Michael A. Bozarth

A psychomotor stimulant theory of addiction.

The theory is advanced that the common denominator of a wide range of addictive substances is their ability to cause psychomotor activation. This view is related to the theory that all positive reinforcers activate a common biological mechanism associated with approach behaviors and that this mechanism has as one of its components dopaminergic fibers that project up the medial forebrain bundle from the midbrain to limbic and cortical regions. Evidence is reviewed that links both the reinforcing and locomotor-stimulating effects of both the psychomotor stimulants and the opiates to this brain mechanism. It is suggested that nicotine, caffeine, barbiturates, alcohol, benzodiazepines, cannabis, and phencyclidine----each ofwhich also has psychomotor stimulant actions--may activate the docaminergic fibers or their output circuitry. The role of physical dependence in addiction is suggested to vary from drug to drug and to be of secondary importance in the understanding of compulsive drug self-administration. Attempts at a general theory of addiction are attempts to isr late--from a variety of irrelevant actionsmthose drug actions that are responsible for habitual, compulsive, nonmedical drug self-administration. The common assumption of addiction theorists is that general principles of addiction can be learned from the study of one drug and that these principles will have heuristic value for the study of other drugs. Thus far, attempts at a general theory of addiction have failed to isolate common actions that can account for addiction across the range of major drug classes. A major stumbling block has been the psychomotor stimulants--amph etamine and cocainemwhich do not readily fit models traditionally based on depressant drug classes. The present article offers a new attempt at a general theory of addiction. It differs from earlier theories (e.g., Collier, 1968; Himmelsbach, 1943; Jaffe & Sharpless, 1968; Jellinek, 1960; Kalant, 1977; Lindsmith, 1947; Solomon & Corbit, 1974) in that it is based on the common denominator of the psychomotor stimulants---amphetamine, cocaine, and related drugs---rather than on the common denominator of the socalled depressant drugs~opiates, barbiturates, alcohol, and others. We take up two topics before presenting the new theory. First, we briefly discuss the heuristic value of a biological approach and suggest that the biologists distinction between homology and analogy offers a useful insight. Next we discuss the shortcomings of earlier theories--variants of dependence theory. Then we outline the new theory and review the relevant evidence for its three major assertions: (a) that all addictive drugs have psychomotor stimulant actions, (b) that the stimulant actions of these different drugs have a shared biological mechanism, and (c) that the biological mechanism of these stimulant

Intracranial self-administration of morphine into the ventral tegmental area in rats

Abstract The rewarding properties of morphine injected directly into the ventral tegmental area were investigated using a self-administration procedure. Experimentally naive rats demonstrated rapid acquisition of a lever-pressing response which produced a 100 ng infusion of morphine sulfate solution. Response rates were relatively stable and markedly exceeded lever-press rates of rats passively receiving the same pattern of infusions (i.e., yoked control procedure). Intracranial self-administration was effectively blocked by naloxone suggesting that this behavior is mediated through opiate receptors and is not the consequence of mechanical trauma, or changes in osmolarity or pH.

Heroin reward is dependent on a dopaminergic substrate

Abstract The rewarding property of heroin was blocked by pretreatment with either naloxone or pimozide, suggesting that this opiate-receptor mediated effect is dependent on a dopaminergic substrate. The involvement of a dopaminergic mechanism in this effect supports the notion that opiates and other sources of reward activate a similar neural substrate.

Brain reward circuitry: Four circuit elements “wired” in apparent series

Activation of a variety of anatomically distinct sites in the central nervous system can produce rewarding states. Four central reward phenomena are amphetamine injections into nucleus accumbens, morphine injections into the ventral tegmental area, electrical stimulation of the ventral tegmental area, and electrical stimulation of the lateral hypothalamic medial forebrain bundle. Current evidence suggests that these four rewarding events trigger activity in elements of a common reward circuit and that the elements are connected in series. The four partially identified elements in this circuit are (1) descending, fast-recovering, short refractory period fibers of the medial forebrain bundle, (2) separate, opioid peptide-containing afferents to the ventral tegmental area, (3) the dopaminergic cells projecting from the ventral tegmental area to nucleus accumbens, and (4) the dopaminoceptive cells of nucleus accumbens.

Action of drugs of abuse on brain reward systems: An update with specific attention to opiates

In addressing the role that the substrate of brain stimulation reward might play in drug abuse, Wise [47] reviewed evidence relating brain stimulation and psychomotor stimulant reward to dopaminergic but not noradrenergic elements identified with brain reward circuitry. He then speculated that one possible mechanism of opiate, ethanol, barbiturate or benzodiazepine reward might involve a specified disinhibition of the dopaminergic element. He suggested that these drugs might have inhibitory actions on locus coeruleus, which in turn might send an inhibitory projection to the dopaminergic link in reward circuitry. This speculation is challenged with respect to ethanol in the companion article [1] and with respect to opiates in the present article. Recent evidence indicates that the rewarding action of opiates is mediated in the region of the dopaminergic cells of the ventral tegmentum and not in the region of the noradrenergic cells of locus coeruleus. Rewarding opiate injections appear to activate the same or a similar dopaminergic link in brain reward circuitry as that thought to be activated through its afferent inputs in the case of brain stimulation reward and activated at its synaptic terminals in the case of psychomotor stimulant reward. Whether other drugs of abuse activate links in brain reward circuitry which function in parallel or in series with the dopaminergic link identified with opiates and stimulants remains an open question.

L-name and MK-801 attenuate sensitization to the locomotor-stimulating effect of cocaine

Locomotor activity was tested daily following cocaine injections across 21 consecutive days. Subjects were pretreated 30-min before testing with physiological saline, the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NAME), or the NMDA-receptor antagonist MK-801. Other rats received daily injections of physiological saline instead of cocaine just prior to testing. Rats pretreated with saline and injected daily with cocaine showed increased locomotor activity across the 21-day test period. L-NAME pretreatment depressed cocaine-stimulated locomotor activity, while MK-801 pretreatment increased locomotor activity. To test for behavioral sensitization to cocaine, rats were injected with cocaine 72 hours after their last daily injections. Sensitization was seen in saline pretreated subjects injected daily with cocaine compared to subjects injected daily with saline only, but both L-NAME and MK-801 pretreatment strongly attenuated cocaine sensitization. This finding is consistent with the proposed roles of nitric oxide and NMDA-receptors in cellular adaptation and learning.

Neuroanatomical boundaries of the reward-relevant opiate-receptor field in the ventral tegmental area as mapped by the conditioned place preference method in rats

The conditioned place preference produced by morphine microinjected into the ventral tegmental area was studied in rats. Cannula placements were varied along the rostrocaudal plane to determine the approximate anatomical focus of morphines rewarding effect. Microinjections within a 1.4-mm range produced a significant change in place preference suggesting that morphine injected into this zone is rewarding. Injection sites rostral and caudal to this zone were ineffective as were injections ventral to this region. The approximate anatomical boundaries of the reward-relevant opiate-receptor field within the ventral tegmental area correspond well with the distribution of the A10 dopamine-containing cell bodies.

Evidence for the rewarding effects of ethanol using the conditioned place preference method.

Rats were tested for the rewarding effects of ethanol using a place preference conditioning procedure. After receiving a total of 15 daily conditioning trials under 1.0 g/kg ethanol (IP), a significant place preference was produced. Subjects conditioned using saline or 0.5 g/kg ethanol showed no changes in place preference. This study suggests that failures to demonstrate rewarding effects from ethanol with the conditioned place preference method may be due to an insufficient number of conditioning trials or to an inadequate exposure to the drug. The fact that place preference conditioning was effective in demonstrating ethanol reward while other methods have been equivocal suggests that this method may be a valuable technique for studying the mechanisms of ethanol reward.

Conditioned Place Preference: A Parametric Analysis Using Systemic Heroin Injections

A series of experiments is described that explores some of the parametric aspects of place preference conditioning. Several procedures that affect classical conditioning were used, such as increasing the intensity of the unconditioned stimulus and increasing the number of conditioning trials. These manipulations had little effect on the strength of the conditioned response. Alternative explanations for the shift in place preference were also examined, and none of these factors could adequately account for the data. Although place preference is usually tested in drug-free subjects, the strongest place preference was seen when subjects were tested following injections of the conditioning drug. This suggests that the drug cue may be the most salient stimulus associated with the rewarding action of the drug, and the absence of this stimulus may limit the strength of the conditioning seen in most place preference studies.

Neural basis of psychomotor stimulant and opiate reward: Evidence suggesting the involvement of a common dopaminergic system

Data are reviewed that suggest a common neural system may be involved in the rewarding properties of psychomotor stimulant and opiate drugs. This neural system corresponds to elements in the ventral tegmental dopamine system with cell bodies in the ventral tegmentum and axon terminals in the nucleus accumbens. Several lines of evidence have shown that psychomotor stimulant reward involves a drug action in the nucleus accumbens and that opiate reward involves a drug action in the ventral tegmentum. Activation of the ventral tegmental system at either synaptic element can produce reinforcement by an enhancement of dopaminergic neurotransmission in the nucleus accumbens. Although additional brain systems may be involved in the rewarding actions of these compounds, their ability to activate the ventral tegmental dopamine system appears to make an important contribution to their net reinforcing impact.