with no augmented response to stereotypic effects. The expression of the sensitized response was dose-dependent and mainly observed with the 0.6 and 2.5 mg/kg challenge dose groups. The development of sensitization to MPD was also time-dependent with the most robust sensitization occurring during the light phase, while no sensitization was observed during the middle of the dark phase. In addition, repeated MPD administration caused a significant increase in the amount of nocturnal forward ambulation that persisted long after cessation of drug treatment.     

Inhibition of GSK3 attenuates amphetamine-induced hyperactivity and sensitization in the mouse

Glycogen synthase kinase 3 (GSK3) is implicated in mediating dopamine-dependent behaviors. Previous studies have demonstrated the ability of amphetamine, which increases extracellular dopamine levels and influences behavior, to regulate the activity of GSK3. This study used valproic acid and the selective GSK3 inhibitor, SB 216763, to examine the role of GSK3 in amphetamine-induced hyperactivity and the development of sensitized stereotypic behavior. Pretreatment with valproic acid (50-300 mg/kg, i.p.) or SB 216763 (2.5-5 mg/kg, i.p.) prior to amphetamine (2 mg/kg, i.p.) significantly reduced amphetamineinduced ambulation and stereotypy. To assess the development of sensitization to the stereotypic effects of amphetamine, mice were pretreated daily with valproic acid (300 mg/kg) or SB 216763 (5 mg/kg) prior to amphetamine (2 mg/kg) for 5 days. Upon amphetamine challenge (1 mg/kg) 7 days later, mice pretreated with valproate or SB 216763 showed a significant attenuation of amphetamine-induced sensitization of stereotypy. To determine whether regulation of GSK3 activity was associated with attenuation of acute amphetamine-induced hyperactivity by valproic acid, valproate (300 mg/kg) or vehicle was injected prior to amphetamine (2 mg/kg) or saline and brain tissue obtained. Analysis of the levels of phospho-GSK3α and β by immunoblot indicated that valproate increased phosphorylation of ser21-GSK3α in the frontal cortex, as well as ser?-GSK3β in the frontal cortex and caudate putamen of amphetamine-injected mice. These data support a role for GSK3 in acute amphetamine-induced hyperactivity and the development of sensitization to amphetamine-induced stereotypy.     

Methylphenidate sensitization is prevented by prefrontal cortex lesion

Methylphenidate (MPD), also known as Ritalin, is a widely used treatment for Attention Deficit Hyperactivity Disorder. Repeated administration of MPD causes dose-dependent sensitization. MPD binds to dopamine (DA) transporters, and DA, therefore, remain in the synaptic cleft for longer time, resulting in an indirect DA agonist effect. MPD affects neurotransmission in brain regions including the prefrontal cortex (PFC). The mechanisms of sensitization to MPD are not clear.

The aim of this study was to investigate the role of prefrontal cortex in effects of acute and chronic MPD administration, using the open field assay and male Sprague–Dawley rats with bilateral electrolytic lesions of PFC. After 1 day of control recording, following saline injection, the animals were divided randomly into three groups, (1) an intact control group, (2) a sham group, and (3) a lesion group. Then, groups 2 and 3 underwent surgery, followed by 5 days of recovery. Recordings were resumed following 1 day of saline injection and following six consecutive daily injections of 2.5 mg/kg MPD, 3 days of washout period, and another day of re-challenge injection of 2.5 mg/kg MPD.

Acute MPD elicited increases in locomotor activity, similar to those observed from intact animals, in both sham and lesion groups. The sham group was behaviorally sensitized while the PFC lesion group failed to exhibit behavioral sensitization.

These results suggest that the PFC does not interfere with the acute effects of MPD on locomotor activity but is required for development of behavioral sensitization to MPD.     

Behavioral and dorsal raphe neuronal activity following acute and chronic methylphenidate in freely behaving rats

Concomitant behavioral and dorsal raphe (DR) neuronal activity were recorded following acute and chronic dose response of methylphenidate (MPD) in freely moving rats previously implanted with permanent semi-microelectrodes using telemetric (wireless) technology. On experimental day (ED) 1, the neuronal and locomotor activity were recorded after saline (baseline) and MPD (0.6, 2.5 or 10.0 mg/kg) injection (i.p.). Animals were injected daily with a single dose of MPD for five consecutive days (ED 2–6) to elicit behavioral sensitization or tolerance. After three washout days, the neuronal and locomotor activity recording was resumed on ED 10 followed by saline and MPD rechallenge injection. The main findings were: (1) the same dose of chronic MPD administration elicited behavioral sensitization in some animals and behavioral tolerance in others. (2) 46%, 56% and 73% of DR units responded to acute 0.6, 2.5 and 10.0 mg/kg MPD respectively. (3) 89%, 70% and 86% of DR units changed their baseline activity on ED 10 compared to that on ED 1 in the 0.6, 2.5 and 10.0 mg/kg MPD groups respectively. (4) A significant difference in ED 10 baseline activity was observed in the DR neuronal population recording from animals expressing behavioral sensitization compared to that of animals expressing behavioral tolerance. (5) 89%, 78% and 88% of DR units responded to chronic 0.6, 2.5 and 10.0 mg/kg MPD respectively. (6) The DR neuronal population recording following acute MPD on ED 1 and rechallenge MPD on ED 10 from animals expressing behavioral sensitization was significantly different from the neuronal population recorded from animals exhibited behavioral tolerance. The correlation between the DR neuronal activity and animal's behavior following chronic MPD exposure suggested that the DR neuronal activity may play an important role in the expression of behavioral sensitization and tolerance induced by chronic MPD administration.     

Evidence for an involvement of muscarinic cholinergic systems in the induction but not expression of behavioral sensitization to cocaine

The present study was designed to determine whether the muscarinic cholinergic antagonist scopolamine can prevent the expression and induction of sensitization to the locomotor-activating effects of cocaine. Rats received one daily injection of cocaine (20 mg/kg i.p.) for 5 days. Two days after withdrawal of pretreatment, rats were pretreated with scopolamine (3.0 mg/kg s.c.) or its vehicle and challenged 15 min later with either saline or cocaine (20–30 mg/kg i.p.). In a second set of experiments, scopolamine (3.0 mg/kg s.c.) or its vehicle was given in combination with either saline or cocaine (20 mg/kg i.p.) for 5 days. Activity in response to saline and to cocaine (20 mg/kg i.p.) was assessed on day 7. The effects of acute administration of acopolamine (3.0 mg/kg s.c.) on cocaine-induced locomotor activity were also assessed. Acute administration of scopolamine increased both distance traveled and time spent in stereotypy. When scopolamine was administered 15 min prior to an acute injection of cocaine, a significant increase in the behavioral response to cocaine was seen. Daily injections of cocaine for 5 days produced sensitized behavioral responses to a subsequent cocaine challenge. Acute administration of scopolamine to animals preexposed and sensitized to cocaine did not disrupt the expression of sensitization to the locomotor and stereotypic effects of cocaine. In contrast, when scopolamine was given in combination with cocaine for 5 days, sensitization to the locomotor-activating effects of cocaine was prevented. These results suggest an important role of cholinergic muscarinic systems in mediating sensitization to the locomotor-activating effects of cocaine, which occurred after the repeated context-independent administration of this agent. In contrast, the enhanced stereotypic effects in response to the repeated administration of cocaine seem to be independent of alterations in muscarinic cholinergic transmission. (This article is a US Govemernment work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

Cervical artery dissection: risk factors, treatment, and outcome; a 5-year experience from a tertiary care center

Eight groups of male adolescent and adult spontaneous hyperactive rats (SHR) were used in a dose response (saline, 0.6, 2.5, and 10 mg/kg) experiment of methylphenidate (MPD). Four different locomotor indices were recorded for 2 hours postinjection using a computerized monitoring system. Acutely, the 0.6 mg/kg dose of MPD did not elicit an increase in locomotor activity in either the adolescent or in the adult male SHR. The 2.5 and the 10.0 mg/kg doses increased activity in the adolescent and the adult rats. Chronically, MPD treatment when comparing adolescent and adult gave the following results: the 0.6 mg/kg dose of MPD failed to cause sensitization in the adolescent group but caused sensitization in the adult group, while the 2.5 and 10 mg/kg both caused sensitization in the adolescent and adult groups.     

Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior

Methylphenidate (MPD) is used to treat ADHD and as a cognitive enhancement and recreationally. MPD’s effects are not fully understood. One of the sites of psychostimulant action is the ventral tegmental area (VTA). The VTA neuronal activity was recorded from freely behaving rats using a wireless system. 51 animals were divided into groups: saline, 0.6, 2.5, and 10.0 mg/kg MPD. The same repetitive MPD dose can elicit either behavioral sensitization or tolerance; thus the evaluation of the VTA neuronal activity was based on the animals’ behavioral response to chronic MPD exposure: animals exhibiting behavioral tolerance or sensitization. Acute MPD elicits dose-related increases in behavioral activity. About half of the animals exhibited behavioral sensitization or tolerance to each of the MPD doses. 361 units were recorded from the VTA and exhibited similar spike shape on experimental day 1 (ED1) and on ED10. 71, 84, and 79 % of VTA units responded to acute 0.6, 2.5, and 10.0 mg/kg MPD, respectively. The neuronal baseline activity at ED10 was significantly modified in 94, 95, and 100 % of VTA units following 0.6, 2.5 and 10.0 mg/kg MPD, respectively. Following chronic MPD exposure, 91, 98, and 100 % exhibit either electrophysiological tolerance or sensitization of 0.6, 2.6, or 10.0 mg/kg MPD, respectively. In conclusion, the chronic administration of the same dose of MPD caused some animals to exhibit behavioral sensitization and other animals to exhibit tolerance. The VTA units recorded from animals exhibiting behavioral sensitization responded significantly differently to MPD from animals that exhibited behavioral tolerance.     

The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects

Children with attention deficit hyperactivity disorder (ADHD) are treated for extended periods of time with the psychostimulant methylphenidate (MPD). The psychostimulants cocaine, amphetamine, and MPD exhibit similar structural configuration and pharmacological profile. The consequence of the long-term use of psychostimulants such as MPD as treatment for ADHD in the developing brain of children is unknown. Repeated treatment with psychostimulants has been shown to elicit adverse effects in behavior, such as dependence, paranoia, schizophrenia, and behavioral sensitization. Behavioral sensitization and cross-sensitization between two drugs are used as experimental markers to determine the potential of a drug to develop dependence/addiction. Although there are many reviews written about behavioral sensitization involving psychostimulants, scarcely any have focused specifically on MPD-elicited behavioral sensitization and cross-sensitization with other psychostimulants. Moreover, the response to MPD and the expression of ADHD vary among females and males and among different populations due to genetic variability. Since the interpretation and synthesis of the data reported are controversial, this review focuses on the adverse effects of MPD and the role of age, sex, and genetic composition on the acute and chronic effects of MPD, such as MPD-elicited behavioral sensitization and cross-sensitization with amphetamine in animal models. Animal models of drug-induced locomotor stimulation, particularly locomotor sensitization, can be used to understand the mechanisms underlying human drug-induced dependence.     

Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone

Repeated intermittent exposure to psychostimulants was found to produce behavioral sensitization. The present study was designed to establish a mouse model and by which to investigate whether opioidergic system plays a role in methamphetamine-induced behavioral sensitization. Mice injected with 2.5 mg/kg of methamphetamine once a day for 7 consecutive days showed behavioral sensitization after challenge with 0.3125 mg/kg of the drug on day 11, whereas mice injected with a lower daily dose (1.25 mg/kg) did not. Mice received daily injections with either 1.25 or 2.5 mg/kg of methamphetamine showed behavioral sensitization after challenge with 1.25 mg/kg of the drug on days 11, 21, and 28. To investigate the role of opioidergic system in the induction and expression of behavioral sensitization, long-acting but non-selective opioid antagonist naltrexone was administrated prior to the daily injections of and challenge with methamphetamine, respectively. Our results show that the expressions of behavioral sensitization were attenuated by pretreatment with 10 or 20 mg/kg of naltrexone either during the induction period or before methamphetamine challenge when they were tested on days 11 and 21. These results indicate that repeated injection with methamphetamine dose-dependently induced behavioral sensitization in mice, and suggest the involvement of opioid receptors in the induction and expression of methamphetamine-induced behavioral sensitization.     

Ethanol enhances naloxone sensitization and disrupts morphine discrimination--comparison to dizocilpine and pentobarbital: explanation of enhancing acute and attenuating chronic effects

1. Ethanol affects ligand-gated ion channels as a positive modulator of gamma-aminobutyric acid (GABA(A)) receptor function and an N-methyl-D-aspartate (NMDA) antagonist. NMDA antagonists attenuate chronic drug effects. Accordingly, we found that ethanol decreased morphine dependence and locomotor sensitization. We now test whether ethanol alters sensitization to the disrupting effects of naloxone on schedule-controlled responding after morphine administration or affects the acute stimulus effects of morphine. 2. Groups of rats, trained to lever-press for food, were co-administered ethanol (1 g/kg; i.p.), the NMDA antagonist dizocilpine (DZ; 0.05 mg/kg; i.p.), the GABA(A) agonist pentobarbital (PB; 3 mg/kg i.p.), or vehicle with morphine (5 mg/kg s.c.). Separate groups received naloxone (0.1-1 mg/kg s.c.) 4-hrs later, prior to food sessions (FR15; 30 min) on three consecutive days. Ethanol enhanced the suppressive effects of higher naloxone doses on all three days. DZ and PB altered this behavior differentially by day and naloxone dose. 3. Next, we examined the effects of ethanol, DZ, PB, and naloxone (0.3 mg/kg; s.c.) on morphine discrimination. Rats, trained to discriminate morphine (3.2 mg/kg s.c.) from saline in a two-lever, food-reinforced procedure, were tested with morphine (0, 1-5.6 mg/kg) after vehicle and drug administrations. Naloxone blocked dose-related responding to morphine, demonstrating pharmacological specificity, and altered response rates. Both ethanol and DZ, but not PB, disrupted morphine-appropriate responding. 4. The paradox that ethanol and DZ attenuate chronic morphine effects while enhancing acute effects may reflect a temporal pattern of primary mu opiate receptor function followed by secondary NMDA-mediated processes induced by morphine administration.     

Strain differences in the behavioral responses of male rats to chronically administered methylphenidate

Genetic variability in the behavioral responses of experimental subjects to psychostimulants such as amphetamine and cocaine have been reported. However, genetic differences in the locomotor responses of rat strains to methylphenidate (MPD), a commonly used psychostimulant in the treatment of attention deficit/hyperactivity disorder, have not been extensively investigated. Research using genetically defined rodent strains can enhance our understanding of the role genetic factors play in drug-related behaviors and the development of animal models for drug-sensitive diseases or behaviors. The objective of the present study was to investigate strain differences in the locomotor responses to MPD among three rat strains: Sprague-Dawley (SD), Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR). Eight-week-old adult, male SD, WKY, and SHR were given a regimen of daily MPD administration (0.6, 2.5, or 10 mg/kg, i.p.) for 6 consecutive days followed by 3 days of washout and a day of MPD re-challenge with similar dosages as previously used. An automated activity monitoring system recorded their horizontal activity, total distance traveled, rearing, stereotypic movements, and number of discrete movements. Repeated administration of 0.6 mg/kg MPD produced no significant effect on locomotor activity compared with saline in all three strains. However, there were strain differences in the locomotor activity of SD, SHR, and WKY rats to repeated 2.5- and 10-mg/kg MPD treatment. Repeated administration of 2.5 mg/kg MPD elicited locomotor sensitization in SD and WKY rats but not in SHR. Repeated administration of 10 mg/kg MPD induced locomotor tolerance in SD and WKY rats, while SHR had variable locomotor responses to this MPD dose. In conclusion, rat strains play a significant role in the response to acute and chronic administration of MPD.     

Subchronic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine lesion of dopamine neurons results in a sensitization of enhanced GABA release in the substantia nigra, pars reticulata

L-DOPA is the most effective pharmacological agent used for the symptomatic treatment of Parkinson's disease but long-term L-DOPA treatment induces involuntary abnormal movements such as dyskinesias. The present study, using in vivo microdialysis, investigated the effects of a single or subchronic administration of L-DOPA to adult rats with a unilateral 6-OHDA lesion of dopamine neurons on GABA release in the substantia nigra, pars reticulata (SNr). The results indicate that a challenge injection of L-DOPA (50 mg/kg, i.p.) significantly increases GABA levels in the SNr of rats treated with a daily repeated administration of L-DOPA (50 mg/kg, i.p.). Further statistical analysis between groups also showed that extracellular GABA levels were significantly higher in the subchronic L-DOPA group than in the group receiving only one injection of L-DOPA. These results show that the subchronic administration of L-DOPA results in a sensitization of enhanced extracellular GABA levels in the SNr.     

Different effects of valproate on methamphetamine- and cocaine-induced behavioral sensitization in mice

Repetitive exposure to psychostimulants elicits behavioral sensitization. Accumulating evidence have shown that the central GABAergic system is involved in psychostimulants sensitization. Valproate, a clinically widely used anticonvulsant mood-stabilizing agent, can modulate central GABAergic neurotransmission. Herein, the effects of valproate on the development and expression of behavioral sensitization to methamphetamine (METH) and cocaine was studied in mice. Behavioral sensitization of METH and cocaine was rendered by injection of METH (2.0mg/kg) or cocaine (20mg/kg) once daily for seven days. Locomotor activity was measured by an ambulometer. Single or multiple administration of valproate (37.5, 75, 150 mg/kg) could not decrease acute METH- and cocaine-induced hyperactivity. Co-administration of valproate with METH or cocaine dose-dependently inhibited the development of behavioral sensitization. Single administration of valproate (37.5, 75, 150 mg/kg) did not affect the expression of behavioral sensitization induced by METH and cocaine. Multiple administration of valproate (37.5, 75, 150 mg/kg) dose-dependently inhibited the expression of behavioral sensitization to METH, but not to cocaine. The present results supported that METH- and cocaine-induced behavioral sensitization possesses distinct neural mechanisms, which implies that valproate may have different modulatory effect on METH and cocaine addiction in humans.     

Sensitization does not develop to cocaine-induced potentiation of the antinociceptive effect of morphine

Repeated intermittent cocaine administration produces a progressive increase (sensitization) in the motor stimulatory action of cocaine. Previous studies have shown that cocaine produces antinociception and also enhances the antinociceptive effect of opioid analgesics. The present study was designed to investigate if sensitization to these effects of cocaine develops. In the first part of the study, we determined if acute cocaine administration (3, 10, 30 mg/kg, intraperitoneal [i.p.]) increases the antinociceptive effect of morphine (5 mg/kg, subcutaneous [s.c.]) in rats using the hot plate test. Cocaine (30 mg/kg, i.p.), alone, produced a small but significant antinociceptive effect at 15 min after drug administration. When administered 15 min prior to morphine, cocaine dose-dependently enhanced the effect of morphine (5 mg/kg, s.c.) at the time (45 min post-cocaine) when cocaine by itself did not significantly change the hot plate latency. In the second part of the study, we examined if sensitization develops to cocaine-induced antinociception and its ability to increase the antinociceptive effect of morphine. Na?ve rats were injected with either saline or cocaine (30 mg/kg) once daily for 3 days and tested on the hot plate apparatus either 24 h or 1 wk after the last cocaine injection. Some of the rats from each group were also tested for motor stimulation induced by cocaine (5 mg/kg, i.p.) 24 h after the hot plate test to confirm that sensitization had occurred to the motor stimulatory action of the drug. Additional rats were treated with saline or cocaine for 3 days, but neither treated with morphine nor tested on the hot plate apparatus, and tested for behavioral sensitization to the motor stimulatory action of cocaine (5 mg/kg, i.p.) 24 h or 1 wk later. Sensitization developed to the motor stimulatory effect of cocaine in both groups, regardless of morphine treatment on the prior day. Sensitization also developed to the antinociceptive effect of cocaine 24 h but not 1 wk after the last cocaine injection. No sensitization was observed in the ability of cocaine to enhance the antinociceptive effect of morphine. Overall, our data suggest that while cocaine enhanced the antinociceptive effect of morphine, sensitization did not develop to this action of cocaine.     

Single restraint stress sensitizes acute chewing movements induced by haloperidol, but not if the 5-HT1A agonist 8-OH-DPAT is given prior to stress

The objective of this study was two-fold: (i) to analyze behavioral sensitization to haloperidol 2 weeks after single restraint stress, and (ii) to establish the effects of 8-OH-DPAT treatment prior to stress on sensitized behavioral responses. Overall behavior was analyzed and not only catalepsy, but also sedation (immobility), grooming, exploration and vacuous chewing movements were evaluated. Results indicated that single restraint stress induced a long-lasting sensitization of acute vacuous chewing movements induced by haloperidol (0.25, 0.5 mg/kg i.p.). Interestingly, this behavioral sensitization was prevented by 8-OH-DPAT (0.35 mg/kg s.c.) prior to stress. Finally, haloperidol-induced sedation was not disrupted by either restraint stress or 8-OH-DPAT treatment.     

Influence of acute or repeated restraint stress on morphine-induced locomotion: involvement of dopamine,opioid and glutamate receptors

The development of restraint stress-induced sensitization to the locomotor stimulating effect of morphine (2 mg/kg i.p.) was investigated. In experiment 1, both a single restraint session (2 h) and a repeated restraint stress (2 h per day for 7 days), similarly enhanced the effects of morphine on motor activity. In experiment 2, we observed that this sensitization was prevented by administration of both D(1) and D(2) dopaminergic antagonist [SCH-23390 (0.5 mg/kg i.p.) and (+/-)-sulpiride (60 mg/kg i.p.)] 10 min prior to the stress session. In experiment 3, we showed that an opioid antagonist pretreatment [naltrexone (1 mg/kg i.p.) 10 min prior to stress session, suppressed the stress-induced sensitization after morphine administration. In experiment 4, pretreatment with a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors [(+)-MK-801 (0.1 mg/kg i.p.)], 30 min prior to the acute restraint session, prevented the development of sensitization to morphine. All these results suggest that: (1) sensitization to morphine on stimulating locomotor effect does not depend on the length of exposure to stress (acute vs. repeated); (2) stimulation of both D(1) and D(2) dopaminergic receptors is necessary for the development of restraint stress-induced sensitization to morphine; (3) an opioid system is also involved in this sensitization process; and (4) the stimulation of glutamatergic NMDA receptors is involved in this acute restraint-induced effect.