Promoción de conocimientos, capacidades y actitudes

7.5.1 Substantia Nigra and Dorsal Striatum

The Substantia Nigra (SN) and Dorsal Striatum (DS) were selected for

Densitometry analysis shortly after formal hypothesis testing began. The SN is another hub (along with the VTA) of dopamine cell bodies; SN dopamine neurons project to the DS. The only significant differences in Substantia Nigra expression found was a function of Age; Adolescent rat brains expressed a greater density of a6 nAChRs, compared to neonates (across Treatment and Sex).

Density of α4β2 nAChRs in DS (which receives projections from SN) were significantly higher for the PS Treatment group, compared to the PN-exposed offspring. This region also had increased α4β2 nAChR density in adolescence, compared to the neonatal group.

7.5.2 BLA & Cingulate Cortex

The Anterior Cingulate Cortex (CC) is recognized in clinical literature, characterized by reduced activation during cognitive processing for drug-addicted subjects (Goldstein et al., 2009). Because of its involvement in attention processing and drug addiction, the CC was analyzed for nAChR receptor densitometry.

α4β2 nAChR expression pattern variability was significantly different as a

function of Treatment, with PN offspring expressing significantly greater density of α4β2 nAChRs in the CC, compared to PS offspring. For both α4β2 and α7 nAChRs, the CC offspring had greater receptor density binding in adolescence, compared to the neonatal group.

The BLA is functionally connected with the Hippocampus, as a part of

neurocircuitry underlying the emotional processing of stimuli, emotional memory, and learning, (Pidoplichko et al, 2013; Subramaniyan & Dani, 2015). Acquisition of

stimulant-seeking behavior is regulated by efferents sent from the BLA to the NAc, and lesions of the BLA prevent the acquisition of drug-seeking behavior (Whitelaw et al. 1996). Activation of both α7 and α4β2 nAChRs in the BLA are a function of reward- based learning and seeking behavior.

This study found one significant difference in the BLA; Males expressed greater density of the α7 nAChR, compared to females.

7.5.3 Medial Habenula, Interpeduncular Nucleus, Raphe Nucleus

The Medial Habenula (MHb) was examined for nAChR densitometry, as it is often-cited for its involvement in tobacco smoking dependence (Kenny et al., 2012); although the MHb is commonly associated with the α5 containing nAChR subunits, both α4β2 and α6 nAChR subunits are expressed in the MHb (Shih et al., 2014).

However, no statistically significant, sufficiently powered main effects were found for the MHb in this sample.

The Interpeduncular Nucleus (IPN) and Raphe Nucleus (RN)were selected for analysis; both of these regions are involved in directing and maintaining sleep-wake cycles. The clinical literature indicates that sleep problems are common, especially early in life, for offspring exposed to maternal tobacco (Blood-Siegried et al., 2010); Boychuck et al., (2011) found that newborns experience withdrawals following parturition, and nicotine withdrawal during the early days of birth, shifts sleep-wake patterns, potentially making offspring more vulnerable to cardiac complications.

No significant, sufficiently powered differences were found for any receptor subtype in either the IPN or the RN.

7.5.4 Cortices: Insular (Agranular) Cortex, Auditory Cortex, Motor Cortex, Parietal Cortex, Somatosensory Cortex

The Insular Cortex was selected for densitometry because of this region’s involvement in smoking behavior. The insular cortex is important for tobacco addiction

in human smokers, and it’s ablation can dramatically decrease, and even eliminate smoking behaviors (Hollander et al., 2008). In the Insular Cortex, receptor density was altered as a function of Treatment; the PN group had greater levels of α7 nAChR expression density, and both α4β2 and α7 levels were significantly different between neonatal and adolescent groups; adolescents expressed greater density for both types of nAChR.

The Auditory Cortex function is appreciably damaged by nicotine perinatal nicotine exposure (Armamakis et al., 2000). Moreover, the Auditory Cortex is part of the circuitry involved in attention and sensory processing (along with the Parietal and

Somatosensory Cortices), and nicotine exposure during prenatal and perinatal periods underlies several attention and sensory processing cognitive deficits among offspring (Heath & Piccioto, 2008).

Densitometry results in the Auditory Cortex were mixed, but nAChR expression was changed for both α4β2 and α7 nAChRs; PN animals had lower levels of α4β2 nAChRs compared to PS animals, but the opposite was found for density of α7 nAChR expression; PN animals had significantly higher levels of nAChR expression.

The Motor Cortex was included as a control region; as expected, the only

significant difference for this region was a function of Age, with adolescents expressing higher nAChR levels. The Parietal Cortex densitometry revealed fewer α4β2 nAChRs expressed in the PN group. In the Somatosensory Cortex, nAChR expression varied as a function of Treatment and Age, with a significant interaction revealed.

PN animals expressed fewer α4β2 nAChRs, but adolescents expressed higher levels of α4β2 nAChRs. The graphic in this report shows that PN animals, as neonates,

have significantly higher α4β2 levels, but by adolescence, both PN and PS groups appear to approach similar means.

7.6SUMMARY

The results of this study indicate low-dose IV prenatal nicotine has complex effects on nAChR expression levels in the neonatal and adolescent rat brain. The upregulation of nAChRs in brain regions underlying motivated behavior, point to a potential mechanism for the long-term changes in motivated, drug-seeking behavior seen in the population of maternal-tobacco smoke exposed offspring.