Pmch expression during early development is critical for normal energy homeostasis.

Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch(-/-) rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch(-/-) rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries.

Differences in the cellular mechanism underlying the effects of amphetamine on prepulse inhibition in apomorphine-susceptible and apomorphine-unsusceptible rats.

BACKGROUND: Amphetamine is often used to mimic certain aspects of schizophrenia in laboratory animals, such as a decreased prepulse inhibition. MATERIALS AND METHODS: Apomorphine-susceptible and apomorphine-unsusceptible rats represent a well-characterized animal model for individual differences in the sensitivity to dopaminergic drugs. Moreover, apomorphine-susceptible rats show a wide variety of schizophrenia-like abnormalities. The differential response to administration of amphetamine (1-4 mg/kg, i.p.) was investigated in these two rat lines using the prepulse inhibition paradigm. Because amphetamine promotes dopamine release, the cellular mechanism underlying the line-specific effects of amphetamine was investigated by administration of alpha-methyl-para-tyrosine (aMpT) and reserpine, substances that are known to deplete the cytosolic dopamine pool and the vesicular dopamine pool, respectively, the former being primarily implicated in mediating the effects of amphetamine. RESULTS: All doses of amphetamine decreased prepulse inhibition in apomorphine-susceptible rats, whereas only the highest doses (2 and 4 mg/kg, i.p.) of amphetamine decreased prepulse inhibition in apomorphine-unsusceptible rats. Alpha-methyl-para-tyrosine, but not reserpine, blocked the amphetamine-induced disruption in prepulse inhibition in apomorphine-unsusceptible rats, whereas both substances alone had no effect in apomorphine-susceptible rats. However, the combination of alpha-methyl-para-tyrosine and reserpine did block the amphetamine-induced effects in the latter rat line. DISCUSSION: The present study suggests that apomorphine-susceptible rats are more sensitive to systemic administration of amphetamine than apomorphine-unsusceptible rats. In addition, the data show that the cellular mechanism underlying the effects of amphetamine differs between apomorphine-susceptible and apomorphine-unsusceptible rats. Whereas the effects of amphetamine on prepulse inhibition in apomorphine-unsusceptible rats just require the alpha-methyl-para-tyrosine sensitive dopamine pool, the effects in apomorphine-susceptible rats require both the alpha-methyl-para-tyrosine sensitive and the reserpine sensitive dopamine pool. Because apomorphine-susceptible rats share many features with schizophrenic patients, these data open the perspective that in these patients amphetamine may induce dopamine release from both types of dopamine pool. This might provide an explanation for the increased dopamine release after this psychostimulant drug in patients vs controls.

Cocaine strongly reduces prepulse inhibition in apomorphine-susceptible rats, but not in apomorphine-unsusceptible rats: regulation by dopamine D2 receptors.

Dopaminergic agonists, such as apomorphine and amphetamine, have been shown to drastically reduce prepulse inhibition of the acoustic startle reflex. The effects of the indirect dopamine agonist cocaine on prepulse inhibition have only been described in a few reports and have yielded conflicting results, possibly due to individual differences within and between rat strains. In this study we therefore used apomorphine-susceptible and apomorphine-unsusceptible rats, as an animal model for individual differences, to study the effects of cocaine (20, 30 mg/kg i.p.) on prepulse inhibition. In addition we tested whether the cocaine-induced deficit in prepulse inhibition could be reversed by the D2-antagonist remoxipride (5 mg/kg i.p.), the alpha-1 adrenoceptor antagonist prazosin (2.5 mg/kg i.p.) and the 5-HT2-antagonist ketanserin (2.0 mg/kg i.p.). Cocaine strongly reduced prepulse inhibition in apomorphine-susceptible rats, but had no effect at all on apomorphine-unsusceptible rats. Remoxipride had no effect on prepulse inhibition, but prazosin and ketanserin increased prepulse inhibition. Both remoxipride and prazosin reversed the cocaine-induced deficit in prepulse inhibition, whereas ketanserin did not. We conclude that apomorphine-susceptible rats are extremely sensitive to the effects of cocaine on prepulse inhibition, while apomorphine-unsusceptible rats are not. The effects of cocaine on prepulse inhibition in apomorphine-susceptible rats were mediated by D2-receptors, but not by 5-HT2-receptors or alpha-1 adrenoceptors.

Individual differences in drug dependence in rats: the role of genetic factors and life events.

Drug dependence and addiction is a chronic mental illness that has far reaching consequences for society in terms of economic loss, health costs and judicial problems. A crucial question in drug addiction, is what factors are involved in its aetiology, and especially what mediates the shit from use to abuse. As in most other mental illnesses, addiction can best be described using the so-called three hit model, which states that a disease results from an interaction between genetic factors, early lie events and late environmental factors. However, the precise nature of these factors still remains to be elucidated. This present review discusses the results from an animal model in which these three different hit are currently being investigated. The apomorphine susceptible (APO-SUS) and apomorphine unsusceptible (APO-UNSUS) rats, originally selected on the basis of their behavioural response to the dopaminergic agonist apomorphine, were recently found to be genetically different in the number of gene copies of a component of the gamma-secretase complex called Aph-1b. Whereas APO-UNSUS rats have three copies of the gene, APO-SUS rats have either 1 or 2 copies. In addition we have shown that these rats show differences in cocaine and alcohol self-administration, and that both early life events and late environmental factors can alter this self-administration behaviour. Thus, the data so far support the hypothesis that the APO-SUS and APO-UNSUS rats offer an interesting animal model for drug dependence in which genes and environment interact. We finally propose a theoretical model which can explain this gene-environment interaction.

A single exposure to novelty differentially affects the accumbal dopaminergic system of apomorphine-susceptible and apomorphine-unsusceptible rats.

Individual differences in responses to mild, acute stressors in laboratory animals have commonly been observed in behavioural tests and at the level of hypothalamic-pituitary-adrenal axis responses. These differences are associated with dopamine transmission in the nucleus accumbens. Although the effect of mild stressors on dopamine transmission has been studied with microdialysis, it has not been studied at the level of the catecholaminergic network in the nucleus accumbens. In this study we have used microdialysis to measure extracellular concentrations of dopamine in vivo and immunocytochemistry for the enzyme tyrosine hydroxylase to assess the effect of a single exposure to novelty on the neurochemistry of the nucleus acc umbens in apomorphine-susceptible and apomorphine-unsusceptible rats. These rats are a valid animal model for studying individual differences in responses to environmental stressors and drugs of abuse. We demonstrated that a mild stressor like novelty increased the extracellular concentration of dopamine in the nucleus accumbens in apomorphine-susceptible rats to a larger and longer-lasting degree than in apomorphine-unsusceptible rats. Furthermore we demonstrated that novelty increased the tyrosine hydroxylase-immunoreactive fibre network in the nucleus accumbens shell of apomorphine-susceptible rats, which are rats that are particularly reactive to stressors, but not in the shell of apomorphine-unsusceptible rats, which are rats that are relatively stress-resistant. In conclusion, we have shown that the accumbal dopaminergic system of apomorphine-susceptible rats is more sensitive to an environmental stressor than that of apomorphine-unsusceptible rats. Combined with the fact that these animals also differ in their sensitivity to drugs of abuse, which are known to affect the dopaminergic system, these data provide a solid basis for further studying the differences in the dopaminergic responsiveness to drugs of abuse between apomorphine-susceptible and apomorphine-unsusceptible rats.

Apomorphine-susceptible rats and apomorphine-unsusceptible rats differ in the tyrosine hydroxylase-immunoreactive network in the nucleus accumbens core and shell.

Individual variability in behavioural responses to stressors such as novelty and drugs of abuse is a well-known phenomenon in both animals and man. These individual differences are largely associated with differences in dopamine transmission in mesolimbic areas such as the nucleus accumbens. Apomorphine-susceptible (APO-SUS) rats and apomorphine-unsusceptible (APO-UNSUS) rats serve as a valid animal model for individual differences and these two types of rat differ in a number of behavioural, physiological, endocrinological and pharmacological parameters. In order to study the differences in the catecholaminergic network in the nucleus accumbens, possibly underlying at least some of the differences between the two types of rat, we quantified the extent of the tyrosine-hydroxylase immunoreactive (TH-IR) network and the number of TH-IR varicosities in subareas of the nucleus accumbens core and shell in naive rats. This study shows that the nucleus accumbens of APO-SUS rats has a more extensive fibre network and more varicosities than the nucleus accumbens of APO-UNSUS rats, and that the subarea of the shell contains more varicosities than the subarea of the core. These data provide a basis for further studying the structural and neurochemical properties of the nucleus accumbens contributing to individual differences in response to stressors such as novelty and drugs of abuse.