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In this research, a non-fragile synchronization of bidirectional association memory (BAM) delayed neural networks is taken into consideration. The controller gain fluctuation seems in a very random manner, that obeys sure Bernoulli distributed noise sequences. Delay dependent criteria are derived to confirm the asymptotic stability of the BAM delayed neural networks. The non-fragile controller are often obtained by determination a collection of linear matrix inequalities (LMIs). A simulation example is used to demonstrate the efficiency of the developed control.

The synthesis of hemiaminals of isatin derivatives is described by the reaction of isatin with formaldehyde in the presence of TBAF in water at ambient temperature. The procedure is very simple, convenient, and efficient, which provides high yield of product. Additionally the method is applicable for both varieties of substituted isatins derivatives. Moreover, the environmentally benign nature of reaction media makes the procedure attractive alternative over earlier methods.

In this paper, stability for a class of stochastic memristor Cohen–Grossberg BAM neural networks with time-varying delays and reaction–diffusion are considered. A set of novel sufficient conditions on p th moment exponential stability of the equilibrium point are investigated for the considered system. We constructed Lyapunov functional and utilized stochastic stability theory and It o ˆ ’s differential formula. Finally, two examples are provided to illustrate the effectiveness of the derived main results.

G protein-gated inwardly rectifying K+ (GIRK) channels form highly active heterotetramers in the body, such as in neurons (GIRK1/GIRK2 or GIRK1/2) and heart (GIRK1/GIRK4 or GIRK1/4). Based on three-dimensional atomic resolution structures for GIRK2 homotetramers, we built heterotetrameric GIRK1/2 and GIRK1/4 models in a lipid bilayer environment. By employing a urea-based activator ML297 and its molecular switch, the inhibitor GAT1587, we captured channel gating transitions and K+ ion permeation in sub-microsecond molecular dynamics (MD) simulations. This allowed us to monitor the dynamics of the two channel gates (one transmembrane and one cytosolic) as well as their control by the required phosphatidylinositol bis 4-5-phosphate (PIP2). By comparing differences in the two trajectories, we identify three hydrophobic residues in the transmembrane domain 1 (TM1) of GIRK1, namely, F87, Y91, and W95, which form a hydrophobic wire induced by ML297 and de-induced by GAT1587 to orchestrate channel gating. This includes bending of the TM2 and alignment of a dipole of two acidic GIRK1 residues (E141 and D173) in the permeation pathway to facilitate K+ ion conduction. Moreover, the TM movements drive the movement of the Slide Helix relative to TM1 to adjust interactions of the CD-loop that controls the gating of the cytosolic gate. The simulations reveal that a key basic residue that coordinates PIP2 to stabilize the pre-open and open states of the transmembrane gate flips in the inhibited state to form a direct salt-bridge interaction with the cytosolic gate and destabilize its open state.

Glutamate signalling through the N-methyl-d-aspartate receptor (NMDAR) activates the enzyme neuronal nitric oxide synthase (nNOS) to produce the signalling molecule nitric oxide (NO). We hypothesized that disruption of the protein-protein interaction between nNOS and the scaffolding protein postsynaptic density 95 kDa (PSD95) would block NMDAR-dependent NO signalling and represent a viable therapeutic route to decrease opioid reward and relapse-like behaviour without the unwanted side effects of NMDAR antagonists. We used a conditioned place preference (CPP) paradigm to evaluate the impact of two small-molecule PSD95-nNOS inhibitors, IC87201 and ZL006, on the rewarding effects of morphine. Both IC87201 and ZL006 blocked morphine-induced CPP at doses that lacked intrinsic rewarding or aversive properties. Furthermore, in vivo fast-scan cyclic voltammetry (FSCV) was used to ascertain the impact of ZL006 on morphine-induced increases in dopamine (DA) efflux in the nucleus accumbens shell (NAc shell) evoked by electrical stimulation of the medial forebrain bundle (MFB). ZL006 attenuated morphine-induced increases in DA efflux at a dose that did not have intrinsic effects on DA transmission. We also employed multiple intravenous drug self-administration approaches to examine the impact of ZL006 on the reinforcing effects of morphine. Interestingly, ZL006 did not alter acquisition or maintenance of morphine self-administration, but reduced lever pressing in a morphine relapse test after forced abstinence. Our results provide behavioural and neurochemical support for the hypothesis that inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse-like behaviour, highlighting a previously unreported application for these novel therapeutics in the treatment of opioid addiction.

Blockade of cannabinoid type 1 (CBsub1/sub)-receptor signaling decreases the rewarding properties of many drugs of abuse and has been proposed as an anti-addiction strategy. However, psychiatric side-effects limit the clinical potential of orthosteric CBsub1/subantagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenuate CBsub1/subsignaling by decreasing affinity and/or efficacy of CBsub1/subligands. We hypothesized that a CBsub1/sub-NAM would block opioid reward while avoiding the unwanted effects of orthosteric CBsub1/subantagonists. GAT358, a CBsub1/sub-NAM, failed to elicit cardinal signs of direct CBsub1/subactivation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CBsub1/subagonist CP55,940, suggesting that a CBsub1/sub-NAM blocked cardinal signs of CBsub1/subactivation. Next, GAT358 was evaluated using in vivo assays of opioid-induced dopamine release and reward in male rodents. In the nucleus accumbens shell, a key component of the mesocorticolimbic reward pathway, morphine increased electrically-evoked dopamine efflux and this effect was blocked by a dose of GAT358 that lacked intrinsic effects on evoked dopamine efflux. Moreover, GAT358 blocked morphine-induced reward in a conditioned place preference (CPP) assay without producing reward or aversion alone. GAT358-induced blockade of morphine CPP was also occluded by GAT229, a CBsub1/subpositive allosteric modulator (CBsub1/sub-PAM), and absent in CBsub1/sub-knockout mice. Finally, GAT358 also reduced oral oxycodone (but not water) consumption in a two-bottle choice paradigm. Our results support the therapeutic potential of CBsub1/sub-NAMs as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side-effects.

Background The α7 nicotinic acetylcholine receptor (α7 nAChR) negatively regulates the synthesis and release of pro-inflammatory cytokines by immune cells. Our previous studies showed that in encephalitogenic T cells, α7 nAChR expression is upregulated and that activation of the cholinergic system can attenuate experimental autoimmune encephalomyelitis (EAE). GAT107 is an allosteric agonist and positive allosteric modulator (ago-PAM) of α7 nAChR that can produce persistent activation of this receptor. Therefore, in the present study, we investigated the effect of GAT107 on neuroinflammation in EAE, the animal model used for the study of multiple sclerosis (MS) via α7 nAChR, and the inflammatory pathways involved. Methods EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35–55) in C57BL/6 mice. EAE mice were treated with the ago-PAM GAT107 or a placebo for 9 days, starting from the day of EAE induction. Clinical assessment and immunological evaluation of immune cells and cytokine production was performed. Results Following activation of the α7 nAChR by GAT107 during EAE, disease severity was significantly reduced by 70% and was correlated with a reduction in the extent of neuroinflammation in the CNS. The treatment reduced encephalitogenic T cell proliferation and the production of pro-inflammatory cytokines, as well as increased the production of the anti-inflammatory cytokine IL-10. Furthermore, the expression of immune cell markers was altered by GAT107 treatment, which induced a significant reduction in macrophages, dendritic cells, and B cells, as well as a reduction in anti-MOG35–55 antibodies. Additionally, GAT107 was found to directly activate α7 nAChR in murine macrophage RAW264.7 cells and in human PBMCs derived from MS patients and healthy donors. Conclusions Our results show that GAT107 can be a useful molecule for harnessing the cholinergic anti-inflammatory pathway for long-lasting and wide-ranging modulation and downregulation of neuroinflammation in EAE.

We report the development of novel cannabinergic probes that can stabilize the cannabinoid receptors (CBRs) through tight binding interactions. Ligand design involves the introduction of select groups at a judiciously chosen position within the classical hexahydrocannabinol template (monofunctionalized probes). Such groups include the electrophilic isothiocyanato, the photoactivatable azido, and the polar cyano moieties. These groups can also be combined to produce bifunctionalized probes potentially capable of interacting at two distinct sites within the CBR-binding domains. These novel compounds display remarkably high binding affinities for CBRs and are exceptionally potent agonists. A key ligand (27a, AM11245) exhibits exceptionally high potency in both in vitro and in vivo assays and was designated as "megagonist," a property attributed to its tight binding profile. By acting both centrally and peripherally, 27a distinguishes itself from our previously reported "megagonist" AM841, whose functions are restricted to the periphery.

Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3–3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.

This article, we explore the stability analysis of stochastic fractional-order competitive neural networks with leakage delay. The main objective of this paper is to establish a new set of sufficient conditions, which is for the uniform stability in mean square of such stochastic fractional-order neural networks with leakage. Specifically, the presence and uniqueness of arrangements and stability in mean square for a class of stochastic fractional-order neural systems with delays are concentrated by using Cauchy-Schwartz inequality, Burkholder-Davis-Gundy inequality, Banach fixed point principle and stochastic analysis theory, respectively. Finally, four numerical recreations are given to confirm the hypothetical discoveries.

The currents of α7 nicotinic acetylcholine receptors activated by acetylcholine (ACh) are brief. The channel has high permeability to calcium relative to monovalent cations and shows inward rectification. It has been previously noted that in the presence of positive allosteric modulators (PAMs), currents through the channels of α7 receptors differ from normal α7 currents both in sensitivity to specific channel blockers and their current-voltage (I-V) relationships, no longer showing inward rectification. Linear I-V functions are often associated with channels lacking calcium permeability, so we measured the I-V functions of α7 receptors activated by ACh when PAMs were bound to the allosteric binding site in the transmembrane domain. Currents were recorded in chloride-free Ringer’s solution with low or high concentrations of extracellular calcium to determine the magnitude of the reversal potential shift in the two conditions as well as the I-V relationships. ACh-evoked currents potentiated by the allosteric agonist–PAMs (ago-PAMs) (3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (GAT107) and 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propenamide (B-973B) showed reduced inward rectification and calcium-dependent reversal potential shifts decreased by 80%, and 50%, respectively, compared with currents activated by ACh alone, indicative of reduced calcium permeability. Currents potentiated by 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide were also linear and showed no calcium-dependent reversal potential shifts. The ago-PAMs GAT-107 and B-973B stimulated increases in intracellular calcium in stably transfected HEK293 cells. However, these calcium signals were delayed relative to channel activation produced by these agents and were insensitive to the channel blocker mecamylamine. Our results indicate that, although allosterically activated α7 nicotinic ACh receptor may affect intracellular calcium levels, such effects are not likely due to large channel-dependent calcium influx. SIGNIFICANCE STATEMENT: Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor can increase channel activation by two or more orders of magnitude, raising the concern that, due to the relatively high calcium permeability of α7 receptors activated by acetylcholine alone, such efficacious PAMs may have cytotoxic side effects. We show that PAMs alter the ion conduction pathway and, in general, reduce the calcium permeability of the channels. This supports the hypothesis that α7 effects on intracellular calcium may be independent of channel-mediated calcium influx.

Many synthetic compounds to which we attribute specific activities are produced as racemic mixtures of stereoisomers, and it may be that all the desired activity comes from a single enantiomer. We have previously shown this to be the case with the α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS) and the α7 ago-PAM 4BP-TQS. Cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-te-trahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (2,3,5,6TMP-TQS), previously published as a "silent allosteric modulator" and an antagonist of α7 allosteric activation, shares the same scaffold with three chiral centers as the aforementioned compounds. We isolated the enantiomers of 2,3,5,6TMP-TQS and determined that the (-) isomer was a significantly better antagonist than the (+) isomer of the allosteric activation of both wild-type α7 and the nonorthosterically activatible C190A α7 mutant by the ago-PAM GAT107 (the active isomer of 4BP-TQS). In contrast, (+)2,3,5,6TMP-TQS proved to be an α7 PAM. (-)2,3,5,6TMP-TQS was shown to antagonize the allosteric activation of α7 by the structurally unrelated ago-PAM B-973B as well as the allosteric activation of the TQS-sensitive α4β2L15'M mutant. In silico docking of 2,3,5,6TMP-TQS in the putative allosteric activation binding site suggested a specific interaction of the (-) enantiomer with α7T106, and allosteric activation of α7T106 mutants was not inhibited by (-)2,3,5,6TMP-TQS, confirming the importance of this interaction and supporting the model of the allosteric binding site. Comparisons and contrasts between 2,3,5,6TMP-TQS isomers and active and inactive enantiomers of other TQS-related compounds identify the orientation of the cyclopentenyl ring to the plane of the core quinoline to be a crucial determinate of PAM activity. SIGNIFICANCE STATEMENT: Many synthetic ligands are in use as racemic preparations. We show that one enantiomer of the TQS analog Cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-te-trahydro-3H-cyclopenta[c]quinoline-8-sulfonamide, originally reported to lack activity when used as a racemic preparation, is an α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM). The other enantiomer is not a PAM, but it is an effective allosteric antagonist. In silico studies and structural comparisons identify essential elements of both the allosteric ligands and receptor binding sites important for these allosteric activities.

G-protein–gated inwardly-rectifying K(+) (GIRK) channels are targets of G(i/o)-protein–signaling systems that inhibit cell excitability. GIRK channels exist as homotetramers (GIRK2 and GIRK4) or heterotetramers with nonfunctional homomeric subunits (GIRK1 and GIRK3). Although they have been implicated in multiple conditions, the lack of selective GIRK drugs that discriminate among the different GIRK channel subtypes has hampered investigations into their precise physiological relevance and therapeutic potential. Here, we report on a highly-specific, potent, and efficacious activator of brain GIRK1/2 channels. Using a chemical screen and electrophysiological assays, we found that this activator, the bromothiophene-substituted small molecule GAT1508, is specific for brain-expressed GIRK1/2 channels rather than for cardiac GIRK1/4 channels. Computational models predicted a GAT1508-binding site validated by experimental mutagenesis experiments, providing insights into how urea-based compounds engage distant GIRK1 residues required for channel activation. Furthermore, we provide computational and experimental evidence that GAT1508 is an allosteric modulator of channel–phosphatidylinositol 4,5-bisphosphate interactions. Through brain-slice electrophysiology, we show that subthreshold GAT1508 concentrations directly stimulate GIRK currents in the basolateral amygdala (BLA) and potentiate baclofen-induced currents. Of note, GAT1508 effectively extinguished conditioned fear in rodents and lacked cardiac and behavioral side effects, suggesting its potential for use in pharmacotherapy for post-traumatic stress disorder. In summary, our findings indicate that the small molecule GAT1508 has high specificity for brain GIRK1/2 channel subunits, directly or allosterically activates GIRK1/2 channels in the BLA, and facilitates fear extinction in a rodent model.

The transient receptor potential (TRP) superfamily of cation channels, of which the TRP vanilloid type 1 (TRPV1) receptor plays a critical role in inflammatory and neuropathic pain, is expressed on nociceptors and spinal cord dorsal horn neurons. TRPV1 is also expressed on spinal astrocytes and dorsal root ganglia (DRG) satellite cells. Agonists of the cannabinoid type 2 receptor (CB

[Image: see text] Positive allosteric modulation of the cannabinoid 1 receptor (CB1R) has demonstrated distinct therapeutic advantages that address several limitations associated with orthosteric agonism and has opened a promising therapeutic avenue for further drug development. To advance the development of CB1R positive allosteric modulators, it is important to understand the molecular architecture of CB1R allosteric site(s). The goal of this work was to use Force-Biased MMC Simulated Annealing to identify binding sites for GAT228 (R), a partial allosteric agonist, and GAT229 (S), a positive allosteric modulator (PAM) at the CB1R. Our studies suggest that GAT228 binds in an intracellular (IC) TMH1–2–4 exosite that would allow this compound to act as a CB1 allosteric agonist as well as a CB1 PAM. In contrast, GAT229 binds at the extracellular (EC) ends of TMH2/3, just beneath the EC1 loop. At this site, this compound can act as CB1 PAM only. Finally, these results were successfully validated through the synthesis and biochemical evaluation of a focused library of compounds.

Homomeric α7 nicotinic acetylcholine receptors (nAChR) have an intrinsically low probability of opening that can be overcome by α7-selective positive allosteric modulators (PAMs), which bind at a site involving the second transmembrane domain (TM2). Mutation of a methionine that is unique to α7 at the 15′ position of TM2 to leucine, the residue in most other nAChR subunits, largely eliminates the activity of such PAMs. We tested the effect of the reverse mutation (L15′M) in heteromeric nAChR receptors containing α4 and β2, which are the nAChR subunits that are most abundant in the brain. Receptors containing these mutations were found to be strongly potentiated by the α7 PAM 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS) but insensitive to the alternative PAM 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea. The presence of the mutation in the β2 subunit was necessary and sufficient for TQS sensitivity. The primary effect of the mutation in the α4 subunit was to reduce responses to acetylcholine applied alone. Sensitivity to TQS required only a single mutant β subunit, regardless of the position of the mutant β subunit within the pentameric complex. Similar results were obtained when β2L15′M was coexpressed with α2 or α3 and when the L15′M mutation was placed in β4 and coexpressed with α2, α3, or α4. Functional receptors were not observed when β1L15′M subunits were coexpressed with other muscle nAChR subunits. The unique structure-activity relationship of PAMs and the α4β2L15′M receptor compared with α7 and the availability of high-resolution α4β2 structures may provide new insights into the fundamental mechanisms of nAChR allosteric potentiation. SIGNIFICANCE STATEMENT Heteromeric neuronal nAChRs have a relatively high initial probability of channel activation compared to receptors that are homomers of α7 subunits but are insensitive to PAMs, which greatly increase the open probability of α7 receptors. These features of heteromeric nAChR can be reversed by mutation of a single residue present in all neuronal heteromeric nAChR subunits to the sequence found in α7. Specifically, the mutation of the TM2 15′ leucine to methionine in α subunits reduces heteromeric receptor channel activation, while the same mutation in neuronal β subunits allows heteromeric receptors to respond to select α7 PAMs. The results indicate a key role for this residue in the functional differences in the two main classes of neuronal nAChRs.

Huntington’s disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB(1)) levels in the striatum, which is strongly correlated with HD pathogenesis. CB(1) positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB(1) allosteric modulators GAT211 (racemic), GAT228 (R-enantiomer), and GAT229 (S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB(1) PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB(1) PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB(1) PAMs to treat the signs and symptoms of HD.

Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of ligand-gated ion channels. Typically, channel activation follows the binding of agonists to the orthosteric binding sites of the receptor. α7 nAChRs have a very low probability of channel activation, which can be reversed by the binding of α7 selective positive allosteric modulators (PAMs) to putative sites within the transmembrane domains. Although typical PAMs, like PNU-120596, require coapplication of an orthosteric agonist to produce large channel activations, some, like GAT107 and B-973B [(S)-3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propanamide], are characterized as allosteric activating PAMs, which also bind to an allosteric activation (AA) site in the extracellular domain and activate the α7 ion channel by themselves. We had previously characterized N,N-diethyl-N′-phenylpiperazine analogs with various functions. In this work, we docked members of this family to a homology model of the α7 receptor extracellular domain. The compound 1,1-diethyl-4(naphthalene-2-yl)piperazin-1-ium (2NDEP) a weak partial agonist, showed particularly favorable docking and binding energies at the putative AA site of the receptor. We hypothesized that 2NDEP could couple with PAMs through the AA site. This hypothesis was tested with the α7 mutant C190A, which is not activated by orthosteric agonists but is effectively activated by GAT107. The results showed that 2NDEP acts as an allosteric agonist of α7C190A when coapplied with the PAM PNU-120596. Also, the allosteric activity was nearly abolished upon coapplication with the AA site–selective antagonist 2,3,5,6MP-TQS (cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide), consistent with AA site involvement. Overall, our findings show a novel mode of agonism through an allosteric site in the extracellular domain of α7 nAChR.

Graph theory has various applications but sometimes it provides uncertain solutions and hence in order to overcome this, fuzzy graph theory is adopted. Fuzzy graph for any application will be proce...

The low sensitivity (α4)3(β2)2 (LS) and high sensitivity (α4)2(β2)3 (HS) nAChR isoforms may contribute to a variety of brain functions, pathophysiological processes, and pharmacological effects associated with nicotine use. In this study, we examined the contributions of the LS and HS α4β2 nAChR isoforms in nicotine self-administration, withdrawal symptoms, antinociceptive and hypothermic effects. We utilized two nAChR positive allosteric modulators (PAMs): desformylflustrabromine (dFBr), a PAM of both the LS and HS α4β2 nAChRs, and CMPI, a PAM selective for the LS nAChR. We found that dFBr, but not CMPI, decreased intravenous nicotine self-administration in male mice in a dose-dependent manner. Unlike dFBr, which fully reverses somatic and affective symptoms of nicotine withdrawal, CMPI at doses up to 15 mg/kg in male mice only partially reduced nicotine withdrawal-induced somatic signs, anxiety-like behavior and sucrose preference, but had no effects on nicotine withdrawal-induced hyperalgesia. These results indicate that potentiation of HS α4β2 nAChRs is necessary to modulate nicotine's reinforcing properties that underlie nicotine intake and to reverse nicotine withdrawal symptoms that influence nicotine abstinence. In contrast, both dFBr and CMPI enhanced nicotine's hypothermic effect and reduced nicotine's antinociceptive effects in male mice. Therefore, these results indicate a more prevalent role of HS α4β2 nAChR isoforms in mediating various behavioral effects associated with nicotine, whereas the LS α4β2 nAChR isoform has a limited role in mediating body temperature and nociceptive responses. These findings will facilitate the development of more selective, efficacious, and safe nAChR-based therapeutics for nicotine addiction treatment.