Drug-activation of brain reward pathways

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Introduction

A wide variety of biologically important stimuli can serve as rewards and establish adaptive behavior patterns in higher animals. Such stimuli act through brain mechanisms that evolved long before the human invention of the hypodermic syringe, the human harnessing of fire, or the human development of methods for refining and concentrating psychoactive substances that occur in nature. These brain mechanisms utilize endogenous neurotransmitters that are blocked or mimicked by a variety of addictive exogenous substances. The brain mechanisms for feeding, for example, have depended on endogenous opioid peptide neurotransmitters from the earliest stages of our evolutionary history (Josefsson and Johansson, 1979, Kavaliers and Hirst, 1987). A complete understanding of the brain mechanisms of addiction will require an understanding of the anatomy and normal functions of brain pathways that evolved because they served basic adaptive functions.

Our current understanding of the brain circuitry through which various rewards gain control over behavior has developed from studies of brain stimulation reward (Olds and Milner, 1954). Rewarding brain stimulation is useful in anatomical localization of reward-relevant circuit elements because focal electrical stimulation of the brain only activates nerve fibers passing within a fraction of a millimetre of the electrode tip (Fouriezos and Wise, 1984). However, while stimulation differentially activates fibers of different sizes, the stimulation is indiscriminate with respect to the neurotransmitter a given set of fibers carry. Thus our knowledge of the neurochemical subtypes of reward-relevant neurons derives primarily from pharmacological studies; the rewarding effects of brain stimulation can be attenuated or augmented by drugs that are selective for various neurotransmitter systems (Wise and Rompré, 1989), and neurochemically selective drugs can be rewarding in their own right (Wise, 1978). Moreover, laboratory animals can be trained to self-administer drugs injected directly into the brain (Bozarth and Wise, 1981); such injections are, to a significant degree, both anatomically and neurochemically selective.

Section snippets

Activation of reward circuitry by direct brain stimulation

Olds and Milner (1954)first discovered that direct electrical stimulation of the brain can be powerfully rewarding. The initial finding was that rats would return to places where they received stimulation of the septal area (Olds and Milner, 1954). Subsequent mapping studies showed that stimulation of many other, seemingly disparate (Phillips, 1984), brain regions was rewarding (Olds and Olds, 1963); these included structures with presumed sensory (Phillips, 1970), motor (Van Der Kooy and

Activation of reward circuitry by drugs of abuse

Most psychoactive drugs act in the central nervous system Fig. 1 as agonists or antagonists at the receptors for endogenous chemical messengers (neurotransmitters or neuromodulators). Opiates act at receptors for endogenous opioid neurotransmitters (Goldstein et al., 1971); nicotine acts at a subclass (nicotinic) of acetylcholine receptors (Marks et al., 1986); cannabis acts at receptors (Devane et al., 1988) for an endogenous cannabanoid (Devane et al., 1992); phencyclidine acts at the N

Endogenous reward circuitry: current candidates

At the present time, the only firmly identified elements in brain reward circuitry are the mesolimbic dopamine system, its efferent targets in nucleus accumbens, and its local GABAergic afferents. As mentioned above, the reward-relevant actions of amphetamine and cocaine are in the dopaminergic synapses of NAS and perhaps mPFC. The lowest-threshold site for rewarding opiate effects involves μ- and δ-opioid actions on GABAergic neurons in the VTA; a secondary site of opiate rewarding actions

Synaptic inputs to drug reward circuitry

While not yet identified as links crucial to the rewarding effects of drugs of abuse, there are several inputs to the mesolimbic dopamine system that might modulate drug reward by modulating mesolimbic activation. One source of input is GABAergic feedback from NAS; NAS medium spiny neurons project not only to VTA but also to other GABAergic neurons linked to VTA and NAS (Alexander and Crutcher, 1990, Kalivas et al., 1993, Van Bockstaele and Pickel, 1995). Opiates have rewarding actions in some

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