Impact of adolescent alcohol use across the lifespan: Long-lasting tolerance to high-dose alcohol coupled with potentiated spatial memory impairments to moderate-dose alcohol.

Understanding how alcohol exposure during adolescence affects aging is a critical but understudied area. In the present study, male rats were exposed to either alcohol or saline during adolescence, then tested every 4 months following either an ethanol or saline challenge; animals were tested until postnatal day (PD) 532. It was found that long-lasting tolerance to high-dose ethanol exists through the test period, as measured by loss of righting reflex, while tolerance to lower doses of ethanol is not found. In addition, alcohol exposure during adolescence facilitated spatial memory impairments to acute ethanol challenges later in life. The current work demonstrates that exposure to ethanol during adolescent development can produce long-lasting detrimental impairments.

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice.

Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0-100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher and lower order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with⩾95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher order cognitive flexibility, lower order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher and lower order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.

Impaired hypercarbic and hypoxic responses from developmental loss of cerebellar Purkinje neurons: implications for sudden infant death syndrome.

Impaired responsivity to hypercapnia or hypoxia is commonly considered a mechanism of failure in sudden infant death syndrome (SIDS). The search for deficient brain structures mediating flawed chemosensitivity typically focuses on medullary regions; however, a network that includes Purkinje cells of the cerebellar cortex and its associated cerebellar nuclei also helps mediate responses to carbon dioxide (CO2) and oxygen (O2) challenges and assists integration of cardiovascular and respiratory interactions. Although cerebellar nuclei contributions to chemoreceptor challenges in adult models are well described, Purkinje cell roles in developing models are unclear. We used a model of developmental cerebellar Purkinje cell loss to determine if such loss influenced compensatory ventilatory responses to hypercapnic and hypoxic challenges. Twenty-four Lurcher mutant mice and wild-type controls were sequentially exposed to 2% increases in CO2 (0-8%) or 2% reductions in O2 (21-13%) over 4 min, with return to room air (21% O2/79% N2/0% CO2) between each exposure. Whole body plethysmography was used to continuously monitor tidal volume (TV) and breath frequency (f). Increased f to hypercapnia was significantly lower in mutants, slower to initiate, and markedly lower in compensatory periods, except for very high (8%) CO2 levels. The magnitude of TV changes to increasing CO2 appeared smaller in mutants but only approached significance. Smaller but significant differences emerged in response to hypoxia, with mutants showing smaller TV when initially exposed to reduced O2 and lower f following exposure to 17% O2. Since cerebellar neuropathology appears in SIDS victims, developmental cerebellar neuropathology may contribute to SIDS vulnerability.

High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains.

Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio-molecular substrates and genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict the occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4-methylenedioxymethamphetamine; "ecstasy" (MDMA), morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity and sleep/wake cycles. All traits have been measured in both sexes in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.

A relationship between cerebellar Purkinje cells and spatial working memory demonstrated in a lurcher/chimera mouse model system.

New emphasis has been placed upon cerebellar research because of recent reports demonstrating involvement of the cerebellum in non-motor cognitive behaviors. Included in the growing list of cognitive functions associated with cerebellar activation is working memory. In this study, we explore the potential role of the cerebellum in spatial working memory using a mouse model of Purkinje cell loss. Specifically, we make aggregation chimeras between heterozygous lurcher (Lc/+) mutant embryos and +/+ (wildtype) embryos and tested them in the delayed matching-to-position (DMTP) task. Lc/+ mice lose 100% of their Purkinje cells postnatally due to a cell-intrinsic gain-of-function mutation. Lc/+<->+/+ chimeras therefore have Purkinje cells ranging from 0 to normal numbers. Through histological examination of chimeric mice and observations of motor ability, we showed that ataxia is dependent upon both the number and distribution of Purkinje cells in the cerebellum. In addition, we found that Lc/+ mice, with a complete loss of Purkinje cells, have a generalized deficit in DMTP performance that is probably associated with their motor impairment. Finally, we found that Lc/+<->+/+ chimeric mice, as a group, did not differ from control mice in this task. Rather, surprisingly, analysis of their total Purkinje cells and performance in the DMTP task revealed a significant negative relationship between these two variables. Together, these findings indicate that the cerebellum plays a minor or indirect role in spatial working memory.

Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice.

RATIONALE: It has been suggested that GABA(B) receptors may be part of a neural substrate mediating some of the effects of ethanol. OBJECTIVE: The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA(B) receptors. METHODS: Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice. RESULTS: Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance. CONCLUSIONS: Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA(B) drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.

Long term modulation of the HPA axis by the hippocampus. Behavioral, biochemical and immunological endpoints in rats exposed to chronic mild stress.

Mature rats were given lesions of the hippocampus (HIPPO), subiculum (SUBIC) or fimbria-fornix (FIFO) and then received the mild chronic stressors of food deprivation and isolation housing for ten months prior to testing. Group differences in circadian activity were investigated along with locomotion elicited by amphetamine (AMP 1.0-2.0 mg/kg i.p.) alone, and following the corticosterone (CORT) synthesis inhibitor, metyrapone (MET 10.0-25.0 mg/kg i.p.). Basal levels of plasma CORT, (ng/ml), plasma glucose (GLUC, mmol/l), thymic and splenic wet weights were subsequently determined along with complete blood counts (CBC). In comparison to age matched, unoperated controls, selective SUBIC lesions altered the circadian periodicity of locomotion, while rats with FIFO lesions were spontaneously hyperactive. Both HIPPO and FIFO animals showed significantly higher levels of amphetamine-induced locomotion. In all groups metyrapone significantly enhanced locomotion elicited by amphetamine, probably due to a pharmacokinetic interaction between these drugs. In comparison to controls, animals in the HIPPO group showed significant reductions in plasma glucose levels, decreased thymic wet weights and reductions in lymphocyte numbers, indicating lesion-related immuno-suppression. These findings highlight a functional difference among the effects of these specific hippocampal lesions on neural regulation of the HPA axis, under conditions of chronic mild stress, suggesting that the modulatory influence of the hippocampus on the stress axis is dependent on the neuroanatomical location and total extent of cell loss within this structure. They further suggest that the heightened response to amphetamine occurs independently of any lesion-induced changes in modulation of the HPA axis.

Effects of hippocampal damage on reward threshold and response rate during self-stimulation of the ventral tegmental area in the rat.

The main purpose of this study was to explore the role of the hippocampus in motivated behavior. Rats with bilateral excitotoxic lesions of the hippocampus and controls were trained to lever press for electrical stimulation of the ventral tegmental area. Rate intensity functions were generated from an ascending and descending series of current intensities. Lesion-induced changes in sensitivity to reward were distinguished from enhancements in motor output by calculating reward thresholds and maximal response rates from the rate-intensity functions. Rats with hippocampal damage showed lower reward thresholds and higher maximal response rates than controls. These results provide further evidence of hippocampal modulation of the nucleus accumbens, suggesting that lesions of this structure enhance sensitivity to reward and increase motor output.

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

Structural abnormalities in the hippocampal formation and overactive dopamine neurotransmission in the ventral striatum are thought to be key pathologies in schizophrenia. This experiment examined the functional contribution of different hippocampal subfields to locomotion elicited by D-amphetamine (0.32-3.2 mg/kg) and the direct agonists quinpirole (0.025-0.5 mg/kg) and SKF 38393 (2.5-15.0 mg/kg). Male rats served as unoperated controls or received one of six different lesions (hippocampal formation, fimbria-fornix, subiculum, CA3-4, entorhinal cortex or dentate gyrus (DG)). The main results indicated that extensive ibotenic acid-induced lesions of the hippocampal formation, or colchicine-induced lesions of the DG enhanced locomotion elicited by the D2 agonist quinpirole. Electrolytic lesions of the fimbria-fornix, in comparison, had much larger effects and resulted in increases in the locomotor response to amphetamine and quinpirole. These results extend previous demonstrations of hippocampal modulation of the ventral striatum by showing that this modulatory influence is dependent on both the location and total extent of cell loss within the hippocampal formation. The results are discussed in relation to the causes of and neurophysiological mechanisms involved in enhanced drug-induced locomotion and in terms of their implications for mental diseases including schizophrenia.

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.

The hippocampus and reward: effects of hippocampal lesions on progressive-ratio responding.

Two experiments investigated the effects of ibotenic-acid lesions of the hippocampus on food-rewarded performance under a progressive-ratio 10 schedule of reinforcement. The results of Experiment 1 indicated that rats with hippocampal lesions showed profound increases in breakpoint and enhancements in the efficiency of responding. In a second experiment the same rats were challenged with prefeeding, increases in the height of the response lever, and the substitution of sucrose- for grain-based reward pellets. Responding in both groups was similarly reduced by prefeeding and increases in the effortfulness of responding, but lesioned rats were significantly more responsive to the change to sucrose reward. Overall, the results indicated that hippocampal damage increased responding by enhancing the activational or hedonic properties of the delivered food pellets, while not affecting food-motivation or the motor capacity to respond.

Visuospatial attention in the rat and posterior parietal cortex lesions.

Covert attention to visuospatial stimuli was assessed in rats using a modified version of a task designed for human subjects. Rats were trained to respond toward bright target lights presented to the right or left visual space. Dim cue lights served to attract their attention prior to the onset of the bright target lights. Consistent with previous research using similar paradigms, rats in this experiment displayed longer reaction times during trials in which the cue and target lights were presented on opposite sides of visual space. Throughout pre- and post-operative testing, individual subjects showed lateralized differences in the performance of this task as indicated by asymmetries in reaction time, the percentage of correct responses, and the number of responses made to each side of visual space (response bias). Lesioning the area of cortex thought to be a possible homolog of the posterior parietal cortex in primates produced no specific effects on performance. It is suggested that this paradigm may tap into an evolutionarily conserved attentional process, but that this process may be subserved by somewhat different neural structures in different species.

Schizophrenia and psychostimulant abuse: a review and re-analysis of clinical evidence.

The authors selected articles from those published between 1975 and 1994 that specifically documented psychostimulant abuse in patients determined to be schizophrenic according to recent and relatively uniform diagnostic criteria. These articles indicated that the incidence of psychostimulant abuse in schizophrenics is 2-5 times higher than that of the general public. Additionally, unlike the decline in stimulant use seen in older adults in the general population, high rates of abuse appeared to be maintained in schizophrenics. Although the incidence of abuse in this group was high, comparisons of abuse rates generated by self report with those obtained by urinalysis indicated that the frequency of abuse is being underestimated by 15-21%. Potential factors contributing to stimulant abuse in schizophrenics, including the disease process, and the influence of chronic neuroleptic medication, were evaluated. Results indicated that the incidence of psychostimulant abuse was neither a common property of psychiatric patients, nor exclusive to schizophrenics, but appeared to be related to chronic treatment with neuroleptic drugs. Symptom severity was generally similar in schizophrenic abusers and non-abusers, which also suggested a degree of independence from the disease process. In a majority of the studies surveyed, abuse of stimulants followed disease onset. It was also found that stimulant abuse was associated with marked increases in hospitalization in this patient group, including those known to be neuroleptic medication compliant. Possible explanations for the initiation and maintenance of psychostimulant abuse in schizophrenics are discussed in relation to clinical and preclinical evidence on drug addiction.

Polydipsia and dopamine: behavioral effects of dopamine D1 and D2 receptor agonists and antagonists.

Substantial evidence implicates dopaminergic neural systems in the occurrence of polydipsia in both animals and humans. Two experiments were conducted in order to specify the behavioral mechanisms whereby manipulation of dopaminergic neural transmission can affect scheduled-induced polydipsia (SIP). The role of dopamine D1 and D2 receptors was investigated by comparing the behavioral effects of dopamine D1 agonists (SKF 38393 and SKF 82958) and antagonists (SCH 23390 and SKF 83566) to those of a dopamine D2 agonist (quinpirole) and antagonist (haloperidol) by using an animal model of excessive water consumption, drinking evoked in the SIP paradigm. Additionally, the behavioral effects of these relatively specific compounds were compared to those of the indirect agonist d-amphetamine sulfate and the nondopaminergic drug, diazepam. All of the drugs produced dose-related decreases in SIP. With the exception of SKF 38393 and SCH 23390, the decreased drinking appeared to be a behaviorally nonspecific drug effect in that changes in activity consistently preceded or accompanied reductions in water consumption. Some of the drugs tested, including quinpirole, haloperidol and SKF 83566, also produced changes in behavior consistent with decreased hunger, which may have also contributed to the reductions in SIP. These results are generally suggestive that dopamine neural systems are involved mainly in the motor or performance aspects of established SIP and that disruptions in established SIP produced by dopamine agonists or antagonists may result from a change in the balance of activation of dopamine D1 and D2 receptors. These results may be relevant to understanding the factors influencing polydipsia in humans.

Lack of involvement of 4-hydroxynorephedrine in phenylpropanolamine-induced anorexia in rats.

The anorexic effects of phenylpropanolamine (PPA) appear to be qualitatively different in humans and rats. One factor that may account for these differences is that PPA is excreted essentially unchanged in humans, while nearly 30% is metabolized into 4-hydroxynorephedrine (4-OHN) in rats. To investigate the contribution of 4-OHN to the anorexic properties of PPA, this experiment compared the effects of equal doses (0.0-20.0 mg/kg, IP) of both drugs on eating and drinking during restricted feeding trials in the same group of food-deprived, female rats. Both 15.0 and 20.0 mg/kg of PPA significantly decreased eating when compared to saline vehicle, while 5.0-20.0 mg/kg of the drug reduced prandial drinking. In comparison, only the highest dose of 4-OHN (20.0 mg/kg) significantly suppressed food and water intake. When the percentage of reduction produced by corresponding doses of the two drugs was compared, PPA proved to be more than twice as potent as 4-OHN. It is concluded that, at the doses used, 4-OHN is unlikely to significantly contribute to reductions in deprivation-induced eating produced by the acute administration of PPA.

Effects of phenylpropanolamine on regulatory and nonregulatory ingestion in adult rats.

This experiment examined the effects of phenylpropanolamine (0.0, 5.0, 10.0, 20.0 mg/kg PPA) on regulatory (RG) and nonregulatory (NRG) eating and drinking in rats using a within-subjects design. Administration of PPA produced dose-dependent reductions in eating in animals deprived to 80-85% of baseline weight, and reduced drinking after 23.5-h of water deprivation. Nonregulatory eating, elicited by tail pinch in nondeprived animals, was similarly inhibited. Nonregulatory drinking was elicited in the schedule-induced polydipsia (SIP) paradigm. Water consumption, locomotion, licking, lick efficiency (licks/ml water), and entries into the food magazine were simultaneously measured. At the lowest dose, only locomotion was significantly reduced. At 10.0 mg/kg, lick efficiency and entries into the food magazine were also significantly reduced, while all measured behaviors, including licking and water consumption, were decreased by the highest dose of PPA. The reduction in lick efficiency suggested a PPA-induced motor impairment in the capacity for licking. Considered together, these results indicated that the observed decreases in regulatory and nonregulatory eating and drinking could be at least partially accounted for by the drug's effects on behaviors contributing to ingestion, as well as apparent motor impairments in ingestive behavior at higher doses.

Effects of phenylpropanolamine infusion and withdrawal on body weight and dietary composition in male and female rats.

Male and female rats with ad lib access to separate sources of carbohydrate, fat, and protein were implanted with minipumps providing one of three dosages (0.0, 40.0, or 80.0 mg/kg/day) of phenylpropanolamine (PPA) for 2 weeks. Body weight, macronutrient intake, and water consumption were measured daily before, during, and after PPA treatment. Phenylpropanolamine lowered body weight and caloric intake in males and females, and water consumption in females, but did not alter dietary composition in either sex. After PPA termination, caloric intake returned to control levels in both males and females. However, body weight returned to control levels in males only, while PPA-treated females continued to weigh less than controls. Phenylpropanolamine termination was associated with significant increases in water consumption and the percentage of total calories consumed from protein and reductions in the percentage of calories from carbohydrate in males. In contrast, water and macronutrient consumption was similar comparing PPA-treated females to controls after drug termination. These results suggest there are sex differences in the effects of PPA termination on water and macronutrient consumption that result in differential weight gain in males and females.

Enhancement of amphetamine-induced locomotor activity and dopamine release in nucleus accumbens following excitotoxic lesions of the hippocampus.

This study tested the hypothesis that the hippocampus modulates dopamine-dependent function of the nucleus accumbens using behavioural and neurochemical evidence. Rats with bilateral lesions of the hippocampus induced by colchicine and kainic acid exhibited equivalent levels of spontaneous locomotor activity but a potentiation of the hyperactivity produced, dose-dependently, by D-amphetamine measured in photo-cell activity cages. The same rats subsequently received unilateral implantations of a microdialysis probe aimed at the nucleus accumbens and showed elevated levels of extracellular dopamine in response to D-amphetamine but no significant difference in basal values in comparison with sham-operated controls. The results are discussed in terms of functional interactions between the hippocampus and nucleus accumbens involving the control of mesolimbic dopamine release.

Relationship between schedule-induced polydipsia and amphetamine intravenous self-administration. Individual differences and role of experience.

It has been suggested that drug abuse belongs to a larger class of addictive behaviors, including smoking, eating or gambling, which are mediated by common processes. Since laboratory animals can be induced to develop drug self-administration as well as indulge in compulsive eating or drinking, the present experiments were designed to find out if the same animals were susceptible to both behaviors. Only certain rats develop amphetamine intravenous self-administration (SA), and this susceptibility can be predicted from their enhanced locomotor response in a novel environment. Furthermore, excessive, non-regulatory drinking, referred to as schedule-induced polydipsia (SIP), in response to the periodic delivery of small amounts of food is only observed in certain rats. Since the propensity to SA has been shown to be influenced by experimental factors and testing for SIP was found to modify behavioral and biological parameters related to the propensity for drug-seeking, we also investigated whether experience of SIP influenced the subsequent development of SA. In Expt. 1, the rats that developed SA also acquired SIP, and had a higher locomotor response to novelty. The results of Expt. 2 showed that testing for SIP influenced the predisposition to develop amphetamine SA. When animals were tested for SIP first, the polydipsic rats subsequently failed to acquire SA, and had a reduced locomotor response to novelty. These changes seemed to be specific to the experience of SIP, as individual differences in the locomotor response to novelty were unchanged when animals were housed in standard laboratory conditions over a period of one month between the two tests.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of D1 and D2 receptors in the heightened locomotion induced by direct and indirect dopamine agonists in rats with hippocampal damage: an animal analogue of schizophrenia.

Rats with limbic system damage display increases in responsivity to sensory stimulation and changes in the sensitivity to amphetamine, suggesting that their condition may parallel that of human schizophrenia. This experiment examined locomotion and stereotyped behavior in mature, male rats that had received aspirative lesions of the hippocampus, control lesions of the overlying parietal cortex, or were unoperated controls. Locomotion, measured as photocell beam breaks, was recorded during 2- or 3-h test sessions. Behavioral stereotypy was simultaneously rated. Hippocampal lesioned rats exhibited a selective enhancement in locomotion following D-amphetamine (0.0-5.6 mg/kg) when compared to animals in the control groups. Similar results were observed following injections of apomorphine (0.0-0.25 mg/kg), a mixed D1 and D2 agonist. In order to determine if D1 or D2 receptors were involved in this increased locomotion, the D1 agonist SKF 38393 (0.0-15 mg/kg) and the D2 agonist quinpirole (0.0-0.5 mg/kg) were tested alone and in combination. Hippocampal-ablated rats showed significantly increased locomotion only in response to quinpirole, suggesting that these lesion-induced increases were largely mediated by D2 receptors. When both drugs were administered together, SKF 38393 further enhanced the locomotor stimulating effects of quinpirole in hippocampal lesioned rats, indicating a synergistic interaction between D1 and D2 receptors in the modulation of locomotion. These findings provide further evidence of hippocampal modulation of locomotion and suggest that dopaminergic mechanisms in the nucleus accumbens, probably involving changes in receptor sensitivity, are involved. The results are discussed in relation to the functional roles of the nucleus accumbens and in terms of their implications for mental diseases including schizophrenia.