Risk of transition to schizophrenia following first admission with substance-induced psychotic disorder: a population-based longitudinal cohort study.

BACKGROUND: The potential for drugs of abuse to induce acute psychotic symptoms is well recognised. However, the likelihood of transition from initial substance-induced psychotic disorder (SIPD) to chronic psychosis is much less well understood. This study investigated the rate of SIPD transition to schizophrenia (F20), the time to conversion and other possible related factors. METHODS: Using data from the Scottish Morbidity Record, we examined all patients (n = 3486) since their first admission to psychiatric hospital with a diagnosis of SIPD [International Classification of Diseases, Tenth Revision (ICD-10) codes F10-F19, with third digit five] from January 1997 to July 2012. Patients were followed until first episode of schizophrenia (ICD-10 code F20, with any third digit) or July 2012. Any change in diagnosis was noted in the follow-up period, which ranged from 1 day to 15.5 years across the groups. RESULTS: The 15.5-year cumulative hazard rate was 17.3% (s.e. = 0.007) for a diagnosis of schizophrenia. Cannabis, stimulant, opiate and multiple drug-induced psychotic disorder were all associated with similar hazard rates. The mean time to transition to a diagnosis of schizophrenia was around 13 years, although over 50% did so within 2 years and over 80% of cases presented within 5 years of SIPD diagnosis. Risk factors included male gender, younger age and longer first admission. CONCLUSIONS: SIPD episodes requiring hospital admission for more than 2 weeks are more likely to be associated with later diagnosis of schizophrenia. Follow-up periods of more than 2 years are needed to detect the majority of those individuals who will ultimately develop schizophrenia.

Fusion of diphtheria toxin and urotensin II produces a neurotoxin selective for cholinergic neurons in the rat mesopontine tegmentum.

Urotensin II is a neuropeptide first isolated from fish and later found in mammals: where it has potent cardiovascular, endocrine and behavioral effects. In rat brain the urotensin II receptor (UII-R) is predominately expressed in the cholinergic neurons of the pedunculopontine (PPTg) and laterodorsal tegmental nuclei. Typically, the function of the PPTg has been examined using excitotoxins, destroying both cholinergic and non-cholinergic neurons, which confounds interpretation. We took advantage of UII-R's unique expression profile, by combining UII with diphtheria toxin, to engineer a toxin specific for cholinergic neurons of the PPTg. In vitro, two different toxin constructs were shown to selectively activate UII-R (average EC50 approximately 30 nmol/L; calcium mobility assay) and to be 10,000-fold more toxic to UII-R expressing CHO cells, than wildtype cells (average LD50 approximately 2 nmol/L; cell viability). In vivo, pressure injection into the PPTg of rats, resulted in specific loss of choline transporter and NADPH diaphorase positive neurons known to express the UII-R. The lesions developed over time, resulting in the loss of over 80% of cholinergic neurons at 21 days, with little damage to surrounding neurons. This is the first highly selective molecular tool for the depletion of mesopontine cholinergic neurons. The toxin will help to functionally dissect the pedunculopontine and laterodorsal tegmental nuclei, and advance the understanding of the functions of these structures.

An examination of d-amphetamine self-administration in pedunculopontine tegmental nucleus-lesioned rats.

The pedunculopontine tegmental nucleus (PPTg) has long been suggested to have a role in reward-related behaviour, and there is particular interest in its possible role in drug reward systems. Previous work found increased i.v. self-administration (IVSA) of d-amphetamine following PPTg lesions when training had included both operant pre-training and priming injections. The present study examined the effect of excitotoxin lesions of the PPTg on d-amphetamine IVSA under three training conditions. Naive: no previous experience of d-amphetamine or operant responding. Pre-trained: given operant training with food before lesion surgery took place. Primed: given single non-contingent d-amphetamine infusion (0.1 mg/0.l ml) at the start of each session. Rats in all conditions were given either ibotenate or phosphate buffer control lesions of the PPTg before d-amphetamine (0.1 mg/0.1 ml infusion) IVSA training took place. Rats received eight sessions of training under a fixed ratio (FR2) schedule of d-amphetamine IVSA, followed by four sessions under a progressive ratio (PR5) schedule. In the naive condition, PPTg-lesioned rats were attenuated in their responding under FR2, and took significantly fewer infusions under PR5 than the control group. Under FR2 in the pre-trained condition, there was no difference between PPTg excitotoxin and control lesioned rats; however, PPTg-lesioned rats took significantly fewer infusions under the PR5 schedule. In the primed condition, there were no differences between PPTg-lesioned and control rats under either FR2 or PR5 schedules. These data demonstrate that operant training prior to PPTg lesion surgery corrects some, but not all, of the deficits seen in the naive condition. PPTg-lesioned rats in both naive and pre-trained conditions showed reduced responding for d-amphetamine under a PR5 schedule. These deficits are overcome by priming with d-amphetamine. We suggest that alterations in striatal dopamine activity following PPTg lesions underlie these effects.

Behavioural sensitisation to repeated d-amphetamine: effects of excitotoxic lesions of the pedunculopontine tegmental nucleus.

The pedunculopontine tegmental nucleus (PPTg) interacts with anatomical systems thought to be involved in mediating sensitisation of the locomotor response to repeated d-amphetamine. The PPTg has direct and indirect connections with the nucleus accumbens and prefrontal cortex, and also influences midbrain dopamine activity through direct projections to substantia nigra and ventral tegmental area. In this experiment, the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine was examined in rats bearing excitotoxic lesions of the PPTg, and sham-lesioned controls. Rats were given repeated d-amphetamine (1.5 mg/kg i.p.) treatment in an on-off procedure, with saline and d-amphetamine given on alternate days, such that rats received a total of seven d-amphetamine and seven saline treatments. Locomotor responses were measured in photocell cages. On the first day of d-amphetamine treatment, there was no difference between excitotoxin and sham-lesioned rats. Development of sensitisation to the locomotor stimulant effects of d-amphetamine was delayed in PPTg-lesioned rats, relative to the sham-lesioned control rats. However, there was no difference between lesion and control groups in the locomotion seen on saline-treatment days. These data suggest that the PPTg is involved in the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine, and indicate that traditional striatal circuitry models of the mechanisms underlying sensitisation should be extended to include the PPTg.

The effect of excitotoxic lesions of the pedunculopontine tegmental nucleus on performance of a progressive ratio schedule of reinforcement.

The pedunculopontine tegmental nucleus has connections with sites in both dorsal and ventral striatum, and a number of studies have suggested that it has a role in reward-related behaviour. The present experiment aimed to investigate the perception of reward in pedunculopontine tegmental nucleus-lesioned rats responding for food under a progressive ratio schedule, which measures willingness to work for a given reward. Rats were trained on a progressive ratio-5 schedule for food reward, then given ibotenic acid or sham lesions of the pedunculopontine tegmental nucleus. Their performance under this schedule was examined again following recovery from surgery. Compared with sham-lesioned rats, those with lesions of the pedunculopontine tegmental nucleus showed significantly reduced breaking points and significantly longer post-reinforcement pauses. However, there was no difference between the groups in their latency to collect food pellets once earned, suggesting that pedunculopontine tegmental nucleus excitotoxin and sham-lesioned rats were equally motivated by the presence of food. Excitotoxin-lesioned rats made significantly more responses on the control lever and more entries to the food hopper as progressive ratio increment increased, but did not differ from controls when the schedule requirement was low. These results are interpreted as indicating no global loss of motivation, since lesioned rats performed normally at low schedule requirements, and were as fast as controls to collect pellets. But as the schedule requirement increased, excitotoxin-lesioned rats showed reductions in responding on the active lever (that is, a reduction in breaking point) and an increase in inappropriate responses towards the food hopper and the control lever.We consider these data to indicate that the behavioural deficits in pedunculopontine-lesioned rats arise not from a sensory or hedonic change, but from alteration in the control of motor output.

The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats.

RATIONALE: It has been suggested that the nucleus accumbens (NAcc) may be involved in heroin reward, and the core and shell regions respond differently following administration of a number of drugs of abuse. OBJECTIVE: The possible role of the NAcc core and shell subregions in the acquisition of heroin self-administration behaviour was investigated. METHODS: Rats were given selective excitotoxic lesions of either the nucleus accumbens core or shell before the acquisition of responding for i.v. heroin (0.04 mg/infusion) under a continuous reinforcement schedule in daily 3 h sessions. After sham-lesioned rats reached a stable baseline, a between-sessions heroin dose-response function was established. RESULTS: Rats with lesions of the NAcc shell did not differ significantly from sham controls in either the acquisition of heroin self-administration or in their heroin dose-response function. The NAcc core lesion group showed reduced levels of responding during the acquisition of heroin self-administration and a reduction in responding during the heroin dose-response function, although this behaviour was sensitive to changes in the dose of heroin. CONCLUSIONS: The NAcc shell does not appear to be critical for heroin self-administration, whereas the NAcc core, although apparently not essential in mediating the rewarding effect of i.v. heroin, may mediate processes that are of special importance during the acquisition of instrumental behaviour.

The effects of excitotoxic lesions of the pedunculopontine tegmental nucleus on conditioned place preference to 4%, 12% and 20% sucrose solutions.

A number of studies have suggested that the pedunculopontine tegmental nucleus (PPTg) may play a role in reward-related behaviour. The present study was intended to investigate this further using conditioned place preference. In conditioned place preference paradigms the amount of time spent in a preferred environment is proportional to the value of the reinforcement present, until a maximum is reached. In the present experiments we aimed to determine whether this relationship was affected by lesions of the PPTg by examining the formation of a conditioned place preference to either 4%, 12% or 20% sucrose solutions in food-deprived PPTg lesioned rats. The conditioned place preference apparatus had two compartments different in colour, smell and floor texture. During conditioning, rats were restricted to one compartment or the other, one of which was paired with sucrose. This was carried out during 30 min sessions, alternating conditioned or nonconditioned trials for 14 days. On the test day, rats were given access to both compartments through a connecting chamber, and were scored for side preference over 15 min. Both PPTg and sham lesioned rats showed a conditioned place preference to 12% and 20% sucrose, but no place preference was formed by either group to 4% sucrose. There was no significant difference between the groups in the place preference shown. Consumption of 4% sucrose was not affected by excitotoxic lesions of the PPTg, but PPTg lesioned rats consumed significantly more 12% and 20% sucrose than sham controls. This suggests that perception of reward value, as judged by CPP formation, is unchanged by excitotoxic lesions of the PPTg. The increased consumption of 12% and 20% sucrose shown by rats bearing such lesions is therefore not likely to be a product of altered reward perception.

The effects of excitotoxic lesions of the basolateral amygdala on the acquisition of heroin-seeking behaviour in rats.

RATIONALE: Second-order schedules of drug-self-administration provide a method of examining drug-seeking behaviour, which is maintained in part by the presentation of a discrete, drug-associated light CS. Previous results have found that lesions of the basolateral amygdala (BLA) impair the acquisition of i.v. cocaine self-administration under this type of schedule. OBJECTIVES: The present experiments examined the effects of excitotoxic lesions of the BLA on the acquisition of i.v. heroin self-administration under both continuous reinforcement and second-order schedules, in order to investigate possible commonalties in the neural basis of heroin- and cocaine-seeking behaviour. METHODS: Rats received quinolinic acid or sham vehicle lesions of the BLA prior to i.v. self-administration training. Initially, heroin self-administration under a continuous reinforcement schedule was acquired. Each active lever-press resulted in a 0.04 mg i.v. heroin infusion, paired with presentation of a 20-s light conditioned stimulus. Following acquisition of responding under this schedule, the response requirement was gradually increased to a second-order schedule of FI15(FR5:S). RESULTS: There was no effect of lesions of the BLA on the acquisition of heroin self-administration under a continuous reinforcement schedule. The acquisition of heroin-seeking behaviour under a second-order schedule of self-administration was not affected by lesions of the BLA, but lesioned rats showed a significantly higher baseline level of responding. CONCLUSIONS: These results indicate that the rewarding effects of heroin do not depend on the integrity of the BLA. The BLA is also not critically involved in mediating heroin-seeking behaviour under a second-order schedule of reinforcement, and this stands in marked contrast to the effects of BLA lesions on the acquisition of cocaine-seeking behaviour. These findings suggest that discrete heroin cues were not critical in maintaining heroin-seeking behaviour under the second-order schedule used here and that other learning systems are engaged in the control of this behaviour.

Heroin self-administration under a second-order schedule of reinforcement: acquisition and maintenance of heroin-seeking behaviour in rats.

RATIONALE: Second-order schedules of heroin self-administration provide a method of measuring heroin-seeking behaviour independently of the effects of the drug on motor behaviour and of investigating the role of heroin-associated stimuli in such heroin-seeking behaviour. OBJECTIVES: These experiments aimed to establish a second-order schedule of heroin self-administration in rats, similar to that already established in this laboratory for cocaine self-administration and to investigate the role of discrete heroin-associated stimuli in the maintenance of heroin-seeking behaviour under a second-order schedule of reinforcement. METHODS: Heroin i.v. self-administration (0.04 mg/infusion) was initially contingent upon a lever press, and each infusion was paired with presentation of a 20-s light-conditioned stimulus (CS). Following acquisition of heroin self-administration, the response requirement was progressively increased so that, ultimately, responding was maintained under a fixed interval (FI) 15 min [fixed ratio (FR)5:S] second-order schedule. The effects of varying the dose of heroin (0.01 mg and 0.08 mg/infusion) and pre-treatment with the mu-opiate receptor antagonist, naloxone, on responding under a FI15(FR5:S) schedule were investigated. In addition, the role of the heroin-associated CS on responding was assessed by measuring the effects of omitting the CS during heroin-seeking behaviour and during extinction of responding, as well as the effect of CS presentation on the reinstatement of heroin-seeking behaviour following extinction. RESULTS: A second-order schedule of heroin self-administration was established. There were no clear effects on heroin-seeking behaviour of increasing or decreasing the dose of heroin. Although no effect of naloxone pre-treatment was seen on heroin-seeking behaviour during the first, drug-free interval of responding, an extinction-like pattern of responding was seen in that interval during subsequent sessions. Omission of the light CS resulted in a reduction in levels of responding for i.v. heroin, indicating its role in maintaining heroin-seeking behaviour. However, under extinction conditions, response-contingent CS presentations did not affect the rate of extinction, nor did non-contingent presentations of the CS following extinction reinstate heroin-seeking behaviour. CONCLUSIONS: These experiments have established a method of measuring heroin-seeking behaviour in rats by adopting a second-order schedule of i.v. heroin self-administration. The results indicate a relatively weak impact of discrete, heroin-associated cues on heroin-seeking behaviour relative to cocaine-seeking behaviour studied under similar conditions.