Reserpine attenuates d-amphetamine and MDMA-induced transmitter release in vivo: a consideration of dose, core temperature and dopamine synthesis

Amphetamine releases dopamine through a transporter-mediated mechanism. The purpose of this report was to further our understanding of the intracellular pool from which amphetamine releases dopamine: the cytoplasmic pool, the vesicular pool, or both. Rats were treated with -amphetamine (AMPH) (1.0 or 10.0 mg/kg) or an amphetamine analog, methylenedioxymethamphetamine (MDMA) (2.0, 5.0, or 10.0 mg/kg). Pre-treatment with 10.0 mg/kg reserpine (18 h prior to AMPH or MDMA) attenuated dopamine release for high and low AMPH doses; however the low-dose effect showed borderline significance. Pre-treatment with 10.0 mg/kg reserpine attenuated dopamine and serotonin release induced by MDMA. The dopamine effect was seen at all three MDMA doses; the effect on serotonin was only measured at the 10.0 mg/kg dose. Reserpine pre-treatment caused reductions in core body temperature; heating the rats to normal body temperature for 3 h prior to AMPH or MDMA, and during the 4 h post-treatment period partially reversed the reserpine-induced attenuation of dopamine release. However, the intermediate level of dopamine release for the reserpinized-heated animals was not significantly different from either the reserpine group (not heated) or the AMPH or MDMA alone groups. In a separate group of rats, the effects of reserpine and reserpine+heat on dopamine synthesis were measured. DOPA accumulation after treatment with the aromatic acid decarboxylase inhibitor NSD-1015 (100 mg/kg, 30 min before sacrifice), was greater in rats treated with reserpine compared to controls; heating the reserpinized rats did not significantly alter the amount of DOPA accumulation; however there was a trend towards further increase. These results suggest that -amphetamine releases dopamine that is stored in both vesicles and the cytoplasm. Cooling may contribute to the attenuation of AMPH or MDMA-induced dopamine release observed after reserpine; however, AMPH or MDMA dependence upon vesicular stores most likely explains the diminished release after reserpine. The attenuation of AMPH or MDMA-induced transmitter release by reserpine is thought to be counteracted by a reserpine-induced replenishment of stores. Therefore, all doses of -amphetamine may use vesicular stores; the degree to which new synthesis counteracts the vesicular depletion may be the variable which differentiates low from high doses of -amphetamine.     

Sex differences in K+-evoked striatal dopamine output from superfused striatal tissue fragments of reserpine-treated CD-1 mice

Reserpine inhibits vesicular monoamine transporter-2 (VMAT-2) function and thereby impairs vesicular dopamine (DA) storage within nerve terminals. The present report compared the effects of reserpine treatment upon the striatal dopaminergic system in male and female mice as a means to assess potential sex differences in VMAT-2/DA storage function. After treatment with reserpine, male mice showed significantly greater striatal DA concentrations and K+ -evoked DA output from the striatum compared to females. By contrast, no statistically significant sex differences were observed in methamphetamine-evoked DA output in reserpine-treated mice. These results demonstrate a clear sex difference in the striatal dopaminergic responses to reserpine and suggest that females possess a more active VMAT-2/DA storage capacity, as indicated by the greater degree of deficits observed when VMAT-2/DA storage function is inhibited by reserpine. Such findings have important implications for understanding some of the bases for sex differences in neurotoxicity and neurodegeneration of the nigrostriatal dopaminergic system.     

Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: Sex differences

Amphetamine (AMPH)-induced rotational behavior in non-lesioned rats and AMPH-stimulated dopamine (DA) release from striatal tissue fragments in vitro were used to study the long-term effects of a single injection of AMPH on activity in the mesostriatal DA system. A single injection of a low dose of AMPH (1.25 mg/kg) greatly enhanced the rotational behavior produced by a second injection of AMPH given 3–4 weeks later in intact female, ovariectomized female and castrated male rats. The effect of AMPH pretreatment in intact males differed from that in the other groups. When only 7–8 days separated the two test sessions both intact male and female rats showed sensitization of rotational behavior, but the magnitude of the change was greater in females. In addition, a single injection of 1.25 mg/kg of AMPH in vivo produced a long-lasting (3–5 weeks) enhancement of AMPH-stimulated DA release from striatal tissue in vitro. It is suggested that: (1) repeated injections of AMPH are not necessary to produce a long-lasting facilitation of behaviors mediated by the mesostriatal DA system; (2) gender and/or hormonal state influences the development of long-term changes in the mesostriatal DA system; and (3) changes in DA release from presynaptic terminals may contribute to the behavioral sensitization produced by stimulant drugs. The phenomena reported here may provide complementary in vitro and in vivo models for studying neuroplasticity in brain DA systems.     

Concomitant characterization of behavioral and striatal neurotransmitter response to amphetamine using in vivo microdialysis

The temporal and dose-related behavioral and striatal monoamine response to amphetamine (AMPH) was examined using in vivo microdialysis in freely moving rats. Extracellular dopamine (DA), serotonin (5-HT), and their metabolites were monitored concomitant with detailed characterization of the locomotor and stereotypy profiles. Consistent with previous results, AMPH (0.5-5.0 mg/kg) induced a rapid dose-dependent increase in DA concentration and decrease in the concentrations of the DA metabolites, DOPAC and HVA. DA and its metabolites exhibited contrasting temporal and dose-related patterns, suggesting that the decline in DA metabolites is functionally dissociated from the AMPH-enhanced DA release. In addition, AMPH at doses of 2.0 mg/kg and greater significantly increased extracellular concentrations of 5-HT, which, in contrast to the changes in dopamine, persisted for only 20-40 min. Comparisons of concentrations of DA and 5-HT for individual animals revealed significant correlations both during baseline and drug response, suggesting a possible functional interdependence between dopaminergic and serotonergic activity in striatum. Dose-response comparisons revealed a significant relationship between AMPH-induced increases in behavioral perseveration and the magnitude and duration of the DA release. However, the temporal patterns of the neurotransmitter response and individual components of stereotypy were not parallel, suggesting that the presence of stereotypies is not associated simply with quantitative differences in striatal DA release. By contrast, some features of the behavioral response were significantly correlated with AMPH-induced changes in striatal 5-HT concentrations. Our results suggest that the behavioral response to AMPH may be influenced by the interaction between levels of DA and 5-HT release, as well as by the state of their respective receptors.     

Withdrawal from chronic amphetamine reduces dopamine transmission in the rat lateral septum

The lateral septum (LS) is a brain nucleus implicated in the addictive process. This study investigated whether withdrawal from chronic amphetamine (AMPH) induces alterations in dopamine (DA) transmission within the LS. Male Sprague‐Dawley rats were injected with AMPH (2.5 mg/kg i.p.) or saline during 14 days and thereafter subjected to 24 hr or 14 days of withdrawal. After these withdrawal periods, we measured DA extracellular levels by in vivo microdialysis, DA tissue levels, and tyrosine hydroxylase (TH) and vesicular monoamine transporter‐2 (VMAT2) expression in the LS. Our results showed a significant decrease in K⁺‐induced release of DA in the LS of AMPH‐treated rats, 14 days after withdrawal compared with saline‐treated rats. There were no significant differences in DA tissue content and TH expression. Interestingly, there was a decrease of LS VMAT2 expression in AMPH‐treated rats, 14 days after withdrawal compared with saline‐treated rats. This is the first neurochemical evidence showing that withdrawal from repeated AMPH administration decreases K⁺‐induced DA release in the rat LS. Our results suggest that this decrease in DA releasability could be due to a decrease in DA vesicular uptake. The possibility that these neurochemical changes are associated with AMPH abstinence syndrome should be further explored. © 2014 Wiley Periodicals, Inc.     

Effects of para-chlorophenylalanine on amphetamine and haloperidol-induced changes in striatal dopamine turnover

Para-chlorophenylalanine (PCPA) was administered to rats, and the animals were sacrificed 48 h later. Animals received various doses of S(+)-amphetamine (AMPH) 31 min before sacrifice or of haloperidol (HAL) 46 min before sacrifcie and an intracerebral injection of [³H]tyrosine 15 min prior to sacrifice. PCPA pretreatment potentiated the increased accumulation of striatal [³H]dopamine (DA) induced by doses of AMPH to 1.5 mg/kg, and inhibited the decrease in striatal [³H]DA accumulation observed at higher doses (> 2.5 mg/kg) of AMPH. Furtherm the AMPH-induced increase in endogeneous levels of striatal DA was inhibited by PCPA pretreatment. Similarily, PCPA pretreatment potentiated the HAL-induced increase in striatal [³H]DA accumulation. The data are discussed with respect to an inhibitory serotonergic influence on nigrostriatal DA function, and the relationship of nigrostriatal biochemical events to AMPH-induced behavioral changes.     

Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics.

Using in vivo microdialysis, the caudate and nucleus accumbens dopamine (DA) responses to the psychomotor stimulants amphetamine (AMPH), cocaine (COC), and fencamfamine (FCF) were evaluated in rats concurrent with characterization of their behavioral response profiles. Doses of each stimulant that produced either enhanced locomotion or a prolonged period of intense focused stereotypies were examined to evaluate the quantitative relationships between stimulant-induced behaviors and changes in DA dynamics and to test the hypothesis that a balance between mesostriatal and mesolimbic DA activity contributes to the appearance of specific stimulant-induced behaviors. Although 10 mg/kg COC and 1.7 mg/kg FCF promoted levels of locomotor activity substantially greater than 0.5 mg/kg AMPH, the magnitude of the DA increases in both caudate and accumbens were markedly less than was obtained following AMPH. Thus, stimulant-induced locomotion appears to be dissociated from the quantitative DA response in both brain regions. This behavioral/DA dissociation was also apparent at higher doses of AMPH (2.5 mg/kg), COC (40 mg/kg), and FCF (6 mg/kg), doses that promoted a behavioral pattern that included a prolonged period of intense stereotypy. Indeed, the regional DA responses to these high doses of COC and FCF were substantially less than the response to 0.5 mg/kg AMPH. Furthermore, there were no differences in the ratio of the caudate and accumbens DA responses as a function of dose for any of the three drugs. Thus, the balance between the regional DA activation does not appear to regulate the expression of the behavioral response. Additionally, the effects of these stimulants on regional DA metabolite concentrations were compared. The results indicate that AMPH promoted an identical pattern of effects on caudate and accumbens DA metabolites, suggesting that similar mechanisms govern the dynamics of DA in response to AMPH in both brain regions. In contrast, the DA uptake blockers promoted some region-specific effects on DA metabolites that may be due to regional differences in the DA metabolism and rates of impulse flow.     

Conditional involvement of striatal serotonin3 receptors in the control of in vivo dopamine outflow in the rat striatum

Serotonin3 (5-HT3) receptors can affect motor control through an interaction with the nigrostriatal dopamine (DA) neurons, but the neurochemical basis for this interaction remains controversial. In this study, using in vivo microdialysis, we assessed the hypothesis that 5-HT3 receptor-dependent control of striatal DA release is conditioned by the degree of DA and/or 5-HT neuron activity and the means of DA release (impulse-dependent vs. impulse-independent). The different DA-releasing effects of morphine (1 and 10 mg/kg), haloperidol (0.01 mg/kg), amphetamine (1 and 2.5 mg/kg), and cocaine (10 and 20 mg/kg) were studied in the striatum of freely moving rats administered selective 5-HT3 antagonists ondansetron (0.1 mg/kg) or MDL 72222 (0.03 mg/kg). Neither of the 5-HT3 antagonists modified basal DA release by itself. Pretreatment with ondansetron or MDL 72222 reduced the increase in striatal DA release induced by 10 mg/kg morphine but not by 1 mg/kg morphine, haloperidol, amphetamine or cocaine. The effect of 10 mg/kg morphine was also prevented by intrastriatal ondansetron (1 microm) administration. Reverse dialysis with ondansetron also reduced the increase in DA release induced by the combination of haloperidol and the 5-HT reuptake inhibitor citalopram (1 mg/kg). Considering the different DA and 5-HT-releasing properties of the drugs used, our results demonstrate that striatal 5-HT3 receptors control selectively the depolarization-dependent exocytosis of DA only when central DA and 5-HT tones are increased concomitantly.     

Characterization of vinpocetine effects on DA and DOPAC release in striatal isolated nerve endings

The effect of vinpocetine, a nootropic drug with anti-ischemic potential, on the release of DA and its main metabolite, DOPAC, was investigated in striatum isolated nerve endings under resting and depolarized conditions. Vinpocetine does not modify the baseline release of DA or the exocytotic release of DA evoked by high K(+), but inhibits the release of DA evoked by veratridine reversal of the DA transporter. In addition to these results, which confirm the vinpocetine selective blockade of voltage-sensitive presynaptic Na(+) channels (VSSC) previously reported [Neurochem. Res. 24 (1999) 1585], vinpocetine increases DOPAC release either under resting, veratridine or high K(+) depolarized conditions. This latter effect, which does not involve VSSC, was characterized. The parallel determination of the released and retained catecholamine concentrations revealed that vinpocetine increases DOPAC release at the expense of internal DA in a dose-dependent manner (low microM range). In contrast to vinpocetine, the selective MAO-A inhibitor, clorgyline, increases DA and decreases DOPAC formation. The combined action of vinpocetine and clorgyline does not indicate, however, that the activation of MAO is the mechanism responsible for the increase in DOPAC caused by vinpocetine. Reserpine, although more potent and efficient than vinpocetine, qualitatively exerts the same pattern of changes on DA and DOPAC concentrations. It is concluded that, in addition to the inhibition of presynaptic VSSC permeability, which selectively inhibits the transporter-mediated release of all neurotransmitters, vinpocetine increases DOPAC by impairing the vesicular storage of DA. Our results indicate that the cytoplasm extravesicular DA is metabolized by MAO to DOPAC. Most of the DOPAC formed is exported to the extracellular medium.     

Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis

Estrous cycle-dependent variation in amphetamine (AMPH)-stimulated behaviors and striatal dopamine (DA) release were determined for freely moving rats undergoing intracerebral microdialysis. There was greater AMPH-stimulated striatal DA release in the striatum of rats in estrus, during the period from 20 min to 100 min post-AMPH, compared with the response of rats in diestrus (P less than 0.05). Animals in estrus also showed less general activity and greater intensity of stereotyped behaviors than did animals in diestrus (P less than 0.05). Independent experiments examining estrous cycle-dependent differences in AMPH-stimulated striatal DA release in vitro also found that AMPH-stimulated striatal DA release was greater on estrus than on diestrus (P less than 0.05). Thus, striatal DA release and behaviors induced by AMPH are modulated by ovarian hormones. The heightened responsiveness to AMPH during estrus suggests that estrogen and/or progesterone potentiate the striatal DA response to AMPH.     

Markers of dopamine depletion and compensatory response in striatum and cerebrospinal fluid

Summary Though depletion of CSF homovanillic acid (HVA) concentration has often been regarded as a direct indicator of dopamine (DA) deficiency in Parkinson's Disease (PD), CSF HVA is normal in mildly affected patients. To explore why, we measured DA and its metabolites in striatum and CSF in rabbits receiving reserpine for 5 days. Reserpine, which depletes striatal DA by disrupting vesicular storage of the neurotransmitter, results in a compensatory increase of DA turnover. In response to a 96% depletion of striatal DA, its catabolic intermediates 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) decreased 64% and 92% in striatum, although the endproduct, HVA, was unchanged. In contrast, CSF concentrations of HVA and DOPAC increased significantly, though 3-MT and levodopa (LD) were unaltered. A 5-fold rise in striatal LD concentration after reserpine-induced DA depletion provided evidence for enhanced DA synthesis. As in PD, the compensatory increase of DA synthesis after reserpine administration confounds the ability of CSF HVA to reflect DA depletion.     

Dopaminergic response to graded dopamine concentration elicited by four amphetamine doses

We studied the metabolic responses to different DA concentrations elicited by four doses of D‐amphetamine (AMPH, 0, 0.25, 0.5, 1.0, or 3.0 mg/kg). We compared the degree of DA release (via microdialysis) with striatal cAMP activity and whole brain maps of cerebral blood volume (rCBV) changes (via pharmacological MRI, phMRI). Results: AMPH increased DA release in the caudate/putamen (CPu) and cAMP activity in the CPu, nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) in a linear dose‐dependent manner (P < 0.0001). The cAMP data suggest that, postsynaptically, signal transduction induced by D1 receptor is stronger than that of D2 receptor at the higher doses (1–3 mg/kg). phMRI showed that, while higher doses of AMPH (3 mg/kg (n = 7) and 1 mg/kg (n = 6)) induced significant rCBV increases in the CPu and NAc, the degree of rCBV increase was much smaller with AMPH of 0.5 mg/kg (n = 6). In contrast, AMPH of 0.25 mg/kg (n = 8) induced significant rCBV decreases in the anteromedial CPu and NAc. The sign switch of rCBV in response to AMPH from low to high doses likely reflects the switching in the balance of D2/D3 stimulation vs. D1/D5 stimulation. In conclusion, degree of postsynaptic signal transduction is linearly correlated to the extracellular DA concentration. However, the presynaptic binding may dominate the overall DA innervation at the lower range of DA concentration. Synapse 63:764–772, 2009. © 2009 Wiley‐Liss, Inc.     

Distinct patterns of Fos expression induced by systemic amphetamine in the striatal complex of C57BL/6JICo and DBA/2JICo inbred strains of mice

Mice from the inbred strains C57BL/6 and DBA/2 are characterized by striking differences in their behavioral response to addictive drugs. We used Fos expression as a tool to reveal strain differences in the postsynaptic effects of amphetamine (AMPH; 2.5 mg/kg) within the nucleus accumbens (NAc) (core and shell) and the dorsal caudate (dorsomedial and dorsolateral). AMPH stimulated Fos expression in all striatal regions of mice from both strains. However, while C57BL/6 showed a higher Fos response than DBA/2 mice in both NAc shell and core, the opposite was true for the dorsolateral caudate. The effects of AMPH were prevented by D1 blockade in all striatal regions of both strains and mimicked by the D1 agonist, SKF82958 (0.1 mg/kg), in both regions of the caudate and in the NAc shell, but not in the core. Our results suggest that the functional heterogeneity of the striatal complex is under genetic control and that this control may implicate DA transmission and corticostriatal interactions.     

Effects of 250 mg% ethanol on monoamine and amino acid release from rat striatal slices

A single IP injection of 2.5 g ethanol/kg body weight into the rat increased the striatal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) one hour later to 133 and 141% of control values, respectively. Blood alcohol concentrations at this time were approximately 250 mg%. The increased striatal tissue levels of DOPAC and HVA found after IP administration did not appear to be due to a direct effect of ethanol on the efflux of these two metabolites or on the release of dopamine (DA) since in vitro studies with striatal slices demonstrated that 250 mg% ethanol had no effect on the endogenous release of DOPAC, HVA, or DA. However, ethanol did enhance the K+-stimulated, Ca2+-dependent release of glutamate and aspartate from striatal slices to 168 and 214% of control values, respectively. The release of glutamate and aspartate from slices of midbrain (minus colliculi) was also increased by 250 mg% ethanol. On the other hand, the release of GABA, NE and 5-HT did not appear to be significantly altered by 250 mg% ethanol. The in vitro findings have led to the hypothesis that the elevated DOPAC and HVA levels observed in the striatum following an acute IP injection of 2.5 g/kg of ethanol are due to increased release of DA produced by the excitatory actions of glutamate (and/or aspartate) on dopaminergic neurons.     

Effect of the adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine on L-DOPA biotransformation in rat striatum

In the present study, we investigated effects of the new selective adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine (CSC) on L-DOPA-induced dopamine (DA) release in the striatum of intact and reserpine-treated rats. CSC given in a pharmacologically effective dose of 5 mg/kg i.p. significantly increased striatal DA release after joint administration of L-DOPA (100 mg/kg, i.p.) and benserazide (50 mg/kg, i.p.) to intact and reserpine (2.5 mg/kg, s.c.)-injected rats. CSC did not change the elevated level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in intact rats, but raised it in DA-depleted animals. The availability of exogenous L-DOPA in the extracellular space was similar and equally increased by CSC in both intact and reserpinized rats. Our results suggest that the observed effects may be mediated by striatal adenosine A2A receptors, and are probably related to the CSC action on DA metabolism and the increased transport of exogenous L-DOPA into the brain. These observations might be of relevance, considering the use of selective A2A antagonists as potential supplements to L-DOPA therapy of Parkinson's disease.     

Striatal dopamine metabolism in response to apomorphine: the effects of repeated amphetamine pretreatment

The dose-dependent decrease in striatal dopamine (DA) metabolites following apomorphine (APO) administration was utilized as an index of changes in DA receptor sensitivity following the repeated administration of amphetamine (AMPH). The results suggest that: (a) repeated AMPH pretreatment does not alter DA autoreceptor sensitivity; and (b) interpretations of the decline in striatal DA metabolites at high doses of APO (> 50 μg/kg), in terms of activation of postsynaptic DA receptors, may require re-evaluation.     

Pharmacological MRI response to a selective dopamine transporter inhibitor,GBR12909, in awake and anesthetized rats

Pharmacological magnetic resonance imaging (phMRI) is a powerful tool for imaging the effects of drugs on brain activity. In preclinical phMRI studies, general anesthesia used for minimizing head movements is thought to influence the phMRI responses to drugs. In this study we investigated the phMRI responses to a selective dopamine transporter (DAT) inhibitor, GBR12909, and a dopamine (DA) releaser, d ‐amphetamine (AMPH), in the isoflurane anesthetized and awake rats using a relative cerebral blood volume (rCBV) method. AMPH (1 mg/kg i.p.) caused an increase in rCBV in the dopaminergic circuitry in the both anesthetized and awake rats. The striatal rCBV change was correlated with the change of the striatal DA concentration induced by AMPH in the both anesthetized and awake rats. GBR12909 (10 mg/kg i.p.) caused a positive rCBV response and showed a similar regional pattern of rCBV response to AMPH in the awake rats, and the correlation between the change of the striatal rCBV and the striatal DA concentration was observed. However, in the anesthetized rats, GBR12909 induced a widespread negative rCBV response, whereas an increase in striatal DA concentration was observed. These findings indicate that phMRI responses to activation of DA neurotransmission by GBR12909 or AMPH are overall identical in the awake state, while the phMRI response to a DAT inhibitor, GBR12909 but not to AMPH was changed by isoflurane anesthesia. For the evaluation of neuroactive drugs using phMRI, isoflurane anesthesia might be complicated the interpretation of pharmacodynamic effects of drugs in preclinical studies. Synapse, 69:203–212, 2015 . © 2015 Wiley Periodicals, Inc.     

D-amphetamine-induced depletion of energy and dopamine in the rat striatum is attenuated by nicotinamide pretreatment

The present study examined the effects of nicotinamide on the D-amphetamine (AMPH)-induced dopamine (DA) depletion and energy metabolism change in the rat striatum. In chronic studies, co-administration of AMPH with desipramine, a drug that retards the metabolism of AMPH, (10 mg/kg, intraperitoneal [i.p.], respectively) caused a significant decrease of striatal DA content measured 7 days later. Pretreatment with nicotinamide (500 mg/kg, i.p.), the precursor molecule for the electron carrier molecule nicotinamide adenine dinucleotide (NAD), attenuated this effect of AMPH, whereas itself exerted no long-term effect on striatal DA content. In acute studies, a decrease in striatal adenosine triphospate/adenosine diphosphate (ATP/ADP) ratio was found 3 h after co-injection of AMPH and desipramine. However, nicotinamide pretreatment blocked the reduced striatal ATP/ADP ratio and resulted in a striking increase in striatal NAD content in AMPH-treated rats. Furthermore, nicotinamide was noted to increase striatal ATP/ADP ratio and NAD content in saline-treated rats. These findings suggest that nicotinamide protects against AMPH-induced DAergic neurotoxicity in the striatum of rats via energy supplement.     

Altered Guanosine and Guanine Concentrations in Rabbit Striatum Following Increased Dopamine Turnover

The significance of guanine nucleotides and nucleosides in neurodegenerative disorders is suggested by recent reports that these molecules enhance neurite branching and astrocyte proliferation. The objective of this study was to investigate the influence of increased dopamine metabolism, produced by 5-day treatment of rabbits with reserpine (2 mg/kg) or levodopa (LD) (50 mg/kg), on striatal concentrations of guanosine, guanine, and their metabolites. Reserpine treatment decreased striatal guanosine by 41% and increased guanine by 50%, while LD decreased guanosine by 48% (all p < 0.01 vs. vehicle-treated controls). LD also increased guanine by 22% (not statistically significant). Xanthine and uric acid concentrations were unchanged. Because of the neurotrophic properties of guanosine and guanine, changes in striatal concentrations of these purines secondary to increased dopamine (DA) turnover may have relevance for survival of remaining dopaminergic neurons in Parkinson’s disease (PD).     

Food restriction modulates amphetamine-conditioned place preference and nucleus accumbens dopamine release in the rat

Food restriction has been shown to increase self-administration of psychostimulants, including cocaine and amphetamine (AMPH). Consistent with this, food-restricted rats are more sensitized to the rewarding effects of cocaine as measured by conditioned place preference (CPP). This study investigated whether moderate food restriction in rats (15 g/day) results in an increased CPP, relative to ad libitum-fed controls, to a second psychostimulant, AMPH. Conditioning trials consisted of six alternating injections of i.p. AMPH (0.425-6.8 mg/kg) and i.p. saline, paired with distinct environments. On Day 7, a drug-free 20-min choice test for environment was carried out to assess CPP. 0.85 mg/kg AMPH significantly increased CPP in food-restricted vs. ad libitum-fed rats. At 1.7 and 3.4 mg/kg AMPH, food-restricted rats showed decreased CPP, but increased locomotor activity, relative to ad libitum fed controls. To evaluate whether an alteration in extracellular fluid DA levels in the nucleus accumbens (NAc) core could account for these behavioral alterations, DA release was measured by microdialysis. DA release to a single acute i.p. injection of either 0.85 or 1.7 mg/kg AMPH was comparable in food-restricted and ad libitum fed rats. However, ad libitum fed rats demonstrated conditioned DA release after an AMPH conditioning paradigm analogous to the CPP paradigm, whereas food-restricted rats demonstrated no conditioned DA release. In conclusion, altered DA release in the nucleus accumbens core is not a primary effect of moderate food restriction and cannot completely account for either the altered CPP behavior or enhanced locomotor activity observed in this study.