Neural mechanisms of reproduction in females as a predisposing factor for drug addiction

Abstract

There is an increasing awareness that adolescent females differ from males in their response to drugs of abuse and consequently in their vulnerability to addiction. One possible component of this vulnerability to drug addiction is the neurobiological impact that reproductive physiology and behaviors have on the mesolimbic dopamine system, a key neural pathway mediating drug addiction. In this review, we examine animal models that address the impact of ovarian cyclicity, sexual affiliation, sexual behavior, and maternal care on the long-term plasticity of the mesolimbic dopamine system. The thesis is that this plasticity in synaptic neurotransmission stemming from an individual's normal life history contributes to the pathological impact of drugs of abuse on the neurobiology of this system. Hormones released during reproductive cycles have only transient effects on these dopamine systems, whereas reproductive behaviors produce a persistent sensitization of dopamine release and post-synaptic neuronal responsiveness. Puberty itself may not represent a neurobiological risk factor for drug abuse, but attendant behavioral experiences may have a negative impact on females engaging in drug use.

Figure 1

Schematic representation of select cell signaling pathways involved in drug addiction. Activation of cell membrane receptors, such as D1 and Trk receptors, results in the propagation of that signal through multiple intracellular signaling cascades. Specifically, the MAPK and adenylate cyclase/PKA signaling cascades have been shown to be activated via dopaminergic signaling. Ultimately, activation of these intracellular signaling cascades results in gene transcription within the nucleus of the cell. Two of the many downstream gene targets of such signaling are CREB and ΔFosB. Whereas CREB phosphorylation is believed to mediate some of the behavioral plasticity resulting from drugs of abuse, the accumulation of the stable transcription factor ΔFosB is postulated to underlie drug induced structural plasticity. Targets of ΔFosB transcription in turn can affect intrinsic membrane excitability through the insertion of GluR2 subunits into AMPA receptors, as well as structural changes through dendritic spine plasticity via cdk5 activation. Importantly, D2 receptor activation counteracts D1 receptor activation [50].

Figure 2

Plasma concentrations of estradiol (E₂) and progesterone (P₄) throughout the human menstrual and rat estrous cycles. Values represent the means of measurements taken daily from women and at two-hour intervals from rats. The four-day estrous cycle is broken down into its stages: diestrus-1 (D1), diestrus-2 (D2), proestrus (P), and estrus (E). Vertical lines indicate ovulation. Modified from [207] and [66].

Figure 3

Female sexual experience sensitizes the activity response to amphetamine. When exposed to amphetamine for the first time, sexually experienced female hamsters show a significant increase in activity at the 10 min time point (*) when compared to sexually naïve female hamsters. This activity level remains elevated in sexually experienced females through the first 30 min of the test period (data from [24]).

Figure 4

Schematic representation of the proposed circuitry for pair bonding in female prairie voles. Various sensory stimuli ultimately result in dopaminergic and peptidergic release at the level of the nucleus accumbens, thereby positioning the nucleus accumbens in an optimal anatomical location to act as a coincidence detector for pair bond formation [226]. DA, dopamine; MeA, medial amygdala; NAc, nucleus accumbens; NTS, nucleus tractus solitarius; PAG, periaqueductal gray; PFC, prefrontal cortex; PVN, paraventricular nucleus; VTA, ventral tegmental area.