Martine Cador

Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the nucleus accumbens.

Exposure of rats to restraint stress during late pregnancy produces offspring with a variety of behavioral and neurobiological alterations. It has been suggested that prenatal stress leads to long-lasting changes in the hypothalamo-pituitary-adrenal axis in the offspring. One feature of prenatally-stressed rats is a susceptibility to amphetamine self-administration. Since this behavior has been related to amphetamine-induced sensitization and the activity of the mesolimbic dopamine system, we measured dopamine receptor densities and amphetamine-induced sensitization in these animals. The motor response to the first administration of amphetamine was similar in both prestressed and unstressed groups of adult animals, but after repeated drug injections, behavioral sensitization was observed sooner in the prenatally-stressed rats than in the controls. In separate groups of adult animals, densities of D1, D2 and D3 dopamine receptor subtypes in the striatum and nucleus accumbens were measured in prenatally-stressed and control rats by quantitative autoradiography using [3H]SCH23390, [3H]sulpiride and [3H]7-OH-DPAT as ligands respectively. Prenatal stress was found to produce the following alterations in the adult offspring: (i) no significant change in D1 receptor binding in either striatum or nucleus accumbens; (ii) a significant (+24%) increase in D2 receptor binding in the nucleus accumbens; (iii) a significant decrease in D3 receptor binding in both the shell (-16%) and the core (-26%) of the nucleus accumbens. These observations indicate that prenatal stress induces long-lasting changes in the dopamine sensitivity of the nucleus accumbens and in the capacity to develop amphetamine-induced sensitization in adulthood. The possible relationship between an impaired control of corticosterone secretion in prenatally-stressed animals and long-term changes in the mesolimbic dopamine system is discussed.

Modulation of the locomotor response to amphetamine by corticosterone

Abstract In the present experiments, we investigated the influence of chronic modifications of circulating levels of corticosterone on the locomotor response to amphetamine. Different groups of rats were adrenalectomized and implanted subcutaneously with pellets releasing different amounts of corticosterone (0–200 mg). A wide range of corticosterone concentrations was reached in order to saturate selectively either the type I (mineralocorticoid) or the type II (glucocorticoid) corticosteroid receptors. The locomotor response to d -amphetamine (1.5 mg/kg) was studied 10–14 days later. We found that adrenalectomy reduced the response to d -amphetamine by 33% and that a normal response was restored with pellets releasing physiological concentrations of corticosterone (50-mg pellets), and was potentiated in animals with pellets releasing high amounts of corticosterone mimicking chronic stress situations (200-mg pellets). The correlation between plasma corticosterone concentration, locomotor activity following d -amphetamine and thymus weight, which is a reliable indicator of glucocorticoid action, shows that the influence of the locomotor response to d -amphetamine administration is likely to be mediated via a type II receptor. Since the locomotor activating effect of peripheral administration of d -amphetamine has been shown to depend on the integrity of the dopaminergic innervation of the nucleus accumbens, the effect of d -amphetamine at different doses (0, 1, 3, 10μg/gm1) injected directly into the nucleus accumbens was studied. The results demonstrated that removing the circulating corticosterone induced a similar decrease of the locomotor activity elicited by d -amphetamine injection in the nucleus accumbens. This response was restored in animals with the 50- and 200-mg pellets. This modulatory action of corticosterone on the reactivity of the dopaminergic system to psychostimulants may represent a critical step for the interchangeability between Stressors and psychostimulants in sensitization processes.

Critical role of the hypothalamic pituitary adrenal axis in amphetamine-induced sensitization of behavior

Behavioral sensitization can be observed with repeated administration of amphetamine where the intensity of motor stimulation increases over time. The process of sensitization has been well characterized, however, the neurochemical mechanisms that are critical for the development of sensitization are not known. In the present study, the role of the hypothalamic pituitary adrenal axis (HPA) in the development of behavioral sensitization to amphetamine was explored by pretreating rats with an intravenous administration of an antiserum to corticotropin-releasing factor in a volume that has been shown to block significantly stress- and cocaine-induced activation of the HPA. Four groups of eight rats were pretreated intravenously with either heparinized saline or CRF antiserum and subcutaneously with saline or d-amphetamine in a balanced design. The rats were then returned to their home cages and left undisturbed for seven days after which they were given three consecutive behavioral tests with saline SC, 0.75 mg/kg d-amphetamine SC, and 3.0 mg/kg d-amphetamine SC. The rats pretreated with intravenous CRF antiserum showed a significant attenuation of the development of d-amphetamine-induced sensitization but the antiserum did not alter the magnitude of the behavioral response to the initial, sensitizing dose of d-amphetamine. These results suggest that activation of the hypothalamic pituitary adrenal axis may be of critical importance to the development of behavioral sensitization to amphetamine.

Ventral tegmental area infusion of substance P, neurotensin and enkephalin: Differential effects on feeding behavior

The neuropeptides substance P, neurotensin and [Met]enkephalin are found in the ventral tegmental area, site of the A10 dopamine cell bodies. Evidence suggests a functional interaction between these peptides and the dopaminergic neurons. All three peptides have been shown to exert an activating effect on these neurons. The present study analyzed the effects of ventral tegmental area infusion of neurotensin, substance P and D-ala-[Met]enkephalin on feeding behavior. These effects were studied in both food-deprived and satiated rats. During a 30 min test, the following parameters were registered: latency to eat, total food intake, food spillage, number of eating bouts and duration of eating. Similar measures were taken for drinking. In deprived rats substance P (0.5, 3.0 micrograms) increased latency to eat but did not affect other parameters, and substance P did not affect eating in satiated rats. Neurotensin (0.5, 2.5 micrograms) increased latency to eat and markedly reduced food consumption in deprived rats and had no effect in satiated rats. D-Ala-[Met]enkephalin (0.1, 1.0 micrograms) stimulated feeding behavior in both deprived and satiated rats. These results show that although the different peptides are presumed to activate the dopaminergic A10 neurons, their effects on feeding behavior can be differentiated. The findings are discussed in terms of motor and motivational mechanisms, and the relative contributions of specific and non-specific influences on feeding are considered.

Cocaine sensitivity in roman high and low avoidance rats is modulated by sex and gonadal hormone status

Repeated exposure to stressful stimuli or psychostimulants increases sensitivity to the motoric effects of these drugs, i.e. behavioral sensitization. The objective of the present experiment was to determine the interaction between factors that modulate psychostimulant sensitivity, i.e. sex and circulating gonadal hormone levels, in rats with a genetically distinct locomotor response to novelty: Roman Low Avoidance rats (RLA) freeze while Roman High Avoidance rats (RHA) remain motorically active. Ninety-six male and female RHA and RLA rats were gonadectomized (GDX) just after weaning or as adults, or left gonadally intact. Each rat received a total of 9 injections of cocaine hydrochloride (10 mg/kg, IP), at 3-4 day intervals for 5 weeks. Locomotor activity was measured after each injection, and stereotypes were rated 1 x/week. Open field behavior (10 min) and plasma corticosterone were measured 2 weeks after the final injection. Overall, the RHA line was more sensitive to (1) cocaines stereotypic effects, and (2) the influence of ovarian hormones on the cocaines acute and sensitizing effects on locomotor activity. Therefore, genetic background not only determines cocaine sensitivity, but also the influence of gonadal hormones on locomotor activity. These interactions are relevant when considering the genetic contribution to abuse liability.

Neurotensin, substance P, neurokinin-α, and enkephalin: injection into ventral tegmental area in the rat produces differential effects on operant responding

The neuropeptides neurotensin, substance P, neurokinin-α (substance K), and met-enkephalin are present endogenously in the ventral tegmental area (VTA), site of the A10 dopaminergic (DA) cell bodies. In the present study these four peptides were injected bilaterally into the VTA in the rat, and the effects on operant behavior were assessed. Cannulae aimed at the VTA were implanted in four groups of animals, which had been trained to bar-press for food reward on a fixed-interval, 40-s schedule. A fifth group, in which the effects of systemically administered amphetamine were assessed, was also tested. Response rate across the interval was measured, and the index of quarter-life was taken as an indication of the temporal pattern of resonding. In addition, a rate-dependency analysis was carried out for all data. Neurotensin (NT, 0.0175, 0.175, 0.5 μg in 1 μl) dose-dependently decreased response rates without affecting quarter-life, and reduced the number of reinforcements obtained. Substance P (SP, 0.1, 1.0, 3.0 μg) did not affect responding, and neurokinin-α (NKA, 0.1, 1.0, 3.0 μg) induced a small increase in responding. Quarter-life was not affected by SP or NKA, but responding on the nonreinforced lever was significantly increased by both peptides. d-Ala-met-enkephalin (DALA, 0.01, 0.1, 1.0 μg) induced a dose-dependent increase in responding which was also rate-dependent, and reduced quarter-life. DALA effects were similar to the classic pattern of responding observed after systemic amphetamine. These results suggest that although all these peptides elicit behavioral activation and may affect DA neuronal activity, the behavioral responses can be differentiated with respect to operant behavior.

Modulation of the Locomotor Response to Amphetamine by Corticosterone

In the present experiments, we investigated the influence of chronic modifications of circulating levels of corticosterone on the locomotor response to amphetamine. Different groups of rats were adrenalectomized and implanted subcutaneously with pellets releasing different amounts of corticosterone (0-200 mg). A wide range of corticosterone concentrations was reached in order to saturate selectively either the type I (mineralocorticoid) or the type II (glucocorticoid) corticosteroid receptors. The locomotor response to d-amphetamine (1.5 mg/kg) was studied 10-14 days later. We found that adrenalectomy reduced the response to d-amphetamine by 33% and that a normal response was restored with pellets releasing physiological concentrations of corticosterone (50-mg pellets), and was potentiated in animals with pellets releasing high amounts of corticosterone mimicking chronic stress situations (200-mg pellets). The correlation between plasma corticosterone concentration, locomotor activity following d-amphetamine and thymus weight, which is a reliable indicator of glucocorticoid action, shows that the influence of the locomotor response to d-amphetamine administration is likely to be mediated via a type II receptor. Since the locomotor activating effect of peripheral administration of d-amphetamine has been shown to depend on the integrity of the dopaminergic innervation of the nucleus accumbens, the effect of d-amphetamine at different doses (0, 1, 3, 10 micrograms/microliter) injected directly into the nucleus accumbens was studied. The results demonstrated that removing the circulating corticosterone induced a similar decrease of the locomotor activity elicited by d-amphetamine injection in the nucleus accumbens. This response was restored in animals with the 50- and 200-mg pellets.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlling interindividual differences in the unconditioned response to amphetamine in the study of environment-dependent sensitization.

Two subgroups of rats selected on the basis of their emergence latency in a light-dark box test were shown to exhibit significantly different unconditioned responses to d-amphetamine (AMPH, 1mg/kg). The rats presenting a low latency to emerge from the dark side (LL subgroup) responded more to AMPH than the rats presenting a high latency (HL subgroup). These two subgroups were compared for environment-dependent and environment-independent sensitization. The major findings were as follows: (a) when these two subgroups underwent a conditioning procedure to study environment-dependent sensitization, in which the paired groups received AMPH in Environment A (activity cages) and saline in Environment B (plastic housing cages), the unpaired groups received saline in A and AMPH in B, and the control groups received saline in both environments, only the LL subgroup showed conditioned activity and environment-dependent sensitization; (b) when LL and HL subgroups were submitted to a sensitization procedure designed to rule out any conditioning processes (environment-independent sensitization), there was no significant difference in the development and magnitude of sensitization although the amplitude of the response following each injection remained lower in the HL compared with the LL subgroup; (c) when unconditioned responses to AMPH for the two subgroups were equated by increasing the dose of AMPH for the HL rats (1.25mg/kg), there was no longer a significant difference between the two subgroups with respect to conditioned activity and environment-dependent sensitization; (d) in the LL subgroup, an extinction procedure (in which all animals received vehicle in both environments) that completely abolished the conditioned activity in the paired group, suppressed the difference between paired and unpaired groups during the test for environment-dependent sensitization, by reducing the response of the former. Overall, these results provide two major contributions: first, they show that interindividual differences in the unconditioned response to AMPH influence the outcome of the study of environment-dependent sensitization; second, when these differences are controlled, they suggest that environment-dependent sensitization appears to be the result of the addition between conditioned activity and environment-independent effects of AMPH.

d-Ala-met-enkephalin injection into the ventral tegmental area: effect on investigatory and spontaneous motor behaviour in the rat

The mesolimbic dopamine (DA) system, originating in the ventral tegmental area and projecting to limbic forebrain regions, plays a crucial role in mediating several important aspects of behaviour. Proximal to these DA neurons are enkephalin-containing nerve fibers. In an attempt to characterize the behavioural role of enkephalinergic transmission in the VTA, the present experiment examined in detail the investigatory and motor responses to microinfusion of d-ala-met-enkephalin (DALA), a long lasting analogue of enkephalin, into the ventral tegmental area (VTA). Injections into the substantia nigra (SN) and the hippocampus (HPC) were also performed as controls for site specificity. The behavioural apparatus consisted of an eight-hole box monitored by a video camera. Four doses of DALA were injected in the VTA (0.05, 0.1, 1 and 2.5 μg/μl bilaterally in 1 μl volume) and one dose in the SN and HPC (0.1 μg/μl bilaterally in 1 μl volume). The effect of DALA injections in the VTA was characterized by an inverted U-shape dose-effect curve. The low doses (0.05 and 0.1) induced an increase in the frequency of hole visits accompanied by a decrease in the mean duration of visits, whereas the highest doses induced a decrease in hole visit frequency. Low doses of DALA had no effect on strategy or organization of exploration, whereas the high doses produced decreased switching between holes. After low doses of DALA, locomotor activity at the periphery of the testing box was not significantly affected but locomotor activity in the centre was increased. After high doses of DALA, locomotor activity in the center and at the periphery of the box were decreased. Frequency of rearing was either not affected or decreased by DALA treatment. DALA injected in the SN resulted in a small increase in frequency of hole visits and did not affect rearing and locomotor activity. DALA injection in the HPC had no effect on investigatory and spontaneous motor behaviour. The results are discussed in terms of a modulatory role of endogenous enkephalin on mesolimbic dopamine neurons.