A stereotaxic atlas of the rat brain

Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These"hard-wired"changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

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Neurobiologic Processes in Drug Reward and Addiction

This article summarizes the main discussions at a meeting on the biological, social and clinical bases of drug addiction focused on contemporary topics in drug dependence. Four main domains are surveyed, reflecting the structure of the meeting: psychological and pharmacological factors; neurobiological substrates; risk factors (including a consideration of vulnerability from an environmental and genetic perspective); and clinical treatment. Among the topics discussed were tolerance, sensitization, withdrawal, craving and relapse; mechanisms of reinforcing actions of drugs at the behavioural, cognitive and neural levels; the role of subjective factors in drug dependence; approaches to the behavioural and molecular genetics of drug dependence; the use of functional neuroimaging; pharmaceutical and psychosocial strategies for treatment; epidemiological and sociological aspects of drug dependence. The survey takes into account the considerable disagreements and controversies arising from the discussions, but also reaches a degree of consensus in certain areas.

The biological, social and clinical bases of drug addiction: commentary and debate

Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors.

Publisher Summary This chapter presents the dopamine (DA) hypothesis of drug addiction. Drug addiction is a brain disorder caused by the repetitive use of various chemicals that alter the normal functioning of the central nervous system with consequent behavioral abnormalities. A neurotransmitter system (the mesolimbic DA system) appears to be modified in its functioning more than others, and appears to fluctuate differently and predictably depending on acute drug challenge, chronic drug treatments, and withdrawal conditions irrespective of the chemical abused. The DA system participates in the most harmful consequences of repetitive drug use and is a major determinant of craving and relapse even after drug-free periods. The dopamine hypothesis contends that a hypodopaminergic state characterizes animal models of drug addiction and addicted human brains, and the frequently cited increase in activity after acute drug challenge plays only a minor initial role in the disease and its development over time. The mesolimbic DA system displays a reduced spontaneous activity after chronic drug intake and withdrawal— that is, the crucial phases of addiction. In experimental animal models, when direct measures of DA neurons' functioning are employed, a reduction in spontaneous activity is reported irrespective of the addicting chemical. When methods, such as place-conditioning studies, self-administration, and intracranial self-stimulation (ICSS) are applied, aversion, increased self-administration, and higher current thresholds (BP) respectively are observed in similar conditions. Studies of human addicts coherently report a reduction of D 2 receptors and reduction in DA release

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The dopamine hypothesis of drug addiction: hypodopaminergic state.

Two specific 5-HT1A agonists, 8-OH-DPAT (0–300 Μg/kg), and buspirone (0–3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 Μg/kg produced a sustained enhancement of responding while higher doses (100–300 Μg/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT1A autoreceptor-mediated inhibition of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.

5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward.

5-HT3 receptors are abundant in central dopamine (DA) terminal areas. They do not affect basal DA turnover but appear to modulate DA release by e.g. morphine and nicotine. The interpretation of these findings is uncertain, and it is unclear whether 5-HT3 receptors also influence the activity of compounds such as amphetamine and cocaine, which act more directly on the DA synapse. Variable-interval (VI), threshold-current hypothalamic self-stimulation can provide a continuous index of central dopaminergic activity, but is relatively insensitive to changes in 5-HT and thus offers a means of investigating this question. In the present study, a selective 5-HT3 receptor antagonist, ondansetron (GR 38032F) (1.0 to 1000 μg/kg sc), had no effect on VI self-stimulation, nor did a 100 μg/kg dose affect facilitation of responding byd-amphetamine (500 jig/kg ip). Ondansetron (100 μg/kg) reduced the initial depression of self-stimulation by high-dose nicotine (400 μg/kg), but not the ensuing facilitation. Similar results were obtained in rats “sensitized” to nicotine by prior chronic exposure. These results support the proposal that 5-HT3 receptors, normally quiescent under basal conditions, mediate the excitatory effect of compounds acting upstream from the DA neuron, such as nicotine, but do not affect the dopaminergic synapse directly.

The effect of a 5-HT3 receptor antagonist, ondansetron, on brain stimulation reward, and its interaction with direct and indirect stimulants of central dopaminergic transmission.

Nicotine is thought to be an important factor in addiction to tobacco but its psychopharmacological properties are still uncertain. In the present study, rats were trained to operate a pedal to obtain threshold-current, variable-interval hypothalmic stimulation. Response rates were printed out at 10min intervals to provide a continuous record of facilitatory or depressant effects by injected nicotine. Responding was enhanced in all rats but this depended on dose, time after injection, and previous exposure to the drug. In the first 10min after injection, responding by drug-naive rats was either unaffected (40-130mg/kg s.c., as base) or strongly depressed (400µg/kg). This phase was followed by prolonged (>50min) dose-dependent facilitation. Higher doses (1.3mg/kg) caused prostration. Chronic exposure to nicotine (400µg/kg x 10 at 2-5 day intervals) reduced the initial depressant effect; it also augmented subsequent responding, but only in the early minutes after injection; the latter finding indicates that apparent sensitization to chronic nicotine may depend primarily on tolerance to its depressant effects, rather than on receptor upregulation. Stimulant and depressant effects of nicotine were prevented by pretreatment with the centrally acting antagonist, mecamylamine (2.0mg/kg s.c.), but not by the peripheral antagonist, hexamethonium (1.0mg/kg s.c.) or by the muscarinic receptor antagonist, hyoscine (scopolamine; 100-300µg/kg s.c.). Self-stimulation was unaffected by mecamylamine alone. Thus the inhibitory action of nicotine is unlikely to be due to depolarization block, peripheral activity or muscarinic activity. Its facilitatory and depressant effects appear to be narrowly time- and dose-specific, thus accounting for divergent findings in many studies.

Tolerance and sensitization to stimulant and depressant effects of nicotine in intracranial self-stimulation in the rat.

Upward or downward shifts in the level of brain GABAergictransmission have been held to be necessary and sufficient to promote release of endogenous ligands ('endocoids') for the benzodiazepine (BZD) recognition site. To investigate this possibility, variable-interval self-stimulation performance was used to monitor 'intrinsic' benzodiazepine-like and anti- benzodiazepine activity by the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788 (flumazenil) (10 or 30 mg/kg intraperitoneally). Rats were pretreated with either a GABA synthesis blocking agent (isoniazid, 130 mg/kg subcutaneously), or with a GABA agonist (progabide, 30 or 100 mg/kg intraperitoneally). The lower dose of Ro 15-1788 (10 mg/kg), without pretreatment, did not affect self-stimulation; higher doses (30 mg/kg) caused a brief (<20 min) depression. Isoniazid (130 mg/kg) depressed self-stimulation, but did not modify the activity of Ro 15-1788. In rats pretreated with progabide (100 mg/kg), low doses of Ro 15- 1788 (10 mg/kg) that were previously without effect now caused a sharp fall in responding. These findings can be interpreted as showing that even low doses of Ro 15-1788 may affect self-stimulation under certain conditions, and that they do so by competing with an endogenous ligand for the benzodiazepine site, released by upward shifts in GABAergic activity. Alternative explanations in terms of altered receptor function seem less feasible. The results imply that the action of the endogenous ligand would not resemble that of a typical benzodiazepine, but that of an inverse agonist (that is, proconflict and proconvulsant); this conclusion agrees with recent biochemical evidence.

Evidence that background GABAergic tone and possible ligand release may alter the action of the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788, in hypothalamic self-stimulation.

I. C. Rose

Papers

5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward.

The effect of a 5-HT3 receptor antagonist, ondansetron, on brain stimulation reward, and its interaction with direct and indirect stimulants of central dopaminergic transmission.

Tolerance and sensitization to stimulant and depressant effects of nicotine in intracranial self-stimulation in the rat.

Evidence that background GABAergic tone and possible ligand release may alter the action of the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788, in hypothalamic self-stimulation.