M.A.F.M. Gerrits

Endogenous opioids and reward.

The discovery of endogenous opioids has markedly influenced the research on the biology of addiction and reward brain processes. Evidence has been presented that these brain substances modulate brain stimulation reward, self-administration of different drugs of abuse, sexual behaviour and social behaviour. There appears to be two different domains in which endogenous opioids, present in separate and distinct brain regions, are involved. One is related to the modulation of incentive motivational processes and the other to the performance of certain behaviours. It is concluded that endogenous opioids may play a role in the vulnerability to certain diseases, such as addiction and autism, but also when the disease is present, such as alcoholism.

κ-Opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice

Abstract Modulation of the reinforcing effects of cocaine and morphine by the κ-opioid receptor agonist U50,488H ( trans -3,4-dichloro- N -methyl- N -(2-1-pyrrolidinyl)-cyclohexyl-benzeacetamide) was studied by using the method of intravenous (i.v.) self-administration in drug-naive Wistar rats and DBA/2 mice. Self-administration of cocaine (by rats) and morphine (by mice) was readily initiated and showed an inverted U-shaped unit dose–response curve. Treatment with the κ-opioid receptor agonist U50,488H dose dependently decreased the intake of both cocaine and morphine when offered in doses that readily initiated and sustained self-administration behavior. Interestingly, treatment with U50,488H induced self-administration behavior with lower sub-threshold doses of cocaine and morphine. With regard to the inverted U-shaped relation between the dose of the drug and the number of self-infusions, it seems that activation of the κ-opioid receptor with U50,488H procuced an almost parallel shift to the left, indicating an increased sensitivity of the animals for the reinforcing effects of cocaine and morphine. These data demonstrate an involvement of κ-opioid systems in the neurobiological mechanisms underlying drug addiction in general, and sensitivity for drug reward in particular. Furthermore, the dual effect of κ-opioid receptor agonists on drug self-administration may prompt further research into the mechanisms underlying the role of endogenous opioids in drug self-administration.

The effects of neonatal lesions in the amygdala or ventral hippocampus on social behaviour later in life

Disruption of normal social behaviour is seen in psychiatric neurodevelopmental disorders like schizophrenia or autism. In a rat model of neurodevelopmental disorders we investigated the social behavioural changes after damage of limbic brain areas, at two early stages of life. The effects of ibotenic acid lesions made on day 7 or 21 of life in the amygdala (AM) ((baso)lateral/medical) or ventral hippocampal area on social play behaviour, social behaviour unrelated to social play behaviour early in life, and social behaviour in adulthood were assessed. Lesions of the AM, but not lesions of the ventral hippocampal area, resulted in decreased social play behaviour, and no differences were found between lesions made on day 7 or 21 of life. Social behaviour unrelated to social play behaviour early in life and in adulthood was decreased in animals lesioned in the AM on day 7 but not in animals lesioned on day 21 of life. This effect was particularly present in animals with an additional lesion in the medial nuclei of the AM. Lesions in the ventral hippocampal area did not affect social behaviour. It is concluded that the AM is an important structure for social play behaviour. The effects on social behaviour that are dependent on the day of lesioning (day 7 vs. 21) are an indication of a neurodevelopmental deficit of structures connected to the (medial part) of the AM.

Early amygdala damage in the rat as a model for neurodevelopmental psychopathological disorders.

Neurodevelopmental disorders in medial temporal lobe structures may underlie psychopathological diseases such as schizophrenia and autism. To construct an animal model for these developmental disorders, social and non-social behavioural responses were assessed in rats with ibotenic acid lesions of the (baso-)lateral and central amygdala or ventral hippocampus, induced early in life. Lesioning the amygdala on day 7 after birth resulted in a variety of behavioural disturbances later in life, whereas after similar lesions on day 21 after birth no disturbances developed, except for deficits in social behaviours. Lesioning the hippocampus led to much less disturbances. The results show that amygdala and hippocampus damage at a specific point early in life results in enduring behavioural disturbances that become more manifest after puberty. In particular, lesions of the amygdala on day 7 of life may serve as a rat model with face and construct validity for neurodevelopmental disorders in studying psychopathology.

Effect of nucleus accumbens dopamine depletion on motivational aspects involved in initiation of cocaine and heroin self-administration in rats.

The involvement of mesolimbic dopamine (DA) systems in motivational aspects of drug-taking behavior during initiation of drug self-administration was investigated using a recently developed behavioral paradigm. In separate experiments animals were allowed to self-administer cocaine or heroin (0.16 and 0.32 mg . kg-1 per inf) during 5 consecutive daily 3-h sessions. During a 15-min period preceding the last four self-administration sessions lever-press behavior was measured in absence of the drug as an index of the motivational aspects involved in drug-taking behavior. The effect of 6-hydroxydopamine (6-OHDA) lesion of the nucleus accumbens (NAC) on lever-press behavior before and during self-administration was measured. Destruction of DA terminals in the NAC did not affect initiation of heroin self-administration nor the lever-press behavior during the period preceding the self-administration sessions. In cocaine animals 6-OHDA lesion of the NAC decreased the total intake of cocaine during the self-administration sessions and impaired discriminative lever-responding for the drug, both during cocaine self-administration, and during preceding periods when no cocaine was available. It is concluded that DAergic systems in the NAC might be involved in the reinforcement and/or motivational processes underlying cocaine self-administration. The present findings, however, do not support the notion of a critical role of NAC DA in the motivational aspects of drug-taking behavior in general.

Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization

The endogenous cannabinoid system is a relatively novel discovered system consisting of cannabinoid CB1 receptors, which are expressed both in the periphery and in the central nervous system, peripheral cannabinoid CB2 receptors and endogenous cannabinoids, which are anandamide and 2-arachidonyl glycerol. The cannabinoid CB1 receptors have recently been implicated in rewarding aspects of not only the cannabinoid drug Delta9-tetrahydrocannabinol (Delta9-THC), but also of other drugs of abuse, including cocaine. The present study was designed to further investigate the role of CB1 receptors in reward-related effects of cocaine. Using the CB1 receptor selective antagonist SR141716A, the involvement of CB1 receptors in cocaine reinforcement was determined by intravenous cocaine self-administration. In addition, the effects of the CB1 receptor selective antagonist SR141716A upon the development of cocaine-induced behavioural sensitization were investigated. SR141716A did not affect cocaine reinforcement nor did it affect the development of behavioural sensitization to the locomotor stimulant effects of cocaine. These findings suggest that CB1 receptors are not involved in acute cocaine reinforcement nor in cocaine-induced behavioural sensitization.

Opioid blockade attenuates acquisition and expression of cocaine-induced place preference conditioning in rats

Endogenous opioid systems have been implicated in experimental cocaine addiction. One aspect of this involvement may be the modulation of the motivational properties of cocaine by endogenous opioids. The present study assessed the effect of opioid blockade with naloxone (NLX) on cocaines motivational properties using the conditioned place preference procedure. Treatment with doses of NLX that did not induce place aversion (0.01–1.0 mg/kg−1, SC), dose-dependently attenuated place preference induced by cocaine (10 or 20 mg/kg−1, IP). This effect of NLX was present when administered during acquisition of cocaine-induced place preference and when administered before expression of cocaines motivational effects. These data support the notion that the (conditioned) motivational properties of cocaine are modulated through activation of opioid systems by endogenous opioid peptides. Furthermore, it is suggested that an interaction between endogenous opioid systems and dopaminergic systems in the brain might be of importance in the motivational facilitation of experimental cocaine addiction.

Drug dependence and the endogenous opioid system

The discovery of endogenous opioids has markedly influenced the research on the biology of drug dependence. Evidence has been presented that these brain substances are self-administered by laboratory animals. This finding, among others, has led to the hypothesis that endogenous opioids are involved in reinforcing habits, including dependence on drugs of abuse. The course of drug dependence is presented as a continuum from no drug use via controlled use to an actual dependence on the drug. Specific brain opioid systems belonging to four conceptualized brain circuits are described to be involved during the different phases of the drug dependence continuum. More recent research to delineate the role of endogenous opioid systems in drug dependence has focussed on genetic research in humans and animals. Among others, the findings obtained from studies of opioid receptor and opioid peptide precursor knockout mice provided further support for a role of endogenous opioid systems in drug dependence, in agreement with previous pharmacological studies.

Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat.

The involvement of dopamine D1 receptor systems in the reinforcing properties of opiate reward was studied by examining the effect of the dopamine D1 antagonist SCH23390 on the initiation of heroin self-administration in rats. The D1 antagonist was administered daily systemically or locally in the nucleus accumbens (NAC), after which the animals were allowed to self-administer heroin (IV) in a 3-h session for 5 consecutive days. Systemic treatment with SCH23390 (0.17 and 0.5 mg.kg−1) significantly decreased heroin intake during initiation of heroin self-administration, while a dose of 0.06 mg.kg−1 was not effective. Local administration of SCH23390 (0.5 and 2.5 µg/site) in the NAC did not affect heroin intake. Both systemic and intra-accumbal administration of SCH23390 dose dependently decreased motor behavior measured in a small open field. The attenuation of heroin intake during initiation of heroin self-administration by blockade of dopamine D1 receptor systems may be due to a decrease in the reinforcing effects of heroin or more likely to a reduction in non-reinforcement-related behavior. The dopamine D1 receptors present in the NAC are probably not involved in opiate reward.

Naloxone inhibits the reinforcing and motivational aspects of cocaine addiction in mice

The opioid receptor antagonist naloxone is known to influence a wide range of behavioral effects of cocaine, including its addictive property. In the present study the effects of different doses of naloxone and naloxone-methyl-iodide, a methylated analogon of naloxone that does not penetrate the blood-brain barrier, on the action of cocaine in the intravenous self-administration and conditioned place preference (CCP) paradigm were assessed. Systemic naloxone, but not naloxone-methyl-iodide, dose-dependently suppressed cocaine intake during self-administration and decreased the preference for the cocaine-associated compartment in the CCP paradigm. A significant blockade of cocaines effects was only present at a relatively high dose of NLX (1.0 mg/kg, s.c.). In addition, NLX produced a rightward shift in the inverted U-shaped dose-response curve for cocaine reward during self-administration, indicating a decrease in sensitivity for the reinforcing effects of cocaine. These data demonstrate that blockade of opioid receptors in the brain block both the reinforcing and conditioned motivational effects of cocaine. An interaction between endogenous opioid systems and local dopaminergic systems is suggested in mediating the effects of NLX on cocaine.