Jan M. van Ree

Neuroleptic activity of the neuropeptide β-LPH62–77 ([Des-Tyr1]γ-endorphin; DTγE)

In contrast to β-endorphin, α-endorphin, β-LPH61–69 and Met-enkephalin which delay extinction of pole-jumping avoidance behavior (De Wied et al., 1978), γ-endorphin given either subcutaneously (30 ng/rat) or intraventricularly (0.3 ng/rat) facilitated extinction. Removal of the N-terminal amino acid residue tyrosine — yielding the neuropeptide [Des-Tyr1]γ-endorphin (DTγE) — which destroys the opiate-like activity as determined on the electrically driven guinea pig ileum, potentiated the facilitating effect of γ-endorphin on pole-jumping avoidance behavior. Observations on passive avoidance behavior gave essentially the same results. Whereas α-endorphin facilitated this behavior. DTγE attenuated passive avoidance behavior. Amounts of γ-endorphin and DTγE which were highly active on extinction of pole-jumping avoidance behavior (0.3 μg s.c. per rat) were without effect on gross behavior in an open field. Much higher amounts (10–50 μg s.c. per rat) also failed to affect the rate of ambulation in an open field. In relatively high doses (20 μg i.v.t. or 50 μg s.c. per rat), γ-endorphin and in particular DTγE were positive in the various “grip tests”. Haloperidol given s.c. (0.03–0.1 μg/rat) facilitated extinction of pole-jumping avoidance behavior and attenuated passive avoidance behavior. The same amounts decreased ambulation in an open field. In higher doses haloperidol was active in the “grip tests” but in addition caused severe immobility, ptosis and extension of the lower limbs. Intraventricularly administered morphine or β-endorphin induced wide open eyes, exophthalmus, rigidity and reduced reflexes, in contrast to γ-endorphin and DTγE which did not produce such effects. These results are interpreted to indicate that DTγE or a closely related peptide is an endogenous neuroleptic. It may be that a reduced availability as a result of an inborn error in the generation of DTγE is an etiological factor in psychopathological states for which neuroleptic drugs are beneficial.

Low doses of oxytocin facilitate social recognition in rats.

Social recognition of juveniles by adult male residents has been shown to be modulated by neurohypophyseal hormones. The decrease of social investigation behavior during a second encounter with the same juvenile serves as index for social recognition. In the present study it was found that low doses (0.09–6.0 ng · kg−1) of oxytocin (OXT) given subcutaneously dose dependently facilitated social recognition. The effect of OXT appeared specific, since no change in social investigation was found when a novel juvenile was tested during the second encounter. No disturbances of social recognition by the low doses of OXT could be detected, in contrast to higher doses of this hormone. Other neurohypophyseal hormones, vasopressin and vasotocin, did not facilitate social recognition when tested in the same range of low doses.

Scheduled eating increases dopamine release in the nucleus accumbens of food-deprived rats as assessed with on-line brain dialysis.

This study examined the effect of scheduled eating on the in vivo release of dopamine (DA) in the nucleus accumbens of rats that were maintained on a food deprivation schedule. DA release was measured by means of a fully automated on-line brain dialysis system. The initiation of eating increased the release of DA, which remained elevated during the entire eating period. Termination of eating caused a gradual decrease of the release of DA to basal values. Increased motor activities did not change the release of DA. These results indicate a link between eating and DA release and demonstrate the suitability of on-line brain dialysis for behavioural experiments.

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.

Emotional but not physical stress enhances intravenous cocaine self-administration in drug-naive rats

Involvement of stress in the etiology of drug dependence has received little attention. In the present study a number of behavioural manipulations were applied and examined for an effect on intravenous cocaine self-administration in drug-naive rats with no prior training in leverpress responding. Self-administration rate was measured during five consecutive daily sessions. Stress reduction by handling rats daily for two weeks prior to testing for self-administration did not affect cocaine self-administration. Acute physical stress was induced either by a hot plate or by repeated footshocks, and emotional stress was induced by forcing rats to witness another rat being subjected to repeated footshocks. These stressors were applied immediately prior to each cocaine self-administration session. Emotional but not physical stress enhanced the rate of cocaine self-administration. It is concluded that emotional distress may increase the rewarding effects of cocaine and may render an individual more susceptible to development of drug dependence.

Effects of frequent cannabis use on hippocampal activity during an associative memory task

Interest is growing in the neurotoxic potential of cannabis on human brain function. We studied non-acute effects of frequent cannabis use on hippocampus-dependent associative memory, investigated with functional Magnetic Resonance Imaging (fMRI) in 20 frequent cannabis users and 20 non-users matched for age, gender and IQ. Structural changes in the (para)hippocampal region were measured using voxel-based morphometry (VBM). Cannabis users displayed lower activation than non-users in brain regions involved in associative learning, particularly in the (para)hippocampal regions and the right dorsolateral prefrontal cortex, despite normal performance. VBM-analysis of the (para)hippocampal regions revealed no differences in brain tissue composition between cannabis users and non-users. No relation was found between (para)hippocampal tissue composition and the magnitude of brain activity in the (para)hippocampal area. Therefore, lower brain activation may not signify neurocognitive impairment, but could be the expression of a non-cognitive variable related to frequent cannabis use, for example changes in cerebral perfusion or differences in vigilance.

Effects of morphine and β-endorphin on basal and elevated plasma levels of α-MSH and vasopressin

Morphine induced an increase of plasma α-MSH levels and a decrease of AVP levels after peripheral or intracerebroventricular administration. This increase of α-MSH levels and decrease of AVP levels after morphine treatment was observed in non-stimulated animals as well as in rats in which the hormone levels were elevated by water deprivation or by administration of hypertonic saline. These latter effects of morphine on plasma levels of α-MSH and AVP could be blocked by simultaneous administration of naltrexone. β-Endorphin also increased plasma α-MSH levels and lowered plasma AVP levels. From these effects only the increase of the plasma α-MSH level and not the decrease of plasma AVP could be blocked by naltrexone. Moreover PLG treatment was ineffective with respect to the endorphin-induced decrease in plasma AVP, but it partly blocked the increase of plasma α-MSH when this tripeptide was given in combination with β-endorphin.

Isolation changes the incentive value of sucrose and social behaviour in juvenile and adult rats

The present study was undertaken to assess the motivational aspects of social behaviour in juvenile and adult rats using the conditioned place preference (CPP) test and anticipatory behaviour for social contact. In addition, the consequences of social isolation during different periods of age on the motivational properties of sucrose-drinking and adult social behaviour were studied. Social play and adult social contact could be used as incentives for place preference conditioning and for inducing conditioned hyperactivity (anticipation) in rats. Both social activities have motivational properties for individually housed rats, whereas group-housing dramatically reduced the motivational aspects of adult social contact. In contrast, sucrose-drinking appears to have motivational aspects independent of the housing condition. Adult social behaviour could not induce a CPP in juvenile isolated rats, suggesting that juvenile isolation during 4 5 weeks reduced the motivational aspects of adult social contact. It seems likely that no CPP was established as a result of the reduced level of social behaviour during the conditioning sessions. Additionally, juvenile isolation during 4-5 weeks appeared to also decrease the motivational properties of sucrose-drinking in maturity, because the intensity of anticipation in response to sucrose was significantly suppressed. Thus, the data suggest that juvenile isolation during 4-5 weeks decreases the motivational properties of both social contact and sucrose-drinking in later life.

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.

Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials

Abstract Objective To determine the cost utility of medical co-prescription of heroin compared with methadone maintenance treatment for chronic, treatment resistant heroin addicts. Design Cost utility analysis of two pooled open label randomised controlled trials. Setting Methadone maintenance programmes in six cities in the Netherlands. Participants 430 heroin addicts. Interventions Inhalable or injectable heroin prescribed over 12 months. Methadone (maximum 150 mg a day) plus heroin (maximum 1000 mg a day) compared with methadone alone (maximum 150 mg a day). Psychosocial treatment was offered throughout. Main outcome measures One year costs estimated from a societal perspective. Quality adjusted life years (QALYs) based on responses to the EuroQol EQ-5D at baseline and during the treatment period. Results Co-prescription of heroin was associated with 0.058 more QALYs per patient per year (95% confidence interval 0.016 to 0.099) and a mean saving of €12 793 (£8793,