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Recombinant Adeno-Associated Virus-Mediated Expression of Methamphetamine Antibody Attenuates Methamphetamine-Induced Hyperactivity in Mice

View Article: PubMed Central - PubMed

ABSTRACT

Methamphetamine (Meth) is one of the most frequently abused drugs worldwide. Recent studies have indicated that antibodies with high affinity for Meth reduce its pharmacological effects. The purpose of this study was to develop a technique for virus-based passive immunization against Meth effects. We generated a recombinant adeno-associated virus serotype-8 vector (AAV-MethAb) carrying the gene for a Meth-specific monoclonal antibody (MethAb). Infection of 293 cells with AAV-MethAb resulted in the expression and secretion of antibodies which bind to Meth. The viral vector was then examined in adult ICR mice. Systemic administration of AAV-MethAb resulted in long-term expression of MethAb in the serum for up to 29 weeks. Serum collected from the animals receiving AAV-MethAb retained a high specificity for (+)-Meth. Animals were challenged with Meth five weeks after viral injection. Meth levels in the brain and serum were reduced while Meth-induced locomotor activity was significantly attenuated. In conclusion, AAV-MethAb administration effectively depletes Meth from brain and serum while reducing the behavioral response to Meth, and thus is a potential therapeutic approach for Meth abuse.

No MeSH data available.


Related in: MedlinePlus

Pretreatment with AAV-MethAb attenuates Meth-induced locomotor activity in mice.Mice receiving AAV-MethAb (2.5 × 1010 VGC/animal; n = 8, i.p.) or AAV-mCherry (2.5 × 1010 VGC/animal; n = 6, i.p.) were challenged with Meth (1 mg/kg, i.p.) at five weeks post-infection, and behavioral measurements were performed in the activity chambers for 2 h. The effect of AAV-MethAb was assessed by the following measures (p values in parentheses are for the main effect of treatment, comparing AAV-MethAb to AAV-mCherry). None of the interaction effects (time vs. treatment) were statistically significant. (a) Total distance traveled (TOTDIST) (F1,48 = 5.993, p = 0.018); Time: F3,48 = 7.928, p < 0.001; Interaction: F3,48 = 0.119, p = 0.949. (b) Horizontal activity (HACTV) (F1,48 = 6.289, p = 0.016); Time: F3,48 = 5.027, p = 0.004; Interaction: F3,48 = 0.0154, p = 0.997. (c) Movement number (MOVNO) (F1,48 = 7.229, p = 0.01); Time: F3,48 = 1.975, p = 0.013; Interaction: F3,48 = 0.115, p = 0.951. (d) Stereotype count (STRCNT) (F1,48 = 4.708, p = 0.035); Time: F3,48 = 3.850, p = 0.015; Interaction: F3,48 = 0.02, p = 0.996. (e) Stereotype number (STRNO) (F1,48 = 5.49, p = 0.023); Time: F3,48 = 1.166, p = 0.332; Interaction: F3,48 = 0.192, p = 0.901. (f) Vertical movement number (VMOVNO) (F1,48 = 4.535, p = 0.038); Time: F3,48 = 0.772, p = 0.544; Interaction: F3,48 = 0.0297, p = 0.993.
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f3: Pretreatment with AAV-MethAb attenuates Meth-induced locomotor activity in mice.Mice receiving AAV-MethAb (2.5 × 1010 VGC/animal; n = 8, i.p.) or AAV-mCherry (2.5 × 1010 VGC/animal; n = 6, i.p.) were challenged with Meth (1 mg/kg, i.p.) at five weeks post-infection, and behavioral measurements were performed in the activity chambers for 2 h. The effect of AAV-MethAb was assessed by the following measures (p values in parentheses are for the main effect of treatment, comparing AAV-MethAb to AAV-mCherry). None of the interaction effects (time vs. treatment) were statistically significant. (a) Total distance traveled (TOTDIST) (F1,48 = 5.993, p = 0.018); Time: F3,48 = 7.928, p < 0.001; Interaction: F3,48 = 0.119, p = 0.949. (b) Horizontal activity (HACTV) (F1,48 = 6.289, p = 0.016); Time: F3,48 = 5.027, p = 0.004; Interaction: F3,48 = 0.0154, p = 0.997. (c) Movement number (MOVNO) (F1,48 = 7.229, p = 0.01); Time: F3,48 = 1.975, p = 0.013; Interaction: F3,48 = 0.115, p = 0.951. (d) Stereotype count (STRCNT) (F1,48 = 4.708, p = 0.035); Time: F3,48 = 3.850, p = 0.015; Interaction: F3,48 = 0.02, p = 0.996. (e) Stereotype number (STRNO) (F1,48 = 5.49, p = 0.023); Time: F3,48 = 1.166, p = 0.332; Interaction: F3,48 = 0.192, p = 0.901. (f) Vertical movement number (VMOVNO) (F1,48 = 4.535, p = 0.038); Time: F3,48 = 0.772, p = 0.544; Interaction: F3,48 = 0.0297, p = 0.993.

Mentions: A total of 14 mice were infected with AAV-MethAb (2.5 × 1010 VGC/animal; i.p., n = 8) or AAV-mCherry (2.5 × 1010 VGC/animal; i.p., n = 6). At five weeks post-infection, mice were injected with a dose of Meth (1 mg/kg, i.p.) and placed individually into activity chambers to record behavioral activity for 2 h. Horizontal activity, total distance traveled, movement number, stereotype count, stereotype number, and vertical movement number were significantly reduced in AAV-MethAb infected animals compared to AAV-mCherry infected animals (Fig. 3) (Each p < 0.05 for the main effect of treatment by 2-way ANOVA. For complete statistical results see Fig. 3 legend). These results demonstrate that AAV-mediated expression of the anti-Meth antibody in the periphery can reduce Meth-induced hyperactivity in mice.


Recombinant Adeno-Associated Virus-Mediated Expression of Methamphetamine Antibody Attenuates Methamphetamine-Induced Hyperactivity in Mice
Pretreatment with AAV-MethAb attenuates Meth-induced locomotor activity in mice.Mice receiving AAV-MethAb (2.5 × 1010 VGC/animal; n = 8, i.p.) or AAV-mCherry (2.5 × 1010 VGC/animal; n = 6, i.p.) were challenged with Meth (1 mg/kg, i.p.) at five weeks post-infection, and behavioral measurements were performed in the activity chambers for 2 h. The effect of AAV-MethAb was assessed by the following measures (p values in parentheses are for the main effect of treatment, comparing AAV-MethAb to AAV-mCherry). None of the interaction effects (time vs. treatment) were statistically significant. (a) Total distance traveled (TOTDIST) (F1,48 = 5.993, p = 0.018); Time: F3,48 = 7.928, p < 0.001; Interaction: F3,48 = 0.119, p = 0.949. (b) Horizontal activity (HACTV) (F1,48 = 6.289, p = 0.016); Time: F3,48 = 5.027, p = 0.004; Interaction: F3,48 = 0.0154, p = 0.997. (c) Movement number (MOVNO) (F1,48 = 7.229, p = 0.01); Time: F3,48 = 1.975, p = 0.013; Interaction: F3,48 = 0.115, p = 0.951. (d) Stereotype count (STRCNT) (F1,48 = 4.708, p = 0.035); Time: F3,48 = 3.850, p = 0.015; Interaction: F3,48 = 0.02, p = 0.996. (e) Stereotype number (STRNO) (F1,48 = 5.49, p = 0.023); Time: F3,48 = 1.166, p = 0.332; Interaction: F3,48 = 0.192, p = 0.901. (f) Vertical movement number (VMOVNO) (F1,48 = 4.535, p = 0.038); Time: F3,48 = 0.772, p = 0.544; Interaction: F3,48 = 0.0297, p = 0.993.
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f3: Pretreatment with AAV-MethAb attenuates Meth-induced locomotor activity in mice.Mice receiving AAV-MethAb (2.5 × 1010 VGC/animal; n = 8, i.p.) or AAV-mCherry (2.5 × 1010 VGC/animal; n = 6, i.p.) were challenged with Meth (1 mg/kg, i.p.) at five weeks post-infection, and behavioral measurements were performed in the activity chambers for 2 h. The effect of AAV-MethAb was assessed by the following measures (p values in parentheses are for the main effect of treatment, comparing AAV-MethAb to AAV-mCherry). None of the interaction effects (time vs. treatment) were statistically significant. (a) Total distance traveled (TOTDIST) (F1,48 = 5.993, p = 0.018); Time: F3,48 = 7.928, p < 0.001; Interaction: F3,48 = 0.119, p = 0.949. (b) Horizontal activity (HACTV) (F1,48 = 6.289, p = 0.016); Time: F3,48 = 5.027, p = 0.004; Interaction: F3,48 = 0.0154, p = 0.997. (c) Movement number (MOVNO) (F1,48 = 7.229, p = 0.01); Time: F3,48 = 1.975, p = 0.013; Interaction: F3,48 = 0.115, p = 0.951. (d) Stereotype count (STRCNT) (F1,48 = 4.708, p = 0.035); Time: F3,48 = 3.850, p = 0.015; Interaction: F3,48 = 0.02, p = 0.996. (e) Stereotype number (STRNO) (F1,48 = 5.49, p = 0.023); Time: F3,48 = 1.166, p = 0.332; Interaction: F3,48 = 0.192, p = 0.901. (f) Vertical movement number (VMOVNO) (F1,48 = 4.535, p = 0.038); Time: F3,48 = 0.772, p = 0.544; Interaction: F3,48 = 0.0297, p = 0.993.
Mentions: A total of 14 mice were infected with AAV-MethAb (2.5 × 1010 VGC/animal; i.p., n = 8) or AAV-mCherry (2.5 × 1010 VGC/animal; i.p., n = 6). At five weeks post-infection, mice were injected with a dose of Meth (1 mg/kg, i.p.) and placed individually into activity chambers to record behavioral activity for 2 h. Horizontal activity, total distance traveled, movement number, stereotype count, stereotype number, and vertical movement number were significantly reduced in AAV-MethAb infected animals compared to AAV-mCherry infected animals (Fig. 3) (Each p < 0.05 for the main effect of treatment by 2-way ANOVA. For complete statistical results see Fig. 3 legend). These results demonstrate that AAV-mediated expression of the anti-Meth antibody in the periphery can reduce Meth-induced hyperactivity in mice.

View Article: PubMed Central - PubMed

ABSTRACT

Methamphetamine (Meth) is one of the most frequently abused drugs worldwide. Recent studies have indicated that antibodies with high affinity for Meth reduce its pharmacological effects. The purpose of this study was to develop a technique for virus-based passive immunization against Meth effects. We generated a recombinant adeno-associated virus serotype-8 vector (AAV-MethAb) carrying the gene for a Meth-specific monoclonal antibody (MethAb). Infection of 293 cells with AAV-MethAb resulted in the expression and secretion of antibodies which bind to Meth. The viral vector was then examined in adult ICR mice. Systemic administration of AAV-MethAb resulted in long-term expression of MethAb in the serum for up to 29 weeks. Serum collected from the animals receiving AAV-MethAb retained a high specificity for (+)-Meth. Animals were challenged with Meth five weeks after viral injection. Meth levels in the brain and serum were reduced while Meth-induced locomotor activity was significantly attenuated. In conclusion, AAV-MethAb administration effectively depletes Meth from brain and serum while reducing the behavioral response to Meth, and thus is a potential therapeutic approach for Meth abuse.

No MeSH data available.


Related in: MedlinePlus