Table 2. Cellular and Molecular Findings.
| Measuring variable | Species | Control groups | Dose, route | Testing age | Outcomes | References |
|---|---|---|---|---|---|---|
| Monoamine expression | Guinea Pig | Saline injected pregnant dams | 20 mg/kg 2× daily, SC | E25, 30, 35, 40, 50 | Transient initial downregulation of DA, 5HT, and NE receptor expression followed by upregula-tion of DA and NE receptor expression. | Lidow et al., 1999 |
| 5HT system | Rat | Saline injected pregnant dams | 15 mg/kg 2×daily, SC | P30, 60, 180 | 5-HT its metabolite 5-HIAA reduced at P60 but normalized by P180 | Henderson and McMillen, 1993 |
| DA system | Rabbit | Saline injected pregnant dams | 2–4 mg/kg 2×daily, IV | E22, E25, P1, P10, P20, P50, P100 E15 |
Reduction in D1R coupling to GPCR in frontal and cingulate cortices due to improper D1R trafficking to the cell membrane. |
Wang et al., 1995a, 1995b, 1995c Friedman et al., 1996 Friedman and Wang 1998 Jones et al., 2000 Zhen et al., 2001 Harvey, 2004 Stanwood and Levitt, 2007 |
| DA system | Mouse | Saline injected pregnant dams | 20 mg/kg 2×daily, SC | E15 | Reduction in DAT activity, attenuation of D1R function and upregulation of D2R function in the dorsal and basal forebrain | Kubrusly and Bhide, 2010 |
| DA system | Rhesus Monkey Mouse |
Saline injected pregnant dams | 3 mg/kg, 4×daily, IM 3 mg/kg, 4×daily, IM 20 mg/kg 2×daily, SC |
E60 E70 E15 |
Transient changes in D1R and D2R expression in cortical and subcortical regions of the embryonic brain |
Choi and Ronnekleiv, 1996 Fang et al., 1997 Kubrusly et al., 2010 |
| DA system | Rabbit Rat |
Saline injected pregnant dams | 4 mg/kg 2×daily, IV 10 mg/kg 2×daily, SC |
P10, 50, 100 P40–190 |
Brain region specific alterations in DA release on stimulation by either K+ in vitro or by in vivo cocaine injection |
Wang et al., 1995b Keller et al., 1996a |
| Cortical lamination (inclusive of all neuronal types) | Mouse, Rhesus Monkey | Saline injected pregnant dams and cocaine absent fruit | 10, 20 mg/kg 2×daily, IP 20 mg/kg 2×daily, SC 10 mg/kg 2×daily, oral |
E15, E17, PI, P3, P60 P60, 3 yrs |
Lack of discernable lamination in specific regions of the frontal cortex. |
Gressens et al., 1992a, 1992b Kosofsky et al., 1994 Lidow, 1995 Lidow et al., 2001 |
| GABAergic system | Mouse Rat |
Saline injected pregnant dams | 10 and 20mg/kg 2×daily, SC 20mg/kg 2×daily, SC 20 mg/kg 2×daily, IP |
E13,15,17 E15,17,19 |
Decreased tangential migration of GABA neurons and reduced GABA neuron numbers in the dorsal forebrain |
Crandall et al., 2004 McCarthy et al., 2011 Lee et al., 2011 |
| GABAergic system | Mouse | Saline injected pregnant dams | 20 mg/kg 2×daily, SC | P60 | Reduced numerical density of PV + GABA neurons and decreased GABA-to-projection neuron ratio in the mPFC | McCarthy et al., 2012a, 2012b |
| GABAergic system | Rat | Saline injected pregnant dams | 3 mg/kg 2×daily, IV | P45 | Decreased number of spindle-shaped PV-ir neurons, PV-ir dendrites, and candles impinging on oyramidal neurons in the mPFC |
Morrow et al., 2003a Morrow et al., 2005 |
| Glutamatergic system | Rat | Saline injected pregnant dams | 20 mg/kg 2×daily, IP | E15, E17, E19 | Altered radial migration of pyramidal cells in the dorsal forebrain | Lee et al., 2011 |
| Glutamatergic system | Mouse Rabbit |
PF and non-PF saline injected and non-injected pregnant dams | 20 mg/kg 2×daily, SC 2–4 mg/kg 2×daily, IV |
P60 P1, 3, 5, 7, 10, 14, 20, 58 |
Reduced dendritic bundling and wavy appearance in frontal and anterior cingulate cortical pyramidal neurons |
Kosofsky et al., 1994 Jones et al., 1996 Murphy et al., 1997 Stanwood et al., 2001a, 2001b |
| Excitation and Inhibition | Rat | Saline injected pregnant dams | 15 mg/kg, IP3mg/kg, IV | P16, P42 P22–24 |
Reduced GABA receptor surface expression and decreased inhibition resulting in long-term potentiation of excitatory synapses in the mPFC |
Lu et al., 2009 Huang et al., 2011 |
| Glial cells | Mouse Rhesus Monkey |
Saline injected pregnant dams and cocaine absent fruit | 10, 20 mg/kg 2×daily, IP 10 mg/kg 2×daily, oral |
E17 P60 3 yrs |
Transient reduction in GFAP expression |
Gressens et al., 1992b Lidow, 1995 Lidow et al., 2001 |
| BDNF | Rat Mouse |
Saline injected pregnant dams | 30 mg/kg 1×daily, SC 20 mg/kg 2×daily, SC |
E13, 15, 17, P7, P30, P60 | Transient decrease in basal fore-brain BDNF protein expression at E15. Normalized constitutive expression in postnatal mPFC and striatum |
Yan et al., 2004 McCarthy et al., 2011 Kabir et al., 2013 Kabir et al., 2014 McCarthy et al., 2014 |
| Epigenetic modifications | Mouse | Saline injected pregnant dams | 20 mg/kg 2×daily, SC | P30, P60 | Increased Ach3k9,14 and decreased MeCP2 binding at BDNF exons in the mPFC | Kabir et al., 2013, 2014 |
| Proliferation & differentiation | Mouse | Saline injected pregnant dams | 20 mg/kg 2×daily, SC | E18 | Increased β-catenin protein levels in the dorsal forebrain | Novikova et al., 2005b |
| Proliferation | Rhesus Monkey | cocaine absent fruit | 10 mg/kg 2×daily, Oral (fruit) | E73, 113 | Periodic fluctuations in cell production within the fetal cortical proliferative zones at 1.5 and 10 hr following 3-HT injections. No change at E113 | Lidow and Song, 2001a, 2001b |
| Proliferation | Human primary neurons and A2B5+ progenitor cells | Control medium | 1, 10, 100 μM | 20 week old fetal cells and A2B5 + progenitor cells | Down regulated cyclin A2 induced reduction in proliferation | Lee et al., 2008 |
| Apoptosis and cell surviva | Mouse Rhesus Monkey Mouse Human |
Control medium cocaine absent fruit Saline injectedPregnant Dams |
100–500 μM 10 mg/kg 2×daily, Oral (fruit) 20 mg/kg 2×daily, SC 100 μM |
E15 E65 E18 E140 |
Increased cell death within cortical regions and within specific cell populations. Upregulation of the expression of apoptosis and cell survival genes |
Nassogne et al., 1995 Nassogne et al., 1997 He et al., 1999 Novikova et al., 2005a, 2005b Lee et al., 2009 |