Repeated morphine injections induce behavioural sensitization in Roman high- but not in Roman low-avoidance rats

The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for, respectively, rapid vs poor active avoidance acquisition has resulted in two phenotypes that differ in their behavioural and neurochemical responses to addictive drugs, including morphine. To compare the ability of these lines to develop behavioural sensitization to morphine, female RHA and RLA rats were treated twice daily with either saline or escalating doses of morphine (5, 10, and 20 mg/kg, s.c. on the 1st, 2nd, and 3rd day of treatment, respectively), and were challenged with morphine (0.5 or 2 mg/kg, s.c.) 1 day before and 3 weeks after repeated morphine administration. The locomotor activation produced by either challenge dose of morphine was more pronounced in RHA rats repeatedly treated with morphine vs the respective saline-treated controls, whereas no significant change in locomotor activity was observed in RLA rats. The results show that behavioral sensitization to morphine was induced in RHA but not in RLA rats.     

The psychogenetically selected Roman high- and low-avoidance rat lines: a model to study the individual vulnerability to drug addiction

The Roman high- (RHA) and low-avoidance (RLA) rat lines were selected for, respectively, rapid vs poor acquisition of two-way active avoidance in the shuttle-box. Here, we review experimental evidence indicating that, compared with their RLA counterparts, RHA rats display a robust sensation/novelty seeking profile, a marked preference and intake of natural or drug rewards, and more pronounced behavioral and neurochemical responses to the acute administration of morphine and psychostimulants. Moreover, we show that (i) the repeated administration of morphine and cocaine elicits behavioral sensitization in RHA, but not RLA, rats, (ii) in sensitized RHA rats, acute morphine and cocaine cause a larger increment in dopamine output in the core, and an attenuated dopaminergic response in the shell of the nucleus accumbens, as compared with RHA rats repeatedly treated with saline, and (iii) such neurochemical changes are not observed in the mesoaccumbens dopaminergic system of the sensitization-resistant RLA line. Behavioral sensitization plays a key role in several cardinal features of addiction, including drug craving, compulsive drug seeking and propensity to relapse following detoxification. Comparative studies in the Roman lines may therefore represent a valid approach to evaluate the contribution of the genotype on the neural substrates of drug sensitization and addiction.     

Stress-induced cross-sensitization to amphetamine is related to changes in the dopaminergic system

Repeated stress engenders behavioral sensitization. The mesolimbic dopamine system is critically involved in drug-induced behavioral sensitization. In the present study we examined the differences between adolescent and adult rats in stress-induced behavioral sensitization to amphetamine and changes in dopamine (DA) and its metabolite levels in the mesolimbic system. Adolescent or adult rats were restrained for 2 h, once a day, for 7 days. Three days after the last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded for 40 min. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens (NAcc), ventral tegmental area (VTA) and amygdala (AM) were removed to measure tissue levels of DA and its metabolites by HPLC. Exposure to repeated restraint stress promoted behavioral sensitization to amphetamine in both adult and adolescent rats. In adult rats, amphetamine administration increased DA levels in both the stress and control groups in the NAcc and VTA. In adolescent rats, amphetamine increased DA levels in the NAcc in rats exposed to stress. Furthermore, in the AM of adolescent rats in the control group, amphetamine increased the DA levels; however, amphetamine reduced this neurotransmitter in the rats that were exposed to stress. No alteration was observed in the dopamine metabolite levels. Therefore, stress promoted behavioral sensitization to amphetamine and this may be related to changes in DA levels in the mesolimbic system. These changes appear to be dependent on ontogeny.     

Different effects of chronic THC on the neuroadaptive response of dopamine D2/3 receptor‐mediated signaling in roman high‐ and roman low‐avoidance rats

The Roman high (RHA)‐ and low (RLA)‐avoidance rat sublines have been identified as an addiction‐prone and addiction‐resistant phenotype based on their high vs. low locomotor responsiveness to novelty and high vs. low ability to develop neurochemical and behavioral sensitization to psychostimulants, respectively. Most studies though have focused on psychostimulants and little is known about the neuroadaptive response of these two lines to cannabinoids. This study investigated the effects of chronic exposure to Δ⁹‐tetrahydrocannabinol (THC) on dopamine D_2/3 receptor (D_2/3R) availabilities and functional sensitivity in the mesostriatal system of RHA and RLA rats. At baseline, RLA rats exhibited higher densities of mesostriatal D2/3R but lower levels of striatal CB₁R mRNA and displayed a lower locomotor response to acute THC as compared to RHAs. Following chronic THC treatment, striking changes in D_2/3R signaling were observed in RLA but not in RHA rats, namely an increased availability and functional supersensitivity of striatal D_2/3R, as evidenced by a supersensitive psychomotor response to the D_2/3R agonist quinpirole. Moreover, in RLA rats, the lower was the locomotor response to acute THC, the higher was the psychomotor response to quinpirole following chronic THC. These results showing a greater neuroadaptive response of RLA vs. RHA rats to chronic THC thus contrast with previous studies showing a resistance to neuroadaptive response of RLAs to psychostimulants, This suggests that, contrasting with their low proneness to psychostimulant drug‐seeking, RLAs may exhibit a heightened proneness to cannabinoid drug‐seeking as compared to RHA rats.     

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.     

Critical role of alpha1-adrenergic receptors in acute and sensitized locomotor effects of D-amphetamine, cocaine, and GBR 12783: influence of preexposure conditions and pharmacological characteristics.

Psychostimulant-induced locomotor hyperactivity is commonly associated with an inhibition of dopamine reuptake. However, a physiological coupling between noradrenergic and dopaminergic neurons occurring through the stimulation of alpha1-adrenergic receptors has recently been proposed. This possibility was tested on locomotor responses induced either by D-amphetamine and cocaine, which both interfere with noradrenergic and dopaminergic transmissions, or by GBR 12783, a specific dopamine reuptake inhibitor. In an attempt to control the effects of stress and novelty on noradrenergic neurons activity, rats were submitted to habituation procedures consisting of either a 15-h period of habituation to the experimental environment ("long-habituation") or to repeated exposure to intraperitoneal saline injections for 3 consecutive days ("three-session"). Three-session-exposed animals exhibited a pronounced locomotor reactivity to saline injection which did not occur after noradrenergic depletion, clonidine (20 microg/kg) or prazosin (0.5 mg/kg) pretreatments, or in long-habituation-preexposed animals. Cocaine and GBR 12783 locomotor hyperactivities were doubled in three-session vs. long-habituation-preexposed rats, whereas D-amphetamine responses were similar in both conditions. Prazosin (0.5 mg/kg) pretreatment reduced the acute locomotor effects of the three psychostimulants in both procedures and blocked the behavioral sensitization induced by repeated injections of D-amphetamine (0.75 mg/kg) or cocaine (5 mg/kg). GBR 12783 (5 mg/kg) failed to induce significant behavioral sensitization. In addition to their role in the acute and sensitized locomotor responses to psychostimulants possessing different pharmacological characteristics, alpha1-adrenergic receptors are involved in animal reactivity to previously experimented procedures. This suggests an implication of noradrenergic neurons in the vulnerability to psychostimulants.     

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

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

Behavioral responses to cocaine and amphetamine administration in mice lacking the dopamine D1 receptor

Cocaine and amphetamine can induce both short-term and long-term behavioral changes in rodents. The major target for these psychostimulants is thought to be the brain dopamine system. To determine whether the dopamine D1 receptor plays a crucial role in the behavioral effects of psychostimulants, we tested both the locomotor and stereotyped behaviors in D1 receptor mutant and wild-type control mice after cocaine and amphetamine treatments. We found that the overall locomotor responses of D1 receptor mutant mice to repeated cocaine administration were significantly reduced compared to those of the wild-type mice and the responses of the D1 receptor mutant mice to cocaine injections were never significantly higher than their responses to saline injections. D1 receptor mutant mice were less sensitive than the wild-type mice to acute amphetamine stimulation over a dose range even though they exhibited apparently similar behavioral responses as those of the wild-type mice after repeated amphetamine administration at the 5 mg/kg dose. Immunostaining experiments indicated that there was no detectable neurotoxicity in the nucleus accumbens in both D1 receptor mutant and wild-type mice after repeated amphetamine administration. The data suggest that the D1 receptor plays an essential role in mediating cocaine-induced behavioral changes in mice. Moreover, the D1 receptor also participates in behavioral responses induced by amphetamine administration.     

D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine

D(3) dopamine receptor agonists inhibit locomotor activity in rodents and modulate the reinforcing effect of psychostimulants; however, their functional role during behavioral sensitization remains unclear. In the present study, we intend to investigate if D(3) dopamine receptors alter during the amphetamine sensitization and test if manipulation of D(3) receptors would affect the development of locomotor sensitization to amphetamine. We have found that D(3) dopamine receptors are down-regulated in the limbic forebrain in chronic amphetamine-treated (5 mg/kg x 7 days) animals. The levels of both D(3) receptor protein (B(max) value) and mRNA decreased significantly in the behaviorally sensitized rats compared to the saline-treated controls. When animals were co-administered a putative D(3) receptor antagonist (U99194A or GR103691; 20 microg x 7 days; intracerebroventricle) and amphetamine (5 mg/kg x 7 days, i.p.), the locomotor sensitization to amphetamine was significantly inhibited. However, when the putative D(3) receptor antagonist U99194A was administered during the amphetamine withdrawal period at day 10, it did not affect the development of locomotor sensitization. Furthermore, pretreatment with the preferential D(3) agonist 7-hydroxydipropylaminotetralin partially blocked the inhibitory effect of U99194A on locomotor sensitization. These data prove the participation of D(3) dopamine receptors in the development of amphetamine sensitization and, in addition, suggest a potential application for D(3) antagonists in the prevention of amphetamine addiction.     

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.     

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.     

Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats

Behavioral sensitization to nicotine, which appears following repeated nicotine administration, has been suggested to take part in the development of smoking habit in humans. The mesolimbic dopaminergic system plays a role in this process and a hypersensitivity of postsynaptic neurons of the nucleus accumbens as been proposed as a mechanism, but changes in dopamine D(1) or D(2) receptors have not been demonstrated to date. A challenge administration of nicotine (0.5 mg/kg s.c.) produced a strong increase in locomotor activity in rats repeatedly pretreated with nicotine (0.5 mg/kg s.c.), but not saline, once a day for 5 days. This behavioral sensitization was accompanied by an increase in D(3) receptor binding and mRNA in the shell of nucleus accumbens. D(3) receptor expression was unchanged in the core of nucleus accumbens and dorsal striatum, as it was in the shell of nucleus accumbens after an acute administration of nicotine to naive rats. In contrast, no changes were noticed in D(1) and D(2) receptor expressions in any brain region examined after chronic or acute treatment with nicotine. In addition, nicotine challenge decreased preprodynorphin and preprotachykinin mRNA levels in naive rats, but only preprotachykinin mRNA levels in rats pretreated with nicotine. These biochemical changes resemble those occurring during behavioral sensitization to levodopa of dopamine-denervated rats, which had been causally related to the induction of D(3) receptor expression. We propose that a similar mechanism is responsible for behavioral sensitization to nicotine.     

Alterations in calmodulin content and localization in areas of rat brain after repeated intermittent amphetamine.

To assess whether calmodulin (CaM) could have a role in the behavioral sensitization induced by repeated intermittent amphetamine, CaM content was determined in several brain areas from rats repeatedly administered saline or amphetamine. Rats were treated with amphetamine using an escalating dose paradigm and withdrawn for either 4 weeks (withdrawn group) or 30 min (non-withdrawn group). CaM content was measured in cytosol and 100,000 x g membrane fractions from striatum, limbic forebrain, medial prefrontal cortex, hippocampus and cerebellum. In the withdrawn group, CaM was significantly increased in both striatal membranes and cytosol and in the mesolimbic membranes from amphetamine-treated rats. There were no changes in CaM in the medial prefrontal cortex, hippocampus or cerebellum. In the non-withdrawn group, there was no significant change in CaM in striatal or mesolimbic fractions but CaM was significantly decreased in cytosol of the medial prefrontal cortex and hippocampus as compared to saline controls. This decrease could be related to the tolerance that has developed to the amphetamine after the repeated treatments. In the withdrawn group, challenge with a low dose of amphetamine (1 mg/kg) elicited a translocation of CaM from membranes to cytosol in the striatum and limbic forebrain of rats repeatedly treated with amphetamine, but not in saline-treated rats. Our findings that the change in CaM occurs in striatum and limbic forebrain, requires time after treatment to develop and exhibits persistence after withdrawal correlate with known characteristics of behavioral sensitization to amphetamine. These results suggest that CaM could contribute to neurochemical events underlying behavioral sensitization to amphetamine.     

The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization

The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral sensitization to cocaine.     

Interleukin-6 increases sensitivity to the locomotor-stimulating effects of amphetamine in rats

Interleukin (IL)-6 mediates brain-immune interactions, influences the survival of postnatal mesencephalic and basal forebrain cells, influences mesocorticolimbic dopamine and serotonin neurotransmission, and is linked with various central nervous system disorders. In the present study, single injections of IL-6 (1 or 2 microg/Long-Evans rat, i.p.) induced modest elevations of locomotor activity. The locomotor increases were not augmented by repeated intermittent injections of IL-6 (five daily injections; 1 microg/rat), however. Nonetheless, repeated IL-6 treatment increased sensitivity to the locomotor-stimulating effects of 1.0 and 0.5 mg/kg amphetamine, when tested 5, 7, or 14 days following interruption of the cytokine treatment. The ability of acute IL-6 injections to alter locomotor activity and the ability of repeated IL-6 injections to produce long-lasting sensitization to the locomotor-stimulating effects of amphetamine suggest an interaction of this cytokine with the mesolimbic dopamine system, a system implicated in aspects of schizophrenia, addiction, and movement disorders. The fact that IL-6 caused a lasting change in responsiveness to amphetamine implies a mechanism by which immunogenic stimuli can alter brain circuitry, changing its sensitivity to seemingly unrelated subsequent stimuli or events.     

Differential effects of cocaine on extracellular signal‐regulated kinase phosphorylation in nuclei of the extended amygdala and prefrontal cortex of psychogenetically selected roman high‐ and low‐avoidance rats

Roman high (RHA)‐ and low (RLA)‐avoidance rats are selectively bred for rapid vs. poor acquisition of active avoidance, respectively, and differ markedly in emotional reactivity, coping style, and behavioral and neurochemical responses to morphine and psychostimulants. Accordingly, acute cocaine induces more robust increments in locomotion and dopamine output in the nucleus accumbens shell (AcbSh) of RHA than of RLA rats. Cocaine induces short‐ and long‐term neuronal plasticity via activation of the extracellular signal‐regulated kinase (ERK) pathway. This study compares the effects of acute cocaine on ERK phosphorylation (pERK) in limbic brain areas of Roman rats. In RHA but not RLA rats, cocaine (5 mg/kg) increased pERK in the infralimbic prefrontal cortex and AcbSh, two areas involved in its acute effects, but did not modify pERK in the prelimbic prefrontal cortex and Acb core, which mediate the chronic effects of cocaine. Moreover, cocaine failed to affect pERK immunolabeling in the bed nucleus of stria terminalis pars lateralis and central amygdala of either line but increased it in the basolateral amygdala of RLA rats. These results extend to pERK expression previous findings on the greater sensitivity to acute cocaine of RHA vs. RLA rats and confirm the notion that genetic factors influence the differential responses of the Roman lines to addictive drugs. Moreover, they support the view that the Roman lines are a useful tool to investigate the molecular underpinnings of individual vulnerability to drug addiction. © 2014 Wiley Periodicals, Inc.     

The effect of dopamine receptor blockade on the development of sensitization to the locomotor activating effects of amphetamine and morphine

The effect of dopamine (DA) receptor blockade on the development of sensitization to the locomotor activating effects of systemic amphetamine and intra-ventral tegmental area (intra-VTA) morphine was investigated. Rats were pretreated with the D-1 DA receptor antagonist, SCH-23390 (0.04 or 0.2 mg/kg, i.p.) or one of two D-2 DA receptor antagonists, pimozide (0.5 mg/kg, i.p.) and Ro 22-2586 (0.2 mg/kg, i.p.), prior to each of 5 exposures to the sensitizing drug. SCH-23390 blocked the development of sensitization to amphetamine but not to intra-VTA morphine. Pimozide had the opposite effect and Ro 22-2586 had no effect on the development of sensitization to either amphetamine or intra-VTA morphine. All 3 antagonists, at the doses tested, completely blocked the acute locomotor activating effects of these two drugs. Pretreatment in separate animals with low autoreceptor doses of sulpiride (25 mg/kg, i.p. with amphetamine and 10 mg/kg, i.p. with intra-VTA morphine) slightly potentiated the acute locomotor effect and produced a slight enhancement of the sensitized response to amphetamine and intra-VTA morphine. Pretreatment with a higher dose of sulpiride (50 mg/kg, i.p.) blocked the acute locomotor effect of intra-VTA morphine but had no effect on the development of sensitization to this drug. These results suggest that the mechanisms underlying the development of sensitization to the locomotor activating effects of amphetamine and intra-VTA morphine are different even though these may ultimately result in similar changes in the activity of mesencephalic DA neurons. Implications of these findings for the differential involvement of D-1 and D-2 DA receptors and for neural hypotheses of behavioral sensitization are discussed.     

Differential effects of endomorphin-1 and -2 on amphetamine sensitization: neurochemical and behavioral aspects

Mu-opioid receptors are known to modulate mesolimbic dopaminergic activity in the ventral tegmental area via disinhibition of GABA-containing neurons. Recently, two novel tetrapeptides, endomorphin-1 and endomorphin-2, were identified in the mammalian brain and reported to have high binding affinities toward mu-opioid receptors. To determine if endomorphins would modulate the development of amphetamine sensitization, we administered endomorphins locally into the rat brain followed by behavioral and neurochemical examinations. The results indicate that rats pretreated with endomorphin-1 or -2 (5 microg per side for 7 days) in the ventral tegmental area developed locomotor sensitization to the challenge injection of amphetamine (1 mg/kg). On the other hand, when endomorphins were given in the lateral ventricle (20 microg for 5 days) of amphetamine-sensitized rats (5 mg/kg x 14 days) during the withdrawal period (w5-w9), neither peptide had a modulatory effect on locomotor sensitization. Biochemical analyses revealed that treatment with endomorphins in the ventral tegmental area significantly increased the levels of glutamate in the medial prefrontal cortex and ventral and dorsal striatum to levels comparable to those observed in the amphetamine-sensitized rats. In the same animals, endomorphins also caused decreases in the levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid, in the medial prefrontal cortex. Interestingly, although there was no behavioral significance, endomorphin-1 treatment in the lateral ventricle of control and amphetamine-sensitized rats during withdrawal resulted in decreases of GABA, aspartate, dopamine, and its metabolite 3,4-dihydroxyphenylacetic acid in the ventral striatum. We conclude that endomorphins, by stimulating the mu-opioid receptors in the ventral tegmental area, could sensitize the behavioral response to amphetamine. The results also demonstrate that there are differential responses between endomorphin-1 and -2 on behavioral amphetamine sensitization and the underlying neurochemical substrates.     

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.     

Behavioral sensitization to amphetamine is dependent on corticosteroid receptor activation

Thirty rats received 3 amphetamine injections (1.5 mg/kg, s.c.) 6 days apart and the locomotor response was measured. One day before the second injection they were adrenalectomized or sham operated. Corticosteroid replacement treatments (500 μg/kg, s.c.) were given every evening. Sham adrenalectomized animals exhibited behavioral sensitization to successive injections of amphetamine, which was prevented by adrenalectomy. Treatment with corticosterone or deoxycorticosterone did not reverse the effect of adrenalectomy, whereas dexamethasone completely restored and even potentiated sensitization to amphetamine. These results demonstrate that corticosteroids are necessary for sensitization of the dopaminergic system to occur and that they most probably act through the type II (or glucocorticoid) receptor subtype.