Aspects Of Drug Addiction Research Articles

A Brief Overview of the Neuropharmacology of Opioid Addiction.

The world is in the midst of an opioid crisis. Nearly 92,000 persons in the U.S. alone died from illicit drugs and prescription opioids in 2020 [1]. This number does not include the countless other individuals who die as a result of the violent crime that accompanies the illicit drug trade. To address this crisis, we need to appreciate aspects of drug addiction. The goal of this brief review is to highlight some major facets of addiction neurobiology, focused on opioids, to provide a basic understanding of the research and terminology encountered in more detailed in-depth articles and discussions on addiction.

Cocaine-Induced Changes in Tonic Dopamine Concentrations Measured Using Multiple-Cyclic Square Wave Voltammetry in vivo.

For over 40 years, in vivo microdialysis techniques have been at the forefront in measuring the effects of illicit substances on brain tonic extracellular levels of dopamine that underlie many aspects of drug addiction. However, the size of microdialysis probes and sampling rate may limit this technique’s ability to provide an accurate assessment of drug effects in microneural environments. A novel electrochemical method known as multiple-cyclic square wave voltammetry (M-CSWV), was recently developed to measure second-to-second changes in tonic dopamine levels at microelectrodes, providing spatiotemporal resolution superior to microdialysis. Here, we utilized M-CSWV and fast-scan cyclic voltammetry (FSCV) to measure changes in tonic or phasic dopamine release in the nucleus accumbens core (NAcc) after acute cocaine administration. Carbon-fiber microelectrodes (CFM) and stimulating electrodes were implanted into the NAcc and medial forebrain bundle (MFB) of urethane anesthetized (1.5 g/kg i.p.) Sprague-Dawley rats, respectively. Using FSCV, depths of each electrode were optimized by determining maximal MFB electrical stimulation-evoked phasic dopamine release. Changes in phasic responses were measured after a single dose of intravenous saline or cocaine hydrochloride (3 mg/kg; n = 4). In a separate group, changes in tonic dopamine levels were measured using M-CSWV after intravenous saline and after cocaine hydrochloride (3 mg/kg; n = 5). Both the phasic and tonic dopamine responses in the NAcc were augmented by the injection of cocaine compared to saline control. The phasic and tonic levels changed by approximately x2.4 and x1.9, respectively. These increases were largely consistent with previous studies using FSCV and microdialysis. However, the minimal disruption/disturbance of neuronal tissue by the CFM may explain why the baseline tonic dopamine values (134 ± 32 nM) measured by M-CSWV were found to be 10-fold higher when compared to conventional microdialysis. In this study, we demonstrated phasic dopamine dynamics in the NAcc with acute cocaine administration. M-CSWV was able to record rapid changes in tonic levels of dopamine, which cannot be achieved with other current voltammetric techniques. Taken together, M-CSWV has the potential to provide an unprecedented level of physiologic insight into dopamine signaling, both in vitro and in vivo, which will significantly enhance our understanding of neurochemical mechanisms underlying psychiatric conditions.

Effects of caffeine on ethanol-elicited place preference, place aversion and ERK phosphorylation in CD-1 mice.

Epidemiological studies indicate a rise in the combined consumption of caffeinated and alcoholic beverages, which can lead to increased risk of alcoholic-beverage overconsumption. However, the effects of the combination of caffeine and ethanol in animal models related to aspects of drug addiction are still underexplored. To characterize the pharmacological interaction between caffeine and ethanol and establish if caffeine can affect the ability of ethanol (2 g/kg) to elicit conditioned place preference and conditioned place aversion, we administered caffeine (3 or 15 mg/kg) to male CD-1 mice before saline or ethanol. Moreover, we determined if these doses of caffeine could affect ethanol (2 g/kg) elicited extracellular signal-regulated kinase phosphorylation in brain areas, nucleus accumbens, bed nucleus of stria terminalis, central nucleus of the amygdala, and basolateral amygdala, previously associated with this type of associative learning. In the place-conditioning paradigm, caffeine did not have an effect on its own, whereas ethanol elicited significant conditioned-place preference and conditioned-place aversion. Caffeine (15 mg/kg) significantly prevented the acquisition of ethanol-elicited conditioned-place preference and, at both doses, also prevented the acquisition of ethanol-elicited conditioned-place aversion. Moreover, both doses of caffeine also prevented ethanol-elicited extracellular signal-regulated kinase phosphorylation expression in all brain areas examined. The present data indicate a functional antagonistic action of caffeine and ethanol on associative learning and extracellular signal-regulated kinase phosphorylation after an acute interaction. These results could provide exciting grounds for further studies, also in a translational perspective, of their pharmacological interaction modulating other processes involved in drug consumption and addiction.

Effect of chronic methamphetamine injection on levels of BDNF mRNA and its CpG island methylation in prefrontal cortex of rats.

Methamphetamine (METH) is a highly addictive psychostimulant. Its abuse causes problems in cognition, attention, or psychiatric conditions such as psychosis. Prefrontal cortex is involved in many aspects of drug addiction and in mental disorders similar to those triggered by METH. Brain-derived neurotrophic factor (BDNF), plays important roles in modulating different aspects of addiction, and is implicated in psychiatric conditions reminiscent of those suffered by METH-abusers. Male Wistar rats were intra-peritoneally injected with METH (8 mg/kg/day) for 14 days while control group received normal saline. After extraction of prefrontal cortices, expression of BDNF IV splice variant and methylation level of its CpG island were evaluated. The relative expression of BDNF IV in METH-treated group was 2.15 fold higher than the control group. Seven out of 29 CpG sites were significantly hypomethylated in the METH group, although none survived Bonferroni adjustment. However, the overall methylation level of the 29 CpGs was significantly lower in METH cases than in controls. We discuss the importance of our results and its implications in detail.

Context- and time-dependent neurobiological and behavioral sensitization induced by a single morphine exposure in mice.

Drug-induced sensitization in the mesocorticolimbic systems is thought to play an important role in certain aspects of drug addiction, including the involvement of drug-associated cues and environments in mediating drug-seeking behaviors. Our previous studies have identified the significance of heat shock protein 70 (Hsp70) in the development of a single morphine exposure-induced behavioral sensitization. The present study expands upon these findings by investigating the effect of environment on the expression of behavioral sensitization induced by a single morphine exposure, and the potential involvement of Hsp70 protein levels in these effects. Mice were pretreated with a single morphine injection in test chambers (morphine-paired) or home cages (morphine-unpaired) on day 1 and challenged on day 2 or 8, in test chambers. Hsp70 expression in the nucleus accumbens (NAc) was analyzed after the challenge. The expression of single morphine exposure-induced behavioral sensitization was accompanied by a significant increase in Hsp70 expression in NAc. In contrast, the unpaired morphine-treated group failed to exhibit behavioral sensitization or higher Hsp70 expression. Additionally, by adding a habituation process prior to the challenge, we demonstrated that conditioned hyperactivity, which was not accompanied by an increased expression of Hsp70, is not essential for behavioral sensitization. Behavioral sensitization induced by a single morphine exposure in mice exhibits context and time dependency, with environmental context likely functioning via an inhibitory conditioning mechanism. Furthermore, alterations in Hsp70 expression in the NAc may represent a neurobiological sensitization mechanism mediating context- and time-dependent behavioral sensitization.

Cocaine-, caffeine-, and stress-evoked cocaine reinstatement in high vs. low impulsive rats: Treatment with allopregnanolone

BackgroundPrevious research indicates that individual differences in traits such as impulsivity, avidity for sweets, and novelty reactivity are predictors of several aspects of drug addiction. Specifically, rats that rank high on these behavioral measures are more likely than their low drug-seeking counterparts to exhibit several characteristics of drug-seeking behavior. In contrast, initial work suggests that the low drug-seeking animals are more reactive to negative events (e.g., punishment and anxiogenic stimuli). The goal of this study was to compare high and low impulsive rats on reinstatement of cocaine-seeking behavior elicited by cocaine (COC) and by negative stimuli such as the stress-inducing agent yohimbine (YOH) or a high dose of caffeine (CAFF). An additional goal was to determine whether treatment with allopregnanolone (ALLO) would reduce reinstatement (or relapse) of cocaine-seeking behavior under these priming conditions. MethodsFemale rats were selected as high (HiI) or low (LoI) impulsive using a delay-discounting task. After selection, they were allowed to self-administer cocaine for 12 days. Cocaine was then replaced with saline, and rats extinguished lever responding over 16 days. Subsequently, rats were pretreated with either vehicle control or ALLO, and cocaine seeking was reinstated by injections of COC, CAFF, or YOH. ResultsWhile there were no phenotype differences in maintenance and extinction of cocaine self-administration or reinstatement under control treatment conditions, ALLO attenuated COC- and CAFF-primed reinstatement in LoI but not HiI rats. ConclusionsOverall, the present findings suggest that individual differences in impulsive behavior may influence efficacy of interventions aimed to reduce drug-seeking behavior.

Addictive potential of modafinil and cross‐sensitization with cocaine: a pre‐clinical study

Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine.

Naltrexone attenuates amphetamine-induced locomotor sensitization in the rat

Amphetamine, and other stimulants, readily induces behavioral sensitization, an effect hypothesized to reflect neurobiological changes that may underlie certain aspects of drug addiction. Apart from the effects on the dopamine system, previous studies have also shown that amphetamine interacts with other neurotransmitters, including the endogenous opioid system. The unselective opioid receptor antagonist naltrexone (NTX) modulates amphetamine-induced effects in both laboratory animals and humans. To further examine this interaction, the aim of the present study was to investigate the effect of NTX on the expression of locomotor sensitization and conditioned locomotor response in animals previously conditioned with amphetamine. Sensitization was induced by repeated administration of amphetamine (2 mg/kg) for 10 consecutive days. After a 10-day drug-free period, the rats were administered NTX (3 mg/kg) 30 minutes prior to the administration of a challenge dose of either amphetamine (0.5 mg/kg) (test for drug-induced sensitization) or saline (test for conditioned locomotor response). NTX had no effect on acute amphetamine-induced locomotor activity or on general locomotor activity in animals without a history of amphetamine conditioning. However, animals previously conditioned with amphetamine showed a sensitized locomotor response to the amphetamine challenge following the 10-day drug-free period. This sensitized response was significantly inhibited by NTX pre-treatment. In addition, NTX pre-treatment blocked the conditioned locomotor response when the amphetamine-conditioned animals were placed in the previously amphetamine-paired context. This study showed that NTX attenuates drug- and cue-induced locomotor behavior in amphetamine-conditioned animals, supporting recent clinical findings that indicated a potential role of NTX as a treatment for amphetamine dependence.

Role of NMDA Receptors in Dopamine Neurons for Plasticity and Addictive Behaviors

A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.

Psychiatrists, Patients Praise Benefits of Telehealth

Back to table of contents Previous article Next article Community NewsFull AccessPsychiatrists, Patients Praise Benefits of TelehealthAaron LevinAaron LevinSearch for more papers by this authorPublished Online:2 May 2008https://doi.org/10.1176/pn.43.9.0013aUniversity of New Mexico psychiatrists use computer-based video teleconferencing systems to overcome the barriers of distance and provider scarcity in a state where patients might otherwise need to drive hours to see a doctor, explained child and adolescent psychiatrist Avi kreichman, M.D., an assistant professor and the telehealth specialist at the Center for Rural and Community Behavioral Health in Albuquerque (see Original article: Rural Psychiatry Isn't Easy, but Rewards are Ample).An Internet-based system carries one-on-one or group conferences with up to 40 remote sites, although psychiatry usually uses only 10, explained technology manager Wesley Pak, M.B.A., recently. Sessions can be recorded and encrypted to meet Health Insurance Portability and Accountability Act standards. The big projection screen at the front of the room is divided into as many small screens as there are participants. When someone speaks, a voice-actuated system enlarges that person's screen area.“Patients like it because it saves them money and hours of travel time,” said Pak.There have been two traditional ways to use telehealth, said Kreichman, sitting in the large studio a few blocks from the university's Health Sciences Center. Specialists either offered consulting services to a primary care provider, or they assessed and treated patients who came to the remote site, sometimes with a local clinician.“We follow those models, but we also help train primary care providers in rural areas, as well as teachers, school psychologists, nurses, parents, children, and health assistants at schools,” he said. He has even trained school security guards, bus drivers, and cafeteria workers in aspects of drug addiction or other topics.These may be didactic programs or case conferences followed up with phone calls or e-mails.One morning in March, Kreichman opened a teleconference with counselors at a rural high school concerned about a rash of teenage pregnancies. The discussion ranged from parent-child relationships to the pregnant girls' emotional states. Kreichman reinforced efforts by the adults to support the teenagers and get them prenatal care and appropriate counseling.Later one participant expressed her frustration at the way teen pregnancy was considered only as an individual matter by local school authorities, rather than one involving broader social and cultural attitudes. Kreichman's knowledge of health systems led him to offer her specific suggestions for approaching state education officials to find some solutions.Another faculty member, assistant professor Florian Birkmayer, M.D., an addiction specialist, spends one day a week on camera, half for the Indian Health Service and half for a clinic in Carlsbad, N.M.The emotional connection can be as intense using telehealth as it is in person, said Birkmayer, although he's noticed one interesting phenomenon about telepsychiatry. “At Carlsbad, when I start with a new patient in person, [the patient is] often reluctant to move to telehealth services, but if we begin with telehealth, it goes much more easily,” he said. ▪ Original article: ISSUES NewArchived

Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area

Intact endogenous cannabinoid signaling is involved in several aspects of drug addiction. Most importantly, endocannabinoids exert pronounced influence on primary rewarding effects of abused drugs, including exogenous cannabis itself, through the regulation of drug-induced increase in bursting activity of dopaminergic neurons in the ventral tegmental area (VTA). Previous electrophysiological studies have proposed that these dopaminergic neurons may release endocannabinoids in an activity-dependent manner to regulate their various synaptic inputs; however, the underlying molecular and anatomical substrates have so far been elusive. To facilitate understanding of the neurobiological mechanisms involving endocannabinoid signaling in drug addiction, we carried out detailed analysis of the molecular architecture of the endocannabinoid system in the VTA. In situ hybridization for sn-1-diacylglycerol lipase-alpha (DGL-α), the biosynthetic enzyme of the most abundant endocannabinoid, 2-arachidonoylglycerol (2-AG), revealed that DGL-α was expressed at moderate to high levels by most neurons of the VTA. Immunostaining for DGL-α resulted in a widespread punctate pattern at the light microscopic level, whereas high-resolution electron microscopic analysis demonstrated that this pattern is due to accumulation of the enzyme adjacent to postsynaptic specializations of several distinct morphological types of glutamatergic and GABAergic synapses. These axon terminal types carried presynaptic CB1 cannabinoid receptors on the opposite side of DGL-α-containing synapses and double immunostaining confirmed that DGL-α is present on the plasma membrane of both tyrosine hydroxylase (TH)-positive (dopaminergic) and TH-negative dendrites. These findings indicate that retrograde synaptic signaling mediated by 2-AG via CB1 may influence the drug-reward circuitry at multiple types of synapses in the VTA.

Dopamine D2 Receptor Modulation of K+ Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials

The nucleus accumbens (NAc) is a forebrain area in the mesocorticolimbic dopamine (DA) system that regulates many aspects of drug addiction. Neuronal activity in the NAc is modulated by different subtypes of DA receptors. Although DA signaling has received considerable attention, the mechanisms underlying D(2)-class receptor (D(2)R) modulation of firing in medium spiny neurons (MSNs) localized within the NAc remain ambiguous. In the present study, we performed whole cell current-clamp recordings in rat brain slices to determine whether and how D(2)R modulation of K(+) channel activity regulates the intrinsic excitability of NAc neurons in the core region. D(2)R stimulation by quinpirole or DA significantly and dose-dependently decreased evoked Na(+) spikes. This D(2)R effect on inhibiting evoked firing was abolished by antagonism of D(2)Rs, reversed by blockade of voltage-sensitive, slowly inactivating A-type K(+) currents (I(As)), or eliminated by holding membrane potentials at levels in which I(As) was inactivated. It was also mimicked by inhibition of cAMP-dependent protein kinase (PKA) activity, but not phosphatidylinositol-specific phospholipase C (PI-PLC) activity. Moreover, D(2)R stimulation also reduced the inward rectification and depolarized the resting membrane potentials (RMPs) by decreasing "leak" K(+) currents. However, the D(2)R effects on inward rectification and RMP were blocked by inhibition of PI-PLC, but not PKA activity. These findings indicate that, with facilitated intracellular Ca(2+) release and activation of the D(2)R/G(q)/PLC/PIP(2) pathway, the D(2)R-modulated changes in the NAc excitability are dynamically regulated and integrated by multiple K(+) currents, including but are not limited to I(As), inwardly rectifying K(+) currents (I(Kir)), and "leak" currents (I(K-2P)).

Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor epsilon1 subunit.

N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamate receptors (GluRs) formed by assembly of the GluRzeta subunit (called NR1 in rats) with any one of four GluRepsilon subunits (GluRepsilon1-4; NR2A-D), play an important role in excitatory neurotransmission, synaptic plasticity and brain development. Recent pharmacological studies have also indicated a role for NMDA receptors in drug addiction. In the present study, we investigated the behavioural adaptations to addictive drugs such as phencyclidine (PCP), methamphetamine (MAP) and morphine (MOR) in mice lacking the GluRepsilon1 subunit of the NMDA receptor. GluRepsilon1 mutant mice exhibited a malfunction of NMDA receptors, as evidenced by the reduction of [3H]MK-801 binding in an autoradiographic receptor binding assay. GluRepsilon1 mutant mice showed an attenuation of acute PCP- and MAP-induced hyperlocomotion. The development of sensitization by repeated treatment with PCP and MAP at a low, but not high, dose was also suppressed. The development of MOR-induced analgesic tolerance and naloxone-precipitated MOR withdrawal symptoms were attenuated in GluRepsilon1 mutant mice. In the place conditioning test, PCP-induced place aversion in naive mice and place preference in PCP-pretreated mice, as well as MOR-induced place preference, were diminished whereas MAP-induced place preference was not affected in GluRepsilon1 mutant mice. These findings provide genetic evidence that GluRepsilon1 subunit-containing NMDA receptors are involved in certain aspects of drug addiction.

Intermittent morphine treatment induces a long-lasting increase in cholinergic modulation of GABAergic synapses in nucleus accumbens of adult rats

Repeated exposure to drugs of abuse causes persistent behavioral sensitization and associated adaptations of striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Microdialysis and neurochemical studies suggest that intermittent morphine treatment may lead to a long-term increase in both ACh and dopaminergic neurotransmission in the nucleus accumbens (NAc). This implies that both cholinergic modulation of GABA synapses and their sensitivity to dopaminergic transmission might be changed, ultimately leading to a modified NAc output. Here we investigate to what extent cholinergic modulation and sensitivity to amphetamine, causing endogenous dopamine efflux, of GABAergic transmission in the nucleus accumbens are affected 3 weeks after a period of daily morphine injections in adult rats. To this end, we recorded medium spiny neurons using whole cell voltage clamp and monitored the frequency and amplitude of spontaneous GABAergic synaptic currents. We observed that the effect of nicotine on the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was suppressed in rats pretreated with morphine, whereas the effects of mecamylamine and tetrodotoxin (TTX) were increased. These results indicate that the probability of GABA release was increased and that this effect resulted from an upregulation of the endogenous activation of presynaptic nicotinic receptors. In addition, we observed an increased sensitivity to in vitro application of amphetamine. This suggests that the long-term increase in dopaminergic transmission caused by the morphine treatment affects GABA synapses in the NAc. Hence, there may be two parallel synaptic mechanisms by which drugs of abuse may affect processing and integration of NAc inputs.

Early consolidation of instrumental learning requires protein synthesis in the nucleus accumbens.

It is widely held that long-term memories are established by consolidation of newly acquired information into stable neural representations, a process that requires protein synthesis and synaptic plasticity. Plasticity within the nucleus accumbens (NAc), a major component of the ventral striatum, is thought to mediate instrumental learning processes and many aspects of drug addiction. Here we show that the inhibition of protein synthesis within the NAc disrupts consolidation of an appetitive instrumental learning task (lever-pressing for food) in rats. Post-trial infusions of anisomycin immediately after the first several training sessions prevented consolidation, whereas infusions delayed by 2 or 4 hours had no effect. However, if the rats were allowed to learn the task, the behavior was not sensitive to disruption by intra-accumbens anisomycin. Control infusions into the medial NAc shell or the dorsolateral striatum did not impair learning; in fact, an enhancement was observed in the latter case. These results show that de novo protein synthesis within the NAc is necessary for the consolidation, but not reconsolidation, of appetitive instrumental memories.

A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats.

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long-lasting sensitization. The present study was designed to evaluate whether long-lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate-putamen, was assessed. In morphine-pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate-putamen from morphine-pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long-lasting behavioural sensitization and associated neuroadaptations.

Creating a DIN to tackle drug-related deaths in the community

Brighton and Hove has one of the highest rates of drug-related deaths in the UK. The deceased commonly have had contact with a number of organizations isolated from each other. The aim of this study was to explore aspects of drug addiction in Brighton as the first stage in the creation of a local Drug addiction Intervention Network (DIN) and to make recommendations about improving the effectiveness of medical contacts so that modifiable risk factors could be addressed appropriately and consistently. The coroner's records of the drug-related deaths in 1998 for Brighton and Hove were cross-referenced with computerized records of the Accident & Emergency department of the local hospital and the police station. Of the 36 drug misusers who died during the year, most were male, mean age 34 years. Alcohol was a common comorbid finding. Seventy-eight per cent were known to the A&E department and 62% had been arrested locally during 1997 or 1998. Such retrospective data can only give limited information. We, therefore, performed a prospective survey. It was carried out by the forensic medical examiner (FME) in 1997-1998, interviewing 41 arrestees to give a profile of the criminally involved drug misusers. With the information obtained, the A&E doctors and FMEs were able to review the medical advice given and establish a protocol for the transfer of severely intoxicated arrestees.

Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats.

The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative antiaddictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies

Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and mu-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization. The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.

Interactions between 18-methoxycoronaridine (18-MC) and cocaine: dissociation of behavioural and neurochemical sensitization

The phenomenon of sensitization has been implicated in various aspects of drug addiction. As such, the present study determined the effects of a potential anti-addictive agent, 18-methoxycoronaridine (18-MC; 40 mg/kg, IP, 19 h earlier), on the expression of sensitization following the repeated administration of cocaine (COC; five once daily injections of 15 mg/kg, IP) or saline. The effects of 18-MC on COC metabolism were also assessed. Compared to vehicle controls, 18-MC significantly enhanced the expression of COC-induced locomotion (0, 10, 20 and 40 mg/kg, IP) in chronic COC treated rats only. In both acute and chronic COC rats, 18-MC potentiated the stereotypy induced by higher COC doses (20 and 40 mg/kg, IP). In contrast, 18-MC abolished the sensitized dopamine (DA) response in the nucleus accumbens (NAC) to COC (20 mg/kg), without altering the DA response of acute COC rats. None of the interactions between 18-MC and COC appear to be related to alterations in COC metabolism as no effect of 18-MC pretreatment was observed on extracellular levels of COC or two of its metabolites, benzoylecogonine and norcocaine. From the present findings, it is concluded that the enhancement of COC-induced behaviour produced by 18-MC pretreatment is independent of effects on either COC pharmacokinetics or COC-induced alterations in DA transmission. However, given that 18-MC decreases the self-administration of COC in laboratory animals, it is proposed that the anti-addictive efficacy of 18-MC might be related to an ability to selectively block the expression of sensitized extracellular levels of DA in the NAC in rats with previous COC experience.