Darryl B. Neill

INDIVIDUAL DIFFERENCES IN LOCOMOTOR ACTIVITY AND SENSITIZATION

Male rats were screened for locomotor activity in a novel environment and divided into high (HR) and low (LR) responders based on whether their locomotor activity score for the first hour was above or below the median locomotor activity for the subject sample. Subsequently, the locomotor response to repeated administration of either amphetamine (AMPH; 0.5 mg/kg), cocaine (10 mg/kg), scopolamine (0.5 mg/kg) or saline was monitored in separate groups of HR and LR rats. HR rats had significantly higher overall activity scores than LR rats for all 3 drugs. Both HR and LR rats developed tolerance at the same rate to repeated scopolamine administration. In contrast, only HR rats showed pronounced sensitization to the locomotor stimulating properties of AMPH and a direct correlation was evident between the locomotor response to novelty and the magnitude of sensitization. These results suggest that an individuals response to a novel environment can, to a certain extent, predict drug-induced locomotor activity and that individual differences in the response to novelty and sensitization to AMPH may result from individual variations in a common neural mechanism.

A new animal model of endogenous depression: a summary of present findings.

In 1982 our laboratory proposed a new animal model of endogenous depression. The proposal was that in rats, neonatally administered clomipramine (CLI) will produce adult animals that model endogenous depression. We summarize here several tests of the validity of the model. Results were that after neonatal CLI, adult male rats showed behavioral abnormalities of the human disorder: decreased sexual, aggressive, and intracranial self-stimulation activities, as well as motor hyperactivity in a stressful situation. Preliminary evidence suggested that behavioral abnormalities in rats (sexual, aggressive, and motor) briefly treated with antidepressant treatments (imipramine, REM sleep deprivation) begin to normalize. Lastly, after neonatal CLI, the adult rats showed REM sleep abnormalities of endogenous depression, viz, low REM latency, frequent sleep onset REM periods, and abnormal temporal course of REM rebound after REM sleep deprivation. These results supported the hypothesis that in rats neonatal CLI produced adult animals that modelled endogenous depression.

Detecting behaviorally relevant changes in extracellular dopamine with microdialysis

A method is described for monitoring extracellular levels of striatal dopamine in the rat during behavior. The extracellular fluid is sampled using a microdialysis probe modified for use in behaving animals. Dopamine concentration in the perfusate is determined every 5 min using an automated smallbore chromatographic system with electrochemical detection. The system is capable of detecting behaviorally related changes of 5 nM, in extracellular dopamine.

Individual differences in amphetamine sensitization: Dose-dependent effects

Rats were screened for locomotor activity in a novel environment and divided into high (HR) or low (LR) responders based on whether their locomotor score for the first hour was above or below the median. In the first experiment, HR and LR rats were compared for their locomotor response following repeated administration of either 0.0, 0.5, 1.0, or 1.5 mg/kg d-amphetamine sulfate (AMPH). Injections of either 0.5 or 1.0 mg/kg AMPH produced higher locomotor activity in HR rats than in LR rats. Furthermore, there was a correlation between the locomotor response to novelty and the response to either 0.5 or 1.0 mg/kg AMPH. In addition, whereas both groups of rats developed the same degree of sensitization to 0.5 mg/kg AMPH, only the HR rats developed pronounced sensitization to repeated administration of 1.0 mg/kg AMPH. When both HR and LR were considered, there was a significant correlation between response to novelty and the extent of sensitization to the locomotor-stimulating properties of 1.0 mg/kg AMPH. There were no differences in locomotor activity or sensitization between HR and LR rats following the highest dose of AMPH (1.5 mg/kg). In a separate experiment, HR and LR rats were compared for locomotor activity following a series of intracranial infusions of AMPH. There were no overall differences in locomotor activity between the HR and LR groups following AMPH infusions into either the nucleus accumbens (NACC) or the anterior dorsal striatum (ADS). However, the locomotor activity scores in the novel environment significantly correlated with the locomotor response to 3.0 micrograms AMPH infused into either the NACC or ADS.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine depletion in a striatal subregion disrupts performance of a skilled motor task in the rat

Unilateral 6-hydroxydopamine injections into the lateral neostriatum disrupted the ability of rats to retrieve small food pellets with the contralateral forepaw. Similar injections into the medial striatum did not interfere with performance accuracy. Dopamine assays indicated that of the 5 striatal subregions analyzed, the lateral striatum at the level of the anterior commissure was most directly related to the behavioral deficit. The behavioral results are interpreted as providing evidence in support of a sensory role for the lateral striatal dopamine system.

Conditioned place preference and locomotor activation produced by injection of psychostimulants into ventral pallidum

The ventral pallidum (VP) is often viewed as an output structure of the nucleus accumbens septi (NAS). However, VP, like NAS, receives a dopaminergic input from the ventral tegmental area. These experiments investigated some behavioral effects of microinjection into VP of drugs which enhance dopaminergic transmission. Injection of 25 micrograms dopamine or 5-10 micrograms amphetamine into VP produced hypermotility. In contrast, injection of 12.5-50 micrograms cocaine initially suppressed, then increased, activity. Injection of 100 micrograms cocaine only produced hypomotility in the 1-h period examined. The hypomotility following cocaine seemed to be a local anesthetic effect, because it was mimicked by 50-200 micrograms procaine. Procaine did not, however, produce subsequent hypermotility. Conditioned place preference (CPP) was produced by 10 micrograms amphetamine and 50 micrograms cocaine but not 100 micrograms procaine. We conclude that injection of cocaine into VP unlike similar injections into NAS, produces CPP. These results support the idea of an involvement of dopamine in VP in reward and locomotor activation, independent of dopamine in NAS. The use of intracerebral injections of cocaine is complicated, however, by an apparent local anesthetic effect of the drug.

6-Hydroxydopamine lesion of ventral pallidum blocks acquisition of place preference conditioning to cocaine.

In parallel with nucleus accumbens (NAS), ventral pallidum (VP) also receives a dopaminergic projection from the ventral tegmental area (VTA). The present study examined the involvement of this mesopallidal dopaminergic system in the action of cocaine. In the first experiment, the effect of cocaine injections on VP dopamine was examined by microdialysis. Intraperitoneal (i.p.) injections of cocaine 5-20 mg/kg dose-dependently increased the extracellular dopamine level in VP 2.5-4.5-fold. In addition, intra-VP perfusion of 20 microM cocaine induced a 12-fold increase of dopamine locally. The second experiment examined the role of VP dopamine in cocaine-induced conditioned place preference (CPP) and locomotor activation. Rats received bilateral intra-VP injections of 3-4 microg 6-OHDA or ascorbic acid vehicle in 0.5 microl volume. Tissue assays indicated that the 6-OHDA-lesioned rats had significantly lowered dopamine concentration in VP, but not in NAS or striatum. As a group, 6-OHDA lesions blocked the development of CPP to 5 mg/kg cocaine but not to 10 mg/kg cocaine. However, rats with more than 60% depletion in VP dopamine did not develop CPP to cocaine at either dose. Preference for the cocaine-paired side correlated significantly with dopamine concentration in VP, but not in NAS or striatum. It was concluded that VP dopamine may play a critical role in the initial rewarding effect of cocaine. 6-OHDA lesions also blocked locomotor activation induced by 5 mg/kg cocaine but had no effect on 10 mg/kg cocaine-induced locomotion. Dopamine concentration in VP did not correlate with the locomotor activation response to cocaine at either dose. These findings further establish the involvement of the mesopallidal dopaminergic system in the action of cocaine.

Dopamine D1/D2 agonists injected into nucleus accumbens and ventral pallidum differentially affect locomotor activity depending on site

Ventral pallidal dopamine has been recently shown to play an important role in psychostimulant reward and locomotor activation. The aim of the present study was to compare the roles of ventral pallidal D1 and D2 receptors in evoking locomotor activity with those in the nucleus accumbens. The D1 agonist SKF 38393 and the D2 agonist quinpirole hydrochloride (0.3-3 microg/ 0.5 microl) were bilaterally injected into ventral pallidum or nucleus accumbens through pre-implanted cannulae. In the ventral pallidum, 0.3-1 microg SKF 38393 increased locomotor activity while 3 microg had no effect; 3 microg quinpirole suppressed locomotion while 0.3-1 microg had no effect. Locomotor activity induced by an equigram (0.3 microg) mixture of SKF 38393 and quinpirole, while significantly higher than that induced by 0.3 microg quinpirole was not significantly higher than that induced by 0.3 microg SKF 38393 alone. At the 3 microg dose, SKF 38393 injections into anterior ventral pallidum increased activity; injections into posterior ventral pallidum decreased activity. In the nucleus accumbens, 0.3-3 microg SKF 38393 dramatically increased locomotor activity while quinpirole moderately increased locomotion. In the group that had previously received the full quinpirole dose range, injection of the equigram (0.3 microg) mixture of SKF 38393 and quinpirole induced locomotor activation which was higher than that induced by either drug alone or by the addition of the effect of each drug alone, i.e. synergy occurred. Moreover, rats that had previously received SKF 38393 developed a sensitized locomotor response to subsequent SKF 38393, quinpirole or the mixture of these two drugs. The difference in locomotor response to dopamine agonists between the ventral pallidum and nucleus accumbens is consistent with electrophysiological evidence collected at these two sites. These findings suggest that, unlike the nucleus accumbens, where D1 and D2 receptor activation may facilitate each other to induce a synergistic effect on locomotor activity, ventral pallidal D1 and D2 receptors may be located on different neurons and coupled with different, if not opposite, behavioral output.

Conditioned locomotor activity but not conditioned place preference following intra-accumbens infusions of cocaine

In the first experiment, the conditioned place preference (CPP) paradigm was used to examine the rewarding properties of bilateral microinfusions of cocaine HCl into the nucleus accumbens (0, 12.5, 25, 50, or 100 µg). No dose of intra-accumbens cocaine induced a significant CPP. However, bilateral intra-accumbens infusions ofd-amphetamine sulfate (10 µg) or intraperitoneal administration of cocaine HCl (5 or 10 mg/kg) both produced a significant preference for the drug-paired compartment. In the second experiment, the ability of bilateral intra-accumbens infusions of cocaine HCl (50 µg) to elicit conditioned locomotor activity (CLA) was examined. During the conditioning trials, intra-accumbens cocaine significantly increased locomotor activity. On the test day, when no drug was administered, the group that had previously received cocaine in the activity chamber showed significantly greater locomotor activity than the vehicle control group. This demonstration of CLA indicates that rats are able to associate the effects of intra-accumbens infusions of cocaine with environmental stimuli; however, these infusions are not rewarding as measured by the CPP paradigm. In addition, these results may indicate important differences between the neural substrates for cocaine and amphetamine reward and reveal a dissociation between CPP and CLA.

Diminished sexual activity in a new animal model of endogenous depression

Our laboratory has proposed a new animal model of endogenous depression. The proposal is that in rats neonatal clomipramine (CLI) produces adult animals that model endogenous depression. Diminished sexual activity is a salient behavioral abnormality found in endogenous depression. This suggests that an animal model of endogenous depression should show diminished sexual activity. We report here a test of the prediction that after neonatal treatment with CLI, adult male rats show decreased sexual activity. We found that after neonatal CLI, adult male Long-Evans rats had a pervasive diminution of sexual activities including decreased mounts, intromissions, ejaculations, and increased mount latencies and postejaculatory pause. Sprague-Dawley and Wistar strains also tended to show decreased intromissions and ejaculations, but their baseline sexual activity was too low to give interpretable data. The results with the sexually active Long-Evans strain are consistent with the hypothesis that neonatal CLI produces adult rats that model human endogenous depression.