Barbiturate dependence and drug preference

Rats were administered chronic multiple injections of amphetamine (AMPH) using dosage regimens which produce tolerance to the AMPH facilitation of self-stimulation responding, or reverse tolerance (sensitization) to the locomotor stimulant and stereotypy-producing effects of the drug. Subsequently rats were challenged with AMPH at behaviorally relevant doses and times and striatal and mesolimbic dopamine (DA) dynamics were assessed using the conversion of ³H-tyrosine to ³H-DA, and endogenous levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as indices of dopaminergic function. Acute administration of AMPH produced dose and time related changes in all indices of DA function in both the striatal and mesolimbic brain regions. Co-administration of haloperidol during chronic AMPH pretreatment prevented the appearance of most of the behavioral changes induced by chronic AMPH, suggesting an important role for DA systems. However, following chronic AMPH treatment, no additional biochemical changes in striatal or mesolimbic DA metabolism could be detected which would parallel the development of tolerance to AMPH facilitation of self-stimulation behavior or reverse tolerance to AMPH as reflected in enhanced post-stereotypy locomotor activity or a suggested increased intensity of stereotypy. Challenge with AMPH after chronic AMPH pretreatment did accelerate the changes in striatal but not mesolimbic DA metabolism, correlating with the more rapid onset of stereotypy induced by chronic AMPH. Thus, while DA systems appear to be a critical link, not only in the acute effects of AMPH, but also in the development of tolerance and reverse tolerance, most of the behavioral differences between acutely and chronically treated animals are not reflected by comparable differences in DA synthesis and metabolism.     

Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats

This experiment was designed to characterize the withdrawal syndrome produced by discontinuation of treatment with escalating, non-neurotoxic doses ofd-amphetamine (AMPH). AMPH withdrawal was associated with both transient and persistent changes in behavior and postmortem brain tissue catecholamine concentrations. During the first week of withdrawal rats showed a significant decrease in spontaneous nocturnal locomotor activity. This behavioral depression was most pronounced on the first 2 days after the discontinuation of AMPH pretreatment, was still evident after 1 week, but had dissipated by 4 weeks. Behavioral depression was not due to a simple motor deficit, because AMPH-pretreated animals showed a normal large increase in locomotion when the lights initially went out, but they did not sustain relatively high levels of locomotor activity throughout the night, or show the early morning rise in activity characteristic of controls. Behavioral depression was associated with a transient decrease in the concentration of norepinephrine (NE) in the hypothalamus, and a transient decrease in the ability of an AMPH challenge to alter dopamine (DA) concentrations in the caudateputamen and nucleus accumbens. AMPH pretreatment also produced persistent changes in brain and behavior. The persistent effects of AMPH were not evident in spontaneous locomotor activity, but were revealed by a subsequent challenge injection of AMPH. AMPH pretreated animals were markedly hyper-responsive to the stereotypy-producing effects of an AMPH challenge. This behavioral sensitization was not fully developed until 2 weeks after the discontinuation of AMPH pretreatment, but then persisted undiminished for at least 1 year. It is suggested that the transient changes in brain and behavior described here may represent an animal analogue of the distress syndrome seen in humans during AMPH withdrawal, which is associated with symptoms of depression and alterations in catecholamine function. On the other hand, persistent behavioral sensitization may be analogous to the enduring hypersensitivity to the psychotogenic effects of AMPH seen in former AMPH addicts.     

Prenatal cadmium and ethanol increase amphetamine-evoked dopamine release in rat striatum

To explore interactive deleterious effects of the teratogens ethanol and cadmium, pregnant rats were given cadmium (CdCl(2), 50 ppm) and/or ethanol (10%), or tap water (controls) in the drinking water for the entire 21 days of pregnancy. At 3 months after birth, in vivo microdialysis was used to determine that there was a 4000% evoked release of DA by AMPH (AMPH, 4.0 mg/kg i.p.) in the striatum of rats exposed prenatally to both ethanol and cadmium, vs. a 2000% evoked release by AMPH in rats exposed prenatally to only ethanol or cadmium or tap water. Haloperidol (HAL)-evoked DA release was suppressed in groups exposed prenatally to ethanol, while HAL-evoked DOPAC and HVA release was greatest after co-exposure to prenatal cadmium and ethanol. These in vivo microdialysis results indicate that ontogenetic co-exposure to cadmium, and ethanol produces a long-lived suppressive effect on HAL-evoked DA release and a long-lived enhancing effect on AMPH-evoked DA release in rat striatum. These findings clearly demonstrate that there is marked alteration in dopaminergic regulation after ontogenetic cadmium and ethanol co-exposure, which in this regard resembles the reaction of the striatonigral pathway on AMPH-evoked DA release in rats with behavioral sensitization.     

Behavioral sensitization to beta-phenylethylamine (PEA): enduring modifications of specific dopaminergic neuron systems in the rat

Repeated daily administration of an endogenous trace amine, beta-phenylethylamine (PEA), produces behavioral sensitization such that the intensity of PEA-induced stereotyped behaviors in rats increases gradually during the treatment, and a challenge injection with PEA reinstates the enhanced stereotypy even long after withdrawal. In the present study, we examined the neurochemical changes in the central dopaminergic neuron systems in the rat for 7 drug-free days after repeated treatment with PEA (50 mg/kg, IP day for 14 or 28 days). During withdrawal, a decrease in steady-state levels of tissue dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC), was found in the mesolimbic DA nerve terminal areas of the rat brain receiving repeated PEA treatment. Fifteen minutes after challenge administration of PEA at varying doses from 6.3 to 75 mg/kg, the rats with repeated PEA treatment required smaller doses of PEA challenge than the rats with acute PEA treatment in order to obtain a significant decrease in striatal DOPAC content compared to the saline control in each treatment group. These results imply that the behavioral sensitization to PEA is accompanied by enduring modifications of the specific dopaminergic neuron systems in the rat brain. This suggestion was strongly supported by the results of the study using in vivo intracerebral dialysis, which indicated that 25 mg/kg PEA challenge elicited a remarkable increase in the extracellular DA concentrations in striatal perfusates collected from the PEA-pretreated rats, in accordance with the intensity of stereotyped behaviors. These findings argue that the hyper-responsiveness to PEA of the striatal dopaminergic neuron systems persists long after withdrawal from repeated treatment with PEA.     

Clorgyline-induced increases in presynaptic DA: changes in the behavioral and neurochemical effects of amphetamine using in vivo microdialysis.

Microdialysis was used in behaving rats to further characterize the behavioral and regional dopamine (DA) response to the monoamine oxidase (MAO) inhibitor clorgyline and determine how MAO inhibition affects amphetamine (AMPH)-induced changes in behavioral and extracellular DA dynamics. Although clorgyline (4.0 mg/kg) did not significantly alter behavior, it produced prolonged increases in caudate and accumbens extracellular DA and 3MT and corresponding decreases in homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Clorgyline pretreatment altered the behavioral response to both low (0.25 mg/kg) and moderate (2.5 mg/kg) doses of AMPH, which was characterized by a shift to more intense forms of stereotype and corresponding decreases in locomotion. The caudate and accumbens DA response to AMPH (0.25 mg/kg) was also significantly augmented, consistent with an increase in AMPH-releasable cytoplasmic DA. Thus, the potentiated DA response in clorgyline-pretreated animals may be responsible for the changes in the stereotypy profile. Possible implications of these observations for the augmented behavioral response observed with repeated AMPH administration are discussed.     

Amphetamine-induced enhancement of neostriatal in vivo microdialysate dopamine content in rats, quinpirole-primed as neonates

Amphetamine (AMPH)-induced sensitization of central dopamine (DA) receptors, produced by repeated AMPH treatments, is associated with increased AMPH-induced DA release in the rat forebrain. However, for DA receptor sensitization produced by repeated DA receptor agonist treatments, the effects on forebrain DA release are not known. The objective of our study was to determine this. DA receptor sensitization was produced by administering the DA D2 agonist quinpirole (50 microg/kg/day) to rats, from the 1st to 11th days after birth - a process known as 'priming'. When these rats were tested at 3 months, DA receptor sensitization was manifested as increased quinpirole-induced yawning. We also found that AMPH (1.0 mg/kg, ip) acutely induced a 5-fold greater increase in DA content in the neostriatal in vivo microdialysate of these quinpirole-primed rats (vs. controls), accompanied by a reduction in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in the microdialysate. Conversely, an acute injection of quinpirole x HCl (100 microg/kg, ip) reduced the microdialysate contents of DA, DOPAC and HVA to comparable levels in quinpirole-primed and control rats. Therefore, we can conclude that long-lived DA receptor sensitization, produced by repeated DA D2 agonist treatments in ontogeny, is associated with enhanced AMPH-induced DA release in the neostriatum in adulthood, but is not accompanied by evident alteration in quinpirole-induced DA release.     

Cholecystokinin modulates both the development and the expression of behavioral sensitization to amphetamine in the rat

Rationale: Repeated administration of psychostimulants such as amphetamine (AMPH) produces an enduring augmentation of their locomotor effects. Previous research suggests that this phenomenon, termed sensitization, is related to changes within the mesolimbic dopamine (DA) system. Objectives: The present experiments were designed to investigate the contribution of endogenous cholecystokinin (CCK), a neuropeptide co-localized with DA in the mesolimbic system, to the development (experiment 1) and the expression (experiment 2) of locomotor sensitization to AMPH. Methods: In experiment 1, rats were injected (IP) with the CCK_A antagonist devazepide (0, 0.001, 0.01, or 0.1 mg/kg) or the CCK_B antagonist L-365,260 (0, 0.001, 0.01, 0.1, or 1.0 mg/kg) followed by AMPH (1.5 mg/kg) once daily for seven days. Following 10 days withdrawal, rats were administered AMPH (0.75 mg/kg) and their locomotor activity recorded. In experiment 2, rats were administered AMPH (1.5 mg/kg) once daily for 7 days. Following 10 days withdrawal, rats were injected with devazepide (0, 0.0001, 0.001, 0.01, 0.1, or 1.0 mg/kg) or L-365,260 (0, 0.001, 0.01, or 0.1 mg/kg) followed 30 min later by AMPH (0.75 mg/kg) and their locomotor activity recorded. Results: When administered during the AMPH pretreatment phase of experiment 1, the two highest doses of L-365,260 attenuated, and the lowest dose of L-365,260 potentiated, the sensitized locomotor response to AMPH challenge. When administered prior to the AMPH challenge phase of experiment 2, devazepide attenuated the sensitized locomotor response to AMPH. Conclusions: These results suggest that CCK_B and CCK_A receptors modulate the development and the expression of behavioral sensitization to AMPH, respectively. Received: 27 August 1999 / Accepted: 29 February 2000     

Behavioral sensitization and extracellular dopamine responses to amphetamine after various treatments

The repeated administration of amphetamine (AMPH) results in a pattern of behavioral changes which includes an augmentation of some behaviors, generally referred to as behavioral sensitization. Some investigators have suggested that an increased dopamine (DA) response to AMPH challenge may underlie behavioral sensitization, while others have reported behavioral sensitization in the absence of an enhanced DA response. Because temporal and dosage parameters of the AMPH pretreatment regimen have been suggested to play a role in the appearance of an enhanced DA response, we utilized a variety of AMPH pretreatment regimens to assess the relationship between pretreatment dose of AMPH, duration of withdrawal and the DA response in caudate-putamen and nucleus accumbens to a subsequent AMPH challenge. Under our experimental conditions, behavioral sensitization was observed after each of these treatments in the absence of an enhanced DA response in either brain region. Received: 9 October 1996 /Final version: 15 May 1997     

Expression of sensitization to amphetamine and dynamics of dopamine neurotransmission in different laminae of the rat medial prefrontal cortex

The present study investigated the effect of acute and repeated administrations of amphetamine (AMPH) on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the two main cytoarchitectonic subterritories of the medial prefrontal cortex (mPFC) (anterior cingulate and dorsocaudal prelimbic cortices vs ventral prelimbic and rostral infralimbic cortices). Both the acute locomotor effects of AMPH and the expression of behavioral sensitization following its repeated administration were also simultaneously assessed. The repeated, intermittent administration of AMPH over five consecutive days led to a significant sensitized locomotor response to a subsequent challenge that occurred following a 48-h withdrawal period. Basal dialysate DA levels were higher in the ventral mPFC compared with its dorsal counterpart in naive animals, that is prior to the acute administration of AMPH. However, the inverse relationship was observed in animals that had developed sensitization: basal dialysate DA levels were significantly lower in the ventral mPFC compared with the dorsal mPFC. In na?ve animals, AMPH produced a significant decrease in DA levels in both the ventral and dorsal subregions of the mPFC. However, the inverse relationship was observed in animals that had developed sensitization: dialysate DA levels in response to AMPH remained significantly decreased in the dorsal mPFC, whereas DA went back to baseline levels in the ventral mPFC. Given that a critical concentration of DA is required for normal function of the mPFC, our results suggest that AMPH-induced changes in DA levels in different subregions of the mPFC are critical for both the acute effects of the drug and the expression of behavioral sensitization to its repeated administration by producing either less or more selectivity or sharpening of stimuli to cortico-cortical dendrites and subcortical synaptic afferents to the pyramidal cells located in the dorso-ventral axis of the mPFC.     

Stereospecific long-term effects of amphetamine on striatal dopamine neurons in rats

The chronic infusion of amphetamine or a single injection of the drug to iprindole-treated rats produces long-term, possibly neurotoxic, effects on strialal dopamine (DA) neurons. Significant decreases in striatal DA. dihydroxphenylacetic acid (DOPAC), and homovanillic acid (HVA) were observed one week after the administration of 6.9 and 9.2 mg/kg of S(+)- but not after doses of R(?)-amphetamine sulfate up to 46 mg/kg to iprindole-treated rats. Concentrations and half-lives of the isomers in the brains of iprindole-treated rats were not different.     

Ontogeny of phencyclidine and apomorphine-induced startle gating deficits in rats

NMDA antagonists and dopamine (DA) agonists produce neuropathological and/or behavioral changes in rats that may model specific abnormalities in schizophrenia patients. In adult rats, NMDA antagonists and DA agonists disrupt sensorimotor gating-measured by prepulse inhibition (PPI)-modeling PPI deficits in schizophrenia patients. In addition, high doses of NMDA antagonists produce limbic system pathology that may model neuropathology in schizophrenia patients. We examined these behavioral and neuropathological models across development in rats. Both the NMDA antagonist phencyclidine (PCP) and the DA agonist apomorphine disrupted PPI in 16 day pups, demonstrating early developmental functionality in substrates regulating these drug effects on PPI. In contrast, PCP neurotoxicity was evident only in adult rats. Brain mechanisms responsible for the PCP disruption of PPI, and PCP-induced neurotoxicity, are dissociable across development.     

Dissociation between long-lasting behavioral sensitization to amphetamine and impulsive choice in rats performing a delay-discounting task

RATIONALE: Repeated amphetamine (AMPH) exposure is known to cause long-term changes in AMPH-induced locomotor behavior (i.e., sensitization) that are associated with similarly long-lasting changes in brain function. It is not clear, however, if such exposure produces long-lasting changes in a cognitive behavior that, in humans, is hypothesized to contribute to addiction. OBJECTIVES: To examine whether repeated AMPH exposure induces both locomotor sensitization and alters impulsive choice in a delay-discounting task. MATERIALS AND METHODS: Adult, male Sprague-Dawley rats (n = 29) were pretreated with 3.0 mg/kg AMPH or saline every other day for 20 days and were then trained to lever press for small, immediately delivered food reinforcement or larger reinforcements delivered after delays. We subsequently assessed the effects of acute AMPH (0.1-2.0 mg/kg) on delay-discounting. Lastly, we tested for long-lasting effects of pretreatment by giving an AMPH challenge (3.0 mg/kg) 1 week after the final delay-discounting session. RESULTS: Repeated AMPH produced sensitization to the drug's stereotypy-inducing effects but did not alter acquisition or baseline behavior in the delay-discounting task. Following acute AMPH, impulsive choice and other measures of delay-discounting were altered, but to a similar extent in both saline- and AMPH-pretreated groups. The AMPH challenge, given approximately 3 months after the last pretreatment injection, revealed that sensitization was still evident. CONCLUSIONS: Our results suggest that one behavioral consequence of repeated AMPH exposure-sensitization-does not overlap with another potential outcome-increased impulsivity. Furthermore, the neuroadaptations known to be associated with sensitization may be somewhat distinct from those that lead to changes in impulsive choice.     

Behavioral sensitization: Characterization of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats

Factors influencing the behavioral sensitization (reverse tolerance) produced by intermittent amphetamine (AMPH) injections were studied by quantifying rotational behavior in rats that had a unilateral 6-hydroxydopamine lesion of the substantia nigra. The results indicate that (1) a single injection of a low dose of AMPH enhances rotational behavior induced by a second injection of AMPH for up to 12 weeks; (2) multiple, weekly injections of AMPH produce a progressive enhancement in rotational behavior, over-and-above that produced by a single injection; (3) female rats show more robust sensitization than males following single or multiple injections of AMPH; (4) this sex difference may be due to the suppression of sensitization by an androgen, because removal of testicular hormones potentiates sensitization; (5) the long-lasting sensitization of rotational behavior produced by infrequent injections of AMPH is not due to drug-environment conditioning effects, but perhaps to a persistent AMPH-induced change(s) in brain catecholamine systems; and (6) a simple change in DA receptors is probably no involved, because the sensitization produced by infrequent injections of AMPH does not influence the rotation produced by a subsequent injection of apomorphine. The results illustrate an intriguing example of neuroplasticity that may have clinical relevance.     

Differential effects of d-fenfluramine and p-chloroamphetamine on H75/12-induced depletion of 5-hydroxytryptamine and dopamine in the rat brain.

The effects of the two 5-HT-releasing drugs, p-chloroamphetamine and d-fenfluramine, on central serotoninergic and dopaminergic systems were compared in adult rats. Both drugs (0.5-5.0 mg/kg i.p., 2 hr before death) produced a dose-dependent reduction in levels of 5-HT, but only p-chloroamphetamine decreased the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus, striatum and cerebral cortex. Within the dose range tested, d-fenfluramine did not affect the levels of DA and of its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in brain. By contrast, p-chloroamphetamine significantly increased the levels of DA and HVA and decreased the levels of DOPAC, notably in the striatum. As expected of a 5-HT uptake inhibitor, d-fenfluramine at small doses (0.2-0.5 mg/kg) prevented the depletion of 5-HT due to 4-methyl-alpha-ethyl-meta-tyramine (H75/12, 40 mg/kg i.p.), whereas at large doses (1.0-5.0 mg/kg) d-fenfluramine, like p-chloroamphetamine (0.2-1.0 mg/kg), slightly enhanced the effect of H75/12. Neither d-fenfluramine (0.5 mg/kg) nor p-chloroamphetamine (0.5 mg/kg) affected the depletion of DA due to H75/12. These data indicate that p-chloroamphetamine is a 5-HT-releasing drug, at any dose between 0.2 and 5.0 mg/kg, whereas d-fenfluramine acts as a 5-HT uptake inhibitor at 0.2-0.5 mg/kg and as a 5-HT releasing drug at larger doses. On account of the potential neurotoxicity of 5-HT-releasing drugs but not 5-HT uptake inhibitors, it can be inferred that d-fenfluramine is very probably devoid of any neurotoxic action in the dose range (less than 1.0 mg/kg) required for its anorectic action.     

Comparison of the long-term consequences of withdrawal from repeated amphetamine exposure in adolescence and adulthood on information processing and locomotor sensitization in mice

Repeated administration of the indirect dopamine receptor agonist amphetamine (AMPH) produces robust locomotor sensitization and additional behavioral abnormalities. Accumulating evidence suggests that the developmental timing of drug exposure can critically influence this effect. The present study compared the consequences of withdrawal from repeated AMPH exposure in adolescence and adulthood on information processing and locomotor sensitization in C57BL/6 mice. Animals were injected daily with AMPH (1 or 2.5 mg/kg) or vehicle on 7 consecutive days starting either from postnatal day 35 to 42, or from postnatal day 70 to 77, following which they were given a 4 week withdrawal period before behavioral and pharmacological testing commenced. We found that withdrawal from the higher dose of AMPH (2.5 mg/kg/day) given either in adolescence or adulthood similarly disrupted selective associative learning as measured by the latent inhibition paradigm. None of the AMPH withdrawal groups displayed alterations in sensorimotor gating in the form of prepulse inhibition. Withdrawal from adult AMPH exposure at both doses induced marked locomotor sensitization, whereas adolescent pre-treatment with the higher (2.5 mg/kg/day) but not lower (1 mg/kg/day) dose of AMPH potentiated the locomotor-enhancing effects of acute AMPH re-challenge. Our study suggests that withdrawal from repeated AMPH exposure in adolescence and adulthood has similar consequences on selective associative learning, but the two manipulations differ with respect to their efficacy to induce long-term locomotor sensitization to the drug. The latter finding supports the hypothesis that the precise developmental timing determines, at least in part, the impact on long-term dopamine-associated sensitization processes.     

3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings

Rationale 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate.Objective The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of “interspecies scaling” to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions.Results MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1–2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10–20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits.Conclusions MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks.     

Withdrawal, tolerance, and sensitization to dopamine mediated interoceptive cues in rats trained on a three-lever drug-discrimination task

In the present experiment rats were trained on a three-lever, drug-discrimination task to discriminate the cues associated with 0.30 mg/kg of the indirect dopamine (DA) agonist, amphetamine (AMPH), saline (SAL), and 0.03 mg/kg of the DA, D2 receptor antagonist, haloperidol (HAL). Choice behavior determined from tests on 0.30 and 0.15 mg/kg AMPH, SAL 0.03 and 0.015 mg/kg HAL provided a behavioral baseline presumed to represent changes along a continuum of DA mediated, interoceptive cues. Results from separate groups tested on 0.30 and 0.15 mg/kg AMPH, SAL, 0.03 and 0.015 mg/kg HAL, 24 h post-treatment with an acute 7.5 mg/kg dose of AMPH, showed rapid tolerance and withdrawal to the AMPH cue and sensitization to the HAL cue. The same tests 24 h following treatment with 1.0 mg/kg HAL showed rapid tolerance to the HAL cue, sensitization to the AMPH cue, but not AMPH-like withdrawal cues. Analysis of the results showed that tolerance to the AMPH and HAL cues reflected neuroadaptive baseline shifts and not weaker cue properties. These findings are consistent with predictions from opponent process theory of motivation and provide an animal model to study the motivational consequences that aversive symptoms of AMPH withdrawal such as dysphoria and anhedonia can have on drug-taking behavior.     

Amphetamine withdrawal does not produce a depressive-like state in rats as measured by three behavioral tests

Administration of amphetamine (AMPH) can induce symptoms of psychosis in humans and locomotor sensitization in rats; in contrast, withdrawal from a period of AMPH intake is most often associated with symptoms of human endogenous depression. The aim of this study was to determine whether AMPH withdrawal produces a depressive-like state in rats. The present study examined the effects of withdrawal from an escalating-dose AMPH schedule (ESC; three daily injections over 6 days, 1-5 mg/kg, i.p.) and an intermittent-dose AMPH schedule (INT; one daily injection over 6 days, 1.5 mg/kg, i.p.) on animals' performance in three behavioral paradigms related to depression: the Porsolt swim test, the learned helplessness assay and operant responding for sucrose on a progressive ratio schedule. ESC and INT AMPH withdrawal had no effect on any of these tests or on stress responsiveness as measured by increased plasma levels of corticosterone (CORT) and adrenocorticotropin following the swim test, although basal CORT levels were higher in AMPH-withdrawn animals compared to controls. Finally, we confirmed the presence of locomotor sensitization for both AMPH schedules after 30 days of withdrawal. Our results suggest that the ability of AMPH withdrawal to produce symptoms of depression may not be evident in all behavioral screens for depressive symptoms in the rat.     

Effects of alpha-phenyl-N-tert-butyl nitrone and N-acetylcysteine on hydroxyl radical formation and dopamine depletion in the rat striatum produced by d-amphetamine.

Previous studies have shown that treatment with free radical scavengers attenuated the D-amphetamine (AMPH) neurotoxicity. But several of these agents also prevent AMPH-induced elevation of body temperature in the rat. Thus, further studies are needed to determine if blockade of the production of free radical or hypothermia are related to the neuroprotective mechanism of the free radical scavengers for AMPH neurotoxicity. In the present study, we examined the effects of the free radical scavengers alpha-phenyl-N-tert-butyl nitrone (PBN) and N-acetylcysteine (NAC) on long-term depletion of striatal dopamine (DA) and lipid peroxidation formation and on hyperthermia induced by AMPH. We also determined their effects on acute hydroxyl radical formation after direct intrastriatal infusion of AMPH. The results showed that both significantly attenuated long-term DA depletion and lipid peroxidation formation in the rat striatum at the dose range that did not block hyperthermia induced by AMPH. These agents also completely inhibited the production of hydroxyl radical after AMPH infusion into the striatum. Our results suggest that free radical scavengers such as PBN and NAC could protect against AMPH-induced oxidative stress and DAergic terminal toxicity via their free radical removing property independent of lowering the core body temperature of rats, and imply that supplement with antioxidants is a potential strategy in the treatment of AMPH neurotoxicity.     

Sensitization to systemic amphetamine produces an enhanced locomotor response to a subsequent intra-accumbens amphetamine challenge in rats

Repeated amphetamine (AMPH) administration into the nucleus accumbens does not enhance (sensitize) the locomotor activity produced by a subsequent systemic AMPH challenge. We report here, however, that pretreatment with systemic injections of AMPH does produce a significant enhancement in the locomotor stimulant effects produced by intra-accumbens AMPH given 21 days after the last pretreatment injection of AMPH. These data support the hypothesis that neural adaptations in dopamine (DA) terminal fields are sufficient for theexpression of AMPH sensitization, although an action on DA cell bodies may be required for theinduction of AMPH sensitization.