Cocaine Delirium

Delirium symptoms suggest dysfunction of multiple brain regions.12 Clinical subtypes of delirium with unique and definable phenomenological or physical characteristics are not widely accepted. At present, very little information is known about the neuropathogenesis of cocaine Figure 6.1 Tracking the incidence of cocaine overdose deaths in Dade County, FL. Medicolegal investigations of the deaths were conducted by forensic pathologists. Forensic pathologists evaluated the scene environment and...

Neurochemistry Of Cocaine Dependence

Many drugs with abuse liability including cocaine have been shown to enhance dopaminergic neurotransmission in the mesolimbic drug reward circuits. Cocaine, an indirect-acting dopaminergic agonist, binds to recognition sites on the plasma membrane dopamine (DA) transporter and increases dopamine levels by preventing the reuptake of released dopamine.1-3 Intravenous injection of cocaine has been shown to significantly inhibit dopamine reuptake within 4 s.4 The reinforcing effects of cocaine are...

The DAT as a Target for Cocaine Pharmacotherapies

One pharmacotherapy strategy for the treatment of cocaine dependence that has received significant attention is the development of drugs that antagonize or substitute for cocaine at its site of action in the brain.40,41 Hypothetically, the ideal cocaine antagonist would manifest high-affinity binding to cocaine recognition sites on the DAT, slow dissociation from these binding sites, minimal inhibition of substrate binding and uptake, a long biological half-life, and low abuse liability.40-42...

METHInduced Effects in Human Brain Imaging Studies

Advances in imaging techniques have furthered our knowledge of the neural circuits involved in addiction. Positron emission tomography (PET), single photon emission tomography (SPECT), and function magnetic resonance imaging (fMRI), among others, allow measurement of relevant neurop-harmacological parameters in the living brain. Recent studies using these techniques in METH abusers reveal a number of abnormalities. For example, a PET 18F fluorodeoxyglucose (a marker of brain glucose metabolism)...

Beyond the Role of DA in Nicotine Reinforcement

Although the research described thus far supports the tenet that nicotine reinforcement is regulated by the ability of nAChRs to enhance mesolimbic DA release, an accumulation of evidence questions the simplicity of this dogma. Despite treatment with neuroleptics that block DA receptor stimulation, the percentage of people with schizophrenia who smoke is several times greater than the population as a whole.3,5 In rats, the effects of intra-VTA infusion of nicotine on behavior are dose dependent...

Nicotineassociated Changes In Intracellular Signaling

At the cellular level, nicotine-induced changes in second messenger signaling are thought to support nicotine-associated changes in neurochemistry and behavioral phenotypes. Due to their putative roles in cellular processes underlying learning and memory (for detailed review, see References 112 and113), the extracellular regulated protein kinase (ERK) and cyclic AMP responsive element binding (CREB) signaling pathways have received the most attention for their potential roles in neuroplasticity...

Cholinergic Adaptations In Smokers

The nicotinic acetylcholine receptor (nAChR) is the initial site of action of nicotine. With the advent of in vivo imaging methods, such as single photon emission computed tomography (SPECT), the amount of nicotine occupying nAChR in brain after smoking a cigarette may be measured. The occupancy of nAChR containing the P2-subunit by nicotine after smoking one and two cigarettes has recently been determined using the nicotinic agonist radioligand 123I 5-IA-85380 and SPECT. Occupancy of P2-nAChR...

Dopaminergic Adaptations In Smokers

Alterations in dopamine (DA) levels are associated with the rewarding effects of abused substances including cigarettes. Specifically, the mesolimbic DA pathway, which originates in the ventral tegmental area (VTA) and projects to nucleus accumbens, is believed to be the primary reward pathway in the brain.30 nAChRs containing the alpha7 subunit (a7-nAChR) are abundant in the VTA. Stimulation of these receptors by nicotine or by endogenous acetylcholine, whose release was induced by nicotine or...

GABAergic Adaptations In Smokers

GABA is a major neurotransmitter in the mammalian brain and controls neuronal excitability. It has been implicated in the addictive and withdrawal processes of nicotine dependence. Nicotine stimulates GABA release via modulation of nAChR on GABAergic neurons, which could lead to a decrease in inhibitory tone from GABAergic stimulation of GABAb autoreceptors.50 Alternatively, nicotine-induced alterations in the levels of neurosteroids that regulate GABAa receptors could also potentially lead to...

Opioidergic Adaptations In Smokers

The endogenous opioid system is believed to be the primary common pathway for all drugs of abuse. However, the role of the opioid system in habitual tobacco smoking has only recently become of interest. Using the short-acting mu-opioid antagonist naloxone, some studies have found decreases in smoking behavior in short-term laboratory paradigms69,70 while others have reported no effect of naloxone on smoking behavior.71 The long-acting mu-opioid antagonist naltrexone has been studied more...

Serotonergic Adaptations In Smokers

Serotonin (5-HT) regulates many bodily functions, including appetite85 and sleep (i.e., modulation of REM latency),86 and may be involved in initiation and maintenance of tobacco smoking. Drugs that enhance 5-HT levels facilitate smoking cessation in highly dependent smokers.87-89 In turn, nicotine has been shown to elevate 5-HT levels by stimulating 5-HT release through binding to the nAChR90 and inhibiting 5-HT reuptake.90,91 5-HT levels are further enhanced in the smoker's brain as a...

Hindbrain Inputs to the VTA

Hindbrain regions including the pedunculopontine tegmental nucleus (PPT) and lateral dorsal tegmental nucleus (LDT) give rise to acetylcholinergic, GABAergic, and glutamatergic projections to the VTA that are thought to regulate drug reward.68-70 Local infusion of GABA receptor agonists and lesions to the PPT result in a marked attenuation of nicotine-associated locomotor activation, nicotine CPP, and nicotine self-administration in rodents.71-73 PPT administration of DHpE also greatly...

Summary And Clinical Implications

Nicotine dependence is a complex biobehavioral phenomenon that is likely regulated by cue-driven incentive motivational processes. As suggested by the work described here, antagonism at mGluR5 glutamate, D3 DA, CBj cannabinoid, and P2*nAChRs might have particular promise for promoting nicotine cessation. Preliminary trials indicate that quit rates for P2*nAChR partial agonist varenicline are twice that reported for more traditional therapies.127 Preclinical evidence suggests that even greater...

Neurochemistry of Cue Driven Behaviors

Although the NAc has received the most attention for its role in nicotine reinforcement, other VTA projection areas including the hippocampus, prefrontal cortex, and amygdala contribute to the control that cues have over behavior, or conditioned reinforcement.30,32 Such behaviors may represent changes in incentive motivation that perpetuate drug use even in the absence of drug reinforcement.34 Sensory cues associated with the act of inhaling regulate the degree to which smokers find pleasure in...

Neurochemical Pathology Of Cocaine Delirium

Neurochemistry Addiction

The mesolimbic dopaminergic (DAergic) system is an important pathway mediating reinforcement and addiction to cocaine and other psychostimulants.22 Cocaine potentiates DAergic neurotransmission by binding to the DA transporter and blocking neurotransmitter uptake, leading to marked elevations in synaptic DA (for review, see Reference 23). Long-term cocaine abuse leads to neuroadaptive changes in the signaling proteins that regulate DA homeostasis. DA transporter binding site densities have been...

The Dopamine Transporter and Addiction

Boja, Ph.D.2 1 Department of Psychology, Indiana University of Pennsylvania, Indiana, Pennsylvania 2 U.S. Consumer Product Safety Commission, Directorate for Health Sciences, Bethesda, Maryland 1.1 Dopamine 1.2 Abused Drugs and the Dopamine 1.3 Abused Drugs and Genetic Polymorphism of the Dopamine Dopamine transporter (DAT) is a distinctive feature of dopaminergic neurons, discovered more than 20 years ago.1-5 DAT is the major mechanism for the removal of...

Neurochemistry of Nicotine Dependence

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 2.1 Nicotinic Receptor 2.2 Neurochemical Systems That Support Nicotine 2.2.1 Nicotine 2.2.1.1 The Mesocorticolimbic Dopamine 2.2.1.2 Hindbrain Inputs to the 2.2.1.3 Beyond the Role of DA in Nicotine 2.2.2 Neurochemistry of Cue-Driven 2.3 Nicotine-Associated Changes in Intracellular 2.4 Summary and Clinical Tobacco use is the leading preventable cause of death in North America and a growing medical problem in...

References

NIDA Research Report Methamphetamine Abuse and Addiction, NIDA Research Report, Vol. 2005, 2002. 2. DEA. Total of All Meth Clandestine Laboratory Incidents, Calendar Year 2003, Vol. 2005, Domestic Strategic Intelligence Unit (NDAS) of the Office of Domestic Intelligence, 2003. 3. DEA. Drug Trafficking in the United States, Vol. 2005, Domestic Strategic Intelligence Unit (NDAS) of the Office of Domestic Intelligence, 2001. 4. Alles, G.A. The comparative physiological actions of the...

Novel Therapeutic Targets for METH Addiction

A number of studies have tested compounds that home in on other novel neurotransmitter systems and reveal important clues to the action of METH. Initially classified as an opioid receptor, sigma (a) receptors (sigma-1 and sigma-2) have been implicated in a variety of psychiatric disorders including depression, anxiety, schizophrenia,143,144 and, more recently, psychostimulant addiction.145 Interestingly, sigma receptors are strategically localized in the nucleus accumbens and other areas within...