Parallel strain-dependent effect of amphetamine on locomotor activity and dopamine release in the nucleus accumbens: an in vivo study in mice

Vulnerability to develop drug abuse could be related to differential sensitivity to some central effects of such drugs. Several results point to mesoaccumbens dopamine release elicited by psychostimulants as the rate-limiting factor of their reinforcing, hence addictive, effects and to locomotor stimulation as an indirect index of such a response. In this paper, we report parallel differences in sensitivity to amphetamine-induced locomotor stimulation and mesoaccumbens dopamine release in two inbred strains of mice characterized by differential susceptibility to develop drug self-administration. Thus, mice of the C57BL/6 strain responded with a simultaneous increase of locomotor activity and mesoaccumbens dopamine release measured by intracerebral microdialysis to amphetamine challenge. On the contrary, mice of the DBA/2 strain did not present either response. No strain differences in mesoaccumbens dopamine outflow or 3,4-dihydroxyphenylacetic acid concentration were found in basal conditions or following saline challenges. However, mice of the C57BL/6 strain were characterized by higher levels of accumbal homovanillic acid in basal conditions, in line with the results obtained in rats rendered more sensitive to the locomotor effects of psychostimulants by repeated administration. Finally, in both strains amphetamine decreased accumbal levels of the two metabolites. These results suggest that genotype modulates the locomotor effects of amphetamine through sensitivity of the mesoaccumbens system to amphetamine-stimulated dopamine release. Moreover, they provide a basis to test the hypothesis of mesoaccumbens dopamine involvement in individual susceptibility to the addictive effects of drugs by quantitative trait loci analysis in recombinant inbred strains.     

The role of ATP-sensitive potassium channels in striatal dopamine release: an in vivo microdialysis study

Inactivation of the retinoblastoma (RB) gene is known to be implicated in the pathogenesis of several types of human cancers. Since structural alterations of the RB gene have not been well examined in human bladder cancer, we looked for mutations in the entire coding region of this gene using polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis of RNA. We also examined allelic loss of the RB gene using PCR-based restriction fragment length polymorphism analysis. Of 30 samples obtained from patients with bladder cancer, eight (27%) were found to have RB gene mutations. DNA sequencing of the PCR products revealed five cases with single point mutations and three cases with small deletions. These mutations included one (10%) of ten low-grade (grade 1) tumours, four (50%) of eight intermediate-grade (grade 2) tumours and three (25%) of 12 high-grade (grade 3) tumours. Likewise, mutations were found in four (21%) of 19 superficial (pTa and pT1) tumours and four (36%) of 11 invasive (pT2 or greater) tumours. In 15 informative cases, loss of heterozygosity at the RB locus was shown in five cases (33%), three cases with RB mutations and two without them. These results suggest that RB gene mutations are involved in low-grade and superficial bladder cancers as well as in high-grade and invasive cancers.     

Tetanus toxin-induced effects on extracellular amino acid levels in rat hippocampus: an in vivo microdialysis study

Tetanus toxin is a potent neurotoxin that is widely considered to produce its effect through impairment of inhibitory neurotransmission. We report the effect of a single unilateral intrahippocampal injection of tetanus toxin on extracellular levels of neuroactive amino acids in freely moving rats, at times ranging between 1 and 7 days posttreatment. Tetanus toxin treatment did not alter extracellular levels of aspartate, glutamate, and taurine at any time during the study. However, although extracellular GABA levels were unaffected by toxin injection 1, 2, and 3 days after treatment, they were reduced (45 +/- 8% of contralateral vehicle-injected level) at day 7. Challenge with a high K+ concentration, 7 days after treatment, produced elevations in extracellular levels of taurine and GABA in both vehicle- and toxin-injected hippocampi, with evoked levels of GABA being lower in the toxin-treated side (39 +/- 16% of contralateral vehicle-injected level). Aspartate and glutamate levels were not increased by high-K+ infusion. These findings are discussed in relation to the possible role that an imbalance in excitatory/inhibitory tone may play in the production of tetanus toxin-induced neurodegeneration.     

Effect of transient cerebral ischaemia on acetylcholine release in the gerbil hippocampus

To clarify the relationship between presynaptic cholinergic dysfunction and postsynaptic cell death in the hippocampus, extracellular levels of acetylcholine (ACh) were assayed and CA1 pyramidal cells were histologically investigated in gerbils which had undergone 2, 5 and 10 min ischaemia. It was found that the KCl- and atropine-induced release of ACh, an index of the functioning cholinergic system at the presynaptic terminals, was significantly lower in the ischaemic groups than in control groups. The hippocampal CA1 pyramidal cell area of the 5 and 10 min ischaemic animals was also significantly decreased, but the 2 min ischaemia caused no cell damage. These findings indicate that the presynaptic terminals of the cholinergic neurone are vulnerable to ischaemic insult and that cholinergic dysfunction precedes postsynaptic CA1 pyramidal cell death in the hippocampus.     

Effect of adenosine receptor agonists on spontaneous and K(+)-evoked acetylcholine release from the in vivo rat cerebral cortex

Repeated applications of elevated K+ (100 mM) in artificial cerebrospinal fluid (CSF) were used to evoke an efflux of acetylcholine (ACh) from the in vivo rat cerebral cortex using a cortical cup technique. Elevated K+ reproducibly increased the levels of ACh in cup superfusates by a factor of 3-5-fold above basal levels (27.2 +/- 9.7 nM). The adenosine A1 receptor agonist N6-cyclopentyl adenosine (CPA), at a concentration of 10(-8) M, depressed basal, but not K(+)-evoked ACh efflux. 10(-6) M CPA increased basal, but did not alter K(+)-evoked, ACh efflux. The A2 selective agonist CGS 21680 did not alter either basal, or K(+)-evoked, ACh efflux. The inhibitory effects of 10(-8) M CPA on ACh efflux would be consistent with the presence of adenosine A1 receptors on cholinergic nerve terminals in the cerebral cortex. At a higher concentration (10(-6) M) CPA elevated basal release, possibly by activating low affinity A2 receptors. The failure of CGS 21680 (10(-8) M) to alter basal ACh release suggests an absence of high affinity A2 receptors in these terminals. Whereas elevated K+ in cup superfusates consistently enhanced ACh efflux from the cerebral cortex, this increase was not affected by either CPA or CGS 21680. High K(+)-evoked release of cerebral cortical ACh may be an inappropriate model for the study of adenosine's actions on neurotransmitter release.     

Activation of non-NMDA receptors stimulates acetylcholine and GABA release from dorsal hippocampus: a microdialysis study in the rat

The effect of the non-N-methyl-D-aspartate (NMDA) agonists (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and quisqualate (QUIS) on the release of acetylcholine (ACh), gamma-amino butyric acid (GABA), aspartate (Asp) and glutamate (Glu) from the hippocampus of freely moving rats was studied by transversal microdialysis. Intracerebroventricular (i.c.v.) administration of the non-NMDA receptor agonist AMPA (0.5 nmol) enhanced (by about 200%) ACh release from the hippocampus. The effect of AMPA was completely antagonized by 6-nitro-7-sulphamoyl-benz(f)quinoxaline-2,3-dione (NBQX; 2 nmol, i.c.v). No effect was seen when AMPA was perfused through the septum. However, AMPA (200 microM) locally applied to the hippocampus, increased (by about 200%) ACh release. QUIS (200 microM) applied locally to the hippocampus produced a long-lasting increase in the release of ACh (by about 215%) and GABA (by about 460%). Local infusion of tetrodotoxin (1 microM) decreased ACh and GABA basal extracellular levels, and abolished the QUIS-induced increase in ACh and GABA. Our results demonstrate that non-NMDA glutamatergic receptors in the hippocampus regulate hippocampal release of GABA and ACh.     

Scavenging effects of dopamine agonists on nitric oxide radicals

It has recently been considered that free radicals are closely involved in the pathogenesis of Parkinson's disease (PD), and the level of nitric oxide radical (.NO), one of the free radicals, is reported to increase in PD brain. In the present study, we established a direct detection system for .NO in an in vitro .NO-generating system using 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-N-methyl-1-propa namine as an .NO donor and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO) by electron spin resonance (ESR) spectrometry and examined the quenching effects of the dopamine agonists pergolide and bromocriptine on the amount of.NO generated. .NO appeared to be scavenged by pergolide and, to a lesser extent, by bromocriptine. In the competition assay, the 50% inhibitory concentration values for pergolide and bromocriptine were estimated to be approximately 23 and 200 microM, respectively. It was previously reported that in vivo treatment of pergolide and bromocriptine completely protected against the decrease in levels of striatal dopamine and its metabolites in the 6-hydroxydopamine-injected mouse. Considering these findings, pergolide and probably bromocriptine may also protect against dysfunction of dopaminergic neurons because of its multiple effects; not only does it stimulate the presynaptic autoreceptors, but it also directly scavenges .NO radicals and hence protects against .NO-related cytotoxicity. This ESR spectrometry method using carboxy-PTIO may be useful for screening other drugs that can quench .NO.     

Galparan induces in vivo acetylcholine release in the frontal cortex

The chimeric peptide galparan (galanin(1-13)-mastoparan) induced the in vivo release of acetylcholine in the frontal cortex of rats when injected intracerebroventricularly, i.c.v. The ACh-releasing effects of galparan are reversible, dose-dependent, and not exerted at galanin receptors or at sites where mastoparan acts. Pertussis toxin pretreatment (i.c.v.) of the rats for 96 h prior to injection of galparan or of mastoparan completely prevented the ACh-releasing effects of both galparan and mastoparan. It appears that galparan acts at a novel site in the release of ACh in the cerebral cortex in vivo.     

Influence of selective opiate antagonists on striatal acetylcholine and dopamine release

Ty3 is a retroviruslike element found in Saccharomyces cerevisiae. It encodes GAG3 and GAG3-POL3 polyproteins which are processed into mature proteins found in the Ty3 viruslike particle. In this study, the region encoding a protease that is homologous to retroviral aspartyl proteases was identified and shown to be required for production of mature Ty3 proteins and transposition. The Ty3 protease has the Asp-Ser-Gly consensus sequence found in copia, Ty1, and Rous sarcoma virus proteases, rather than the Asp-Thr-Gly found in most retroviral proteases. The Asp-Ser-Gly consensus is flanked by residues similar to those which flank the active sites of cellular aspartyl proteases. Mutations were made in the Ty3 active-site sequence to examine the role of the protease in Ty3 particle maturation and to test the functional significance of the Ser active-site variant in the consensus sequence. Mutation of the active-site Asp blocked processing of Gag3 and Gag3-Pol3 and allowed identification of a GAG3-POL3 polyprotein. This protein was turned over rapidly in cells expressing the mutant Ty3. Changing the active-site Ser to Thr caused only a modest reduction in the levels of certain Ty3 proteins. Five putative cleavage sites of this protease in Ty3 GAG3 and GAG3-POL3 polyproteins were defined by amino-terminal sequence analysis. The existence of an additional protein(s) of unknown function, encoded downstream of the protease-coding region, was deduced from the positions of these amino termini and the sizes of known Ty3 proteins. Although Ty3 protease cleavage sites do not correspond exactly to known retroviral protease cleavage sites, there are similarities. Residues P3 through P2' in the regions encompassing each of the five sites are uncharged, and no P1 position is occupied by an amino acid with a branched beta carbon.     

Regional differences in striatal dopamine uptake and release associated with recovery from MPTP-induced parkinsonism: an in vivo electrochemical study

This study directly assessed striatal dopamine (DA) uptake rates and peak release in response to KCl in normal, symptomatic, and recovered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cats using in vivo electrochemistry. DA uptake rates measured after direct application of known concentrations of DA to the striatum were slowed significantly in both dorsal and ventral striatum in symptomatic cats compared with rates recorded in normal animals. DA uptake rates remained significantly slowed in recovered cats and were not significantly different from the rates recorded in symptomatic animals. In symptomatic cats, both DA uptake rates and the signal recorded in response to KCl stimulation were significantly decreased from normal in all dorsal and ventral striatal regions sampled. Reduction/oxidation (redox) ratios recorded in response to KCl stimulation suggested DA to be the predominant electroactive species. In spontaneously recovered MPTP-treated cats, recordings in the ventral striatum subsequent to KCl stimulation again suggested DA to be the predominant electroactive species released, and peak levels were significantly higher than those recorded in symptomatic animals. In the dorsal striatum of recovered cats, redox ratios recorded subsequent to KCl stimulation suggested serotonin rather than DA to be the predominant electroactive species released. Peak levels of release in the dorsal striatum were not significantly greater than those recorded in symptomatic animals. These results suggest that in spontaneously recovered MPTP-treated cats, there is partial recovery of ventral striatal DAergic terminals, persistent loss of dorsal striatal DAergic terminals, and a down-regulation of DA transporter number/function throughout the striatum. These processes may contribute to volume transmission of DA in the striatum and promote functional recovery.     

MDMA induced dopamine release in vivo: role of endogenous serotonin

Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilities DA release, it was hypothesized that increased release of striatal 5-HT after MDMA may influence extracellular levels of DA. Using microdialysis in vivo, we found that (+)-MDMA (4.7 mumol/kg, i.v.) administration increased extracellular striatal DA levels to 501% of control (p < 0.01, n = 12). However, in the presence of fluoxetine (14.4 mumol/kg, s.c.), which prevents (+)-MDMA effects on 5-HT release, the (+)-MDMA-induced increase in DA was significantly less (to 375% of control, p < 0.05, vs. no fluoxetine, n = 8). In vitro studies with striatal slices, to test drug selectivity, showed that (+)-MDMA (0.3-3 microM) increased extracellular levels of both DA and 5-HT in a dose-dependent manner. Fluoxetine (3 microM) completely blocked the effects of (+)-MDMA on 5-HT release, but did not alter (+)-MDMA-induced DA release in vitro. The selective DA transport inhibitor GBR-12909 (1 microM), blocked (+)-MDMA's effect on DA release. It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+)-MDMA's effect on DA release in vivo.     

3-Methoxytyramine as an indicator of impulse-induced dopamine release in rat brain in vivo

Autotransfusions were performed in 80 patients operated upon for thyroid diseases at the Department of Surgery, Institute of Haematology in Warsaw. For autotransfusions patients were selected in good general condition and with haematological indices in the range accepted for blood donors. Planning of autotransfusion is purposeful only in these cases of thyroid disease in which the necessity of blood transfusion can be predicted in advance (e.g. Graves-Basedov-disease, retrosternal goitre, mediastinal goitre). The transfused volume may cover completely or partly the intraoperative blood loss. Autotransfusion protects the patients against possible isoimmunization which may develop after transfusion of blood from donors. Protection of patients against possible immunization is a problem of considerable value. It is important particularly in young subjects, especially young women who may become mothers. Operations connected with blood loss up to 500 ml do not require supplementary transfusions. Intraoperative blood loss in the range from 500 to 1000 ml requires supplementation. The risk of posttransfusion complications is lowest when autotransfusion is done.     

Heterogeneity of the hippocampus: effects of subfield lesions on locomotion elicited by dopaminergic agonists

Oriented calcium oxalate crystals have been grown beneath phospholipid monolayers at the air-solution interface from supersaturated calcium oxalate solutions. Mature calcium oxalate crystals grown beneath zwitterionic dipalmitoylphosphatidylcholine (DPPC) monolayers exhibit the characteristic morphology of calcium oxalate monohydrate (COM) crystals with the elongated (101) crystal face preferentially oriented parallel to the plane of the monolayer. Calcium oxalate crystals grown beneath negatively-charged dimyristoylphosphatidylserine (DMPS) monolayers also show a preferential orientation with respect to the monolayer; they do not, however, exhibit the characteristic COM morphology. Raman spectroscopy strongly suggests that the crystals grown beneath either DPPC or DMPS monolayers are the monohydrate phase of calcium oxalate; therefore, differences in crystal morphology are not due to differences in the crystalline phase. Dimyristoylphosphatidylethanolamine (DMPE), dimyristoylphosphatidic acid (DMPA), eicosanoic acid (C20), and eicosanol (C20-OH) monolayers have also been studied to help elucidate the mechanisms of interaction between the lipid monolayers and the calcium oxalate crystals. We discuss the roles of lattice matching, hydrogen bonding, stereochemistry and electrostatics on crystal orientation and morphology.     

Clonidine reduces dopamine and increases GABA in the nucleus accumbens: an in vivo microdialysis study

The spectrum of infectious disease (ID) emergencies in hospitalized patients was assessed in a prospective study of 3,626 inpatient ID consultations in a 1,350-bed teaching hospital. ID emergencies, defined by a need or anticipated need for advanced life support or by irreversible organ damage leading to permanent functional loss, were encountered in 175 patients. Infections of the central nervous system (26.3%), cardiovascular system (14.9%), alimentary system (13.1%), and lower respiratory tract (7.4%) and adverse reactions to antimicrobial agents (7.4%) were most common. In 18.9% of the cases, the referring clinicians were unaware of the emergency at the time of referral. Drug reactions (46.1%), severe alimentary and peritoneal infections (32.0%), upper respiratory tract infections (28.6%), and skin and soft-tissue infections (27.3%) were most frequently missed. The emergency ID conditions were not recognized because they had an atypical presentation (51.5%), were not commonly seen in the referring specialty (24.2%), were due to rare organisms (15.2%), or had unusual anatomical sites of involvement (9.1%). A close liaison between clinicians and the ID team is crucial for recognition of ID emergencies at their early stages so that appropriate investigations and management can be instituted expediently, before the occurrence of irreversible damage.     

Effects of isoflurane on in vivo release of acetylcholine in the rat cerebral cortex and striatum

BACKGROUND: Acetylcholine (ACh) is one of the major excitatory neurotransmitters in the central nervous system, and changes in neural activity induced by anesthesia alter the release of ACh. However, the effects of isoflurane, one of the most widely used volatile anesthetics, on ACh release are not known. The present study attempts to clarify the dose-effect relationship of isoflurane on the in vivo release of ACh in rat brains. METHODS: Changes in the extracellular concentration of ACh and choline in the cerebral cortex and striatum induced by 0.5, 1.0, and 1.5 minimum alveolar concentration (MAC) of isoflurane were determined using a brain microdialysis technique. RESULTS: In the cortex, the ACh release decreased to 30.8+/-10.1 (mean+/-SEM), 10.2+/-4.1, and 8.1+/-2.9% of basal value by increasing doses of isoflurane, and in the striatum, to 73.3+/-4.4, 49.2+/-4.2, and 40.7+/-4.5%. The ACh release rapidly recovered control levels with the discontinuance of isoflurane. Choline concentration was not changed significantly by isoflurane except for a decrease to 74.8+/-4.6% in the striatum by 0.5 MAC. In both the cortex and striatum, the choline concentration decreased with the discontinuance of isoflurane to 70.3+/-13.3, and 68.2+/-5.4%, respectively. CONCLUSION: The fact that all classic anesthetics reported previously, as well as isoflurane, reduce ACh release supports the hypothesis that the suppression of cholinergic cells is, at least in part one of the mechanisms of anesthesia.     

Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice

Dopamine (DA) autoreceptors expressed along the somatodendritic extent of midbrain DA neurons modulate impulse activity, whereas those expressed at DA nerve terminals regulate both DA synthesis and release. Considerable evidence has indicated that these DA autoreceptors are of the D2 subtype of DA receptors. However, many pharmacological studies have suggested an autoreceptor role for the DA D3 receptor. This possibility was tested with mice lacking the D3 receptor as a result of gene targeting. The basal firing rates of DA neurons within both the substantia nigra and ventral tegmental area were not different in D3 receptor mutant and wild-type mice. The putative D3 receptor-selective agonist R(+)-trans-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin+ ++-9-ol (PD 128907) was equipotent at inhibiting the activity of both populations of midbrain DA neurons in the two groups of mice. In the gamma-butyrolactone (GBL) model of DA autoreceptor function, mutant and wild-type mice were identical with respect to striatal DA synthesis and its suppression by PD 128907. In vivo microdialysis studies of DA release in ventral striatum revealed higher basal levels of extracellular DA in mutant mice but similar inhibitory effects of PD 128907 in mutant and wild-type mice. These results suggest that the effects of PD 128907 on dopamine cell function reflect stimulation of D2 as opposed to D3 receptors. Although D3 receptors do not seem to be significantly involved in DA autoreceptor function, they may participate in postsynaptically activated short-loop feedback modulation of DA release.     

Electrical stimulation of the prefrontal cortex increases cholecystokinin, glutamate, and dopamine release in the nucleus accumbens: an in vivo microdialysis study in freely moving rats

In vivo microdialysis, radioimmunoassay, and HPLC with electrochemical or fluorometric detection were used to investigate the release of cholecystokinin (CCK), glutamate (Glu), and dopamine (DA) in nucleus accumbens septi (NAS) as a function of ipsilateral electrical stimulation of medial prefrontal cortex (mPFC). CCK was progressively elevated by mPFC stimulation at 50-200 Hz. Stimulation-induced CCK release was intensity-dependent at 250-700 microA. NAS Glu and DA levels were each elevated by stimulation at 25-400 Hz; the dopamine metabolites DOPAC and homovanillic acid were increased by stimulation at 100-400 Hz. When rats were trained to lever press for mPFC stimulation, the stimulation induced similar elevations of each of the three transmitters to those seen with experimenter-administered stimulation. Perfusion of 1 mM kynurenic acid (Kyn) into either the ventral tegmental area (VTA) or NAS blocked lever pressing for mPFC stimulation. VTA, but not NAS, perfusion of Kyn significantly attenuated the increases in NAS DA levels induced by mPFC stimulation. Kyn did not affect NAS CCK or Glu levels when perfused into either the VTA or NAS. The present results are consistent with histochemical evidence and provide the first in vivo evidence for the existence of a releasable pool of CCK in the NAS originating from the mPFC. Although dopamine is the transmitter most closely linked to reward function, it was CCK that showed frequency-dependent differences in release corresponding most closely to rewarding efficacy of the stimulation. Although not essential for the reward signal itself, coreleased CCK may modulate the impact of the glutamatergic action in this behavior.     

Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway

Changes in extracellular levels of dopamine (DA), DA metabolites DOPAC and HVA, and the serotonin metabolite 5-HIAA, were measured by microdialysis in the rat nucleus accumbens (n. acc) after treatments with serotonin (5-HT)1A (8-OH-DPAT) or 5-HT1B (RU 24969 and S-CM-GTNH2) receptor agonists. Subcutaneous injections of RU 24969 (0.02-2 mg/kg) dose-dependently decreased 5-HIAA levels (0 to -38%), and also induced long-lasting increases in DA levels (0 to +37%) and DOPAC (+11% at the dose 0.5 mg/kg) in the shell of the n. acc, whereas 8-OH-DPAT (0.25 and 0.5 mg/kg) reduced 5-HIAA levels (-25%) and very slightly increased DOPAC at the lower dose (+4%), but had no effect on DA levels. Three weeks after interruption of the subicular efferent projections, the increase in DA levels previously observed after systemic injections of RU 24969 was abolished. Microinjections of RU 24969 (10 micrograms/microliter) or S-CM-GTNH2 (3 micrograms/microliter) into the ventral subicular area reproduced the effects of systemic injections of RU 24969 cn DA levels and increased DOPAC (+13%; +19%, respectively) and HVA levels (+23%; +24%), with no significant change in 5-HIAA. It is concluded that: (1) serotonin interacts with the mesolimbic dopaminergic system through 5-HT1B, but not 5-HT1A, receptors: and (2) serotonin interaction with the mesolimbic dopaminergic system involves postjunctional 5-HT1B heteroreceptors located in the ventral subicular area, which modulate the activity of glutamatergic hippocampo-accumbens pathways and only secondarily alter DA levels in the n. acc. The possible relevance of these results for schizophrenia is discussed.     

The effects of limbic lesions on locomotion and stereotypy elicited by dopamine agonists in the rat

The purpose of this experiment was to investigate the functional contributions of various limbic structures to locomotion and stereotypy induced by dopaminergic drugs. Female rats were randomly assigned to one of 5 groups (n = 10-14 rats/group) that received either a lesion of the hippocampus (colchicine + kainic acid), basolateral amygdala (quinolinic acid), frontal cortex (aspiration), nucleus accumbens (ibotenic acid), or served as unoperated controls. Beginning at least 2 weeks following surgery locomotion (measured as photocell beam breaks) elicited by D-amphetamine (0.0, 0.32, 1.0 and 3.2 mg/kg), SKF 82958 (0.0, 0.04, 0.08 and 0.16 mg/kg) or quinpirole (0.0, 0.25, 0.1 and 0.5 mg/kg) was determined. In agreement with previous results rats with hippocampal lesions were hyperactive in response to amphetamine. In comparison to these changes in drug-induced locomotion, lesions of the basolateral amygdala, and frontal cortex had only minor effects on drug-induced locomotion. Lesions of the nucleus accumbens produced consistent hyperactivity that was suppressed by doses of amphetamine or quinpirole that elicited behavioral stereotypy. These results provide evidence suggesting that, in comparison to other limbic structures that have substantial inputs to the nucleus accumbens, the hippocampus play a relatively prominent role in the modulation of drug-induced locomotion.