Dianne M. Camp

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

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

The effects of methamphetamine and cocaine on motor behavior and extracellular dopamine in the ventral striatum of Lewis versus Fischer 344 rats

The effects of an acute systemic injection of methamphetamine (mAMP) or cocaine (COC) on motor behavior (stereotypy, locomotor activity, and rearing) and extracellular dopamine (DA) in the ventral striatum were compared in Lewis (LEW) versus Fischer 344 (F344) rats, using in vivo microdialysis in awake freely moving animals. In addition, the behavioral response to repeated mAMP injections (i.e. sensitization) was characterized in LEW and F344 rats, as was the possibility of strain differences in drug pharmacokinetics. The major findings were: (i) LEW rats showed greater behavioral activation to an acute injection of both mAMP and COC, as indicated by a shift to the left in the dose-effect curves relative to F344 rats. (ii) LEW rats were more susceptible to mAMP sensitization. (iii) An acute injection of mAMP or COC enhanced the extracellular concentration of DA to a greater extent in LEW rats, as indicated by a significant shift to the left in the dose-effect curve relative to F344 rats. (iv) Strain differences in the behavioral and neurochemical effects of these drugs were characterized largely by differences in the duration of the drug response. (v) LEW rats had higher plasma and brain levels of mAMP and COC than F344 rats, suggesting that strain differences in pharmacokinetics may contribute to strain differences in the behavioral and neurochemical effects of these drugs.

Time course of recovery of extracellular dopamine following partial damage to the nigrostriatal dopamine system

Partial damage to the nigrostriatal dopamine (DA) system can produce severe behavioral deficits, from which animals gradually recover. Although the compensatory neuroadaptations that contribute to recovery of function have received considerable attention, the exact role of presynaptic versus postsynaptic contributions remains unclear. For example, it has been suggested that presynaptic adaptations may not be sufficient to account for recovery of function, because compensatory increases in DA biosynthesis, metabolism, and release are maximal within 3 d following a unilateral 6-hydroxydopamine (6-OHDA) lesion, before behavioral recovery is complete. The purpose of this study was to examine another presynaptic adaptation, the normalization of extracellular DA. If this is also complete within 3 d postlesion, it, too, would be insufficient to account for the protracted time course of behavioral recovery. But if the normalization of extracellular DA proceeds more gradually, it could potentially account for the time course behavioral recovery. To address this issue, the extracellular concentration of striatal DA ipsilateral and contralateral to a unilateral 6-OHDA lesion was estimated with microdialysis, either 4 d or 3–4 weeks following the lesion. After estimating the basal extracellular concentration of DA, the ability to increase DA release further was assessed by administering an amphetamine challenge. It was found that in animals with a 6-OHDA lesion, the concentration of DA in dialysate was higher than would be predicted by the extent of DA denervation. Furthermore, in groups matched for lesion size, extracellular DA was significantly higher 3–4 weeks following a 6-OHDA lesion than 4 d following the lesion. These findings suggest that the normalization of extracellular DA may be a relatively gradual process, and therefore may be sufficient to account for the protracted time course of behavioral recovery.

Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic D-amphetamine treatment on locomotion, stereotyped behavior and brain monoamines

There are sex differences in a number of behavior elicited by amphetamine (AMPH). The purpose of the present experiment was to determine if there are also sex differences in the sensitization of the locomotor activity and stereotypy produced by repeated intermittent AMPH treatment, and whether this is accompanied by sex differences in dopamine (DA) metabolism. It was found that female rats showed greater and more rapid sensitization of locomotor activity and stereotyped behavior than males. In addition, prior exposure to AMPH was associated with an elevation in resting striatal dihydroxyphenlacetic acid (DOPAC) to DA ratios in female, but not male rats, suggesting a sex difference in one neurochemical correlate of sensitization. As a group, males were more variable and heterogeneous in their response to repeated AMPH treatment, because they were divisible into two neurochemically distinct subgroups on the basis of their change in behavior and females were not. This heterogeneity may make it more difficult to identify neurochemical correlates of sensitization in males. It is suggested that there is a sex difference in the responsiveness of brain DA systems to repetitive activation, and this contributes to individual variation in the susceptibility to sensitization.

A microdialysis study of ventral striatal dopamine during sexual behavior in female Syrian hamsters

Microdialysis was used to study the effects of exposure to a male hamster on extracellular concentrations of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) in the ventral striatum of ovariectomized female Syrian hamsters pretreated with either estradiol and progesterone, or a similar regimen of oil injections. The hormone-treated females showed high levels of lordosis throughout the hour of exposure to the male. In hormone-treated females, there was a rapid elevation of dialysate dopamine within the first 15 min of exposure to the male. Dialysate dopamine gradually declined over the next 45 min, though remaining significantly above baseline during the entire period of exposure to the male. None of the oil-treated females showed any indication of lordosis, and the addition of the male produced only a small increase in dopamine at 30 min, after which dopamine returned to pre-male basal levels. DOPAC, HVA, and 5-HIAA were all elevated following introduction of the male for both groups of females. These results suggest that ovarian hormones modulate the responsivity of ventral striatal dopamine to incentive stimuli associated with mating behavior in females, although extracellular levels of dopamine in the ventral striatum do not seem to be directly coupled to the display of lordosis.

Sex differences in the effects of gonadectomy on amphetamine-induced rotational behavior in rats.

The effects of gonadectomy on amphetamine-induced rotational behavior were studied in male and female rats. Different systemic doses were used to produce equivalent brain concentrations of the drug in each group, thereby controlling for sex differences in the metabolism of amphetamine. Ovariectomy of female rats significantly attenuated amphetamine-induced rotation, whereas castration of males was without effect. The results support the idea that in females, the endogenous gonadal hormones facilitate functional activity in the mesostriatal dopamine system.

Sex differences in the effects of early experience on the development of behavioral and brain asymmetries in rats.

The influence of early experience (preweaning handling) on the development of several postural/motor asymmetries (side bias in an open field, turn preference in a T-maze, amphetamine-induced rotational behavior, tail pinch-induced asymmetries) and the lateralization of brain dopamine was studied in adult male and female rats. In many cases the adult patterns of behavioral and brain asymmetries were modified by early handling in a sexually dimorphic manner. In addition, the direction of postural/motor asymmetries was very much task-dependent, especially in females. We conclude that: early experience may modify the development of behavioral and brain asymmetries; sex differences in asymmetries are very common; early handling may affect males and females differently; and different measures of postural/motor asymmetries may reflect different and multiple brain asymmetries.

SEX DIFFERENCES AND ESTROUS CYCLE DEPENDENT VARIATION IN ROTATIONAL BEHAVIOR ELICITED BY ELECTRICAL STIMULATION OF THE MESOSTRIATAL DOPAMINE SYSTEM

In this study electrical stimulation-induced rotational behavior was used as a behavioral index of mesostriatal dopamine (DA) activity to investigate gender and hormonal influences on the DA system. In female rats we found estrous cycle related variations in electrical stimulation-induced rotational behavior. A constant electrical stimulus produced significantly more turning on the day of estrus, than it did 24 h later, on diestrus 1. Gonadectomy attenuated contraversive rotational behavior in female, but not male rats. In contrast, ovariectomy had no effect on the ipsiversive rotational behavior produced by stimulation of the reticular formation. This evidence supports the idea that endogenous changes in gonadal hormone levels influence the functional activity of the mesostriatal DA system in a sexually dimorphic manner.

The feasibility of repeated microdialysis for within-subjects design experiments : studies on the mesostriatal dopamine system

Publisher Summary This chapter focuses on the experimental studies on the mesostriatal dopamine system using repeated microdialysis technique. It presents the experiments designed to characterize the effects of repeated microdialysis sampling in the mesostriatal dopamine (DA) system of rats. The focus is on the feasibility of using within-subjects design microdialysis experiments to study the long-term consequences of repeated stimulant drug use on dopaminergic activity. The chapter also discusses the acute effects of amphetamine (AMPH) on DA neurotransmission and the effects of repeated AMPH administration on the extracellular concentration of DA determined by between-subjects design microdialysis experiments. It also presents an evaluation of within-subjects design experiments for studying the consequences of repeated stimulant use. The results may be generally applicable to repeated microdialysis sampling for other purposes, and in other neural systems.

Susceptibility to sensitization. II. The influence of gonadal hormones on enduring changes in brain monoamines and behavior produced by the repeated administration of d-amphetamine or restraint stress

Repeated amphetamine use produces an enduring sensitization of brain dopamine (DA) systems and behavior. Repeated exposure to stress can also produce sensitization, and amphetamine and stress may be interchangeable in this regard. There is, however, enormous individual variation in the susceptibility to sensitization by either stimulants or stress. The purpose of the present study was to determine if endogenous gonadal hormones contribute to individual variation in the sensitization of stereotyped behaviors, locomotion or regional brain monoamine metabolism. It was found that removal of testicular hormones by castration of male rats facilitated the behavioral sensitization produced by either repeated amphetamine treatment or repeated restraint stress, but ovariectomy of female rats was without effect. Prior exposure to amphetamine enhanced striatal homovanillic acid (HVA) levels and dihydroxyphenylacetic acid to DA and HVA to DA ratios in intact female, ovariectomized female and castrated male rats, but not gonadally-intact male rats. As a group, intact males were particularly heterogeneous because they were divisible into two neurochemically distinct subgroups based on their degree of behavioral sensitization, and the other groups were not. It is suggested that individual differences in the sensitization of brain DA systems and behavior produced by repeated exposure to amphetamine or stress may be due in part to individual differences in the concentration of a testicular hormone.