Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice

The behavioral sensitization produced by repeated amphetamine treatment may represent the neural adaptations underlying some of the features of psychosis and addiction in humans. Chromatin modification (specifically histone hyperacetylation) was recently recognized as an important regulator of psychostimulant-induced plasticity. We have investigated the effects of treatment with the histone deacetylase (HDAC) inhibitors butyric acid (BA, 630mg/kg, i.p.) and valproic acid (VPA, 175mg/kg, i.p.) on the psyhcostimulant locomotor sensitization induced by amphetamine (AMPH, 2.0mg/kg, i.p.). Neither BA nor VPA had locomotor effects alone, but both significantly potentiated the amphetamine-induced behavioral sensitization in mice. At the molecular level, VPA and amphetamine produced an increase of histone H4 acetylation in the striatum as detected by Western blot analysis, while co-treatment with VPA and AMPH produced an additive effect on histone H4 acetylation. We then administered the HDAC inhibitors after treatment with amphetamine for 8 days to establish locomotor sensitization. We found that repeated administration of VPA or BA for 6 days inhibited the expression of sensitized response following amphetamine challenge. Finally, in a context-specific model we studied the effect of HDAC inhibitors on amphetamine-induced association of the treatment environment (associative learning). We found that VPA and BA enhance the context-specificity of expression of amphetamine sensitization. Thus, HDAC inhibitors differentially modulate the induction and expression of amphetamine-induced effects. Together, these results suggest that dynamic changes in chromatin modification may be an important mechanism underlying amphetamine-induced neuronal plasticity and associative learning.     

GSK‐3β inhibitors reverse cocaine‐induced synaptic transmission dysfunction in the nucleus accumbens

Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine‐induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine‐induced hyperlocomotor activity in rats. By employing single‐unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine‐inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N‐methyl‐D‐aspartic acid receptor (NMDAR)‐mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor‐mediate excitatory postsynaptic current (EPSC) were mimicked by the D₁‐like receptor agonist SKF 38393 and blocked by the D₁‐like receptor antagonist SCH 23390, whereas D₂‐like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor‐mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D₁‐like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D₁ receptor–GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine‐induced hyperlocomotion.     

A novel nicotinic-cholinergic role in behavioral sensitization to amphetamine-induced stereotypy in mice

Cholinergic antagonists were used to investigate the role of the cholinergic system in amphetamine- and cocaine-induced behavioral sensitization to stereotypy in mice. Systemically, mecamylamine (l mg/kg) and dihydro-β-erythroidine (2 mg/kg) - nicotinic antagonists - and atropine (2 mg/kg) - a muscarinic antagonist - were ineffective against psychostimulant-induced stereotypy in naive animals. The nicotinic antagonists, however, blocked both the induction and expression of sensitization to amphetamine; in contrast, atropine was ineffective. All three drugs were ineffective against either the induction or expression of cocaine sensitization. Intrastriatally, the nicotinic antagonists blocked induction but not expression of amphetamine-induced sensitization. The results suggest that the nicotinic system participates in sensitization induced by amphetamine but not cocaine; that the nicotinic component of the amphetamine response in sensitized animals is novel as compared to the response in naive animals; and that the striatum is a locus for the nicotinic involvement in induction but not expression. The data add support to the inference that behavioral sensitization represents not only a quantitative but a qualitative change in response to amphetamine.     

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.     

Chronic corticosterone administration enhances behavioral sensitization to amphetamine in mice

The role of corticosterone (CCS) in regulating sensitization to ampetamine's locomotor activating effects was measured in female DBA/2 mice that had been sham-operated or adrenalectomized and implanted with CCS-containing or cholesterol pellets. Three days following surgery, the mice were injected with saline and circular open field locomotor activity was measured for a 5-min time period starting 15 min after injection. Over the next 4 days, amphetamine (1.0–10.0 mg/kg) was injected and locomotor response measured. Control animals (sham-operated, cholesterol pellet) showed increased locomotor activity following their first injection of 5.0 mg/kg and 10.0 mg/kg amphetamine, while ADX animals showed increased activity only after treatment with the 10 mg/kg dose. Chronic CCS treatment did not significantly alter initial responsiveness to amphetamine in either sham-operated or ADX animals, but it did alter the dose-dependent sensitization to amphetamine. Both sham-operated and ADX animals implanted with cholesterol pellets showed increased locomotor respponse to amphetamine (sensitation) following injection with 2.5, 5.0 and 10.0 mg/kg doses of amphetamine. However, the enhancement of locomotor activity was greater in the sham-operated control animals. CCS-treated sham-operated animals exhibited sensitization to the locomotor-activating effects of amphetamine at the lowest dose used (1.0 mg/kg) and increased stereotypy following treatment with the higher doses. ADX/CCS animals developed sensitization to the locomotor-activating effects of amphetamine following chronic injection with the 2.5 mg/kg dose, and showed sensitization to amphetamine-induced stereotypy at higher doses. These data demonstrate that adrenocortical status modulates the effects of chronic and acute amphetamine administration and suggest that CCS may be an important component of stress-induced alterations in amphetamine sensitivity.     

Awakening properties of newly discovered highly selective H₃ receptor antagonists in rats

The objective of the present study was to compare the awakening effects of two newly discovered H? receptor antagonists (i.e. SAR110894 and SAR110068) with those of reference H? receptor ligands (i.e. ciproxifan, ABT-0239 and GSK189254) and classical psychostimulants (i.e. amphetamine and modafinil) by using EEG recording in rats during their light phase. Results showed that SAR110068 (10 and 30 mg/kg, p.o.) increased wakefulness and decreased slow wave sleep to a similar degree than ciproxifan (10 mg/kg, i.p.), ABT-0239 (10 mg/kg, p.o.) and GSK189254 (10 mg/kg, p.o.), while SAR110894 (3-30 mg/kg, p.o.) did not modify significantly any of the sleep/wakefulness parameters. Time-course analysis revealed that the awakening effects of GSK189254 lasted for about 1h, while ciproxifan, ABT-0239 and SAR110068 produced such effects for 3-4 h. The magnitude of the awakening effects of the psychostimulants, amphetamine (3 mg/kg, i.p.) and modafinil (300 mg/kg, i.p.), was dramatically higher than with the H? compounds, and they lasted for 5 and 6 h, respectively. However, unlike the H? receptor antagonists, both psychostimulants produced a strong increase in theta (θ) rhythm, which is indicative of CNS side effects, such as hyperactivity or abnormal excitation. In conclusion, this study provides further evidence to support the potential use of H? receptor antagonists in the treatment of vigilance and sleep-wake disorders such as narcolepsy.     

The role of the frontal cortex in the mouse in behavioral sensitization to amphetamine

Pharmacological studies have shown that a variety of neuroeffectors are involved in behavioral sensitization to amphetamine-induced stereotypy. In the present work, the effect of some of these drugs on sensitization was studied after intracortical administration in order to determine the role of the cortex in mediating their systemic effects. The dopamine antagonists sulpiride and spiperone were both ineffective against the acute response to amphetamine; nevertheless, both blocked the induction of sensitization, suggesting that the mesocortical dopamine pathway is not involved in the acute response but is necessary for the induction of sensitization. Both CPP, an NMDA receptor antagonist, and THIP, a GABA_A agonist, blocked the acute response and the induction of sensitization to amphetamine. On the other hand, mecamylamine, the nicotinic cholinergic antagonist, failed to affect either the acute response or the induction of sensitization, which suggests that the cortex is not a locus of its activity. Anisomycin, an inhibitor of protein synthesis, and diltiazem, a calcium-channel blocker, were both ineffective against the acute response, but both blocked induction. All of the drugs, except CPP and THIP, were ineffective against the expression of sensitization; therefore, the ability of the other drugs to block expression must reside within another locus. Bicuculline injected intracortically in non-convulsant doses produced a stereotypy indistinguishable from that induced by amphetamine; and the effect was readily antagonized by CPP administered either systemically or intracortically. In contrast, sulpiride by either route of administration failed to block the bicuculline-induced stereotypy; we conclude, therefore, that the stereotypic effect of bicuculline is not mediated by dopamine. These results imply that amphetamine-induced stereotypy is mediated in the cortex by the removal of the inhibitory control of the excitatory system. The data also suggest that cortical dopamine, as well as the NMDA and GABA_A systems, is important in sensitization to amphetamine. In general the data demonstrate that different neuroeffectors involved in sensitization exert their effects at different brain loci.     

Inhibition of nitric oxide synthase in the ventral tegmental area attenuates cocaine sensitization in rats

1. Male Sprague-Dawley rats were pretreated via bilateral infusion of the VTA with the selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (0, 8, or 40 ng/hemisphere), prior to each of 7 daily systemic cocaine (30 mg/kg, i.p.) or saline (1 ml/kg) treatments. 2. After a 7-day treatment withdrawal period, rats received a final systemic challenge with either cocaine (30 mg/kg, i.p.) or saline (1 ml/kg). 3. Locomotor and stereotypic activity were measured following the first and last treatments. 4. Daily cocaine treatment led to the development of sensitization to its stereotypic effects as revealed upon drug challenge. 5. The development of sensitization of cocaine-induced stereotypy was completely blocked by daily intra-VTA pretreatment with 7-nitroindazole. 6. In addition, attenuation of the locomotor effects of cocaine challenge was also observed in animals that received daily intra-VTA 7-nitroindazole (40 ng/hemisphere) infusions. 7. The results indicate that VTA nitric oxide is necessary for the development of sensitization of cocaine-induced stereotypic behavior, and that its repeated inhibition may produce lasting effects on the locomotor response to the drug.     

Enhanced acetylcholine release in striatum after chronic amphetamine is NMDA-dependent

Behavioral sensitization to chronic amphetamine develops in parallel with an enhancement of amphetamine-stimulated efflux of acetylcholine (ACh) in striatum. The present study investigated the role of NMDA receptors in the latter phenomenon. Rats were treated with either saline (1.0 ml/kg, i.p.) or amphetamine (4.0 mg/kg, i.p., b.i.d.) for 12 days followed by a withdrawal period of 2-3 weeks. In vivo microdialysis was employed to measure striatal ACh efflux. Amphetamine challenge (4.0 mg/kg, i.p.) evoked a significant increase in striatal ACh efflux in rats withdrawn from chronic amphetamine while having no significant effect on ACh efflux in saline-pretreated rats. Inclusion of the NMDA receptor antagonist (+/-)-2-amino-5-phoshonopentanoic acid (APV; 100 microM) in the perfusion solution blocked the amphetamine-induced increase in striatal ACh efflux observed in amphetamine-pretreated rats. In saline-pretreated animals, the presence of APV had no apparent effect on the profile of striatal ACh efflux following amphetamine challenge. Thus, the stimulatory effect of amphetamine challenge on striatal ACh efflux that selectively is observed in animals withdrawn from chronic amphetamine is dependent upon NMDA receptor activation.     

The amphetamine-chlordiazepoxide mixture, a pharmacological screen for mood stabilizers, does not enhance amphetamine-induced disruption of prepulse inhibition

In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (−) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3 mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16 mg/kg) and (−) ephedrine (50 mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d-amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120-240 mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d-amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited.     

Differential effects of para-chlorophenylalanine on amphetamine-induced locomotion and stereotypy.

Amphetamine-induced locomotion and stereotypy were concurrently evaluated in order to determine if pretreatment with para-chlorophenylalanine (PCPA) (which is reported to facilitate some of the effects of amphetamine) results in a behavioral pattern similar to the augmentation previously reported to occur with repeated amphetamine administration. In the present study the behavioral response of rats was characterized after administration of saline or various doses of D-amphetamine (0.5, 2.5 and 4.0 mg/kg) for 48 h following PCPA (300 mg/kg) or vehicle injection. The predominant effects produced by the low dose of D-amphetamine (0.5 mg/kg), i.e., enhanced crossovers and rearings, were found to be significantly elevated after PCPA administration. This effect persisted (relative to PCPA controls) when the response of non-PCPA pretreated animals returned to corresponding control levels, thus indicating that the two drugs acted synergistically. However, while the locomotor component of the amphetamine response was potentiated by PCPA pretreatment, the more focused stereotypies produced by higher doses of amphetamine (2.5 and 4.0 mg/kg) were significantly displaced by enhanced crossovers and rearings. These differential effects of PCPA on amphetamine-induced locomotion and stereotypy are in contrast to the uniform pattern of behavioral augmentation resulting from repeated amphetamine administration. The relationship between the various behavioral components of the amphetamine response and the possible neurochemical mechanisms subserving their interaction are discussed.     

Behavioral and neurochemical sensitization to amphetamine following early postnatal administration of methylmercury (MeHg)

Perinatal exposure to methylmercury (MeHg) in rodents has been linked to changes in sensitivity to dopaminergic agents later in life. In an effort to determine the behavioral and neurochemical response to the indirect dopaminergic and serotonergic agonist amphetamine following neonatal exposure to MeHg, male BALB/c mice were administered MeHg during critical periods of neural development and challenged with amphetamine as adults. Mice were observed 15, 30 and 60 min after a single amphetamine injection (7.5 mg/kg i.p.) for presence of stereotypic and self-injurious behaviors, abnormal posture, and hyperthermia. Mice treated with 2 or 4 mg/kg MeHg on alternate days 3-15 of life demonstrated an increase in body temperature and the appearance of stereotypic and self-injurious behaviors not observed when amphetamine was administered to either vehicle-exposed mice or those treated with an equivalent total amount of MeHg administered on postnatal days 13 and 15. Neurochemical analysis of MeHg- and vehicle-exposed mice challenged with amphetamine or saline revealed alterations in dopaminergic and serotonergic activity which corresponded to the sensitized behavioral response to amphetamine. These observations demonstrate a critical window for MeHg exposure affecting the later appearance of amphetamine-induced self-injurious behavior and support the hypothesis that early exposure to environmental neurotoxicants may predispose individuals to engage in aberrant, intrusive behaviors later in life.     

Apparent serotonergic modulation of the dose-dependent biphasic response of neostriatal neurons produced by d-amphetamine

Previous reports indicate that amphetamine produces a dose-dependent shift in the firing rate of neurons in the anterior neostriatum that parallels the shift in behavior from locomotion to focused stereotypy. To determine if para-chlorophenylalanine (PCPA), which alters the pattern of the behavioral response to amphetamine, also changes the pattern of the neuronal response to the drug, a dose-response analysis was performed on amphetamine-induced changes in unit activity in the anterior neostriatum of rats pretreated 48 h previously with 300 mg/kg PCPA or vehicle. An intraperitoneal injection of 1.0 mg/kgd-amphetamine, which inhibited neostriatal activity in vehicle controls, produced in PCPA-pretreated animals a prolonged excitation. In contrast, the pronounced increase in firing rate produced by 7.5 mg/kgd-amphetamine in control rats was significantly reduced following PCPA pretreatment. Liquid chromatograhy with electrochemical detection revealed that compared to controls, PCPA produced a significant reduction of serotonin, but not dopamine or norepinephrine, in the telencephalon. The differential effects of PCPA on the action of low and high doses of d-amphetamine in the anterior neostriatum may explain the differential influence of serotonergic systems on amphetamine-induced locomotion and stereotypy.     

Repeated amphetamine administration outside the home cage enhances drug-induced Fos expression in rat nucleus accumbens

Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated amphetamine administration to rats in their home cages. However, this technique has not been used to examine striatal activation after repeated administration outside the home cage, an environment where repeated drug administration produces more robust psychomotor sensitization. We determined the dose-response relationship for amphetamine-induced psychomotor activity and Fos expression in nucleus accumbens and caudate-putamen 1 week after repeated administration of amphetamine or saline in locomotor activity chambers. Repeated administration of amphetamine enhanced amphetamine-induced locomotor activity and stereotypy and Fos expression in nucleus accumbens, but not in caudate-putamen. In comparison, levels of Fos expression induced by 1mg/kg amphetamine were not altered in nucleus accumbens or caudate-putamen by repeated amphetamine administration in the home cage. Double-labeling of Fos protein and enkephalin mRNA indicates that Fos is expressed in approximately equal numbers of enkephalin-negative and enkephalin-positive neurons in nucleus accumbens and caudate-putamen following injections outside the home cage. Furthermore, repeated amphetamine administration increased drug-induced Fos expression in enkephalin-positive, but not enkephalin-negative, neurons in nucleus accumbens. We conclude that repeated amphetamine administration outside the home cage recruits the activation of enkephalin-containing nucleus accumbens neurons during sensitized amphetamine-induced psychomotor activity.     

Neurotensin affects hyperactivity but not stereotypy induced by pre and post synaptic dopaminergic stimulation

The effects of intraventricular administration of neurotensin (0.9, 3.75 and 15.0 micrograms) on hyperactivity and stereotypy induced by either amphetamine (1 mg/kg), nomifensine (20 mg/kg), apomorphine (0.5 mg/kg) or N-n-propylnorapomorphine (0.5 mg/kg) were examined. Results indicate that for each drug treatment, the effects of neurotensin were identical: hyperactivity was significantly reduced while stereotypy remained unaffected. Results also revealed that neurotensin significantly increased the hypothermia induced by apomorphine and N-n-propylnorapomorphine. Possible mechanisms which could underly neurotensin's selective inhibitory action on hyperactivity produced by both pre and post synaptic dopaminergic stimulation are discussed.     

Partial reversal of stress-induced behavioral sensitization to amphetamine following metyrapone treatment

Several studies indicate that blockade of stress-induced corticosterone secretion prevents the development of stress-induced sensitization to the behavioral effects of stimulants. The present study examined whether chronic blockade of corticosterone synthesis with metyrapone could reverse stress-induced amphetamine sensitization in rats. Restraint stress in cylindrical chambers, 2 times 30 min/day for 5 days over an 8-day schedule, was used as the stressor. Following completion of the stress protocol, animals were cannulated with microdialysis guide cannulae over the nucleus accumbens, and then treated with either metyrapone (50 mg/kg, i.p.) or vehicle (1 ml/kg) for 7 days. On the seventh day, animals were implanted with microdialysis probes in the nucleus accumbens, and on the following day, all animals were tested for their locomotor, stereotypy, and nucleus accumbens dopamine and DOPAC release responses to an injection of saline followed 60 min later by d-amphetamine (1.5 mg/kg, i.p.). Neither stress or metyrapone treatment had an effect on the behavioral or dopamine release response to saline. However, amphetamine-stimulated locomotion and stereotypy were strongly enhanced, while amphetamine-stimulated dopamine release response was slightly enhanced (significant only by drug×time interaction), in stressed animals. Metyrapone treatment reduced the stress-induced increase in the locomotor, but not stereotypy, response to amphetamine. In contrast, the dopamine release response to amphetamine was enhanced in metyrapone-treated animals, in both stressed and non-stressed groups, while DOPAC levels were unaffected by treatment group. This augmentation was particularly evident in the stressed-metyrapone-treated animals. Furthermore, non-stressed animals showed an increased locomotor and stereotypy response to amphetamine after treatment with metyrapone. These findings indicate that metyrapone treatment can reverse, or inhibit the expression of, stress-induced sensitization to the behavioral effects of amphetamine. However, the ability of metyrapone treatment to enhance the behavioral (in non-stressed animals) and dopamine release (in non-stressed and stressed animals) responses to amphetamine indicate that chronic metyrapone treatment will produce stimulant sensitization when given alone.     

Sensitization to amphetamine occurs simultaneously at immune level and in met-enkephalin of the nucleus accumbens and spleen: An involved NMDA glutamatergic mechanism

Administration of psychostimulants can elicit a sensitized response to the stimulating and reinforcing properties of the drugs, although there is scarce information regarding their effects at immune level. We previously demonstrated that an acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in met-enkephalin at limbic and immune levels, 4 days following drug administration. In this study, we evaluated the amphetamine-induced effects at weeks one and three after the same single dose treatment (5 mg/kg, i.p.) on the lymphoproliferative response and on the met-enkephalin in the nucleus accumbens (NAc), prefrontal cortex (PfC), spleen and thymus. It was demonstrated that these effects disappeared completely after three weeks, although re-exposure to an amphetamine challenge induced the expression of sensitization to the effects of amphetamine on the lymphoproliferative response and on the met-enkephalin from NAc, spleen and thymus, but not in the PfC. Pre-treatment with MK-801 (0.1 mg/kg, i.p.), an N-methyl-d-aspartate (NMDA) glutamatergic receptor antagonist, blocked the effects of a single amphetamine exposure on the lymphoproliferative response and on met-enkephalin in the NAc and spleen. Furthermore, the NMDA receptor antagonist administered prior to amphetamine challenge also blocked the expression of sensitization in both parameters evaluated. These findings show a long-lasting amphetamine-induced sensitization phenomenon at the immune level in a parallel way to that occurring in the limbic and immune enkephalineric system. A glutamate mechanism is implied in the long-term amphetamine-induced effects at immune level and in the met-enkephalin from NAc and spleen.     

Cholinergic manipulations in the rat basolateral amygdaloid nucleus on locomotor activity induced by amphetamine

Microinjections of cholinergic antagonists in the vicinity of the basolateral amygdaloid nucleus produced a marked reduction of amphetamine-induced hyperactivity when amphetamine was administered i.p. in relatively large doses (1.5 mg/kg). Cholinergic agonists enhanced locomotor activity induced by relatively small doses of amphetamine (0.5 mg/kg). These observations suggest that cholinergic activity in the amygdala modulates the locomotor response to amphetamine.     

Valproate prevents the induction of sensitization to methylphenidate (ritalin) in rats

Repetitive exposure to methylphenidate (MPD) elicits sensitization to its locomotor effects. Drugs that affect the GABA system may modify adaptations to drug exposure. Therefore, we have examined the effect of sodium valproate, which enhances GABA function, on the development of sensitization to MPD using an automated, computerized animal activity monitoring system to record each rat's motor activities for 15 consecutive days. Rats were recorded before and after saline injection (Days 1-2) to provide baseline activity. Animals were then randomly assigned to the following three groups that received: (1) 2.5 mg/kg MPD (s.c.) for six consecutive days (Days 3-8), (2) a single dose of valproate (50 mg/kg; i.p.) 1 h prior to the first (Day 3) of six daily doses of MPD (2.5 mg/kg; s.c. ), or (3) five daily doses of valproate (50 mg/kg, i.p.) 1 h prior to MPD (2.5 mg/kg, s.c.) on Days 4-8. There was no drug treatment during the next 5 days (Days 9-13). All rats were then re-challenged with MPD (2.5 mg/kg, s.c.) on Day 14. Group 2 rats were also re-challenged with 50 mg/kg valproate followed by 2.5 mg/kg MPD 1 h later on Day 15. Administration of MPD alone produced a sensitized response. Multiple valproate injections prevented the induction of MPD-elicited sensitization in all four motor indices, while a single valproate injection prevented the induction of MPD-elicited sensitization in two of four motor indices studied. In conclusion, a single injection 50 mg/kg valproate given prior to any MPD treatment partially blocked the induction of MPD sensitization while repeated injections of valproate co-administered with MPD treatment completely prevented this effect.     

Altered cocaine-induced behavioral sensitization in adult mice exposed to cocaine in utero

Behavioral sensitization induced by psychostimulants is characterized by increased locomotion and stereotypy and may reflect aspects of neuronal adaptations underlying drug addiction in humans. To study the developmental contributions to addictive behaviors, we measured behavioral responses in adult offspring to a cocaine sensitization paradigm following prenatal cocaine exposure. Pregnant Swiss-Webster (SW) mice were injected twice daily from embryonic days 8 to 17 (E8-E17, inclusive) with cocaine (20 or 40 mg/kg/day; COC20 and COC40, respectively), or saline vehicle (SAL and SPF40) subcutaneously (s.c.). A nutritional control group of dams were 'pair-fed' with COC40 dams (SPF40). P120 male offspring from each prenatal treatment group were assigned to a behavioral sensitization group and injected with cocaine (15 mg/kg) or saline intraperitoneally (i.p.) every other day for seven doses. Locomotor activity and stereotypy were measured during habituation, cocaine initiation, and following a cocaine challenge 21 days after the last initiation injection. As expected, animals demonstrated significantly more locomotion and stereotypic behavior following acute and recurrent injection of cocaine compared to saline-injected animals. However, for each prenatal treatment group, cocaine-sensitized animals showed unique temporal profiles for the increase in locomotor sensitization and stereotypy over the course of the sensitization protocol. Two features that distinguished the altered behavioral progression of prenatally cocaine-exposed animals (COC40) from control (SAL) animals included blunted augmentation of locomotion and enhanced patterns of stereotypic behavior. These findings provide evidence that the behavioral activating effects of cocaine in adult animals are altered following exposure to cocaine in utero.