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      Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis

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          Abstract

          In this review we propose that there are sex differences in how men and women enter onto the path that can lead to addiction. Males are more likely than females to engage in risky behaviors that include experimenting with drugs of abuse, and in susceptible individuals, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression. For this reason women enter into the downward spiral further along the path to addiction, and so transition to addiction more rapidly. We propose that this sex difference is due, at least in part, to sex differences in the organization of the neural systems responsible for motivation and addiction. Additionally, we suggest that sex differences in these systems and their functioning are accentuated with addiction. In the current review we discuss historical, cultural, social and biological bases for sex differences in addiction with an emphasis on sex differences in the neurotransmitter systems that are implicated.

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          Most cited references424

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          The neural basis of addiction: a pathology of motivation and choice.

          A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking. While dopamine is critical for acute reward and initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. Pathophysiological plasticity in excitatory transmission reduces the capacity of the prefrontal cortex to initiate behaviors in response to biological rewards and to provide executive control over drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission. Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control (choice), and enhancing glutamatergic drive in response to drug-associated stimuli.
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            D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons.

            Dopamine shapes a wide variety of psychomotor functions. This is mainly accomplished by modulating cortical and thalamic glutamatergic signals impinging upon principal medium spiny neurons (MSNs) of the striatum. Several lines of evidence suggest that dopamine D1 receptor signaling enhances dendritic excitability and glutamatergic signaling in striatonigral MSNs, whereas D2 receptor signaling exerts the opposite effect in striatopallidal MSNs. The functional antagonism between these two major striatal dopamine receptors extends to the regulation of synaptic plasticity. Recent studies, using transgenic mice in which cells express D1 and D2 receptors, have uncovered unappreciated differences between MSNs that shape glutamatergic signaling and the influence of DA on synaptic plasticity. These studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function.
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              Putting a spin on the dorsal-ventral divide of the striatum.

              Since its conception three decades ago, the idea that the striatum consists of a dorsal sensorimotor part and a ventral portion processing limbic information has sparked a quest for functional correlates and anatomical characteristics of the striatal divisions. But this classic dorsal-ventral distinction might not offer the best view of striatal function. Anatomy and neurophysiology show that the two striatal areas have the same basic structure and that sharp boundaries are absent. Behaviorally, a distinction between dorsolateral and ventromedial seems most valid, in accordance with a mediolateral functional zonation imposed on the striatum by its excitatory cortical, thalamic and amygdaloid inputs. Therefore, this review presents a synthesis between the dorsal-ventral distinction and the more mediolateral-oriented functional striatal gradient.
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                Author and article information

                Contributors
                Journal
                Biol Sex Differ
                Biol Sex Differ
                Biology of Sex Differences
                BioMed Central
                2042-6410
                2012
                7 June 2012
                : 3
                : 14
                Affiliations
                [1 ]Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA
                [2 ]Department of Psychology, University of Michigan, Ann Arbor, MI 48109, USA
                [3 ]Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA
                [4 ]Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA
                Article
                2042-6410-3-14
                10.1186/2042-6410-3-14
                3724495
                22676718
                6ada1825-5c42-4bd4-8d46-142a028c567e
                Copyright © 2012 Becker et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 January 2012
                : 7 June 2012
                Categories
                Review

                Human biology
                addiction,dopamine,acetylcholine,norepinephrine,dynorphin,cocaine,heroin
                Human biology
                addiction, dopamine, acetylcholine, norepinephrine, dynorphin, cocaine, heroin

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