Journal: Frontiers in Pharmacology

Article Title: Plasticity of ventral tegmental area disturbance during abstinence after repeated amphetamine exposure: restoration by selective activation of group II metabotropic glutamate receptors

doi: 10.3389/fphar.2025.1534101

Figure Lengend Snippet: Activation of mGluR2, but not mGluR3, rescues hypodopaminergic VTA activity after short-term abstinence and attenuates anxiety-like behavior: role of the indirect NAc VTA connection and lack of effect on AMPH re-exposure. (A) Impact of acute i.p. injections of either VHC (A-VHC: N = 6, n = 12) or the general group II mGluR agonist LY354740 (3 mg/kg; A-agoGII: N = 5, n = 43), the selective mGluR2 PAM LY487379 (30 mg/kg; A-PAM2: N = 5, n = 43), and the selective mGluR3 agonist LY2794193 (10 mg/kg; A-ago3: N = 7, n = 24) on VTA DA neuron population activity in mice during short-term abstinence after repeated AMPH exposure; ****P < 0.0001, ***P < 0.001, ns P > 0.05 vs. A-VHC; +++ P < 0.001 vs. A-agoGII (one-way ANOVA followed by Bonferroni multiple comparison; df (3,22) = 22.86, P < 0.0001). (B) Following repeated AMPH exposure and short-term abstinence, mice were challenged by a LDT task after i.p. injections of either vehicle (A-VHC: N = 15) or the mGluR2 PAM (A-PAM2: N = 15). 1- Shows the latency to the first escape from the bright chamber into the dark (first latency) **P < 0.01 vs. A-VHC (Unpaired t-test; t(28) = 2.509, P = 0.0091). 2- Displays the total number of entries into the dark chamber. **P < 0.01 vs. A-VHC (Unpaired t-test; t(28) = 3.350, P = 0.0012). 3- Shows the distance travelled during navigation of the dark or lit compartment for mice injected with repeated AMPH and, following short-term abstinence, injected with either VHC or mGluR2 PAM, *P < 0.05, + P < 0.05 (two-way ANOVA followed by Bonferroni multiple comparison; interaction, P = 0.140; treatment, df (1,56) = 5.91, P = 0.0183; compartment, df (1,56) = 6.63, P = 0.0127). (C) Impact of direct infusion of VHC (cn-VHC: N = 5, n = 12), the mGluR2 PAM LY487379 (30µM; cn-PAM2: N = 8, n = 61), or the selective mGluR3 agonist LY2794193 (10µM; cn-ago3: N = 7, n = 10) via acutely implanted cannulas into the NAc of mice during short-term abstinence from repeated AMPH exposure on VTA DA neuron activity. ***P < 0.001 vs. cn-VHC, ns P > 0.05 vs. cn-VHC, +++ P < 0.0001 vs. cn-PAM2 (one-way ANOVA followed by Bonferroni multiple Comparison Test; df (2,19) = 25.99, P < 0.0001). (D) Impact of direct infusion of VHC (cn-VHC: N = 5, n = 47) and kynurenic acid (30µM; cn-KYN-NAc: N = 6, n = 13), respectively, via acutely implanted cannulas into NAc or of TTX into VP (cn-TTX-VP: N = 6, n = 12) prior to i.p. mGluR2 PAM (+PAM2; LY487379 ) injection on VTA DA activity in mice during short-term abstinence from repeated AMPH exposure. ***P < 0.001 vs. cn-VHC, ns P > 0.05 vs. KYN-NAc (one-way ANOVA followed by Bonferroni multiple comparison; df (2,16) = 23.41; P < 0.0001). (E) Impact of i.p. injection of VHC (A-VHC: N = 5, n = 12), the general group II mGluR agonist LY354740 (3 mg/kg; A-agoGII: N = 6, n = 5), or the mGluR2 PAM LY487379 (30 mg/kg; A-PAM2: N = 7, n = 8) in mice during prolonged abstinence from repeated AMPH exposure and injected i.p. with AMPH (2 mg/kg) on VTA DA neuron activity; ns P > 0.05 vs. A-VHC (one-way ANOVA followed by Bonferroni multiple comparison; P = 0.5544). Dashed lines indicate baseline DA neuron population activity.

Article Snippet: SKF81297 ((±)-6-Chloro-2,3,4,5-tetrahydro-1-phenyl-1 H -3-benzazepine) hydrobromide was from Hellobio; LY341495 ((2 S )-2-Amino-2-[(1 S ,2 S )-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid), LY487379 (2,2,2-Trifluoro- N -[4-(2-methoxyphenoxy)phenyl]- N -(3-pyridinylmethyl)ethanesulfonamide hydrochloride) were from Tocris (Biotechne, Austria); LY2794193 ((1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid) from Medchemexpress (Austria).

Techniques: Activation Assay, Activity Assay, Comparison, Injection

Journal: Frontiers in Pharmacology

Article Title: Plasticity of ventral tegmental area disturbance during abstinence after repeated amphetamine exposure: restoration by selective activation of group II metabotropic glutamate receptors

doi: 10.3389/fphar.2025.1534101

Figure Lengend Snippet: Activation of mGluR3, but not mGluR2, restores hyperdopaminergic VTA activity at baseline levels: role of vHPC and lack of effect on AMPH re-exposure. (A) Impact of acute i.p. injections of VHC (A-VHC: N = 7, n = 77), the general group II mGluR agonist LY354740 (3 mg/kg; A-agoGII: N = 6, n = 15), the selective mGluR2 PAM LY487379 (30 mg/kg; A-PAM2: N = 6, n = 19), the selective mGluR3 agonist LY2794193 at 10 mg/kg (A-ago3 (10): N = 7, n = 56), and 5 mg/kg (A-ago3 (5): N = 6, n = 50) on VTA DA neuron activity in mice during prolonged abstinence after repeated AMPH exposure. ***P < 0.001 vs. A-VHC, +++ P < 0.001 vs. A-agoGII ns P > 0.05 vs. A-agoGII; (one-way ANOVA followed by Bonferroni multiple comparison; df (3,25) = 90.97, P < 0.0001). (B) Impact of direct infusion of VHC (cn-VHC: N = 6, n = 70), of the selective mGluR2 PAM LY487379 (30 μM; cn-PAM2: N = 6, n = 19), or of the selective mGluR3 agonist LY2794193 (10 μM; cn-ago3: N = 8, n = 63) via acutely implanted cannulas into vHPC of mice during prolonged abstinence after repeated AMPH exposure on VTA DA neuron activity. ***P < 0.0001 vs. cn-VHC, *P < 0.05 vs. cn-VHC; + P < 0.05 vs. cn-PAM2 (one-way ANOVA followed by Bonferroni multiple comparison; df (2,19) = 16.49, P = 0.0001). (C) Impact of direct infusion of VHC (cn-VHC: N = 5, n = 55), of the selective mGluR2 PAM LY487379 (30 μM; cn-PAM2: N = 7, n = 24), or of the selective mGluR3 agonist LY2794193 (10 μM; cn-ago3: N = 8, n = 18) via acutely implanted cannulas into NAc of mice during prolonged abstinence after repeated AMPH exposure on VTA DA neuron activity. ***P < 0.0001 vs. cn-VHC; ns P > 0.05 vs. cn-PAM2 (one-way ANOVA followed by Bonferroni’s multiple comparison; df (2,19) = 32.99, P < 0.0001). (D) Impact of i.p. injection of VHC (A-VHC: N = 5, n = 6), the general group II mGluR agonist LY354740 (3 mg/kg; A-agoGII: N = 5, n = 11), the selective mGluR2 PAM LY487379 (30 mg/kg; A-PAM2: N = 4, n = 4), or the selective mGluR3 agonist LY2794193 (A-ago3: N = 4, n = 8) in mice during prolonged abstinence from repeated AMPH exposure and injected i.p. with AMPH (2 mg/kg; A-AMPH) on VTA DA neuron activity. ns P > 0.05 vs. A-VHC (one-way ANOVA followed by Bonferroni multiple comparison; P = 0.8158). Dashed lines indicate baseline DA neuron population activity.

Article Snippet: SKF81297 ((±)-6-Chloro-2,3,4,5-tetrahydro-1-phenyl-1 H -3-benzazepine) hydrobromide was from Hellobio; LY341495 ((2 S )-2-Amino-2-[(1 S ,2 S )-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid), LY487379 (2,2,2-Trifluoro- N -[4-(2-methoxyphenoxy)phenyl]- N -(3-pyridinylmethyl)ethanesulfonamide hydrochloride) were from Tocris (Biotechne, Austria); LY2794193 ((1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid) from Medchemexpress (Austria).

Techniques: Activation Assay, Activity Assay, Comparison, Injection