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.     

Enhanced dendritic availability of μ‐opioid receptors in inhibitory neurons of the extended amygdala in mice deficient in the corticotropin‐releasing factor‐1 receptor

Activation of the corticotropin‐releasing factor‐1 (CRF‐1) receptor in the anterolateral BNST (BSTal), a key subdivision of the extended amygdala, elicits opiate‐seeking behavior exacerbated by stress. However, it is unknown whether the presence of CRF‐1 affects expression of the μ‐opioid receptor (μ‐OR) in the many GABAergic BSTal neurons implicated in the stress response. We hypothesized that deletion of the CRF‐1 receptor gene would alter the density and/or subcellular distribution of μ‐ORs in GABAergic neurons of the BSTal. We used electron microscopy to quantitatively examine μ‐OR immunogold and γ‐aminobutyric acid (GABA) immunoperoxidase labeling in the BSTal of CRFr‐1 knockout (KO) compared to wild‐type (WT) mice. To assess regional specificity, we examined μ‐OR distribution in dorsal striatum. The μ‐ORs in each region were predominantly localized in dendrites, many of which were GABA‐immunoreactive. Significantly, more cytoplasmic μ‐OR gold particles per dendritic area were observed selectively in GABA‐containing dendrites of the BSTal, but not of the dorsal striatum, in KO compared to WT mice. In both regions, however, significantly fewer GABA‐immunoreactive axon terminals were present in KO compared to WT mice. Our results suggest that the absence of CRF‐1 results in enhanced expression and/or dendritic trafficking of μ‐ORs in inhibitory BSTal neurons. They also suggest that the expression of CRF‐1 is a critical determinant of the availability of GABA in functionally diverse brain regions. These findings underscore the complex interplay between CRF, opioid, and GABA systems in limbic and striatal regions and have implications for the role of CRF‐1 in influencing the pharmacological effects of opiates active at μ‐ORs. Synapse 65:8–20, 2011. © 2010 Wiley‐Liss, Inc.     

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.     

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.     

Loss of nicotine-induced behavioral sensitization in micro-opioid receptor knockout mice

Repeated administration of nicotine produces behavioral sensitization. However, the possible mechanism of behavioral sensitization to nicotine remains unclear. The present study was undertaken in micro-opioid receptor knockout mice, to examine the hypothesis that micro-opioid receptors play a crucial role in behavioral sensitization to nicotine. All mice received saline or nicotine (0.05 mg/kg, s.c) twice a day for 7 consecutive days. The mice remained drug free for 3 days and on day 11 each group was challenged with saline or nicotine (0.05 mg/kg, s.c.). On day 1, it was observed that the single injection of nicotine (0.05 mg/kg, s.c.) did not influence locomotor activity in either micro-opioid receptor knockout or in wildtype mice. On day 7 (24 h after mice had been treated twice daily for 6 consecutive days with an injection of 0.05 mg/kg of nicotine), the mice were challenged with a single injection of nicotine, which produced behavioral sensitization in the wildtype but not in micro-opioid receptor knockout mice. On day 11, following 3 days of withdrawal after the second injection of nicotine on day 7, nicotine-treated mice were challenged with a single injection of nicotine and showed the behavioral sensitization of wildtype. However, nicotine challenge did not induce behavioral sensitization in micro-opioid receptor knockout mice. Our data indicate that a lack of micro-opioid receptors can inhibit the effects of nicotine-induced behavioral sensitization. This result strongly suggests that the micro-opioid receptor plays an important role in behavioral sensitization to nicotine.     

Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats

Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1 mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5 mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5 mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for 96 h. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life.     

Role of mu-opioid receptor in modulation of preproenkephalin mRNA expression and opioid and dopamine receptor binding in methamphetamine-sensitized mice

We examined mRNA expression of preproenkephalin (PPE), a precursor of the endogenous opioid peptide enkephalin, and ligand binding to opioid and dopamine receptors in the striatum and nucleus accumbens in methamphetamine (METH)-sensitized mu-opioid receptor (mu-OR) knockout mice and their wild-type controls. Animals received daily intraperitoneal (i.p.) injections of METH (0, 0.625, 2.5, or 10 mg/kg) for 7 consecutive days to induce sensitization. Brain tissues were taken for biochemical analysis on experimental day 11 (4 days after the last injection). Expression of PPE mRNA and ligand binding were determined by in situ hybridization and autoradiography, respectively. Results indicate that there is an increase in PPE mRNA expression and a decrease in mu-OR ligand binding in METH-sensitized wild-type mice. These changes were not detected in METH-sensitized mu-OR knockout mice. A significant increase in delta-opioid receptor (delta-OR) ligand binding was found in mu-OR knockout mice. After repeated METH exposure, striatal and nucleus accumbal dopamine D1 receptor binding was decreased in mu-OR knockout mice but was not changed in wild-type mice. D2 receptor ligand binding was increased in wild-type mice and exhibited a biphasic change, with a decrease at 0.625 and 2.5 mg/kg doses of METH and an increase with 10 mg/kg of METH, in mu-OR knockout mice. These findings suggest that the mu-OR is involved in the regulation of METH-induced changes in an endogenous opioid peptide and dopamine receptors.     

Ritanserin reverses repeated methamphetamine-induced behavioral and neurochemical sensitization in mice

Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor activity known as behavioral sensitization. We have recently shown that chronic METH enhanced METH challenge-induced increase in 5-HT levels in the prefrontal cortex and that 5-HT(1A) receptor activation attenuated this neurochemical sensitization as well as behavioral sensitization. This study examined whether the nonselective 5-HT(2) receptor antagonist, ritanserin affects METH-induced behavioral and neurochemical sensitization in mice. Ritanserin at doses of 1 and 3 mg/kg inhibited the development and expression of METH-induced behavioral sensitization in a dose-dependent manner. Furthermore, chronic administration of ritanserin for a week attenuated the maintenance of behavioral sensitization, indicating the improvement of established behavioral sensitization. Microdialysis analysis showed that chronic ritanserin inhibited the neurochemical sensitization that chronic METH enhanced METH challenge-induced increase in extracellular 5-HT levels in the prefrontal cortex. Furthermore, acute ritanserin inhibited METH challenge-induced increase in extracellular 5-HT but not DA levels in the prefrontal cortex. These results suggest that 5-HT(2) receptors are involved in METH-induced hyperactivity and behavioral sensitization in mice.     

Central administration of a CRF antagonist blocks the development of stress-induced behavioral sensitization

This experiment examined the effects of intracerebroventricular (i.c.v.) administration of a corticotropin-releasing factor (CRF) antagonist on the development of stress-induced sensitization of the behavioral response to amphetamine. Restraint stress was found to enhance both the locomotor response to a.s.c. injection of saline and the intensity of stereotypy induced by a s.c. injection of 3.0 mg/kg d-amphetamine. Both of these effects of restraint stress were severely attenuated in rats that had been injected with the CRF antagonist prior to restraint stress. This result is compatible with the hypothesis that CRF is critically involved in initiating behavioral and physiological responses to aversive stimuli.     

Behavioral sensitization to cocaine is not associated with changes in serotonin (5-HT) fiber immunoreactivity in rat forebrain.

We investigated whether cocaine-induced behavioral sensitization is associated with changes in serotonin (5-HT) immunoreactivity. Male Sprague-Dawley rats were injected with either cocaine (15 mg/kg, IP) or saline twice daily for seven days. Their behavior was observed and rated for locomotor activation and stereotypy. One day after the final injection, the brains were processed for 5-HT immunohistochemistry. The intensity of 5-HT immunoreactive staining of 5-HT axons and terminal varicosities was blindly rated in cocaine-sensitized rats and found not to differ from saline-treated rats. The results support the hypothesis that unlike some amphetamine derivatives, repeated cocaine administration which results in behavioral sensitization is not neurotoxic to 5-HT axons and terminals in the forebrain.     

Blockade of neurotensin receptors during amphetamine discontinuation indicates individual variability

Psychostimulant-induced locomotor sensitization has been related to changes within the mesolimbic dopamine system and has been suggested to be useful to study mechanisms underlying drug craving. Neurotensin is a neuropeptide co-localized with dopamine in the mesolimbic system. The response to novelty has been suggested to be a predictor of enhanced vulnerability to behavioral sensitization. The effects of repeated treatment with the neurotensin antagonist SR48692 after amphetamine discontinuation were investigated in mice previously classified as high responders (HRs) or low responders (LRs) to novelty. Mice were repeatedly treated with 2.0mg/kg amphetamine, every other day for 11 days. During the first 7 days after amphetamine discontinuation, the animals received a daily injection of saline or 0.3mg/kg SR48692. On the eighth day after amphetamine discontinuation all subjects received a 2.0mg/kg amphetamine challenge injection. Then, mice were tested for an open field behavior and after 90min, were sacrificed for Fos expression quantification in the nucleus accumbens. Both HRs and LRs expressed amphetamine-induced sensitized locomotor activation and increased expression of Fos protein. Treatment with SR48692 prevented behavioral sensitization and Fos protein expression enhancement in LRs but not in HRs mice. These data suggest that neurotensin plays a role in individual variability to amphetamine-induced sensitization.     

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.     

Endocannabinoid modulation of amphetamine sensitization is disrupted in a rodent model of lesion‐induced dopamine dysregulation

We tested the hypothesis that increased dopaminergic sensitivity induced by olfactory bulbectomy is mediated by dysregulation of endocannabinoid signaling. Bilateral olfactory bulbectomy induces behavioral and neurobiological symptomatology related to increased dopaminergic sensitivity. Rats underwent olfactory bulbectomy or sham operations and were assessed 2 weeks later in two tests of hyperdopaminergic responsivity: locomotor response to novelty and locomotor sensitization to amphetamine. Amphetamine (1 mg/kg i.p.) was administered to rats once daily for 8 consecutive days to induce locomotor sensitization. URB597, an inhibitor of the anandamide hydrolyzing enzyme fatty‐acid amide hydrolase (FAAH), was administered daily (0.3 mg/kg i.p.) to sham and olfactory bulbectomized (OBX) rats to investigate the impact of FAAH inhibition on locomotor sensitization to amphetamine. Pharmacological specificity was evaluated with the CB₁ antagonist/inverse agonist rimonabant (1 mg/kg i.p). OBX rats exhibited heightened locomotor activity in response to exposure either to a novel open field or to amphetamine administration relative to sham‐operated rats. URB597 produced a CB₁‐mediated attenuation of amphetamine‐induced locomotor sensitization in sham‐operated rats. By contrast, URB597 failed to inhibit amphetamine sensitization in OBX rats. The present results demonstrate that enhanced endocannabinoid transmission attenuates development of amphetamine sensitization in intact animals but not in animals with OBX‐induced dopaminergic dysfunction. Our data collectively suggest that the endocannabinoid system is compromised in olfactory bulbectomized rats. Synapse 63:941–950, 2009. © 2009 Wiley‐Liss, Inc.     

Nicotine sensitization and analysis of brain‐derived neurotrophic factor in adolescent ß‐arrestin‐2 knockout mice

Nicotine sensitization and levels of brain‐derived neurotrophic factor (BDNF) were analyzed in adolescent ß‐arrestin‐2 knockout (ßA‐2 KO) and wild type (WT) mice. The ß‐arrestin‐2 protein has been shown to be important in G‐protein hydrolysis and receptor internalization. Four‐ to five‐week‐old adolescent ßA‐2 KO and WT C57/Bl6 mice were administered either nicotine (0.5 mg/kg free base) or saline 10 min before being placed into a locomotor arena on each of 7 (Experiment 1) or 14 (Experiment 2) consecutive days. A nicotine challenge was given 7 days after sensitization was complete. In Experiment 1, ßA‐2 KO mice administered nicotine or saline and WT mice administered nicotine demonstrated significant hypoactivity during early in testing, and neither WT nor ßA‐2 KO mice administered nicotine demonstrated sensitization. On the nicotine challenge, WT mice administered nicotine demonstrated significantly higher activity levels compared to all groups, and this same group demonstrated significantly higher levels of accumbal BDNF compared to all groups. In Experiment 2, ßA‐2 KO mice were again hypoactive compared to WT mice, whereas WT mice administered nicotine demonstrated significant hypoactivity during initial testing and significantly higher levels of activity compared to all other groups late in testing. On the nicotine challenge, WT mice that received nicotine demonstrated a significant increase in activity compared to all groups, and showed increased accumbal BDNF compared to all groups. These results show that the ß‐arrestin‐2 protein is important in induction and expression of nicotine sensitization as well as nicotine's effects on accumbal BDNF. Synapse 63:510–519, 2009. © 2009 Wiley‐Liss, Inc.     

Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine

Repeated amphetamine administration produced behavioral sensitization to subsequent amphetamine challenge. The development of sensitization was blocked by coadministration of the N-methyl-d-aspartate (NMDA) antagonist MK-801. Conditioned locomotion, as revealed by saline challenge, was also blocked by MK-801, suggesting that behavioral sensitization and conditioned locomotion may share a requirement for NMDA receptor stimulation. Repeated MK-801 administration produced behavioral sensitization to MK-801 but not amphetamine challenge, suggesting that MK-801 itself produces sensitization through a different mechanism than amphetamine.     

Caffeine and amphetamine produce cross-sensitization to nicotine-induced locomotor activity in mice

Sensitization development is linked to the addictive potential of the drugs. The same mechanisms might play a role in sensitization development to the different addictive drugs. The aim of the study was to investigate the development of cross-sensitization to caffeine and amphetamine in nicotine-induced locomotor sensitization in mice. Caffeine (2.5-20 mg/kg), amphetamine (1-16 mg/kg) or saline were injected to Swiss-Webster mice and locomotor activity was recorded for 30 min. Nicotine (0.5-2 mg/kg) or saline were injected to mice and locomotor activity was recorded for 30 min. Process was applied for 19 days, every other day (10 sessions). Caffeine (5 mg/kg), amphetamine (4 mg/kg) or saline were challenged to the different groups of nicotine-sensitized mice 2 days later on the last nicotine injection, and locomotor activity was recorded. Repetitive injections of nicotine (0.5-2 mg) produced locomotor sensitization in mice. After caffeine and amphetamine challenge injections, locomotor activity of the nicotine-sensitized mice was found to be significantly higher than saline-pretreated mice. Saline challenge did not produce any significant effect in nicotine- or saline-pretreated mice. Our results suggest that a cross-sensitization developed to both caffeine and amphetamine in nicotine-sensitized mice. In conclusion, similar central mechanisms may be responsible for the development of addiction to these substances.     

Differential action of methamphetamine on tyrosine hydroxylase and dopamine transport in the nigrostriatal pathway of μ-opioid receptor knockout mice

Extensive anatomical and functional interactions exist between central dopaminergic and opioidergic systems and both systems are proposed to be targets for amphetamine-like drugs. We have previously reported that μ-opioid receptor (μ-OR) knockout mice are resistant to the loss of dopamine in the striatum and the development of behavioral sensitization induced by repeated methamphetamine (METH) treatment. The present study assessed whether METH-treated μ-OR knockout mice exhibit a differential response of the expression of dopamine transporter and tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis and maintaining dopamine levels. Mice daily received intraperitoneal injection of METH (0, 0.6, 2.5, or 10 mg/kg) for 7 days and sacrificed on day 11 (4 days after the last injection). The expression of TH protein in the striatum and the levels of TH mRNA and number of TH positive neurons in the substantia nigra were reduced in wild-type mice treated with METH (2.5 and 10 mg/kg), but not in the μ-OR knockout mice. In contrast, METH exposure at the highest dose (10 mg/kg) reduced dopamine transporter levels in both strains of mice. These results suggest that the μ-OR contributes to METH-induced loss of dopamine and behavioral sensitization by decreasing the expression of TH.     

Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology

Behavioral sensitization to the locomotor activating effects of amphetamine refers to the progressive, long lasting increase in locomotor activity that occurs with repeated injections. This phenomenon is thought to result from neuroadaptations occurring in the projection fields of mesocorticolimbic dopaminergic neurons. In the present study, we investigated the effects of amphetamine sensitization on Fos immunoreactivity (Fos-IR) in subterritories of the nucleus accumbens (core and shell) and medial prefrontal cortex (mPFC; dorsal and ventral) using stereology. Rats received five daily injections of amphetamine (1.5 mg/kg, i.p.) or saline. Behavioral sensitization was measured 48 h following the last injection, in response to a challenge injection of 1.5 mg/kg amphetamine. Sensitized rats showed a greater enhancement of locomotor activity upon drug challenge compared with their saline counterparts. Densities of Fos-positive nuclei were enhanced more in the dorsal than the ventral mPFC subterritory, whereas in the nucleus accumbens, densities of Fos-positive nuclei were increased more in the core than the shell of amphetamine-sensitized rats compared to controls. These results represent, to our knowledge, the first published report using stereological methods to quantify Fos-IR in the brain and suggest functional specialization of cortical and limbic regions in the expression of behavioral sensitization 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.     

Distinct roles of dopamine D3 receptors in modulating methamphetamine-induced behavioral sensitization and ultrastructural plasticity in the shell of the nucleus accumbens

Persistent changes in behavior and psychological function that occur as a consequence of exposure to drugs of abuse are thought to be mediated by the structural plasticity of specific neural circuits such as the brain's dopamine (DA) system. Changes in dendritic morphology in the nucleus accumbens (NAc) accompany drug‐induced enduring behavioral and molecular changes, yet ultrastructural changes in synapses following repeated exposure to drugs have not been well studied. The current study examines the role of DA D3 receptors in modulating locomotor activity induced by both acute and repeated methamphetamine (METH) administration and accompanying ultrastructural plasticity in the shell of NAc in mice. We found that D3 receptor mutant (D3^?/?) mice exhibited attenuated acute locomotor responses as well as the development of behavioral sensitization to METH compared with wild‐type mice. In the absence of obvious neurotoxic effects, METH induced similar increases in synaptic density in the shell of NAc in both wild‐type and D3^?/? mice. These results suggest that D3 receptors modulate locomotor responses to both acute and repeated METH treatment. In contrast, the D3 receptor is not obviously involved in modulating baseline or METH‐induced ultrastructural changes in the NAc shell. © 2011 Wiley Periodicals, Inc.