Andrew J. Lawrence

Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk research, problem gamblers and genetic association studies.

There is a longstanding association between substance-use disorders (SUDs) and the psychological construct of impulsivity. In the first section of this review, personality and neurocognitive data pertaining to impulsivity will be summarised in regular users of four classes of substance: stimulants, opiates, alcohol and 3,4-methylenedioxymethamphetamine (MDMA). Impulsivity in these groups may arise via two alternative mechanisms, which are not mutually exclusive. By one account, impulsivity may occur as a consequence of chronic exposure to substances causing harmful effects on the brain. By the alternative account, impulsivity pre-dates SUDs and is associated with the vulnerability to addiction. We will review the evidence that impulsivity is associated with addiction vulnerability by considering three lines of evidence: (i) studies of groups at high-risk for development of SUDs; (ii) studies of pathological gamblers, where the harmful consequences of the addiction on brain structure are minimised, and (iii) genetic association studies linking impulsivity to genetic risk factors for addiction. Within each of these three lines of enquiry, there is accumulating evidence that impulsivity is a pre-existing vulnerability marker for SUDs.

Experimental design and analysis and their reporting: new guidance for publication in BJP

This Editorial is part of a series. To view the other Editorials in this series, visit: http://onlinelibrary.wiley.com/doi/10.1111/bph.12956/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12954/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12955/abstract and http://onlinelibrary.wiley.com/doi/10.1111/bph.13112/abstract

The orexin system regulates alcohol-seeking in rats

1 Orexin‐containing neurons have been implicated in feeding, sleep–wake cycles and more recently in drug‐seeking behaviour. 2 Pretreatment of alcohol‐preferring (iP) rats with an orexin1 receptor antagonist (SB‐334867, 20 mg kg−1, intraperitoneally) completely abolished an olfactory cue‐induced reinstatement of alcohol‐seeking behaviour, and also attenuated alcohol responding under an operant fixed ratio regimen without affecting water responding. 3 The mRNA encoding orexin within the hypothalamus was expressed at a similar density in iP and non‐preferring (NP) rats; chronic consumption of ethanol in iP rats did not significantly regulate the density of this expression, but did increase the area of expression within the lateral, but not medial, hypothalamus. 4 These data indicate that while orexin may not be implicated in the development of an alcohol preference, re‐exposure of cues previously associated with alcohol availability is sufficient and adequate to activate orexin‐containing neurons and drive reinstatement of alcohol‐seeking.

Neurochemical modulation of cardiovascular control in the nucleus tractus solitarius.

The central control of cardiovascular function has been keenly studied for a number of decades. Of particular interest are the homeostatic control mechanisms, such as the baroreceptor heart-rate reflex, the chemoreceptor reflex, the Bezold-Jarisch reflex and the Breuer-Hering reflex. These neurally-mediated reflexes share a common termination point for their respective centrally-projecting sensory afferents, namely the nucleus tractus solitarius (NTS). Thus, the NTS clearly plays a critical role in the integration of peripherally initiated sensory information regarding the status of blood pressure, heart rate and respiratory function. Many endogenous neurochemicals, from simple amino acids through biogenic amines to complex peptides have the ability to modulate blood pressure and heart rate at the level of the NTS. This review will attempt to collate the current knowledge regarding the roles of neuromodulators in the NTS, the receptor types involved in mediating observed responses and the degree of importance of such neurochemicals in the tonic regulation of the cardiovascular system. The neural pathway that controls the baroreceptor heart-rate reflex will be the main focus of attention, including discussion of the identity of the neurotransmitter(s) thought to act at baroafferent terminals within the NTS. In addition, this review will provide a timely update on the use of recently developed molecular biological techniques that have been employed in the study of the NTS, complementing more classical research.

Gambling Near-Misses Enhance Motivation to Gamble and Recruit Win-Related Brain Circuitry

Summary “Near-miss” events, where unsuccessful outcomes are proximal to the jackpot, increase gambling propensity and may be associated with the addictiveness of gambling, but little is known about the neurocognitive mechanisms that underlie their potency. Using a simplified slot machine task, we measured behavioral and neural responses to gambling outcomes. Compared to “full-misses,” near-misses were experienced as less pleasant, but increased desire to play. This effect was restricted to trials where the subject had personal control over arranging their gamble. Near-miss outcomes recruited striatal and insula circuitry that also responded to monetary wins; in addition, near-miss-related activity in the rostral anterior cingulate cortex varied as a function of personal control. Insula activity to near-misses correlated with self-report ratings as well as a questionnaire measure of gambling propensity. These data indicate that near-misses invigorate gambling through the anomalous recruitment of reward circuitry, despite the objective lack of monetary reinforcement on these trials.

Impulsivity and response inhibition in alcohol dependence and problem gambling

IntroductionImpulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown.Materials and methodsThis study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD.ResultsOn the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings.ConclusionInhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry.

Problem gamblers share deficits in impulsive decision-making with alcohol-dependent individuals

Aims Problem gambling has been proposed to represent a ‘behavioural addiction’ that may provide key insights into vulnerability mechanisms underlying addiction in brains that are not affected by the damaging effects of drugs. Our aim was to investigate the neurocognitive profile of problem gambling in comparison with alcohol dependence. We reasoned that shared deficits across the two conditions may reflect underlying vulnerability mechanisms, whereas impairments specific to alcohol dependence may reflect cumulative effects of alcohol consumption. Design Cross-sectional study. Setting Out-patient addiction treatment centres and university behavioural testing facilities. Participants A naturalistic sample of 21 male problem and pathological gamblers, 21 male alcohol-dependent out-patients and 21 healthy male control participants. Measurements Neurocognitive battery assessing decision-making, impulsivity and working memory. Findings The problem gamblers and alcohol-dependent groups displayed impairments in risky decision-making and cognitive impulsivity relative to controls. Working memory deficits and slowed deliberation times were specific to the alcohol-dependent group. Conclusions Gambling and alcohol-dependent groups shared deficits in tasks linked to ventral prefrontal cortical dysfunction. Tasks loading on dorsolateral prefrontal cortex were selectively impaired in the alcohol-dependent group, presumably as a consequence of long-term alcohol use.

Inhalant abuse among adolescents: neurobiological considerations.

Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABAA, glycine and 5HT3 receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long‐term alterations in the function of NMDA and GABAA receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development.

Increased anxiety 3 months after brief exposure to MDMA ("Ecstasy") in rats: association with altered 5-HT transporter and receptor density.

Male Wistar rats were treated with 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) using either a high dose (4 × 5 mg/kg over 4 h) or low dose (1 × 5 mg/kg over 4 h) regimen on each of 2 consecutive days. After 10 weeks, rats were tested in the social interaction and emergence tests of anxiety. Rats previously given either of the MDMA dose regimens were significantly more anxious on both tests. After behavioral testing, and 3 months after the MDMA treatment, the rats were killed and their brains examined. Rats given the high-, but not the low-, dose MDMA treatment regimen exhibited significant loss of 5-hydroxytryptamine (5-HT) and 5-HIAA in the amygdala, hippocampus, striatum, and cortex. Quantitative autoradiography showed loss of SERT binding in cortical, hippocampal, thalamic, and hypothalamic sites with the high-dose MDMA regime, while low-dose MDMA only produced significant loss in the medial hypothalamus. Neither high- nor low-dose MDMA affected 5HT1A receptor density. High-dose MDMA increased 5HT1B receptor density in the nucleus accumbens and lateral septum but decreased binding in the globus pallidus, insular cortex and medial thalamus. Low-dose MDMA decreased 5HT1B receptor density in the hippocampus, globus pallidus, and medial thalamus. High-dose MDMA caused dramatic decreases in cortical, striatal, thalamic, and hypothalamic 5HT2A/2C receptor density, while low-dose MDMA tended to produce similar effects but only significantly in the piriform cortex. These data suggest that even brief, relatively low-dose MDMA exposure can produce significant, long-term changes in 5-HT receptor and transporter function and associated emotional behavior. Interestingly, long-term 5-HT depletion may not be necessary to produce lasting effects on anxiety-like behavior after low-dose MDMA.

Comparative study on the distribution patterns of P2X1–P2X6 receptor immunoreactivity in the brainstem of the rat and the common marmoset (Callithrix jacchus): Association with catecholamine cell groups

The present study investigated the topographical distribution of P2X1–P2X6 receptor subtypes in the rat and common marmoset hindbrain by immunohistochemistry. In addition, double‐labeling immunofluorescence was used to determine the extent of colocalization between catecholamine cell groups and the various P2X receptors. The data demonstrate a widespread distribution pattern for all six P2X receptors throughout both the rat hindbrain and the marmoset hindbrain, although distinctions between species, brain nuclei, and P2X receptor subtypes exist. In rat, dense staining for the P2X receptors was found in the nucleus of the solitary tract (NTS), medial vestibular nucleus, and medial and lateral parabrachial nuclei. Moderate staining was observed in the hypoglossal nucleus, cuneate nucleus, inferior olive, prepositus hypoglossi, rostral ventrolateral medulla (RVLM), and locus coeruleus. Staining was also observed in the gracile nucleus, the mesencephalic trigeminal nucleus, and the central pontine gray. In marmoset, prominent P2X receptor‐like immunoreactivity occurred in the NTS, medial cuneate nucleus, prepositus hypoglossi, and medial vestibular nucleus. Moderate staining was observed in the area postrema, dorsal motor nucleus of the vagus, lateral cuneate, lateral reticular, spinal trigeminal nucleus, RVLM, and inferior olive. Immunofluorescent double labeling of tyrosine hydroxylase (TH)‐containing cells revealed that all subtypes of P2X receptors show some degree of colocalization with TH. The highest proportion of TH and P2X receptor double labeling was in the A5 region (with the P2X2 subunit), whereas the lowest proportion of double‐labeled cells occurred in the C2 region of the NTS for the P2X5 subunit. These findings support a role for extracellular adenosine 5′‐triphosphate in fast synaptic neurotransmission within the brainstem. J. Comp. Neurol. 427:485–507, 2000.